=== Generating (published_papers) ===
=== Generating (research_interests) ===
=== Generating (teaching_experience) ===
=== Generating (education) ===
=== Generating (research_experience) ===
=== Generating (misc) ===
=== Generating (research_projects) ===
=== Generating (books_etc) ===
=== Generating (awards) ===
=== Generating (association_memberships) ===
=== Generating (presentations) ===
==== begin registerFile(/WWW/pub2/data/ERD/person/60644/researchmap/published_papers.jsonl) ====
line:1, {"insert":{"user_id":"1000300291","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=414763","label":"url"}],"paper_title":{"en":"Application of bacterial-derived long cellulose nanofiber to suspension culture of mammalian cells as a shear protectant","ja":"Application of bacterial-derived long cellulose nanofiber to suspension culture of mammalian cells as a shear protectant"},"authors":{"en":[{"name":"Kaneko Eiichiro"},{"name":"Tsujisaki Haruto"},{"name":"Fujiwara Masashi"},{"name":"ANDO Hidenori"},{"name":"Sato Yasushi"},{"name":"Ishida Tatsuhiro"},{"name":"Tani Hirofumi"},{"name":"Tajima Kenji"}],"ja":[{"name":"Kaneko Eiichiro"},{"name":"Tsujisaki Haruto"},{"name":"Fujiwara Masashi"},{"name":"安藤 英紀"},{"name":"Sato Yasushi"},{"name":"石田 竜弘"},{"name":"Tani Hirofumi"},{"name":"Tajima Kenji"}]},"publication_date":"2024-11","publication_name":{"en":"International Journal of Biological Macromolecules","ja":"International Journal of Biological Macromolecules"},"volume":"Vol.280","number":"No.3","starting_page":"135938","ending_page":"135938","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijbiomac.2024.135938"],"issn":["0141-8130"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:2, {"insert":{"user_id":"1000300291","type":"published_papers","id":"48169710"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=414762","label":"url"}],"paper_title":{"en":"A Stealthiness Evaluation of Main Chain Carboxybetaine Polymer Modified into Liposome","ja":"A Stealthiness Evaluation of Main Chain Carboxybetaine Polymer Modified into Liposome"},"authors":{"en":[{"name":"Najmina Mazaya"},{"name":"Kobayashi Shingo"},{"name":"Shimazui Rena"},{"name":"Takata Haruka"},{"name":"Shibata Mayuka"},{"name":"Ishibashi Kenta"},{"name":"Kamizawa Hiroshi"},{"name":"Kishimura Akihiro"},{"name":"Shiota Yoshihito"},{"name":"Ida Daichi"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"},{"name":"Katayama Yoshiki"},{"name":"Tanaka Masaru"},{"name":"Mori Takeshi"}],"ja":[{"name":"Najmina Mazaya"},{"name":"小林 慎吾"},{"name":"Shimazui Rena"},{"name":"髙田 春風"},{"name":"Shibata Mayuka"},{"name":"Ishibashi Kenta"},{"name":"Kamizawa Hiroshi"},{"name":"Kishimura Akihiro"},{"name":"Shiota Yoshihito"},{"name":"Ida Daichi"},{"name":"清水 太郎"},{"name":"石田 竜弘"},{"name":"Katayama Yoshiki"},{"name":"Tanaka Masaru"},{"name":"森 健"}]},"publication_date":"2024-09-28","publication_name":{"en":"Pharmaceutics","ja":"Pharmaceutics"},"volume":"Vol.16","number":"No.10","starting_page":"1271","ending_page":"1271","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/pharmaceutics16101271"],"issn":["1999-4923"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:3, {"insert":{"user_id":"1000300291","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/119625","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/38813140","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=412140","label":"url"}],"paper_title":{"en":"Humoral immune response against SARS-CoV-2 and polyethylene glycol elicited by anti-SARS-CoV-2 mRNA vaccine, and effect of pre-existing anti-polyethylene glycol antibody in patients with hematological and autoimmune diseases.","ja":"Humoral immune response against SARS-CoV-2 and polyethylene glycol elicited by anti-SARS-CoV-2 mRNA vaccine, and effect of pre-existing anti-polyethylene glycol antibody in patients with hematological and autoimmune diseases."},"authors":{"en":[{"name":"Hori Taiki"},{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Okada Naoto"},{"name":"Yamagami Hiroki"},{"name":"Yasui Saya"},{"name":"Hosoki Minae"},{"name":"Tojima Akihiro"},{"name":"Otoda Toshiki"},{"name":"Yuasa Tomoyuki"},{"name":"Aihara Ken-ichi"},{"name":"Takishita Makoto"},{"name":"Yoshida Sumiko"},{"name":"Abe Masahiro"},{"name":"Ishida Tatsuhiro"},{"name":"Nakamura Shingen"}],"ja":[{"name":"Hori Taiki"},{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"岡田 直人"},{"name":"山上 紘規"},{"name":"Yasui Saya"},{"name":"Hosoki Minae"},{"name":"Tojima Akihiro"},{"name":"乙田 敏城"},{"name":"湯浅 智之"},{"name":"粟飯原 賢一"},{"name":"Takishita Makoto"},{"name":"吉田 守美子"},{"name":"安倍 正博"},{"name":"石田 竜弘"},{"name":"中村 信元"}]},"description":{"en":"The effects of vaccination are modified by hematological and autoimmune diseases and/or treatment. Anti-SARS-CoV-2 mRNA vaccine contains polyethylene glycol (PEG), it is largely unknown whether PEG influences the effects of vaccination or induces a humoral response. This study examined whether anti-PEG antibodies before vaccination (pre-existing) influenced the acquisition of SARS-CoV-2 antibodies and evaluated the relationship between the development of anti-SARS-CoV-2 antibodies and anti-PEG antibodies after SARS-CoV-2 vaccination in hematological and autoimmune diseases. Anti-SARS-CoV-2 antibody IgG, anti-PEG IgG, and IgM titers were evaluated in patients with hematological and autoimmune diseases after the second dose of BNT162B2. Anti-PEG IgG and IgM titers were also measured before vaccination to examine changes after vaccination and the relationship with vaccine efficacy. In patients with hematological (n = 182) and autoimmune diseases (n = 96), anti-SARS-CoV-2 and anti-PEG antibody titers were evaluated after a median of 33 days from 2nd vaccination. The median anti-SARS-CoV-2 antibody titers were 1901 AU/mL and 3832 AU/mL in patients with hematological and autoimmune disease, respectively. Multiple regression analysis showed that age and days from 2nd vaccination were negatively associated with anti-SARS-CoV-2 antibody titers. Anti-CD20 antibody treatment was negatively correlated with anti-SARS-CoV-2 antibody titers in hematological disease, and C-reactive protein (CRP) was positively correlated with anti-SARS-CoV-2 antibody titers in autoimmune disease. Baseline anti-PEG antibody titers were significantly higher in patients with autoimmune disease but were not correlated with anti-SARS-CoV-2 antibody titers. Patients with increased anti-PEG IgG acquired higher anti-SARS-CoV-2 antibody titers in patients with autoimmune disease. Anti-SARS-CoV-2 antibody acquisition was suboptimal in patients with hematological disease, but both anti-SARS-CoV-2 antibody and anti-PEG IgG were acquired in patients with autoimmune disease, reflecting robust humoral immune response. Pre-existing anti-PEG antibody titers did not affect anti-SARS-CoV-2 antibody acquisition.","ja":"The effects of vaccination are modified by hematological and autoimmune diseases and/or treatment. Anti-SARS-CoV-2 mRNA vaccine contains polyethylene glycol (PEG), it is largely unknown whether PEG influences the effects of vaccination or induces a humoral response. This study examined whether anti-PEG antibodies before vaccination (pre-existing) influenced the acquisition of SARS-CoV-2 antibodies and evaluated the relationship between the development of anti-SARS-CoV-2 antibodies and anti-PEG antibodies after SARS-CoV-2 vaccination in hematological and autoimmune diseases. Anti-SARS-CoV-2 antibody IgG, anti-PEG IgG, and IgM titers were evaluated in patients with hematological and autoimmune diseases after the second dose of BNT162B2. Anti-PEG IgG and IgM titers were also measured before vaccination to examine changes after vaccination and the relationship with vaccine efficacy. In patients with hematological (n = 182) and autoimmune diseases (n = 96), anti-SARS-CoV-2 and anti-PEG antibody titers were evaluated after a median of 33 days from 2nd vaccination. The median anti-SARS-CoV-2 antibody titers were 1901 AU/mL and 3832 AU/mL in patients with hematological and autoimmune disease, respectively. Multiple regression analysis showed that age and days from 2nd vaccination were negatively associated with anti-SARS-CoV-2 antibody titers. Anti-CD20 antibody treatment was negatively correlated with anti-SARS-CoV-2 antibody titers in hematological disease, and C-reactive protein (CRP) was positively correlated with anti-SARS-CoV-2 antibody titers in autoimmune disease. Baseline anti-PEG antibody titers were significantly higher in patients with autoimmune disease but were not correlated with anti-SARS-CoV-2 antibody titers. Patients with increased anti-PEG IgG acquired higher anti-SARS-CoV-2 antibody titers in patients with autoimmune disease. Anti-SARS-CoV-2 antibody acquisition was suboptimal in patients with hematological disease, but both anti-SARS-CoV-2 antibody and anti-PEG IgG were acquired in patients with autoimmune disease, reflecting robust humoral immune response. Pre-existing anti-PEG antibody titers did not affect anti-SARS-CoV-2 antibody acquisition."},"publication_date":"2024-05-17","publication_name":{"en":"Heliyon","ja":"Heliyon"},"volume":"Vol.10","number":"No.10","starting_page":"e31489","ending_page":"e31489","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.heliyon.2024.e31489"],"issn":["2405-8440"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:4, {"insert":{"user_id":"1000300291","type":"published_papers","id":"44499584"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/119211","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=405317","label":"url"}],"paper_title":{"en":"Human hair keratin responds to oxidative stress via reactive sulfur and supersulfides","ja":"Human hair keratin responds to oxidative stress via reactive sulfur and supersulfides"},"authors":{"en":[{"name":"Hirai Takeru"},{"name":"Ikeda-Imafuku Mayumi"},{"name":"Tasaka Nanami"},{"name":"Victor Tuan Giam Chuang"},{"name":"Ming Xian"},{"name":"Ishida Tatsuhiro"},{"name":"Akaike Takaaki"},{"name":"Ishima Yu"}],"ja":[{"name":"平井 傑琉"},{"name":"池田 真由美"},{"name":"田坂 菜々美"},{"name":"Victor Tuan Giam Chuang"},{"name":"Ming Xian"},{"name":"石田 竜弘"},{"name":"Akaike Takaaki"},{"name":"異島 優"}]},"publication_date":"2024-04","publication_name":{"en":"Advances in Redox Research","ja":"Advances in Redox Research"},"volume":"Vol.10","starting_page":"100091","ending_page":"100091","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.arres.2023.100091"],"issn":["2667-1379"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:5, {"insert":{"user_id":"1000300291","type":"published_papers","id":"45763828"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/38273445","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1360301163936245376/","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85184304070&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=405318","label":"url"}],"paper_title":{"en":"Impact of anti-PEG IgM induced via the topical application of a cosmetic product containing PEG derivatives on the antitumor effects of PEGylated liposomal antitumor drug formulations in mice","ja":"Impact of anti-PEG IgM induced via the topical application of a cosmetic product containing PEG derivatives on the antitumor effects of PEGylated liposomal antitumor drug formulations in mice"},"authors":{"en":[{"name":"Sherif A Gaballa"},{"name":"Shimizu Taro"},{"name":"Takata Haruka"},{"name":"ANDO Hidenori"},{"name":"Mohamed Ibrahim"},{"name":"Sherif Emam Abdallah Emam"},{"name":"Matsuo Amorim Cristina Nana"},{"name":"Kim Yuri"},{"name":"Youssef W Naguib"},{"name":"Fatma M Mady"},{"name":"Khaled A Khaled"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Sherif A Gaballa"},{"name":"清水 太郎"},{"name":"髙田 春風"},{"name":"安藤 英紀"},{"name":"Mohamed Ibrahim"},{"name":"Sherif Emam Abdallah Emam"},{"name":"松尾 アモリムクリスティーナ菜々"},{"name":"金 侑里"},{"name":"Youssef W Naguib"},{"name":"Fatma M Mady"},{"name":"Khaled A Khaled"},{"name":"石田 竜弘"}]},"description":{"en":"Poly(ethylene glycol) (PEG) is used in many common products, such as cosmetics. PEG, however, is also used to covalently conjugate drug molecules, proteins, or nanocarriers, which is termed PEGylation, to serve as a shield against the natural immune system of the human body. Repeated administration of some PEGylated products, however, is known to induce anti-PEG antibodies. In addition, preexisting anti-PEG antibodies are now being detected in healthy individuals who have never received PEGylated therapeutics. Both treatment-induced and preexisting anti-PEG antibodies alter the pharmacokinetic properties, which can result in a subsequent reduction in the therapeutic efficacy of administered PEGylated therapeutics through the so-called accelerated blood clearance (ABC) phenomenon. Moreover, these anti-PEG antibodies are widely reported to be related to severe hypersensitivity reactions following the administration of PEGylated therapeutics, including COVID-19 vaccines. We recently reported that the topical application of a cosmetic product containing PEG derivatives induced anti-PEG immunoglobulin M (IgM) in a mouse model. Our finding indicates that the PEG derivatives in cosmetic products could be a major cause of the preexistence of anti-PEG antibodies in healthy individuals. In this study, therefore, the pharmacokinetics and therapeutic effects of Doxil (doxorubicin hydrochloride-loaded PEGylated liposomes) and oxaliplatin-loaded PEGylated liposomes (Liposomal l-OHP) were studied in mice. The anti-PEG IgM antibodies induced by the topical application of cosmetic products obviously accelerated the blood clearance of both PEGylated liposomal formulations. Moreover, in C26 tumor-bearing mice, the tumor growth suppressive effects of both Doxil and Liposomal l-OHP were significantly attenuated in the presence of anti-PEG IgM antibodies induced by the topical application of cosmetic products. These results confirm that the topical application of a cosmetic product containing PEG derivatives could produce preexisting anti-PEG antibodies that then affect the therapeutic efficacy of subsequent doses of PEGylated therapeutics.","ja":"Poly(ethylene glycol) (PEG) is used in many common products, such as cosmetics. PEG, however, is also used to covalently conjugate drug molecules, proteins, or nanocarriers, which is termed PEGylation, to serve as a shield against the natural immune system of the human body. Repeated administration of some PEGylated products, however, is known to induce anti-PEG antibodies. In addition, preexisting anti-PEG antibodies are now being detected in healthy individuals who have never received PEGylated therapeutics. Both treatment-induced and preexisting anti-PEG antibodies alter the pharmacokinetic properties, which can result in a subsequent reduction in the therapeutic efficacy of administered PEGylated therapeutics through the so-called accelerated blood clearance (ABC) phenomenon. Moreover, these anti-PEG antibodies are widely reported to be related to severe hypersensitivity reactions following the administration of PEGylated therapeutics, including COVID-19 vaccines. We recently reported that the topical application of a cosmetic product containing PEG derivatives induced anti-PEG immunoglobulin M (IgM) in a mouse model. Our finding indicates that the PEG derivatives in cosmetic products could be a major cause of the preexistence of anti-PEG antibodies in healthy individuals. In this study, therefore, the pharmacokinetics and therapeutic effects of Doxil (doxorubicin hydrochloride-loaded PEGylated liposomes) and oxaliplatin-loaded PEGylated liposomes (Liposomal l-OHP) were studied in mice. The anti-PEG IgM antibodies induced by the topical application of cosmetic products obviously accelerated the blood clearance of both PEGylated liposomal formulations. Moreover, in C26 tumor-bearing mice, the tumor growth suppressive effects of both Doxil and Liposomal l-OHP were significantly attenuated in the presence of anti-PEG IgM antibodies induced by the topical application of cosmetic products. These results confirm that the topical application of a cosmetic product containing PEG derivatives could produce preexisting anti-PEG antibodies that then affect the therapeutic efficacy of subsequent doses of PEGylated therapeutics."},"publication_date":"2024-02-05","publication_name":{"en":"Molecular Pharmaceutics","ja":"Molecular Pharmaceutics"},"volume":"Vol.21","number":"No.2","starting_page":"622","ending_page":"632","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acs.molpharmaceut.3c00774"],"issn":["1543-8384"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:6, {"insert":{"user_id":"1000300291","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=405320","label":"url"}],"paper_title":{"en":"Peritoneal B Cells Play a Role in The Production of Anti-Polyethylene Glycol (PEG) IgM Against Intravenously Injected siRNA-PEGylated Liposome Complexes","ja":"Peritoneal B Cells Play a Role in The Production of Anti-Polyethylene Glycol (PEG) IgM Against Intravenously Injected siRNA-PEGylated Liposome Complexes"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Amr S Abu Lila"},{"name":"Kitayama Yuka"},{"name":"Abe Ryo"},{"name":"Takata Haruka"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"Amr S Abu Lila"},{"name":"北山 由佳"},{"name":"阿部 遼"},{"name":"髙田 春風"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"publication_date":"2024-02","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.47","number":"No.2","starting_page":"469","ending_page":"477","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b23-00733"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:7, {"insert":{"user_id":"1000300291","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/119400","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/38256961","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1050582385450085504/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=405319","label":"url"}],"paper_title":{"en":"Acute kidney injury caused by rhabdomyolysis is ameliorated by serum albumin-based supersulfides donors through antioxidative pathways","ja":"Acute kidney injury caused by rhabdomyolysis is ameliorated by serum albumin-based supersulfides donors through antioxidative pathways"},"authors":{"en":[{"name":"Ikeda-Imafuku Mayumi"},{"name":"Fukuta Tatsuya"},{"name":"Victor Tuan Giam Chuang"},{"name":"Sawa Tomohiro"},{"name":"Maruyama Toru"},{"name":"Otagiri Masaki"},{"name":"Ishida Tatsuhiro"},{"name":"Ishima Yu"}],"ja":[{"name":"池田 真由美"},{"name":"福田 達也"},{"name":"Victor Tuan Giam Chuang"},{"name":"Sawa Tomohiro"},{"name":"Maruyama Toru"},{"name":"Otagiri Masaki"},{"name":"石田 竜弘"},{"name":"異島 優"}]},"description":{"en":"Oxidative stress is responsible for the onset and progression of various kinds of diseases including rhabdomyolysis-induced acute kidney injury (AKI). Antioxidants are, therefore, thought to aid in the recovery of illnesses linked to oxidative stress. Supersulfide species have been shown to have substantial antioxidative activity; however, due to their limited bioavailability, few supersulfide donors have had their actions evaluated in vivo. In this study, human serum albumin (HSA) and N-acetyl-L-cysteine polysulfides (NACSn), which have polysulfides in an oxidized form, were conjugated to create a supersulfide donor. HSA is chosen to be a carrier of NACSn because of its extended blood circulation and high level of biocompatibility. In contrast to a supersulfide donor containing reduced polysulfide in HSA, the NACSn-conjugated HSAs exhibited stronger antioxidant activity than HSA and free NACSn without being uptaken by the cells in vitro. The supersulfide donor reduced the levels of blood urea nitrogen and serum creatinine significantly in a mouse model of rhabdomyolysis-induced AKI. Supersulfide donors significantly reduced the expression of oxidative stress markers in the kidney. These results indicate that the developed supersulfide donor has the therapeutic effect on rhabdomyolysis-induced AKI.","ja":"Oxidative stress is responsible for the onset and progression of various kinds of diseases including rhabdomyolysis-induced acute kidney injury (AKI). Antioxidants are, therefore, thought to aid in the recovery of illnesses linked to oxidative stress. Supersulfide species have been shown to have substantial antioxidative activity; however, due to their limited bioavailability, few supersulfide donors have had their actions evaluated in vivo. In this study, human serum albumin (HSA) and N-acetyl-L-cysteine polysulfides (NACSn), which have polysulfides in an oxidized form, were conjugated to create a supersulfide donor. HSA is chosen to be a carrier of NACSn because of its extended blood circulation and high level of biocompatibility. In contrast to a supersulfide donor containing reduced polysulfide in HSA, the NACSn-conjugated HSAs exhibited stronger antioxidant activity than HSA and free NACSn without being uptaken by the cells in vitro. The supersulfide donor reduced the levels of blood urea nitrogen and serum creatinine significantly in a mouse model of rhabdomyolysis-induced AKI. Supersulfide donors significantly reduced the expression of oxidative stress markers in the kidney. These results indicate that the developed supersulfide donor has the therapeutic effect on rhabdomyolysis-induced AKI."},"publication_date":"2024-01-18","publication_name":{"en":"Pharmaceuticals","ja":"Pharmaceuticals"},"volume":"Vol.17","number":"No.1","starting_page":"128","ending_page":"128","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/ph17010128"],"issn":["1424-8247"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:8, {"insert":{"user_id":"1000300291","type":"published_papers","id":"44436381"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/38222647","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85181159256&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=404606","label":"url"}],"paper_title":{"en":"Absence of Anaphylactic Reactions to Injection of Hemoglobin-vesicles (Artificial Red Cells) to Rodents","ja":"Absence of Anaphylactic Reactions to Injection of Hemoglobin-vesicles (Artificial Red Cells) to Rodents"},"authors":{"en":[{"name":"Sakai Hiromi"},{"name":"Kure Tomoko"},{"name":"Kobayashi Naoko"},{"name":"Ito Tadashi"},{"name":"Yamada Yasushi"},{"name":"Yamada Tetsuya"},{"name":"Miyamoto Rina"},{"name":"Imaizumi Takahito"},{"name":"Ando Jiro"},{"name":"Soga Takaomi"},{"name":"Osanai Yasuo"},{"name":"Ogawa Makoto"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"},{"name":"Azuma Hiroshi"}],"ja":[{"name":"Sakai Hiromi"},{"name":"Kure Tomoko"},{"name":"Kobayashi Naoko"},{"name":"Ito Tadashi"},{"name":"Yamada Yasushi"},{"name":"Yamada Tetsuya"},{"name":"Miyamoto Rina"},{"name":"Imaizumi Takahito"},{"name":"Ando Jiro"},{"name":"Soga Takaomi"},{"name":"Osanai Yasuo"},{"name":"Ogawa Makoto"},{"name":"清水 太郎"},{"name":"石田 竜弘"},{"name":"Azuma Hiroshi"}]},"description":{"en":"The safety and efficacy of hemoglobin vesicles (HbVs) as artificial oxygen carriers encapsulating a purified and concentrated Hb solution in liposomes have been studied extensively. The HbV surface, modified with PEG by incorporating a PEG-conjugated phospholipid, is beneficial for storage and biocompatibility. However, it might be possible that interaction of PEG and the pre-existing anti-PEG antibody in the bloodstream causes acute adverse reaction. This study used two sets of experiments with rats and guinea pigs to ascertain whether the anti-PEG antibody generated by the PEG-modified HbV injection can induce anaphylactic reactions. SD rats received repeated intravenous injection of HbV at a dose rate of 16 or 32 mL/kg three times. Not anti-PEG IgG but anti-PEG IgM was detected. Nevertheless, no anaphylactic reaction occurred. Guinea pigs were used to study the presence of active systemic anaphylaxis further after injections of the PEG-modified liposomes used for HbV. The animals were sensitized by three repeated subcutaneous injections of PEG-modified liposomes (PEG-liposome) along with adjuvant at 1 week intervals. For comparison, unmodified liposomes (liposome) and 10 times excessively PEG-modified liposomes with ionizable lipid (10PEG-DODAP-liposome) were used. Inclusion of PEG modification induced not only anti-PEG IgM but also anti-PEG IgG. Three weeks after the final injection, intravenous injection of both PEG-liposome and liposome (1 mL/kg) induced no anaphylactic reaction. However, the injection of 10PEG-DODAP-liposome showed one lethal anaphylaxis case and one mild anaphylaxis case. Antisera obtained from the animal sensitized as described above were inoculated (0.05 mL) intradermally into fresh guinea pigs. The presence of passive cutaneous anaphylaxis was evaluated after intravenous injections (1 mL/kg) of three liposomes with Evans blue. No dye leakage was detected at any inoculated skin point for PEG-liposome or liposome, but a slight leakage was detected in one inoculated skin point for 10PEG-DODAP-liposome. These results indicate the absence of acute allergic reactions at repeated injections of HbVs despite the anti-PEG antibody induction. Not all the PEG-modified liposomes show anaphylaxis, and it may depend on the amount of PEGylated phospholipid and lipid composition of PEG-modified liposomes.","ja":"The safety and efficacy of hemoglobin vesicles (HbVs) as artificial oxygen carriers encapsulating a purified and concentrated Hb solution in liposomes have been studied extensively. The HbV surface, modified with PEG by incorporating a PEG-conjugated phospholipid, is beneficial for storage and biocompatibility. However, it might be possible that interaction of PEG and the pre-existing anti-PEG antibody in the bloodstream causes acute adverse reaction. This study used two sets of experiments with rats and guinea pigs to ascertain whether the anti-PEG antibody generated by the PEG-modified HbV injection can induce anaphylactic reactions. SD rats received repeated intravenous injection of HbV at a dose rate of 16 or 32 mL/kg three times. Not anti-PEG IgG but anti-PEG IgM was detected. Nevertheless, no anaphylactic reaction occurred. Guinea pigs were used to study the presence of active systemic anaphylaxis further after injections of the PEG-modified liposomes used for HbV. The animals were sensitized by three repeated subcutaneous injections of PEG-modified liposomes (PEG-liposome) along with adjuvant at 1 week intervals. For comparison, unmodified liposomes (liposome) and 10 times excessively PEG-modified liposomes with ionizable lipid (10PEG-DODAP-liposome) were used. Inclusion of PEG modification induced not only anti-PEG IgM but also anti-PEG IgG. Three weeks after the final injection, intravenous injection of both PEG-liposome and liposome (1 mL/kg) induced no anaphylactic reaction. However, the injection of 10PEG-DODAP-liposome showed one lethal anaphylaxis case and one mild anaphylaxis case. Antisera obtained from the animal sensitized as described above were inoculated (0.05 mL) intradermally into fresh guinea pigs. The presence of passive cutaneous anaphylaxis was evaluated after intravenous injections (1 mL/kg) of three liposomes with Evans blue. No dye leakage was detected at any inoculated skin point for PEG-liposome or liposome, but a slight leakage was detected in one inoculated skin point for 10PEG-DODAP-liposome. These results indicate the absence of acute allergic reactions at repeated injections of HbVs despite the anti-PEG antibody induction. Not all the PEG-modified liposomes show anaphylaxis, and it may depend on the amount of PEGylated phospholipid and lipid composition of PEG-modified liposomes."},"publication_date":"2024-01","publication_name":{"en":"ACS Omega","ja":"ACS Omega"},"volume":"Vol.9","number":"No.1","starting_page":"1904","ending_page":"1915","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acsomega.3c08641"],"issn":["2470-1343"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:9, {"insert":{"user_id":"1000300291","type":"published_papers","id":"43838491"},"force":{"see_also":[{"@id":"http://id.ndl.go.jp/bib/033181684","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390579686915245568/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=403534","label":"url"}],"paper_title":{"en":"マクロゴール4000の関連する全身性紅斑を呈した女児例","ja":"マクロゴール4000の関連する全身性紅斑を呈した女児例"},"authors":{"en":[{"name":"横山 宏司"},{"name":"儘田 光和"},{"name":"Takata Haruka"},{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"横山 宏司"},{"name":"儘田 光和"},{"name":"髙田 春風"},{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"石田 竜弘"}]},"publication_date":"2023-11-01","publication_name":{"en":"Pediatrics of Japan","ja":"小児科"},"volume":"Vol.64","number":"No.11","starting_page":"1196","ending_page":"1199","languages":["jpn"],"referee":true,"identifiers":{"doi":["10.18888/sh.0000002763"],"issn":["0037-4121"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:10, {"insert":{"user_id":"1000300291","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/37579503","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85169045394&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=402793","label":"url"}],"paper_title":{"en":"Encapsulation of an Antioxidant in Redox-Sensitive Self-Assembled Albumin Nanoparticle for the Treatment of Hepatitis","ja":"Encapsulation of an Antioxidant in Redox-Sensitive Self-Assembled Albumin Nanoparticle for the Treatment of Hepatitis"},"authors":{"en":[{"name":"Yasuda Kengo"},{"name":"Maeda Hitoshi"},{"name":"Kinoshita Ryo"},{"name":"Minayoshi Yuki"},{"name":"Mizuta Yuki"},{"name":"Nakamura Yuka"},{"name":"Imoto Shuhei"},{"name":"Nishi Koji"},{"name":"Yamasaki Keishi"},{"name":"Sakuragi Mina"},{"name":"Nakamura Teruya"},{"name":"Ikeda-Imafuku Mayumi"},{"name":"Iwao Yasunori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"},{"name":"Iwakiri Yasuko"},{"name":"Otagiri Masaki"},{"name":"Watanabe Hiroshi"},{"name":"Maruyama Toru"}],"ja":[{"name":"Yasuda Kengo"},{"name":"Maeda Hitoshi"},{"name":"木下 遼"},{"name":"Minayoshi Yuki"},{"name":"Mizuta Yuki"},{"name":"Nakamura Yuka"},{"name":"Imoto Shuhei"},{"name":"Nishi Koji"},{"name":"Yamasaki Keishi"},{"name":"Sakuragi Mina"},{"name":"Nakamura Teruya"},{"name":"池田 真由美"},{"name":"Iwao Yasunori"},{"name":"異島 優"},{"name":"石田 竜弘"},{"name":"Iwakiri Yasuko"},{"name":"Otagiri Masaki"},{"name":"Watanabe Hiroshi"},{"name":"Maruyama Toru"}]},"description":{"en":"Hepatitis is an inflammation of the liver caused by the inadequate elimination of reactive oxygen species (ROS) derived from Kupffer cells. Edaravone is clinically used as an antioxidant but shows poor liver distribution. Herein, we report on the design of a Kupffer cell-oriented nanoantioxidant based on a disulfide cross-linked albumin nanoparticle containing encapsulated edaravone (EeNA) as a therapeutic for the treatment of hepatitis. Since the edaravone is bound to albumin, this results in a soluble and stable form of edaravone in water. Exchanging the intramolecular disulfide bonds to intermolecular disulfide bridges of albumin molecules allowed the preparation of a redox responsive albumin nanoparticle that is stable in the blood circulation but can release drugs into cells. Consequently, EeNA was fabricated by the nanoscale self-assembly of edaravone and albumin nanoparticles without the additives that are contained in commercially available edaravone preparations. EeNA retained its nanostructure under serum conditions, but the encapsulated edaravone was released efficiently under intracellular reducing conditions in macrophages. The EeNA was largely distributed in the liver and subsequently internalized into Kupffer cells within 60 min after injection in a concanavalin-A-induced hepatitis mouse. The survival rate of the hepatitis mice was significantly improved by EeNA due to the suppression of liver necrosis and oxidative stress by scavenging excessive ROS. Moreover, even through the postadministration, EeNA showed an excellent hepatoprotective action as well. In conclusion, EeNA has the potential for use as a nanotherapeutic against various types of hepatitis because of its Kupffer cell targeting ability and redox characteristics.","ja":"Hepatitis is an inflammation of the liver caused by the inadequate elimination of reactive oxygen species (ROS) derived from Kupffer cells. Edaravone is clinically used as an antioxidant but shows poor liver distribution. Herein, we report on the design of a Kupffer cell-oriented nanoantioxidant based on a disulfide cross-linked albumin nanoparticle containing encapsulated edaravone (EeNA) as a therapeutic for the treatment of hepatitis. Since the edaravone is bound to albumin, this results in a soluble and stable form of edaravone in water. Exchanging the intramolecular disulfide bonds to intermolecular disulfide bridges of albumin molecules allowed the preparation of a redox responsive albumin nanoparticle that is stable in the blood circulation but can release drugs into cells. Consequently, EeNA was fabricated by the nanoscale self-assembly of edaravone and albumin nanoparticles without the additives that are contained in commercially available edaravone preparations. EeNA retained its nanostructure under serum conditions, but the encapsulated edaravone was released efficiently under intracellular reducing conditions in macrophages. The EeNA was largely distributed in the liver and subsequently internalized into Kupffer cells within 60 min after injection in a concanavalin-A-induced hepatitis mouse. The survival rate of the hepatitis mice was significantly improved by EeNA due to the suppression of liver necrosis and oxidative stress by scavenging excessive ROS. Moreover, even through the postadministration, EeNA showed an excellent hepatoprotective action as well. In conclusion, EeNA has the potential for use as a nanotherapeutic against various types of hepatitis because of its Kupffer cell targeting ability and redox characteristics."},"publication_date":"2023-08-14","publication_name":{"en":"ACS Nano","ja":"ACS Nano"},"volume":"Vol.17","number":"No.17","starting_page":"16668","ending_page":"16681","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acsnano.3c02877"],"issn":["1936-086X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:11, {"insert":{"user_id":"1000300291","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/37355210","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=402792","label":"url"}],"paper_title":{"en":"Anti-PEG IgM production induced by PEGylated liposomes as a function of administration route","ja":"Anti-PEG IgM production induced by PEGylated liposomes as a function of administration route"},"authors":{"en":[{"name":"Takata Haruka"},{"name":"Shimizu Taro"},{"name":"Yamade Rina"},{"name":"Elhewan Ali Emam Elsadek Emam Nehal"},{"name":"Emam Abdallah Emam Sherif"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"髙田 春風"},{"name":"清水 太郎"},{"name":"山出 莉奈"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Sherif Emam Abdallah Emam"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Modifying the surface of nanoparticles with polyethylene glycol (PEG) is a commonly used approach for improving the in vitro stability of nanoparticles such as liposomes and increasing their circulation half-lives. We have demonstrated that, in certain conditions, an intravenous (i.v.) injection of PEGylated liposomes (PEG-Lip) induced anti-PEG IgM antibodies, which led to rapid clearance of second doses in mice. SARS-CoV-2 vaccines, composed of mRNA-containing PEGylated lipid nanoparticles, have been widely administered as intramuscular (i.m.) injections, so it is important to determine if PEGylated formulations can induce anti-PEG antibodies. If the favorable properties that PEGylation imparts to therapeutic nanoparticles are to be widely applicable this should apply to various routes of administration. However, there are few reports on the effect of different administration routes on the in vivo production of anti-PEG IgM. In this study, we investigated anti-PEG IgM production in mice following i.m., intraperitoneal (i.p.) and subcutaneous (s.c.) administration of PEG-Lip. PEG-Lip appeared to induce anti-PEG IgM by all the tested routes of administration, although the lipid dose causing maximum responses varied. Splenectomy attenuated the anti-PEG IgM production for all routes of administration, suggesting that splenic immune cells may have contributed to anti-PEG IgM production. Interestingly, in vitro experiments indicated that not only splenic cells but also cells in the peritoneal cavity induced anti-PEG IgM following incubation with PEG-Lip. These observations confirm previous experiments that have shown that measurable amounts of PEG-Lip administered i.p., i.m. or s.c. are absorbed to some extent into the blood circulation, where they can be distributed to the spleen and/or peritoneal cavity, and are recognized by B cells, triggering anti-PEG IgM production. The results obtained in this study have important implications for developing efficient PEGylated nanoparticular delivery system.","ja":"Modifying the surface of nanoparticles with polyethylene glycol (PEG) is a commonly used approach for improving the in vitro stability of nanoparticles such as liposomes and increasing their circulation half-lives. We have demonstrated that, in certain conditions, an intravenous (i.v.) injection of PEGylated liposomes (PEG-Lip) induced anti-PEG IgM antibodies, which led to rapid clearance of second doses in mice. SARS-CoV-2 vaccines, composed of mRNA-containing PEGylated lipid nanoparticles, have been widely administered as intramuscular (i.m.) injections, so it is important to determine if PEGylated formulations can induce anti-PEG antibodies. If the favorable properties that PEGylation imparts to therapeutic nanoparticles are to be widely applicable this should apply to various routes of administration. However, there are few reports on the effect of different administration routes on the in vivo production of anti-PEG IgM. In this study, we investigated anti-PEG IgM production in mice following i.m., intraperitoneal (i.p.) and subcutaneous (s.c.) administration of PEG-Lip. PEG-Lip appeared to induce anti-PEG IgM by all the tested routes of administration, although the lipid dose causing maximum responses varied. Splenectomy attenuated the anti-PEG IgM production for all routes of administration, suggesting that splenic immune cells may have contributed to anti-PEG IgM production. Interestingly, in vitro experiments indicated that not only splenic cells but also cells in the peritoneal cavity induced anti-PEG IgM following incubation with PEG-Lip. These observations confirm previous experiments that have shown that measurable amounts of PEG-Lip administered i.p., i.m. or s.c. are absorbed to some extent into the blood circulation, where they can be distributed to the spleen and/or peritoneal cavity, and are recognized by B cells, triggering anti-PEG IgM production. The results obtained in this study have important implications for developing efficient PEGylated nanoparticular delivery system."},"publication_date":"2023-08","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.360","starting_page":"285","ending_page":"292","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2023.06.027"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:12, {"insert":{"user_id":"1000300291","type":"published_papers","id":"42412573"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/37121563","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=397270","label":"url"}],"paper_title":{"en":"A polyethylene glycol-conjugate of deoxycytidine analog, DFP-14927, produces potential antitumor effects on pancreatic tumor-xenograft murine models via inducing G2/M arrest","ja":"A polyethylene glycol-conjugate of deoxycytidine analog, DFP-14927, produces potential antitumor effects on pancreatic tumor-xenograft murine models via inducing G2/M arrest"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Eshima Kiyoshi"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"Eshima Kiyoshi"},{"name":"石田 竜弘"}]},"description":{"en":"A deoxycytidine analog is a potential agent for the treatment of several cancers, which includes poorly prognostic pancreatic cancer. We previously developed deoxycytidine analog DFP-10917, and long-term/low-dose infusions of this analog has produced antitumor effects in leukemia cancer- and ovarian cancer-xenograft models. DFP-10917 is now undergoing clinical Phase III study in the United States for the treatment of patients with relapsed or refractory acute myeloid leukemia. PEG-drug conjugation has become a promising technique to improve the pharmacokinetic and pharmacodynamic properties of anti-cancer drugs. In the present study, we synthesized a novel PEG-drug conjugate of DFP-10917, referred to hereafter as DFP-14927, using a 4-armed CTPEG system to endow the DFP-10917 drug with favorable long-circulating properties that maximize its utility and antitumor efficacy. Intravenous injection of the synthesized DFP-14927 returned encouraging antitumor effects in a Panc-1 human pancreatic tumor- and a BxPC-3 human pancreatic tumor-xenograft models. These effects were comparable to that of free DFP-10917 as well as to that of gemcitabine, which is considered a standard in the treatment of pancreatic cancer. In vitro studies revealed that DFP-14927 inhibits cell division on human pancreatic cancer cell lines via arrest of the G2/M phase in the cell cycle, which is consistent with the effects of free DFP-10917. Intravenous administration of the newly synthesized DFP-14927 has induced G2/M arrest in human pancreatic tumor-xenograft murine models, which represents an improvement in the pharmacokinetics of DFP-10917. DFP-14927 could be an alternative for patients who cannot accept prolonged or continuous infusions of DFP-10917.","ja":"A deoxycytidine analog is a potential agent for the treatment of several cancers, which includes poorly prognostic pancreatic cancer. We previously developed deoxycytidine analog DFP-10917, and long-term/low-dose infusions of this analog has produced antitumor effects in leukemia cancer- and ovarian cancer-xenograft models. DFP-10917 is now undergoing clinical Phase III study in the United States for the treatment of patients with relapsed or refractory acute myeloid leukemia. PEG-drug conjugation has become a promising technique to improve the pharmacokinetic and pharmacodynamic properties of anti-cancer drugs. In the present study, we synthesized a novel PEG-drug conjugate of DFP-10917, referred to hereafter as DFP-14927, using a 4-armed CTPEG system to endow the DFP-10917 drug with favorable long-circulating properties that maximize its utility and antitumor efficacy. Intravenous injection of the synthesized DFP-14927 returned encouraging antitumor effects in a Panc-1 human pancreatic tumor- and a BxPC-3 human pancreatic tumor-xenograft models. These effects were comparable to that of free DFP-10917 as well as to that of gemcitabine, which is considered a standard in the treatment of pancreatic cancer. In vitro studies revealed that DFP-14927 inhibits cell division on human pancreatic cancer cell lines via arrest of the G2/M phase in the cell cycle, which is consistent with the effects of free DFP-10917. Intravenous administration of the newly synthesized DFP-14927 has induced G2/M arrest in human pancreatic tumor-xenograft murine models, which represents an improvement in the pharmacokinetics of DFP-10917. DFP-14927 could be an alternative for patients who cannot accept prolonged or continuous infusions of DFP-10917."},"publication_date":"2023-07-05","publication_name":{"en":"European Journal of Pharmacology","ja":"European Journal of Pharmacology"},"volume":"Vol.950","starting_page":"175758","ending_page":"175758","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ejphar.2023.175758"],"issn":["1879-0712"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:13, {"insert":{"user_id":"1000300291","type":"published_papers","id":"41379367"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/36805860","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=393938","label":"url"}],"paper_title":{"en":"Ionic liquid-based transcutaneous peptide antitumor vaccine; therapeutic effect in a mouse tumor model","ja":"Ionic liquid-based transcutaneous peptide antitumor vaccine; therapeutic effect in a mouse tumor model"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Matsuzaki Takaaki"},{"name":"Fukuda Shoishiro"},{"name":"Yoshioka Chihiro"},{"name":"Shimazaki Yuna"},{"name":"Takese Shunsuke"},{"name":"Yamanaka Katsuhiro"},{"name":"Nakae Takashi"},{"name":"Ishibashi Masaki"},{"name":"Hamamoto Hidetoshi"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"松﨑 隆朗"},{"name":"福田 翔一郎"},{"name":"吉岡 千尋"},{"name":"島﨑 優奈"},{"name":"竹瀬 俊輔"},{"name":"Yamanaka Katsuhiro"},{"name":"Nakae Takashi"},{"name":"Ishibashi Masaki"},{"name":"Hamamoto Hidetoshi"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Traditional vaccinations need to be injected with needles, and since some people have a strong aversion to needles, a needle-free alternative delivery system is important. In this study, we employed ionic liquids (ILs) for transcutaneous delivery of cancer antigen-derived peptides to obtain anticancer therapeutic effects in a needle-free manner. ILs successfully increased the in vitro skin permeability of a peptide from Wilms tumor 1 (WT1), one of the more promising cancer antigens, plus or minus an adjuvant, resiquimod (R848), a toll-like receptor 7 agonist. In vivo studies demonstrated that concomitant transcutaneous delivery of WT1 peptide and R848 by ILs induced WT1-specific cytotoxic T lymphocyte (CTL) in mice, resulting in tumor growth inhibition in Lewis lung carcinoma-bearing mice. Interestingly, administrating R848 in ILs before WT1 peptides in ILs increased tumor growth inhibition effects compared to co-administration of both. We found that the prior application of R848 increased the infiltration of leukocytes in the skin and that subsequent delivery of WT1 peptides was more likely to induce WT1-specific CTL. Furthermore, sequential immunization with IL-based formulations was applicable to different types of peptides and cancer models without induction of skin irritation. IL-based transcutaneous delivery of cancer antigen-derived peptides and adjuvants, either alone or together, could be a novel approach to needle-free cancer therapeutic vaccines.","ja":"Traditional vaccinations need to be injected with needles, and since some people have a strong aversion to needles, a needle-free alternative delivery system is important. In this study, we employed ionic liquids (ILs) for transcutaneous delivery of cancer antigen-derived peptides to obtain anticancer therapeutic effects in a needle-free manner. ILs successfully increased the in vitro skin permeability of a peptide from Wilms tumor 1 (WT1), one of the more promising cancer antigens, plus or minus an adjuvant, resiquimod (R848), a toll-like receptor 7 agonist. In vivo studies demonstrated that concomitant transcutaneous delivery of WT1 peptide and R848 by ILs induced WT1-specific cytotoxic T lymphocyte (CTL) in mice, resulting in tumor growth inhibition in Lewis lung carcinoma-bearing mice. Interestingly, administrating R848 in ILs before WT1 peptides in ILs increased tumor growth inhibition effects compared to co-administration of both. We found that the prior application of R848 increased the infiltration of leukocytes in the skin and that subsequent delivery of WT1 peptides was more likely to induce WT1-specific CTL. Furthermore, sequential immunization with IL-based formulations was applicable to different types of peptides and cancer models without induction of skin irritation. IL-based transcutaneous delivery of cancer antigen-derived peptides and adjuvants, either alone or together, could be a novel approach to needle-free cancer therapeutic vaccines."},"publication_date":"2023-03","publication_name":{"en":"The AAPS Journal","ja":"The AAPS Journal"},"volume":"Vol.25","number":"No.2","starting_page":"27","ending_page":"27","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1208/s12248-023-00790-w"],"issn":["1550-7416"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:14, {"insert":{"user_id":"1000300291","type":"published_papers","id":"41053469"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=393469","label":"url"}],"paper_title":{"en":"Investigation of anti-PEG antibody response to PEG-containing cosmetic products in mice","ja":"Investigation of anti-PEG antibody response to PEG-containing cosmetic products in mice"},"authors":{"en":[{"name":"Ibrahim Mohamed"},{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Elgarhy Omar Helmy"},{"name":"Sarhan Hatem A"},{"name":"Hussein Amal K"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Ibrahim Mohamed"},{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"Elgarhy Omar Helmy"},{"name":"Sarhan Hatem A"},{"name":"Hussein Amal K"},{"name":"石田 竜弘"}]},"publication_date":"2023-02-01","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.354","starting_page":"260","ending_page":"267","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2023.01.012"],"issn":["0168-3659"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:15, {"insert":{"user_id":"1000300291","type":"published_papers","id":"40768065"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=393337","label":"url"}],"paper_title":{"en":"Potential efficacy of proteasome inhibitor, Delanzomib, for the treatment of renal fibrosis","ja":"Potential efficacy of proteasome inhibitor, Delanzomib, for the treatment of renal fibrosis"},"authors":{"en":[{"name":"Sawa-Aihara Ayano"},{"name":"Hattori Katsuji"},{"name":"Nagao Goshi"},{"name":"Yamada Yoshihisa"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"粟飯原 礼乃"},{"name":"Hattori Katsuji"},{"name":"Nagao Goshi"},{"name":"Yamada Yoshihisa"},{"name":"石田 竜弘"}]},"publication_date":"2023-02-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.46","number":"No.2","starting_page":"279","ending_page":"285","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b22-00713"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:16, {"insert":{"user_id":"1000300291","type":"published_papers","id":"41042834"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/36708147","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=393449","label":"url"}],"paper_title":{"en":"Clinical impact of anti-polyethylene glycol (PEG) antibody in haematological patients administered PEGylated-granulocyte colony-stimulating factor","ja":"Clinical impact of anti-polyethylene glycol (PEG) antibody in haematological patients administered PEGylated-granulocyte colony-stimulating factor"},"authors":{"en":[{"name":"Okada Naoto"},{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Nakamura Shingen"},{"name":"Goda Mitsuhiro"},{"name":"Abe Masahiro"},{"name":"Kitahara Takashi"},{"name":"Ishida Tatsuhiro"},{"name":"Ishizawa Keisuke"}],"ja":[{"name":"Okada Naoto"},{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"Nakamura Shingen"},{"name":"Goda Mitsuhiro"},{"name":"Abe Masahiro"},{"name":"Kitahara Takashi"},{"name":"石田 竜弘"},{"name":"Ishizawa Keisuke"}]},"description":{"en":"Polyethylene glycol (PEG) is a polymer covalently attached to proteins to improve their half-life and efficacy. We previously reported that the PEGylated granulocyte colony-stimulating factor (PEG-G-CSF) is immunogenic, which could adversely impact drug efficacy and safety in animal models. Here, we analyzed the relationship between anti-PEG antibody titers and the clinical impact of PEG-G-CSF in 19 hematological patients. A gradual decrease of anti-PEG antibody titers from baseline was observed after PEG-G-CSF administration. Of the 19 participants, 10 were assessed for noninfectious fever after the first administration of PEG-G-CSF and three experienced this reaction. The receiver operating characteristic curve revealed that the cut-off values of pretreated anti-PEG IgM and IgG titers for noninfectious fever were set at 5.0 and 96.6 U/mL, respectively. All patients who experienced noninfectious fever had anti-PEG antibody titers above this cut-off value (P = .033). An enzyme-linked immunosorbent assay revealed that some anti-PEG antibodies in patients with anti-PEG antibody titers above the cut-off value reacted with the PEGylated liposome. These results indicate the reactivity of the anti-PEG antibodies to PEGylated therapeutics observed in hematologic patients and the possibility of the relationship between high titers of anti-PEG antibodies and the development of adverse events after PEG-G-CSF administration.","ja":"Polyethylene glycol (PEG) is a polymer covalently attached to proteins to improve their half-life and efficacy. We previously reported that the PEGylated granulocyte colony-stimulating factor (PEG-G-CSF) is immunogenic, which could adversely impact drug efficacy and safety in animal models. Here, we analyzed the relationship between anti-PEG antibody titers and the clinical impact of PEG-G-CSF in 19 hematological patients. A gradual decrease of anti-PEG antibody titers from baseline was observed after PEG-G-CSF administration. Of the 19 participants, 10 were assessed for noninfectious fever after the first administration of PEG-G-CSF and three experienced this reaction. The receiver operating characteristic curve revealed that the cut-off values of pretreated anti-PEG IgM and IgG titers for noninfectious fever were set at 5.0 and 96.6 U/mL, respectively. All patients who experienced noninfectious fever had anti-PEG antibody titers above this cut-off value (P = .033). An enzyme-linked immunosorbent assay revealed that some anti-PEG antibodies in patients with anti-PEG antibody titers above the cut-off value reacted with the PEGylated liposome. These results indicate the reactivity of the anti-PEG antibodies to PEGylated therapeutics observed in hematologic patients and the possibility of the relationship between high titers of anti-PEG antibodies and the development of adverse events after PEG-G-CSF administration."},"publication_date":"2023-01-28","publication_name":{"en":"Clinical Pharmacology in Drug Development","ja":"Clinical Pharmacology in Drug Development"},"volume":"Vol.12","number":"No.8","starting_page":"826","ending_page":"831","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/cpdd.1225"],"issn":["2160-7648"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:17, {"insert":{"user_id":"1000300291","type":"published_papers","id":"40510324"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/118017","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=392886","label":"url"}],"paper_title":{"en":"FTY720 reduces lipid accumulation by upregulating ABCA1 through liver X receptor and sphingosine kinase 2 signaling in macrophages","ja":"FTY720 reduces lipid accumulation by upregulating ABCA1 through liver X receptor and sphingosine kinase 2 signaling in macrophages"},"authors":{"en":[{"name":"Tachibana Kohki"},{"name":"Kusumoto Kohshi"},{"name":"Ogawa Mai"},{"name":"ANDO Hidenori"},{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"},{"name":"Okuhira Keiichiro"}],"ja":[{"name":"立花 洸季"},{"name":"楠本 嵩志"},{"name":"小川 真依"},{"name":"安藤 英紀"},{"name":"清水 太郎"},{"name":"異島 優"},{"name":"石田 竜弘"},{"name":"奥平 桂一郎"}]},"publication_date":"2022-11-23","publication_name":{"en":"International Journal of Molecular Sciences","ja":"International Journal of Molecular Sciences"},"volume":"Vol.23","starting_page":"14617","ending_page":"14617","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/ijms232314617"],"issn":["1422-0067"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:18, {"insert":{"user_id":"1000300291","type":"published_papers","id":"39507272"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/117961","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/35939788","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=387843","label":"url"}],"paper_title":{"en":"First-in-human Phase 1 trial of artificial red blood cells, hemoglobin vesicles, developed as a transfusion alternative","ja":"First-in-human Phase 1 trial of artificial red blood cells, hemoglobin vesicles, developed as a transfusion alternative"},"authors":{"en":[{"name":"Azuma Hiroshi"},{"name":"Amano Toraji"},{"name":"Kamiyama Naoya"},{"name":"Takehara Naofumi"},{"name":"Jingu Maki"},{"name":"Takagi Harumi"},{"name":"Sugita Osamu"},{"name":"Kobayashi Naoko"},{"name":"Kure Tomoko"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"},{"name":"Matsumoto Masanori"},{"name":"Sakai Hiromi"}],"ja":[{"name":"Azuma Hiroshi"},{"name":"Amano Toraji"},{"name":"Kamiyama Naoya"},{"name":"Takehara Naofumi"},{"name":"Jingu Maki"},{"name":"Takagi Harumi"},{"name":"Sugita Osamu"},{"name":"Kobayashi Naoko"},{"name":"Kure Tomoko"},{"name":"清水 太郎"},{"name":"石田 竜弘"},{"name":"Matsumoto Masanori"},{"name":"Sakai Hiromi"}]},"publication_date":"2022-11-08","publication_name":{"en":"Blood Advances","ja":"Blood Advances"},"volume":"Vol.6","number":"No.21","starting_page":"5711","ending_page":"5715","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1182/bloodadvances.2022007977"],"issn":["2473-9537"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:19, {"insert":{"user_id":"1000300291","type":"published_papers","id":"39507271"},"force":{"see_also":[{"@id":"https://cir.nii.ac.jp/crid/1390856583390911232/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=387846","label":"url"}],"paper_title":{"en":"A maleimide-terminally modified PEGylated liposome induced the accelerated blood clearance independent of the production of anti-PEG IgM antibodies","ja":"A maleimide-terminally modified PEGylated liposome induced the accelerated blood clearance independent of the production of anti-PEG IgM antibodies"},"authors":{"en":[{"name":"Ishima Yu"},{"name":"Yamazaki Nio"},{"name":"Chuang V"},{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"異島 優"},{"name":"山﨑 仁王"},{"name":"Chuang V"},{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"石田 竜弘"}]},"publication_date":"2022-10-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.45","number":"No.10","starting_page":"1518","ending_page":"1524","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b22-00389"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:20, {"insert":{"user_id":"1000300291","type":"published_papers","id":"40510323"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=397281","label":"url"}],"paper_title":{"en":"アルブミンのボリスルフィドによる新たな生体恒常性維持機構","ja":"アルブミンのボリスルフィドによる新たな生体恒常性維持機構"},"authors":{"en":[{"name":"Ishima Yu"},{"name":"小田切 優樹"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"異島 優"},{"name":"小田切 優樹"},{"name":"石田 竜弘"}]},"publication_date":"2022-09-01","publication_name":{"en":"人工血液","ja":"人工血液"},"volume":"Vol.30","starting_page":"59","ending_page":"64","languages":["jpn"],"referee":true,"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:21, {"insert":{"user_id":"1000300291","type":"published_papers","id":"39656554"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/35988781","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=389908","label":"url"}],"paper_title":{"en":"Oral administration of sodium bicarbonate can enhance the therapeutic outcome of Doxil® via neutralizing the acidic tumor microenvironment","ja":"Oral administration of sodium bicarbonate can enhance the therapeutic outcome of Doxil® via neutralizing the acidic tumor microenvironment"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Ikeda Ai"},{"name":"Tagami Maho"},{"name":"Matsuo Nana"},{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Eshima K"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"池田 愛"},{"name":"田神 舞帆"},{"name":"松尾 菜々"},{"name":"清水 太郎"},{"name":"異島 優"},{"name":"Eshima K"},{"name":"石田 竜弘"}]},"description":{"en":"The pH of the tumor microenvironment in solid tumors is reported to be more acidic than that of normal tissues. The pH is controlled by over-expression of several transporters that are associated with the progression, angiogenesis, and metastasis of solid tumors. Antitumor effects of weak-base anticancer agents, such as doxorubicin (DXR), could be reduced in an acidic environment because of increases in the ionized form of the drug under these conditions, reducing its membrane penetrability. In our previous studies, we demonstrated that oral administration of sodium bicarbonate (NaHCO) can neutralize the acidic tumor microenvironment and enhance the effects of small molecule anticancer drugs. However, it is not known whether or not increasing the tumor pH by oral administration of NaHCO leads to enhanced antitumor effects of lipidic nanoparticle formulations of weak-base anticancer drugs, such as Doxil®. In this study, we investigated the antitumor efficacy of Doxil® in combination with oral administration of NaHCO in a Colon26 tumor-bearing mouse model. NaHCO clearly enhanced the tumor-growth inhibitory effect of Doxil® without exacerbating any systemic side effects. In vitro studies indicated that high levels of DXR were internalized into cells at neutral pH. These studies demonstrate that the neutralization of acidic tumor microenvironment by an oral administration of NaHCO could be a promising approach to enhance the therapeutic outcomes of Doxil®.","ja":"The pH of the tumor microenvironment in solid tumors is reported to be more acidic than that of normal tissues. The pH is controlled by over-expression of several transporters that are associated with the progression, angiogenesis, and metastasis of solid tumors. Antitumor effects of weak-base anticancer agents, such as doxorubicin (DXR), could be reduced in an acidic environment because of increases in the ionized form of the drug under these conditions, reducing its membrane penetrability. In our previous studies, we demonstrated that oral administration of sodium bicarbonate (NaHCO) can neutralize the acidic tumor microenvironment and enhance the effects of small molecule anticancer drugs. However, it is not known whether or not increasing the tumor pH by oral administration of NaHCO leads to enhanced antitumor effects of lipidic nanoparticle formulations of weak-base anticancer drugs, such as Doxil®. In this study, we investigated the antitumor efficacy of Doxil® in combination with oral administration of NaHCO in a Colon26 tumor-bearing mouse model. NaHCO clearly enhanced the tumor-growth inhibitory effect of Doxil® without exacerbating any systemic side effects. In vitro studies indicated that high levels of DXR were internalized into cells at neutral pH. These studies demonstrate that the neutralization of acidic tumor microenvironment by an oral administration of NaHCO could be a promising approach to enhance the therapeutic outcomes of Doxil®."},"publication_date":"2022-08-18","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.350","starting_page":"414","ending_page":"420","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2022.08.031"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:22, {"insert":{"user_id":"1000300291","type":"published_papers","id":"36905615"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/117224","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=385361","label":"url"}],"paper_title":{"en":"Development of a nanocarrier-based splenic B cell-targeting system for loading antigens in vitro","ja":"Development of a nanocarrier-based splenic B cell-targeting system for loading antigens in vitro"},"authors":{"en":[{"name":"Kawaguchi Yoshino"},{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"川口 桂乃"},{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"publication_date":"2022-07-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.45","number":"No.7","starting_page":"926","ending_page":"933","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b22-00222"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:23, {"insert":{"user_id":"1000300291","type":"published_papers","id":"36366793"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=384285","label":"url"}],"paper_title":{"en":"Development of an antigen delivery system for a B cell-targeted vaccine as an alternative to dendritic cell-targeted vaccines","ja":"Development of an antigen delivery system for a B cell-targeted vaccine as an alternative to dendritic cell-targeted vaccines"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Kawaguchi Yoshino"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"川口 桂乃"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"publication_date":"2022-05-01","publication_name":{"en":"Chemical & Pharmaceutical Bulletin","ja":"Chemical & Pharmaceutical Bulletin"},"volume":"Vol.70","number":"No.5","starting_page":"341","ending_page":"350","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/cpb.c22-00047"],"issn":["1347-5223"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:24, {"insert":{"user_id":"1000300291","type":"published_papers","id":"36164910"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=383648","label":"url"}],"paper_title":{"en":"Subvisible particles derived by dropping stress enhance anti-PEG antibody production and clearance of PEGylated proteins in mice","ja":"Subvisible particles derived by dropping stress enhance anti-PEG antibody production and clearance of PEGylated proteins in mice"},"authors":{"en":[{"name":"Nakajima Takaki"},{"name":"Nagano Kazuya"},{"name":"Fukuda Yuka"},{"name":"Ishima Yu"},{"name":"Shibata Hiroko"},{"name":"Isaka Ryo"},{"name":"Zhang Tian-Qi"},{"name":"Haga Yuya"},{"name":"Higashisaka Kazuma"},{"name":"Tsujino Hirofumi"},{"name":"Ishida Tatsuhiro"},{"name":"Ishii-Watabe Akiko"},{"name":"Tsutsumi Yasuo"}],"ja":[{"name":"Nakajima Takaki"},{"name":"Nagano Kazuya"},{"name":"福田 悠花"},{"name":"異島 優"},{"name":"Shibata Hiroko"},{"name":"Isaka Ryo"},{"name":"Zhang Tian-Qi"},{"name":"Haga Yuya"},{"name":"Higashisaka Kazuma"},{"name":"Tsujino Hirofumi"},{"name":"石田 竜弘"},{"name":"Ishii-Watabe Akiko"},{"name":"Tsutsumi Yasuo"}]},"publication_date":"2022-05-01","publication_name":{"en":"Journal of Pharmaceutical Sciences","ja":"Journal of Pharmaceutical Sciences"},"volume":"Vol.111","number":"No.5","starting_page":"1363","ending_page":"1369","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.xphs.2022.01.023"],"issn":["0022-3549"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:25, {"insert":{"user_id":"1000300291","type":"published_papers","id":"39728152"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/36102318","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=391143","label":"url"}],"paper_title":{"en":"Wnt2b and Wnt5a expressions are highly associated with M2 TAMs in non-small-cell lung cancer","ja":"Wnt2b and Wnt5a expressions are highly associated with M2 TAMs in non-small-cell lung cancer"},"authors":{"en":[{"name":"Sumitomo Ryota"},{"name":"Huang Cheng-long"},{"name":"ANDO Hidenori"},{"name":"Ishida Tatsuhiro"},{"name":"Cho Hiroyuki"},{"name":"Date Hiroshi"}],"ja":[{"name":"Sumitomo Ryota"},{"name":"Huang Cheng-long"},{"name":"安藤 英紀"},{"name":"石田 竜弘"},{"name":"Cho Hiroyuki"},{"name":"Date Hiroshi"}]},"description":{"en":"Tumor-associated macrophages (TAMs), particularly M2 macrophages, promote tumor progression, while genes encode a family of multi-functional glycoproteins that serve an important role in tumorigenesis. Immunohistochemical studies were performed to evaluate Wnt2b and Wnt5a expression in tumor and stromal cells in M2 and M1 TAMs and Ki-67 proliferation index in 160 consecutive patients with resected non-small cell lung cancer (NSCLC). Overall, 52 tumors (32.5%) were classified as tumoral Wnt2b-high (Wnt2b-positive tumor cells >30%) and 95 (59.4%) as stromal Wnt2b-high (Wnt2b-positive stromal cells >30%), while 75 (46.9%) were classified as tumoral Wnt5a-high (Wnt5a-positive tumor cells >30%) and 63 (39.4%) as stromal Wnt5a-high (Wnt5a-positive stromal cells >28%). The density of M2 TAMs was significantly higher in the tumoral (P=0.0024) and stromal Wnt2b-high groups (P=0.0054). The density of M2 TAMs was also significantly higher in the tumoral (P=0.0005) and stromal Wnt5a-high groups (P=0.0486). By contrast, no difference in stromal or islet M1 TAM density was observed in relation to tumoral or stromal Wnt2b or Wnt5a status. Furthermore, Ki-67 proliferation index was significantly higher in the tumoral (P=0.0121) and stromal Wnt2b-high (P=0.0019) and tumoral Wnt5a-high (P=0.0088) groups. Overall survival rate was significantly lower in the Wnt2b-high (P=0.0437), Wnt5a-high (P=0.0106) and M2 TAM-high (P=0.0060) groups. Wnt2b and Wnt5a expression in tumor and stromal cells may induce M2 TAMs to produce more aggressive behavior during tumor progression in NSCLC.","ja":"Tumor-associated macrophages (TAMs), particularly M2 macrophages, promote tumor progression, while genes encode a family of multi-functional glycoproteins that serve an important role in tumorigenesis. Immunohistochemical studies were performed to evaluate Wnt2b and Wnt5a expression in tumor and stromal cells in M2 and M1 TAMs and Ki-67 proliferation index in 160 consecutive patients with resected non-small cell lung cancer (NSCLC). Overall, 52 tumors (32.5%) were classified as tumoral Wnt2b-high (Wnt2b-positive tumor cells >30%) and 95 (59.4%) as stromal Wnt2b-high (Wnt2b-positive stromal cells >30%), while 75 (46.9%) were classified as tumoral Wnt5a-high (Wnt5a-positive tumor cells >30%) and 63 (39.4%) as stromal Wnt5a-high (Wnt5a-positive stromal cells >28%). The density of M2 TAMs was significantly higher in the tumoral (P=0.0024) and stromal Wnt2b-high groups (P=0.0054). The density of M2 TAMs was also significantly higher in the tumoral (P=0.0005) and stromal Wnt5a-high groups (P=0.0486). By contrast, no difference in stromal or islet M1 TAM density was observed in relation to tumoral or stromal Wnt2b or Wnt5a status. Furthermore, Ki-67 proliferation index was significantly higher in the tumoral (P=0.0121) and stromal Wnt2b-high (P=0.0019) and tumoral Wnt5a-high (P=0.0088) groups. Overall survival rate was significantly lower in the Wnt2b-high (P=0.0437), Wnt5a-high (P=0.0106) and M2 TAM-high (P=0.0060) groups. Wnt2b and Wnt5a expression in tumor and stromal cells may induce M2 TAMs to produce more aggressive behavior during tumor progression in NSCLC."},"publication_date":"2022-04-20","publication_name":{"en":"Oncology Reports","ja":"Oncology Reports"},"volume":"Vol.48","number":"No.5","starting_page":"189","ending_page":"189","languages":["eng"],"referee":true,"identifiers":{"doi":["10.2139/ssrn.4088768"],"issn":["1791-2431"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:26, {"insert":{"user_id":"1000300291","type":"published_papers","id":"36217199"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/35370275","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=383795","label":"url"}],"paper_title":{"en":"Importance of process parameters influencing the mean diameters of siRNA-containing lipid nanoparticles (LNPs) on the in vitro activity of prepared LNPs","ja":"Importance of process parameters influencing the mean diameters of siRNA-containing lipid nanoparticles (LNPs) on the in vitro activity of prepared LNPs"},"authors":{"en":[{"name":"Nakamura Kazuya"},{"name":"Aihara Keisuke"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"中村 和也"},{"name":"Aihara Keisuke"},{"name":"石田 竜弘"}]},"description":{"en":"Genetic drugs have the potential to treat a variety of diseases. Recently, lipid nanoparticles (LNPs) have attracted much attention among drug delivery systems for genetic drugs. LNPs have been practically used in small interfering RNA (siRNA) drugs and mRNA vaccines. Although LNPs are generally prepared by mixing nucleic acids in acidic aqueous buffer and lipid excipients in alcohol (i.e., ethanol), it is not well understood which process parameters in the LNPs formation affect the physicochemical properties and the functionality of LNPs. In this study, we used siRNA-containing LNPs as a model, and evaluated the effect that aqueous solution parameters (buffering agent type, salt concentration, and pH) and mixing parameters (ratio, speed, and temperature) exert on the physicochemical properties and in vitro gene-knockdown activity of LNPs. Among such parameters, the type of buffering agent, salt concentration (ionic strength), pH in acidic aqueous buffer, as well as the mixing ratio and speed significantly affected the mean particle diameter and in vitro gene-knockdown activity of LNPs. A strong correlation between the mean particle diameters and their in vitro gene-knockdown activities was observed. These observations suggest that the process parameters influencing the mean LNPs diameter are likely to be important in the formation of LNPs and also that these correlate with in vitro gene-knockdown activity. Because LNP systems are being further developed for future clinical applications of genetic drugs, information regarding the LNPs manufacturing process is of utmost importance. The results observed in this study will be useful for the manufacturing of optimal LNPs.","ja":"Genetic drugs have the potential to treat a variety of diseases. Recently, lipid nanoparticles (LNPs) have attracted much attention among drug delivery systems for genetic drugs. LNPs have been practically used in small interfering RNA (siRNA) drugs and mRNA vaccines. Although LNPs are generally prepared by mixing nucleic acids in acidic aqueous buffer and lipid excipients in alcohol (i.e., ethanol), it is not well understood which process parameters in the LNPs formation affect the physicochemical properties and the functionality of LNPs. In this study, we used siRNA-containing LNPs as a model, and evaluated the effect that aqueous solution parameters (buffering agent type, salt concentration, and pH) and mixing parameters (ratio, speed, and temperature) exert on the physicochemical properties and in vitro gene-knockdown activity of LNPs. Among such parameters, the type of buffering agent, salt concentration (ionic strength), pH in acidic aqueous buffer, as well as the mixing ratio and speed significantly affected the mean particle diameter and in vitro gene-knockdown activity of LNPs. A strong correlation between the mean particle diameters and their in vitro gene-knockdown activities was observed. These observations suggest that the process parameters influencing the mean LNPs diameter are likely to be important in the formation of LNPs and also that these correlate with in vitro gene-knockdown activity. Because LNP systems are being further developed for future clinical applications of genetic drugs, information regarding the LNPs manufacturing process is of utmost importance. The results observed in this study will be useful for the manufacturing of optimal LNPs."},"publication_date":"2022-04-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.45","number":"No.4","starting_page":"497","ending_page":"507","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b21-01016"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:27, {"insert":{"user_id":"1000300291","type":"published_papers","id":"36292759"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/35124114","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=384078","label":"url"}],"paper_title":{"en":"A mouse model for studying the effect of blood anti-PEG IgMs levels on the in vivo fate of PEGylated liposomes","ja":"A mouse model for studying the effect of blood anti-PEG IgMs levels on the in vivo fate of PEGylated liposomes"},"authors":{"en":[{"name":"El Sayed Marwa"},{"name":"Shimizu Taro"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Sherif Emam Abdallah Emam"},{"name":"Alaaeldin Eman"},{"name":"Kamal Amal"},{"name":"Sarhan Hatem"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"El Sayed Marwa"},{"name":"清水 太郎"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Sherif Emam Abdallah Emam"},{"name":"Alaaeldin Eman"},{"name":"Kamal Amal"},{"name":"Sarhan Hatem"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"The presence of anti-polyethylene glycol (PEG) antibodies in the systemic circulation might have potential implications for the therapeutic activity of PEGylated products in vivo in the clinic. In order to study the effect of pre-existing anti-PEG antibodies on the in vivo fate and the therapeutic efficiency of PEGylated therapeutics, we developed a BALB/c mouse model by virtue of the intraperitoneal (i.p.) inoculation of hybridoma cells (HIK-M09 and HIK-M11), secreting monoclonal anti-PEG IgM, mimicking the presence of pre-existing anti-PEG antibodies in the blood. In the model, the titers of anti-PEG IgM in the blood increased as a function of hybridoma cells numbers and time after i.p. inoculation. The in vivo levels of anti-PEG IgM decreased in a dose-dependent manner, following i.v. administration of empty PEGylated liposomes. C26 tumor-bearing mice with measurable levels of anti-PEG IgM, receiving i.v. injection of DiR-labeled empty PEGylated liposomes, showed lower levels of liposomal tumor accumulation and higher levels of liver and spleen accumulation, compared to C26 tumor-bearing mice without measurable anti-PEG IgM. This specifies that the presence of anti-PEG IgM in the murine circulation induced accelerated blood clearance of PEGylated liposomes and reduced their tumor accumulation. The biodistribution and antitumor efficacy of commercially available doxorubicin (DXR)-containing PEGylated liposomes, Doxil®, were scrutinized in the anti-PEG IgM mouse model. In C26 tumor-bearing mice having circulating anti-PEG IgM, at 24 h after injection almost no DXR was observed in blood and tumor, and increased DXR accumulation was observed in spleen and liver, compared to tumor-bearing mice with no circulating anti-PEG IgM. The antitumor efficacy of Doxil® was significantly compromised in the C26 tumor-bearing mice in the presence of anti-PEG IgM. These results demonstrate that the anti-PEG IgM mouse model could be a useful prognostic indicator for the therapeutic effectiveness of different formulations of PEGylated therapeutics in pre-clinical studies.","ja":"The presence of anti-polyethylene glycol (PEG) antibodies in the systemic circulation might have potential implications for the therapeutic activity of PEGylated products in vivo in the clinic. In order to study the effect of pre-existing anti-PEG antibodies on the in vivo fate and the therapeutic efficiency of PEGylated therapeutics, we developed a BALB/c mouse model by virtue of the intraperitoneal (i.p.) inoculation of hybridoma cells (HIK-M09 and HIK-M11), secreting monoclonal anti-PEG IgM, mimicking the presence of pre-existing anti-PEG antibodies in the blood. In the model, the titers of anti-PEG IgM in the blood increased as a function of hybridoma cells numbers and time after i.p. inoculation. The in vivo levels of anti-PEG IgM decreased in a dose-dependent manner, following i.v. administration of empty PEGylated liposomes. C26 tumor-bearing mice with measurable levels of anti-PEG IgM, receiving i.v. injection of DiR-labeled empty PEGylated liposomes, showed lower levels of liposomal tumor accumulation and higher levels of liver and spleen accumulation, compared to C26 tumor-bearing mice without measurable anti-PEG IgM. This specifies that the presence of anti-PEG IgM in the murine circulation induced accelerated blood clearance of PEGylated liposomes and reduced their tumor accumulation. The biodistribution and antitumor efficacy of commercially available doxorubicin (DXR)-containing PEGylated liposomes, Doxil®, were scrutinized in the anti-PEG IgM mouse model. In C26 tumor-bearing mice having circulating anti-PEG IgM, at 24 h after injection almost no DXR was observed in blood and tumor, and increased DXR accumulation was observed in spleen and liver, compared to tumor-bearing mice with no circulating anti-PEG IgM. The antitumor efficacy of Doxil® was significantly compromised in the C26 tumor-bearing mice in the presence of anti-PEG IgM. These results demonstrate that the anti-PEG IgM mouse model could be a useful prognostic indicator for the therapeutic effectiveness of different formulations of PEGylated therapeutics in pre-clinical studies."},"publication_date":"2022-03-05","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.615","starting_page":"121539","ending_page":"121539","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2022.121539"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:28, {"insert":{"user_id":"1000300291","type":"published_papers","id":"35684139"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/34980774","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390290617368317184/","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85123166599&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=382877","label":"url"}],"paper_title":{"en":"Using Bio-Layer Interferometry to evaluate anti-PEG antibody-mediated complement activation","ja":"Using Bio-Layer Interferometry to evaluate anti-PEG antibody-mediated complement activation"},"authors":{"en":[{"name":"Mahmoud Mostafa M"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Sherif Emam Abdallah Emam"},{"name":"ANDO Hidenori"},{"name":"Shimizu Taro"},{"name":"Abdelkader H"},{"name":"Ishima Yu"},{"name":"Farghaly Aly U"},{"name":"Sarhan H A"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Mahmoud Mostafa M"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Sherif Emam Abdallah Emam"},{"name":"安藤 英紀"},{"name":"清水 太郎"},{"name":"Abdelkader H"},{"name":"異島 優"},{"name":"Farghaly Aly U"},{"name":"Sarhan H A"},{"name":"石田 竜弘"}]},"description":{"en":"The purpose of this study was to develop a Bio-layer interferometry (BLI) system that could be an alternative approach for the direct evaluation of anti-polyethylene glycol (PEG) immunoglobulin M (IgM)-mediated complement activation of the accelerated blood clearance (ABC) phenomenon. Complement activation is well known to play an important role in the clearance of PEGylated and non-PEGylated nanomedicines following intravenous injection. This complement system is also thought to be responsible for the ABC phenomenon wherein repeated injections of PEGylated products are bound by anti-PEG antibodies. This study used three different sources of anti-PEG antibodies: HIK-M09 monoclonal antibodies (mAbs); HIK-M11 mAbs; and antiserum containing polyclonal anti-PEG IgMs. 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy (polyethylene glycol)-2000] (mPEG-DSPE) was immobilized as an antigen on aminopropyl silane biosensor chips of BLI. All anti-PEG IgMs in the sources increased the signals (thickness of the layer around the sensor tip) regarding binding of anti-PEG antibodies to PEG on the chips. In all anti-PEG IgM sources, further increases in the signals were observed when incubated in naïve mouse serum, which is a complement source, but not in heat inactivated (56 °C, 30 min) mouse serum, which abolishes complement activity. These findings show that the complement activation mediated via anti-PEG IgMs, which occurred on the sensor chips, was detected via BLI analysis. The complement activation induced by all anti-PEG IgM sources was confirmed via conventional enzyme-linked immunosorbent assay (ELISA), which is the conventional mode for detection of complement activation. Our study results show that BLI is a simple alternative method for the detection of complement activation.","ja":"The purpose of this study was to develop a Bio-layer interferometry (BLI) system that could be an alternative approach for the direct evaluation of anti-polyethylene glycol (PEG) immunoglobulin M (IgM)-mediated complement activation of the accelerated blood clearance (ABC) phenomenon. Complement activation is well known to play an important role in the clearance of PEGylated and non-PEGylated nanomedicines following intravenous injection. This complement system is also thought to be responsible for the ABC phenomenon wherein repeated injections of PEGylated products are bound by anti-PEG antibodies. This study used three different sources of anti-PEG antibodies: HIK-M09 monoclonal antibodies (mAbs); HIK-M11 mAbs; and antiserum containing polyclonal anti-PEG IgMs. 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy (polyethylene glycol)-2000] (mPEG-DSPE) was immobilized as an antigen on aminopropyl silane biosensor chips of BLI. All anti-PEG IgMs in the sources increased the signals (thickness of the layer around the sensor tip) regarding binding of anti-PEG antibodies to PEG on the chips. In all anti-PEG IgM sources, further increases in the signals were observed when incubated in naïve mouse serum, which is a complement source, but not in heat inactivated (56 °C, 30 min) mouse serum, which abolishes complement activity. These findings show that the complement activation mediated via anti-PEG IgMs, which occurred on the sensor chips, was detected via BLI analysis. The complement activation induced by all anti-PEG IgM sources was confirmed via conventional enzyme-linked immunosorbent assay (ELISA), which is the conventional mode for detection of complement activation. Our study results show that BLI is a simple alternative method for the detection of complement activation."},"publication_date":"2022-01-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.45","number":"No.1","starting_page":"129","ending_page":"135","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b21-00772"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:29, {"insert":{"user_id":"1000300291","type":"published_papers","id":"35997016"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=383343","label":"url"}],"paper_title":{"en":"I.p.-injected cationic liposomes are retained and accumulate in peritoneally disseminated tumors","ja":"I.p.-injected cationic liposomes are retained and accumulate in peritoneally disseminated tumors"},"authors":{"en":[{"name":"Ando-Matsuoka Rie"},{"name":"ANDO Hidenori"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Maeda Noriyuki"},{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 里英"},{"name":"安藤 英紀"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Maeda Noriyuki"},{"name":"清水 太郎"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"publication_date":"2022-01","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.341","starting_page":"524","ending_page":"532","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2021.12.004"],"issn":["0168-3659"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:30, {"insert":{"user_id":"1000300291","type":"published_papers","id":"33006581"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=376679","label":"url"}],"paper_title":{"en":"Liposomalization of oxaliplatin exacerbates the non-liposomal formulation-induced decrease of sweet taste sensitivity in rats","ja":"Liposomalization of oxaliplatin exacerbates the non-liposomal formulation-induced decrease of sweet taste sensitivity in rats"},"authors":{"en":[{"name":"Mogi Keisuke"},{"name":"Kamiya Ikumi"},{"name":"Makino Aimi"},{"name":"Hirao Ayaka"},{"name":"Abe Reina"},{"name":"Doi Yusuke"},{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Morito Katsuya"},{"name":"Takayama Kentaro"},{"name":"Ishida Tatsuhiro"},{"name":"Nagasawa Kazuki"}],"ja":[{"name":"Mogi Keisuke"},{"name":"Kamiya Ikumi"},{"name":"Makino Aimi"},{"name":"Hirao Ayaka"},{"name":"Abe Reina"},{"name":"土井 祐輔"},{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"Morito Katsuya"},{"name":"Takayama Kentaro"},{"name":"石田 竜弘"},{"name":"Nagasawa Kazuki"}]},"publication_date":"2021-12","publication_name":{"en":"Journal of Pharmaceutical Sciences","ja":"Journal of Pharmaceutical Sciences"},"volume":"Vol.110","number":"No.12","starting_page":"3937","ending_page":"3945","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.xphs.2021.07.004"],"issn":["0022-3549"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:31, {"insert":{"user_id":"1000300291","type":"published_papers","id":"33577519"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116279","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=381696","label":"url"}],"paper_title":{"en":"Efficient construction of the hexacyclic ring core of palau'amine: the pKa concept for proceeding with unfavorable equilibrium reactions","ja":"Efficient construction of the hexacyclic ring core of palau'amine: the pKa concept for proceeding with unfavorable equilibrium reactions"},"authors":{"en":[{"name":"Ohashi Eisaku"},{"name":"Karanjit Sangita"},{"name":"Nakayama Atsushi"},{"name":"Takeuchi Kohei"},{"name":"Emam E Sherif"},{"name":"ANDO Hidenori"},{"name":"Ishida Tatsuhiro"},{"name":"Namba Kosuke"}],"ja":[{"name":"大橋 栄作"},{"name":"カランジット サンギータ"},{"name":"中山 淳"},{"name":"竹内 公平"},{"name":"Sherif Emam Abdallah Emam"},{"name":"安藤 英紀"},{"name":"石田 竜弘"},{"name":"難波 康祐"}]},"publication_date":"2021-08-11","publication_name":{"en":"Chemical Science","ja":"Chemical Science"},"volume":"Vol.12","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1039/D1SC03260G"],"issn":["2041-6539"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:32, {"insert":{"user_id":"1000300291","type":"published_papers","id":"33359793"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=379459","label":"url"}],"paper_title":{"en":"Aseptic meningitis after vaccination of the BNT162b2 mRNA COVID19 vaccine","ja":"Aseptic meningitis after vaccination of the BNT162b2 mRNA COVID19 vaccine"},"authors":{"en":[{"name":"Saito Kazuyuki"},{"name":"Shimizu Taro"},{"name":"Suzuki-Inoue Katsue"},{"name":"Ishida Tatsuhiro"},{"name":"Wada Yoshiaki"}],"ja":[{"name":"Saito Kazuyuki"},{"name":"清水 太郎"},{"name":"Suzuki-Inoue Katsue"},{"name":"石田 竜弘"},{"name":"Wada Yoshiaki"}]},"publication_date":"2021-08-11","publication_name":{"en":"Neurological Sciences","ja":"Neurological Sciences"},"languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s10072-021-05543-1"],"issn":["1590-3478"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:33, {"insert":{"user_id":"1000300291","type":"published_papers","id":"33247700"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116618","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=377858","label":"url"}],"paper_title":{"en":"The therapeutic effect of HSA dimer-doxorubicin complex against human pancreatic tumour","ja":"The therapeutic effect of HSA dimer-doxorubicin complex against human pancreatic tumour"},"authors":{"en":[{"name":"Kinoshita Ryo"},{"name":"Ishima Yu"},{"name":"Chuang T.G. Victor"},{"name":"Watanabe Hiroshi"},{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Okuhira Keiichiro"},{"name":"Otagiri Masaki"},{"name":"Ishida Tatsuhiro"},{"name":"Maruyama Toru"}],"ja":[{"name":"木下 遼"},{"name":"異島 優"},{"name":"Chuang T.G. Victor"},{"name":"Watanabe Hiroshi"},{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"奥平 桂一郎"},{"name":"Otagiri Masaki"},{"name":"石田 竜弘"},{"name":"Maruyama Toru"}]},"publication_date":"2021-08-05","publication_name":{"en":"Pharmaceutics","ja":"Pharmaceutics"},"volume":"Vol.13","number":"No.8","starting_page":"1209","ending_page":"1209","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/pharmaceutics13081209"],"issn":["1999-4923"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:34, {"insert":{"user_id":"1000300291","type":"published_papers","id":"32904112"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116603","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=376567","label":"url"}],"paper_title":{"en":"Doxorubicin embedded into nanofibrillated bacterial cellulose (NFBC) produces a promising therapeutic outcome for peritoneally metastatic gastric cancer in mice models via intraperitoneal direct injection","ja":"Doxorubicin embedded into nanofibrillated bacterial cellulose (NFBC) produces a promising therapeutic outcome for peritoneally metastatic gastric cancer in mice models via intraperitoneal direct injection"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Mochizuki Takashi"},{"name":"Lila Abu Ali Ahmed Selim Amr"},{"name":"Akagi Shunsuke"},{"name":"Tajima Kenji"},{"name":"Fujita Kenji"},{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Matsushima Tokuo"},{"name":"Kusano Takatomo"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"望月 啓志"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"赤木 俊介"},{"name":"Tajima Kenji"},{"name":"藤田 研司"},{"name":"清水 太郎"},{"name":"異島 優"},{"name":"Matsushima Tokuo"},{"name":"Kusano Takatomo"},{"name":"石田 竜弘"}]},"publication_date":"2021-06-28","publication_name":{"en":"Nanomaterials","ja":"Nanomaterials"},"volume":"Vol.11","starting_page":"1697","ending_page":"1697","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/nano11071697"],"issn":["2079-4991"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:35, {"insert":{"user_id":"1000300291","type":"published_papers","id":"32439491"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/33957196","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85105280797&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=375385","label":"url"}],"paper_title":{"en":"Anti-PEG IgM production and accelerated blood clearance phenomenon after the administration of PEGylated exosomes in mice","ja":"Anti-PEG IgM production and accelerated blood clearance phenomenon after the administration of PEGylated exosomes in mice"},"authors":{"en":[{"name":"Sherif Emam Abdallah Emam"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Takata Haruka"},{"name":"Kawaguchi Yoshino"},{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Sherif Emam Abdallah Emam"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"髙田 春風"},{"name":"川口 桂乃"},{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Recently, there is an increasing interest in exosomes or extracellular vesicles as potential candidates for delivering RNAs, proteins, genes, and anticancer agents. Engineering of exosome properties is rapidly evolving as a means of expanding exosome applications. PEGylation of exosomes is a technique used to improve their in vivo stability, circulation half-lives, and sometimes to allow the binding targeting ligands to the exosome exterior. According to FDA guidelines for the development of PEGylated proteins, immunological responses to PEGylated molecules and particles should be examined. In this study, we prepared PEGylated exosomes and investigated the production of anti-PEG IgM antibodies after single i.v. injections in mice. In addition, we monitored blood concentrations and tumor accumulation of a second dose of PEGylated exosomes administered after the initial dose. Single injections of PEGylated exosomes in mice induced anti-PEG IgM production in a T cell-dependent manner. The anti-PEG IgM production decreased when the injection dose of PEGylated exosomes was further increased. Anti-PEG IgM induced by injection of PEGylated exosomes decreased blood concentrations of a second dose of PEGylated exosomes and suppressed their tumor accumulation in a C26 murine colorectal cancer model. Initial injection doses of either PEGylated liposomes or PEGylated ovalbumin (PEG-OVA), both of them induced anti-PEG IgM production, also decreased the blood concentration of PEGylated exosomes. Interestingly, anti-PEG IgM induced by injection of PEGylated exosomes did not affect the blood concentration of PEG-OVA. These results imply the importance of monitoring anti-PEG IgM when repeat PEGylated exosome doses are required and/or when PEGylated exosomes are used together with other PEGylated therapeutics.","ja":"Recently, there is an increasing interest in exosomes or extracellular vesicles as potential candidates for delivering RNAs, proteins, genes, and anticancer agents. Engineering of exosome properties is rapidly evolving as a means of expanding exosome applications. PEGylation of exosomes is a technique used to improve their in vivo stability, circulation half-lives, and sometimes to allow the binding targeting ligands to the exosome exterior. According to FDA guidelines for the development of PEGylated proteins, immunological responses to PEGylated molecules and particles should be examined. In this study, we prepared PEGylated exosomes and investigated the production of anti-PEG IgM antibodies after single i.v. injections in mice. In addition, we monitored blood concentrations and tumor accumulation of a second dose of PEGylated exosomes administered after the initial dose. Single injections of PEGylated exosomes in mice induced anti-PEG IgM production in a T cell-dependent manner. The anti-PEG IgM production decreased when the injection dose of PEGylated exosomes was further increased. Anti-PEG IgM induced by injection of PEGylated exosomes decreased blood concentrations of a second dose of PEGylated exosomes and suppressed their tumor accumulation in a C26 murine colorectal cancer model. Initial injection doses of either PEGylated liposomes or PEGylated ovalbumin (PEG-OVA), both of them induced anti-PEG IgM production, also decreased the blood concentration of PEGylated exosomes. Interestingly, anti-PEG IgM induced by injection of PEGylated exosomes did not affect the blood concentration of PEG-OVA. These results imply the importance of monitoring anti-PEG IgM when repeat PEGylated exosome doses are required and/or when PEGylated exosomes are used together with other PEGylated therapeutics."},"publication_date":"2021-06-10","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.334","starting_page":"327","ending_page":"334","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2021.05.001"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:36, {"insert":{"user_id":"1000300291","type":"published_papers","id":"32234602"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/33896187","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=374835","label":"url"}],"paper_title":{"en":"Incorporating gangliosides into PEGylated cationic liposomes that complexed DNA attenuates anti-PEG antibody production, but not anti-DNA antibody production in mice","ja":"Incorporating gangliosides into PEGylated cationic liposomes that complexed DNA attenuates anti-PEG antibody production, but not anti-DNA antibody production in mice"},"authors":{"en":[{"name":"Milad Reda Qelliny"},{"name":"Shimizu Taro"},{"name":"Elhewan Ali Emam Elsadek Emam Nehal"},{"name":"Emam Abdallah Emam Sherif"},{"name":"Takata Haruka"},{"name":"Zeinab M. A. Fathalla"},{"name":"Amal K. Hussein"},{"name":"Khaled A. Khaled"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Milad Reda Qelliny"},{"name":"清水 太郎"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Sherif Emam Abdallah Emam"},{"name":"髙田 春風"},{"name":"Zeinab M. A. Fathalla"},{"name":"Amal K. Hussein"},{"name":"Khaled A. Khaled"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Gangliosides (glycosphingolipids) reduce antibody production by inhibiting B-cell receptor (BCR) signaling. We have shown that a copresentation of gangliosides and polyethylene glycol (PEG) on the same liposomes suppresses anti-PEG IgM production in mice. In addition, we recently observed that pDNA incorporated in PEGylated cationic liposomes (PCLs) induces anti-DNA IgM, which could be a hurdle to the development of efficient gene delivery systems. Therefore, the focus of this study was to determine if the copresentation of gangliosides and DNA on the same PCL would suppress antibody production against DNA. PCLs including DNA induced both anti-PEG IgM production and anti-DNA IgM production. The extent of anti-PEG and anti-DNA IgM production was likely dependent on the immunogenicity of the complexed DNA. Treatment of clodronate-containing liposomes, which causes a depletion of phagocytic cells, suppressed anti-PEG IgM production from PCLs that did not include DNA but failed to suppress anti-PEG IgM production from PCLs that complexed DNA (PCLD). Both anti-PEG IgM and anti-DNA IgM was induced in T-cell-deficient nude mice as well as in normal mice following treatment with PCLs and PCLD, respectively. These results indicate that phagocytic cells contribute to anti-PEG IgM production but not to anti-DNA IgM production, while T-cells do not contribute to any form of antibody production. The copresentation of gangliosides and DNA significantly reduced anti-PEG IgM production but unfortunately did not reduce anti-DNA IgM production. It appears that the immunosuppressive effect of gangliosides, presumably via the CD22 signaling pathway, is limited only to anti-PEG immunity.","ja":"Gangliosides (glycosphingolipids) reduce antibody production by inhibiting B-cell receptor (BCR) signaling. We have shown that a copresentation of gangliosides and polyethylene glycol (PEG) on the same liposomes suppresses anti-PEG IgM production in mice. In addition, we recently observed that pDNA incorporated in PEGylated cationic liposomes (PCLs) induces anti-DNA IgM, which could be a hurdle to the development of efficient gene delivery systems. Therefore, the focus of this study was to determine if the copresentation of gangliosides and DNA on the same PCL would suppress antibody production against DNA. PCLs including DNA induced both anti-PEG IgM production and anti-DNA IgM production. The extent of anti-PEG and anti-DNA IgM production was likely dependent on the immunogenicity of the complexed DNA. Treatment of clodronate-containing liposomes, which causes a depletion of phagocytic cells, suppressed anti-PEG IgM production from PCLs that did not include DNA but failed to suppress anti-PEG IgM production from PCLs that complexed DNA (PCLD). Both anti-PEG IgM and anti-DNA IgM was induced in T-cell-deficient nude mice as well as in normal mice following treatment with PCLs and PCLD, respectively. These results indicate that phagocytic cells contribute to anti-PEG IgM production but not to anti-DNA IgM production, while T-cells do not contribute to any form of antibody production. The copresentation of gangliosides and DNA significantly reduced anti-PEG IgM production but unfortunately did not reduce anti-DNA IgM production. It appears that the immunosuppressive effect of gangliosides, presumably via the CD22 signaling pathway, is limited only to anti-PEG immunity."},"publication_date":"2021-06-07","publication_name":{"en":"Molecular Pharmaceutics","ja":"Molecular Pharmaceutics"},"volume":"Vol.18","number":"No.6","starting_page":"2406","ending_page":"2415","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acs.molpharmaceut.1c00255"],"issn":["1543-8384"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:37, {"insert":{"user_id":"1000300291","type":"published_papers","id":"32680491"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116506","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/34173723","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=375994","label":"url"}],"paper_title":{"en":"A novel polyethylene glycol (PEG)-drug conjugate of Venetoclax, a Bcl-2 inhibitor, for treatment of acute myeloid leukemia (AML)","ja":"A novel polyethylene glycol (PEG)-drug conjugate of Venetoclax, a Bcl-2 inhibitor, for treatment of acute myeloid leukemia (AML)"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Murakami Yuta"},{"name":"Eshima Kiyoshi"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"Murakami Yuta"},{"name":"Eshima Kiyoshi"},{"name":"石田 竜弘"}]},"description":{"en":"Venetoclax (VTX) is an anticancer drug. It is a selective Bcl-2 inhibitor that is clinically used for the treatment of patients with lymphomas and leukemias. Treatment with VTX, however, is accompanied by severe adverse events such as tumor lysis syndrome and neutropenia, because VTX readily binds to serum proteins, which results in poor pharmacokinetics and poor tumor tissue concentration. To avoid such adverse events, VTX is administered using a daily or weekly ramp-up schedule that is cumbersome in clinical situations. To overcome these shortcomings, we prepared a novel polyethylene glycol (PEG)-drug conjugate of VTX (PEG-VTX) and evaluated its cytotoxic effects on acute myeloid leukemia (AML) both in vitro and in vivo. VTX and 4-armed PEG derivatives were covalently attached through an amide bond linker. In a series of in vitro studies, PEG-VTX selectively induced potent growth inhibition of MV4-11 human AML cells via the inducement of Bcl-2-mediated apoptosis. PEG-VTX had the effect of free VTX, presumably due to the protease-mediated release of VTX from the conjugates. In in vivo studies with AML tumor-xenograft mice models, intravenous PEG-VTX promoted sufficient tumor growth suppression. Compared with a regimen of oral free VTX, the intravenous regimen in those studies used a VTX dosage that was 15-30 times smaller for an OCI-AML-2 xenograft model and a dosing regimen that was less frequent for an MV4-11 xenograft model. The most important development, however, was the absence of weight loss related to severe side effects throughout the treatments. An increase in water solubility and the resultant hydrodynamic size of VTX via PEGylation improved the pharmacokinetics of VTX by avoiding protein interactions and lessening the extravasation from blood. The result was an increase in tumor accumulation and a decrease in the nonspecific distribution of VTX. The results of this study suggest that PEG-VTX could be an alternative therapeutic option for the safe and effective treatment of patients with AML.","ja":"Venetoclax (VTX) is an anticancer drug. It is a selective Bcl-2 inhibitor that is clinically used for the treatment of patients with lymphomas and leukemias. Treatment with VTX, however, is accompanied by severe adverse events such as tumor lysis syndrome and neutropenia, because VTX readily binds to serum proteins, which results in poor pharmacokinetics and poor tumor tissue concentration. To avoid such adverse events, VTX is administered using a daily or weekly ramp-up schedule that is cumbersome in clinical situations. To overcome these shortcomings, we prepared a novel polyethylene glycol (PEG)-drug conjugate of VTX (PEG-VTX) and evaluated its cytotoxic effects on acute myeloid leukemia (AML) both in vitro and in vivo. VTX and 4-armed PEG derivatives were covalently attached through an amide bond linker. In a series of in vitro studies, PEG-VTX selectively induced potent growth inhibition of MV4-11 human AML cells via the inducement of Bcl-2-mediated apoptosis. PEG-VTX had the effect of free VTX, presumably due to the protease-mediated release of VTX from the conjugates. In in vivo studies with AML tumor-xenograft mice models, intravenous PEG-VTX promoted sufficient tumor growth suppression. Compared with a regimen of oral free VTX, the intravenous regimen in those studies used a VTX dosage that was 15-30 times smaller for an OCI-AML-2 xenograft model and a dosing regimen that was less frequent for an MV4-11 xenograft model. The most important development, however, was the absence of weight loss related to severe side effects throughout the treatments. An increase in water solubility and the resultant hydrodynamic size of VTX via PEGylation improved the pharmacokinetics of VTX by avoiding protein interactions and lessening the extravasation from blood. The result was an increase in tumor accumulation and a decrease in the nonspecific distribution of VTX. The results of this study suggest that PEG-VTX could be an alternative therapeutic option for the safe and effective treatment of patients with AML."},"publication_date":"2021-06-01","publication_name":{"en":"Cancer Reports","ja":"Cancer Reports"},"volume":"Vol.5","number":"No.3","starting_page":"e1485","ending_page":"e1485","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/cnr2.1485"],"issn":["2573-8348"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:38, {"insert":{"user_id":"1000300291","type":"published_papers","id":"32065130"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=374661","label":"url"}],"paper_title":{"en":"Increasing tumor extracellular pH by an oral alkalinizing agent improves antitumor responses of anti-PD-1 antibody: Implication of relationships between serum bicarbonate concentrations, urinary pH, and therapeutic outcomes","ja":"Increasing tumor extracellular pH by an oral alkalinizing agent improves antitumor responses of anti-PD-1 antibody: Implication of relationships between serum bicarbonate concentrations, urinary pH, and therapeutic outcomes"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Emam Abdallah Emam Sherif"},{"name":"Kawaguchi Yoshino"},{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Kiyoshi Eshima"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"Sherif Emam Abdallah Emam"},{"name":"川口 桂乃"},{"name":"清水 太郎"},{"name":"異島 優"},{"name":"Kiyoshi Eshima"},{"name":"石田 竜弘"}]},"publication_date":"2021-06-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.44","number":"No.6","starting_page":"844","ending_page":"852","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b21-00076"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:39, {"insert":{"user_id":"1000300291","type":"published_papers","id":"31973248"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=374432","label":"url"}],"paper_title":{"en":"Reduction-responsive and Multi-drug Deliverable Albumin Nanoparticles: an antitumor drug to Abraxane® against Human Pancreatic Tumor-Bearing Mice","ja":"Reduction-responsive and Multi-drug Deliverable Albumin Nanoparticles: an antitumor drug to Abraxane® against Human Pancreatic Tumor-Bearing Mice"},"authors":{"en":[{"name":"Hirakawa Naoki"},{"name":"Ishima Yu"},{"name":"Kinoshita Ryo"},{"name":"Nakano Ryuto"},{"name":"Victor Tuan Giam Chuang"},{"name":"ANDO Hidenori"},{"name":"Shimizu Taro"},{"name":"Okuhira Keiichiro"},{"name":"Maruyama Toru"},{"name":"Otagiri Masaki"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"平川 尚樹"},{"name":"異島 優"},{"name":"木下 遼"},{"name":"中野 琉人"},{"name":"Victor Tuan Giam Chuang"},{"name":"安藤 英紀"},{"name":"清水 太郎"},{"name":"奥平 桂一郎"},{"name":"Maruyama Toru"},{"name":"Otagiri Masaki"},{"name":"石田 竜弘"}]},"publication_date":"2021-05-17","publication_name":{"en":"ACS Applied Bio Materials","ja":"ACS Applied Bio Materials"},"volume":"Vol.4","number":"No.5","starting_page":"4302","ending_page":"4309","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acsabm.1c00110"],"issn":["2576-6422"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:40, {"insert":{"user_id":"1000300291","type":"published_papers","id":"31973249"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=374431","label":"url"}],"paper_title":{"en":"Nucleic acids delivered by PEGylated cationic liposomes in systemic lupus erythematosus-prone mice: a possible exacerbation of lupus nephritis in the presence of pre-existing anti-nucleic acid antibodies","ja":"Nucleic acids delivered by PEGylated cationic liposomes in systemic lupus erythematosus-prone mice: a possible exacerbation of lupus nephritis in the presence of pre-existing anti-nucleic acid antibodies"},"authors":{"en":[{"name":"Takata Haruka"},{"name":"Shimizu Taro"},{"name":"Kawaguchi Yoshino"},{"name":"Ueda Hiro"},{"name":"Elhewan Ali Emam Elsadek Emam Nehal"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"髙田 春風"},{"name":"清水 太郎"},{"name":"川口 桂乃"},{"name":"上田 大"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"publication_date":"2021-05-15","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.601","starting_page":"120529","ending_page":"120529","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2021.120529"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:41, {"insert":{"user_id":"1000300291","type":"published_papers","id":"32225138"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=374827","label":"url"}],"paper_title":{"en":"Evidence for delivery of Abraxane® via a denatured-albumin transport system","ja":"Evidence for delivery of Abraxane® via a denatured-albumin transport system"},"authors":{"en":[{"name":"Hama Maichi"},{"name":"Ishima Yu"},{"name":"Chuang V"},{"name":"ANDO Hidenori"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"濵 眞壱"},{"name":"異島 優"},{"name":"Chuang V"},{"name":"安藤 英紀"},{"name":"清水 太郎"},{"name":"石田 竜弘"}]},"publication_date":"2021-05-05","publication_name":{"en":"ACS Applied Materials & Interfaces","ja":"ACS Applied Materials & Interfaces"},"volume":"Vol.13","number":"No.17","starting_page":"19736","ending_page":"19744","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acsami.1c03065"],"issn":["1944-8244"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:42, {"insert":{"user_id":"1000300291","type":"published_papers","id":"31562211"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=373441","label":"url"}],"paper_title":{"en":"Therapeutic efficacy of a paclitaxel-loaded nanofibrillated bacterial cellulose (PTX/NFBC) formulation in a peritoneally disseminated gastric cancer xenograft model","ja":"Therapeutic efficacy of a paclitaxel-loaded nanofibrillated bacterial cellulose (PTX/NFBC) formulation in a peritoneally disseminated gastric cancer xenograft model"},"authors":{"en":[{"name":"Akagi Shunsuke"},{"name":"ANDO Hidenori"},{"name":"Fujita Kenji"},{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Tajima Kenji"},{"name":"Matsushima Tokuo"},{"name":"Kusano Takatomo"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"赤木 俊介"},{"name":"安藤 英紀"},{"name":"藤田 研司"},{"name":"清水 太郎"},{"name":"異島 優"},{"name":"Tajima Kenji"},{"name":"Matsushima Tokuo"},{"name":"Kusano Takatomo"},{"name":"石田 竜弘"}]},"publication_date":"2021-03","publication_name":{"en":"International Journal of Biological Macromolecules","ja":"International Journal of Biological Macromolecules"},"volume":"Vol.174","starting_page":"494","ending_page":"501","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijbiomac.2021.01.201"],"issn":["0141-8130"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:43, {"insert":{"user_id":"1000300291","type":"published_papers","id":"31396056"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=373094","label":"url"}],"paper_title":{"en":"Lymphoid follicle antigen (Ag) delivery and enhanced rodent humoral immune responses mediated by Ag-containing PEGylated liposomes","ja":"Lymphoid follicle antigen (Ag) delivery and enhanced rodent humoral immune responses mediated by Ag-containing PEGylated liposomes"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Watanabe Yuki"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"渡邉 優希"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"publication_date":"2021-02-12","publication_name":{"en":"Vaccine","ja":"Vaccine"},"volume":"Vol.39","number":"No.7","starting_page":"1131","ending_page":"1139","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.vaccine.2021.01.008"],"issn":["0264-410X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:44, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30915211"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=372417","label":"url"}],"paper_title":{"en":"Neutralization of acidic tumor microenvironment (TME) with daily oral dosing of sodium potassium citrate (K/Na Citrate) increases therapeutic effect of anti-cancer agent in pancreatic cancer xenograft mice model","ja":"Neutralization of acidic tumor microenvironment (TME) with daily oral dosing of sodium potassium citrate (K/Na Citrate) increases therapeutic effect of anti-cancer agent in pancreatic cancer xenograft mice model"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Kiyoshi Eshima"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"Kiyoshi Eshima"},{"name":"石田 竜弘"}]},"publication_date":"2021-02-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.44","number":"No.2","starting_page":"266","ending_page":"270","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b20-00825"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:45, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507466"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=371851","label":"url"}],"paper_title":{"en":"Complement activation induced by PEG enhances humoral immune responses against antigens encapsulated in PEG-modified liposomes","ja":"Complement activation induced by PEG enhances humoral immune responses against antigens encapsulated in PEG-modified liposomes"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Awata Mizuki"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Yoshioka Chihiro"},{"name":"Kawaguchi Yoshino"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"粟田 瑞月"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"吉岡 千尋"},{"name":"川口 桂乃"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"publication_date":"2021-01-10","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.329","starting_page":"1046","ending_page":"1053","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2020.10.033"],"issn":["0168-3659"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:46, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507465"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116247","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=371854","label":"url"}],"paper_title":{"en":"Adjuvant antitumor immunity contributes to the overall antitumor effect of PEGylated liposomal doxorubicin (Doxil®) in C26 tumor-bearing immunocompetent mice","ja":"Adjuvant antitumor immunity contributes to the overall antitumor effect of PEGylated liposomal doxorubicin (Doxil®) in C26 tumor-bearing immunocompetent mice"},"authors":{"en":[{"name":"Takayama Takuma"},{"name":"Shimizu Taro"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Kanazawa Yuki"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"高山 拓磨"},{"name":"清水 太郎"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"金沢 有希"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"publication_date":"2020-10-19","publication_name":{"en":"Pharmaceutics","ja":"Pharmaceutics"},"volume":"Vol.12","number":"No.10","starting_page":"990","ending_page":"990","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/pharmaceutics12100990"],"issn":["1999-4923"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:47, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507453"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=368803","label":"url"}],"paper_title":{"en":"PEG shedding-rate-dependent blood clearance of PEGylated lipid nanoparticles in mice: faster PEG shedding attenuates anti-PEG IgM production","ja":"PEG shedding-rate-dependent blood clearance of PEGylated lipid nanoparticles in mice: faster PEG shedding attenuates anti-PEG IgM production"},"authors":{"en":[{"name":"Suzuki Takuya"},{"name":"Suzuki Yuta"},{"name":"Hihara Taro"},{"name":"Kubara Kenji"},{"name":"Kondo Keita"},{"name":"Hyodo Kenji"},{"name":"Yamazaki Kazuto"},{"name":"Ishida Tatsuhiro"},{"name":"Ishihara Hiroshi"}],"ja":[{"name":"Suzuki Takuya"},{"name":"Suzuki Yuta"},{"name":"Hihara Taro"},{"name":"Kubara Kenji"},{"name":"Kondo Keita"},{"name":"Hyodo Kenji"},{"name":"Yamazaki Kazuto"},{"name":"石田 竜弘"},{"name":"Ishihara Hiroshi"}]},"publication_date":"2020-10-15","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.588","starting_page":"119792","ending_page":"119792","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2020.119792"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:48, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507454"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32989784","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=371803","label":"url"}],"paper_title":{"en":"Indocyanine green-labeled dasatinib as a new fluorescent probe for molecular imaging of gastrointestinal stromal tumors.","ja":"Indocyanine green-labeled dasatinib as a new fluorescent probe for molecular imaging of gastrointestinal stromal tumors."},"authors":{"en":[{"name":"Fuimoto Shota"},{"name":"Muguruma Naoki"},{"name":"Nakao Michiyasu"},{"name":"ANDO Hidenori"},{"name":"Kashihara Takanori"},{"name":"Miyamoto Yoshihiko"},{"name":"Okamoto Koichi"},{"name":"Sano Shigeki"},{"name":"Ishida Tatsuhiro"},{"name":"Sato Yasushi"},{"name":"Takayama Tetsuji"}],"ja":[{"name":"藤本 将太"},{"name":"六車 直樹"},{"name":"中尾 允泰"},{"name":"安藤 英紀"},{"name":"樫原 孝典"},{"name":"宮本 佳彦"},{"name":"岡本 耕一"},{"name":"佐野 茂樹"},{"name":"石田 竜弘"},{"name":"佐藤 康史"},{"name":"高山 哲治"}]},"description":{"en":"It is difficult to differentiate gastrointestinal stromal tumors (GISTs) from other subepithelial lesions under gastrointestinal endoscopy. Because most GISTs express tyrosine kinase receptor c-KIT, fluorescence-labeled c-KIT-specific tyrosine kinase inhibitors seem to be useful agents for molecular imaging of GIST. We aimed to develop a near-infrared fluorescent imaging technology for GIST targeting c-KIT using the novel fluorescent probe indocyanine green-labeled dasatinib (ICG-dasatinib) and to investigate the antitumor effect of ICG-dasatinib on GIST cells. Indocyanine green-labeled dasatinib was synthesized by labeling linker-induced dasatinib with ICG derivative 3-indocyanine-green-acyl-1,3-thiazolidine-2-thione. Human GIST cell lines GIST-T1 and GIST-882M were incubated with ICG-dasatinib and observed by fluorescent microscopy. GIST cells were incubated with ICG-dasatinib, unlabeled dasatinib, or imatinib, and cell viabilities were evaluated. Subcutaneous GIST model mice or orthotopic GIST model rats were intravenously injected with ICG-dasatinib and observed using an IVIS Spectrum. Strong fluorescent signals of ICG-dasatinib were observed in both GIST cell lines in vitro. IC50 values for ICG-dasatinib, unlabeled dasatinib, and imatinib were 13.9, 1.17, and 16.2 nM in GIST-T1 and 26.6, 3.63, and 47.6 nM in GIST-882M cells, respectively. ICG-dasatinib accumulated in subcutaneous xenografts in mice. Fluorescent signals were also observed in liver and gallbladder, indicating biliary excretion; however, fluorescence intensity of tumors was significantly higher than that of intestine after washing. Strong fluorescent signals were observed in orthotopic xenografts through the covering normal mucosa in rats. Indocyanine green-labeled dasatinib could visualize GIST cells and xenografted tumors. The antitumor effect of ICG-dasatinib was preserved to the same degree as imatinib.","ja":"It is difficult to differentiate gastrointestinal stromal tumors (GISTs) from other subepithelial lesions under gastrointestinal endoscopy. Because most GISTs express tyrosine kinase receptor c-KIT, fluorescence-labeled c-KIT-specific tyrosine kinase inhibitors seem to be useful agents for molecular imaging of GIST. We aimed to develop a near-infrared fluorescent imaging technology for GIST targeting c-KIT using the novel fluorescent probe indocyanine green-labeled dasatinib (ICG-dasatinib) and to investigate the antitumor effect of ICG-dasatinib on GIST cells. Indocyanine green-labeled dasatinib was synthesized by labeling linker-induced dasatinib with ICG derivative 3-indocyanine-green-acyl-1,3-thiazolidine-2-thione. Human GIST cell lines GIST-T1 and GIST-882M were incubated with ICG-dasatinib and observed by fluorescent microscopy. GIST cells were incubated with ICG-dasatinib, unlabeled dasatinib, or imatinib, and cell viabilities were evaluated. Subcutaneous GIST model mice or orthotopic GIST model rats were intravenously injected with ICG-dasatinib and observed using an IVIS Spectrum. Strong fluorescent signals of ICG-dasatinib were observed in both GIST cell lines in vitro. IC50 values for ICG-dasatinib, unlabeled dasatinib, and imatinib were 13.9, 1.17, and 16.2 nM in GIST-T1 and 26.6, 3.63, and 47.6 nM in GIST-882M cells, respectively. ICG-dasatinib accumulated in subcutaneous xenografts in mice. Fluorescent signals were also observed in liver and gallbladder, indicating biliary excretion; however, fluorescence intensity of tumors was significantly higher than that of intestine after washing. Strong fluorescent signals were observed in orthotopic xenografts through the covering normal mucosa in rats. Indocyanine green-labeled dasatinib could visualize GIST cells and xenografted tumors. The antitumor effect of ICG-dasatinib was preserved to the same degree as imatinib."},"publication_date":"2020-09-28","publication_name":{"en":"Journal of Gastroenterology and Hepatology","ja":"Journal of Gastroenterology and Hepatology"},"volume":"Vol.36","number":"No.5","starting_page":"1253","ending_page":"1262","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1111/jgh.15281"],"issn":["1440-1746"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:49, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507455"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32879214","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=366419","label":"url"}],"paper_title":{"en":"Pegfilgrastim (PEG-G-CSF) induces anti-polyethylene glycol (PEG) IgM via a T cell-dependent mechanism","ja":"Pegfilgrastim (PEG-G-CSF) induces anti-polyethylene glycol (PEG) IgM via a T cell-dependent mechanism"},"authors":{"en":[{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Sherif Emam Abdallah Emam"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Sherif Emam Abdallah Emam"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Protein-based therapeutics are beginning to be widely used in various clinical settings. Conjugation of polyethylene glycol (PEGylation) to protein therapeutics improves their circulation half-lives in the body. However, we and other groups observed that the initial dose of some PEGylated protein-based therapeutics may induce anti-PEG antibodies (primarily immunoglobulin M (IgM)), resulting in the accelerated clearance of a second dose. The mechanism behind the induction of anti-PEG IgM by PEGylated protein-based therapeutics is still unclear. In this study, we found that Pegfilgrastim (PEG-G-CSF, the PEGylated form of the recombinant human granulocyte colony-stimulating factor) induced anti-PEG IgM in mice when administered via either intravenous or subcutaneous administration. However, the anti-PEG IgM induction is diminished both in athymic nude mice lacking T cells and in splenectomized mice. In addition, anti-PEG IgM production was significantly diminished in the cyclophosphamide-treated mice depleted of B-cells. These results indicate that anti-PEG IgM production by Pegfilgrastim occurs in spleen in a T cell-dependent manner, which differs from anti-PEG IgM induced by PEGylated liposomes. However, B cells, both marginal zone and follicular, are essential for anti-PEG IgM production in both PEGylated preparations.","ja":"Protein-based therapeutics are beginning to be widely used in various clinical settings. Conjugation of polyethylene glycol (PEGylation) to protein therapeutics improves their circulation half-lives in the body. However, we and other groups observed that the initial dose of some PEGylated protein-based therapeutics may induce anti-PEG antibodies (primarily immunoglobulin M (IgM)), resulting in the accelerated clearance of a second dose. The mechanism behind the induction of anti-PEG IgM by PEGylated protein-based therapeutics is still unclear. In this study, we found that Pegfilgrastim (PEG-G-CSF, the PEGylated form of the recombinant human granulocyte colony-stimulating factor) induced anti-PEG IgM in mice when administered via either intravenous or subcutaneous administration. However, the anti-PEG IgM induction is diminished both in athymic nude mice lacking T cells and in splenectomized mice. In addition, anti-PEG IgM production was significantly diminished in the cyclophosphamide-treated mice depleted of B-cells. These results indicate that anti-PEG IgM production by Pegfilgrastim occurs in spleen in a T cell-dependent manner, which differs from anti-PEG IgM induced by PEGylated liposomes. However, B cells, both marginal zone and follicular, are essential for anti-PEG IgM production in both PEGylated preparations."},"publication_date":"2020-09-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.43","number":"No.9","starting_page":"1393","ending_page":"1397","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b20-00345"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:50, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507456"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32561308","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85086721197&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=366302","label":"url"}],"paper_title":{"en":"Blood retention and antigenicity of polycarboxybetaine-modified liposomes","ja":"Blood retention and antigenicity of polycarboxybetaine-modified liposomes"},"authors":{"en":[{"name":"Ryujin Takaaki"},{"name":"Shimizu Taro"},{"name":"Miyahara Ryo"},{"name":"Asai Daisuke"},{"name":"Shimazui Rena"},{"name":"Yoshikawa Takuma"},{"name":"Kishimura Akihiro"},{"name":"Mori Takeshi"},{"name":"Ishida Tatsuhiro"},{"name":"Katayama Yoshiki"}],"ja":[{"name":"Ryujin Takaaki"},{"name":"清水 太郎"},{"name":"Miyahara Ryo"},{"name":"Asai Daisuke"},{"name":"Shimazui Rena"},{"name":"Yoshikawa Takuma"},{"name":"Kishimura Akihiro"},{"name":"Mori Takeshi"},{"name":"石田 竜弘"},{"name":"Katayama Yoshiki"}]},"description":{"en":"Zwitterionic polycarboxybetaines (PCBs) have gained attention as alternative stealth polymers whose liposomal formulation and protein conjugates were reported not to elicit anti-polymer antibodies. Here, we studied the blood retention and antigenicity of liposomes modified with PCBs focusing on their chemical structures and doses. We compared PCBs with either 1 or 3 (PCB1 or PCB3) spacer carbons between the carboxylate and ammonium groups. PCB3-modified liposomes had a short blood retention, whereas PCB1-modified liposomes demonstrated extended blood retention that was somewhat superior to PEGylated liposome. This confirmed the excellent non-fouling nature of PCB1 reported previously. Interestingly, PCB1-liposome as well as PCB3-liposome elicited specific IgMs toward each PCB. The dose-dependent production of specific IgMs to PCB-liposomes was similar to that of PEGylated liposome, i.e., high doses of PCB-liposomes reduced the production of specific IgMs, termed immunological tolerance. These results indicate the importance of investigating the effect of dose to clarify the existence of antigenicity of stealth polymers.","ja":"Zwitterionic polycarboxybetaines (PCBs) have gained attention as alternative stealth polymers whose liposomal formulation and protein conjugates were reported not to elicit anti-polymer antibodies. Here, we studied the blood retention and antigenicity of liposomes modified with PCBs focusing on their chemical structures and doses. We compared PCBs with either 1 or 3 (PCB1 or PCB3) spacer carbons between the carboxylate and ammonium groups. PCB3-modified liposomes had a short blood retention, whereas PCB1-modified liposomes demonstrated extended blood retention that was somewhat superior to PEGylated liposome. This confirmed the excellent non-fouling nature of PCB1 reported previously. Interestingly, PCB1-liposome as well as PCB3-liposome elicited specific IgMs toward each PCB. The dose-dependent production of specific IgMs to PCB-liposomes was similar to that of PEGylated liposome, i.e., high doses of PCB-liposomes reduced the production of specific IgMs, termed immunological tolerance. These results indicate the importance of investigating the effect of dose to clarify the existence of antigenicity of stealth polymers."},"publication_date":"2020-08-30","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.586","starting_page":"119521","ending_page":"119521","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2020.119521"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:51, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507457"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32700691","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=366739","label":"url"}],"paper_title":{"en":"Utilization of Click Chemistry to Study the Effect of Poly(ethylene) Glycol Molecular Weight on the Self-Assembly of PEGylated Gambogic Acid Nanoparticles for the Treatment of Rheumatoid Arthritis","ja":"Utilization of Click Chemistry to Study the Effect of Poly(ethylene) Glycol Molecular Weight on the Self-Assembly of PEGylated Gambogic Acid Nanoparticles for the Treatment of Rheumatoid Arthritis"},"authors":{"en":[{"name":"Nguyen A"},{"name":"ANDO Hidenori"},{"name":"Böttger R"},{"name":"Viswanadham K K"},{"name":"Rouhollahi E"},{"name":"Ishida Tatsuhiro"},{"name":"Li S"}],"ja":[{"name":"Nguyen A"},{"name":"安藤 英紀"},{"name":"Böttger R"},{"name":"Viswanadham K K"},{"name":"Rouhollahi E"},{"name":"石田 竜弘"},{"name":"Li S"}]},"description":{"en":"Many small-molecule drugs exhibit poor aqueous solubility, and various approaches have been developed to improve their solubility and delivery. Chemical conjugation of an insoluble drug to a hydrophilic polymer can promote the self-assembly into nanoparticles (NPs) to increase the apparent solubility and improve the pharmacokinetics of the drug. However, majority of the reports in the field disclose only one composition of the conjugate, while accumulating evidence suggests that structure-activity relationship (SAR) studies must be conducted to identify an optimal construct. In this study, we employed a click chemistry platform to robustly conjugate short-chain methoxypolyethylene glycol (mPEG) of three different molecular weights to a small molecule anti-inflammatory drug, gambogic acid (GA), and studied the SAR. NPs formed with mPEG550 and mPEG5000, referred to as NP-550 and NP-5000, respectively, had larger mean diameters (130.0 ± 16.9 nm and 143.0 ± 0.1 nm, respectively) and higher critical micellar concentrations (CMCs, 9.5 μg mL-1 and 10.5 μg mL-1, respectively) compared to NPs formed with mPEG2000 (NP-2000, mean diameter = 97.8 ± 5.0 nm and CMC = 6.6 μg mL-1). NP-2000 and NP-5000 did not cause significant hemolytic toxicity, whereas NP-550 and free GA induced 90% and 60% hemolysis, respectively. NP-2000 was selected for further studies due to its improved safety, small size and low CMC. In cultured inflammatory macrophages, NP-2000 exhibited activity comparable to free GA in suppressing tumor necrosis factor-α. In mice, NP-2000 showed 185-fold improved drug exposure compared to free GA after intraperitoneal delivery. Treatment with free GA showed little anti-inflammatory activity compared to vehicle control in a murine model of rheumatoid arthritis. In contrast, NP-2000 significantly reduced the paw inflammation by 27% from day 15 to day 29. NP-2000 showed no visible signs of toxicity in mice, while free GA elicited significant irritation at the injection site. Our work emphasizes the importance of performing SAR studies for developing an optimal drug-polymer conjugate for self-assembly into NPs. We also demonstrate a unique application of click chemistry to robustly synthesize a small library of conjugates for the SAR study.","ja":"Many small-molecule drugs exhibit poor aqueous solubility, and various approaches have been developed to improve their solubility and delivery. Chemical conjugation of an insoluble drug to a hydrophilic polymer can promote the self-assembly into nanoparticles (NPs) to increase the apparent solubility and improve the pharmacokinetics of the drug. However, majority of the reports in the field disclose only one composition of the conjugate, while accumulating evidence suggests that structure-activity relationship (SAR) studies must be conducted to identify an optimal construct. In this study, we employed a click chemistry platform to robustly conjugate short-chain methoxypolyethylene glycol (mPEG) of three different molecular weights to a small molecule anti-inflammatory drug, gambogic acid (GA), and studied the SAR. NPs formed with mPEG550 and mPEG5000, referred to as NP-550 and NP-5000, respectively, had larger mean diameters (130.0 ± 16.9 nm and 143.0 ± 0.1 nm, respectively) and higher critical micellar concentrations (CMCs, 9.5 μg mL-1 and 10.5 μg mL-1, respectively) compared to NPs formed with mPEG2000 (NP-2000, mean diameter = 97.8 ± 5.0 nm and CMC = 6.6 μg mL-1). NP-2000 and NP-5000 did not cause significant hemolytic toxicity, whereas NP-550 and free GA induced 90% and 60% hemolysis, respectively. NP-2000 was selected for further studies due to its improved safety, small size and low CMC. In cultured inflammatory macrophages, NP-2000 exhibited activity comparable to free GA in suppressing tumor necrosis factor-α. In mice, NP-2000 showed 185-fold improved drug exposure compared to free GA after intraperitoneal delivery. Treatment with free GA showed little anti-inflammatory activity compared to vehicle control in a murine model of rheumatoid arthritis. In contrast, NP-2000 significantly reduced the paw inflammation by 27% from day 15 to day 29. NP-2000 showed no visible signs of toxicity in mice, while free GA elicited significant irritation at the injection site. Our work emphasizes the importance of performing SAR studies for developing an optimal drug-polymer conjugate for self-assembly into NPs. We also demonstrate a unique application of click chemistry to robustly synthesize a small library of conjugates for the SAR study."},"publication_date":"2020-08-21","publication_name":{"en":"Biomaterials Science","ja":"Biomaterials Science"},"volume":"Vol.8","number":"No.16","starting_page":"4626","ending_page":"4637","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1039/d0bm00711k"],"issn":["2047-4849"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:52, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507458"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32519877","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=366420","label":"url"}],"paper_title":{"en":"Impact of pre-existing or induced anti-PEG IgM on the pharmacokinetics of peginterferon alfa-2a (Pegasys®) in mice","ja":"Impact of pre-existing or induced anti-PEG IgM on the pharmacokinetics of peginterferon alfa-2a (Pegasys®) in mice"},"authors":{"en":[{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Hondoh Eri"},{"name":"Shimizu Taro"},{"name":"Takata Haruka"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Sherif Emam Abdallah Emam"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"本藤 栄里"},{"name":"清水 太郎"},{"name":"髙田 春風"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Sherif Emam Abdallah Emam"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"PEGylation had been used successfully to improve the circulation half-lives and some physicochemical properties of protein therapeutics. However, anti-polyethylene glycol (anti-PEG) antibodies, either pre-existing or treatment-induced, can negatively affect the pharmacokinetics and pharmacological efficacy of PEGylated proteins. We have examined anti-PEG immune responses in mice for peginterferon alfa-2a (Pegasys), a clinically approved PEGylated protein therapeutic, at both the recommended dose (equivalent to 3 μg/kg in mice) and at higher doses (150 μg/kg) for single or repeated subcutaneous (s.c.) administrations. The effect of treatment-induced anti-PEG IgM on serum concentrations of Pegasys, following repeated administrations, was evaluated. In addition, the effect of pre-existing anti-PEG IgM elicited by a different PEGylated protein, PEG-OVA, on the systemic clearance of Pegasys, was investigated. At a s.c. dose of 3 μg/kg, single injections of Pegasys barely elicited anti-PEG immune responses. Four repeated doses of 150 μg/kg Pegasys elicited anti-PEG IgM production, depending on dose frequency, and triggered the rapid clearance of subsequent doses. In addition, anti-PEG-IgM produced in response to prior administration of PEG-OVA caused a rapid blood clearance of Pegasys. Our results, therefore, underscore the importance of screening for both pre-existing and treatment-induced anti-PEG antibodies in patients prior to and during treatment with PEGylated protein drugs.","ja":"PEGylation had been used successfully to improve the circulation half-lives and some physicochemical properties of protein therapeutics. However, anti-polyethylene glycol (anti-PEG) antibodies, either pre-existing or treatment-induced, can negatively affect the pharmacokinetics and pharmacological efficacy of PEGylated proteins. We have examined anti-PEG immune responses in mice for peginterferon alfa-2a (Pegasys), a clinically approved PEGylated protein therapeutic, at both the recommended dose (equivalent to 3 μg/kg in mice) and at higher doses (150 μg/kg) for single or repeated subcutaneous (s.c.) administrations. The effect of treatment-induced anti-PEG IgM on serum concentrations of Pegasys, following repeated administrations, was evaluated. In addition, the effect of pre-existing anti-PEG IgM elicited by a different PEGylated protein, PEG-OVA, on the systemic clearance of Pegasys, was investigated. At a s.c. dose of 3 μg/kg, single injections of Pegasys barely elicited anti-PEG immune responses. Four repeated doses of 150 μg/kg Pegasys elicited anti-PEG IgM production, depending on dose frequency, and triggered the rapid clearance of subsequent doses. In addition, anti-PEG-IgM produced in response to prior administration of PEG-OVA caused a rapid blood clearance of Pegasys. Our results, therefore, underscore the importance of screening for both pre-existing and treatment-induced anti-PEG antibodies in patients prior to and during treatment with PEGylated protein drugs."},"publication_date":"2020-08-03","publication_name":{"en":"Molecular Pharmaceutics","ja":"Molecular Pharmaceutics"},"volume":"Vol.17","number":"No.8","starting_page":"2964","ending_page":"2970","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acs.molpharmaceut.0c00366"],"issn":["1543-8392"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:53, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507459"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32278827","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85083399688&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=364762","label":"url"}],"paper_title":{"en":"Hepatosplenic phagocytic cells indirectly contribute to anti-PEG IgM production in the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes: Appearance of an unexplained mechanism in the ABC phenomenon","ja":"Hepatosplenic phagocytic cells indirectly contribute to anti-PEG IgM production in the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes: Appearance of an unexplained mechanism in the ABC phenomenon"},"authors":{"en":[{"name":"El Sayed M M"},{"name":"Takata Haruka"},{"name":"Shimizu Taro"},{"name":"Kawaguchi Yoshino"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Alaaeldin E"},{"name":"Ishima Yu"},{"name":"ANDO Hidenori"},{"name":"Kamal A"},{"name":"Sarhan H A"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"El Sayed M M"},{"name":"髙田 春風"},{"name":"清水 太郎"},{"name":"川口 桂乃"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"Alaaeldin E"},{"name":"異島 優"},{"name":"安藤 英紀"},{"name":"Kamal A"},{"name":"Sarhan H A"},{"name":"石田 竜弘"}]},"description":{"en":"The accelerated blood clearance (ABC) phenomenon, caused in large degree via in vivo anti-PEG IgM production, is one of obstacles for development of PEGylated liposome and protein formulations, due to decreased efficiency and/or side effects such as anaphylaxis upon repeat administrations. We have shown in murine ABC models that splenectomy suppressed the level of anti-PEG IgM production induced by PEGylated liposomes, indicating that murine splenic B cells play an important role in its production. However, splenectomy did not completely inhibit production of anti-PEG IgM, suggesting that other cells may contribute to its production in the ABC phenomenon. In this study, we examined the contribution of hepatosplenic phagocytic cells to anti-PEG IgM production and clearance of PEGylated liposomes during the ABC phenomenon. Depletion of hepatosplenic phagocytic cells by pretreatment of mice with clodronate-containing non-PEGylated liposomes suppressed anti-PEG IgM production to a considerable degree, without a change in the number of splenic B cells, and attenuated the enhanced clearance of second dose of PEGylated liposomes. These results suggest that hepatosplenic phagocytic cells, in addition to splenic B cells, contribute to the production of anti-PEG IgM and the ABC phenomenon against PEGylated liposomes. The mechanism whereby splenic B cells interact with hepatosplenic phagocytic cells to produce anti-PEG IgM, upon administration of an initial dose of PEGylated liposomes remains to be elucidated.","ja":"The accelerated blood clearance (ABC) phenomenon, caused in large degree via in vivo anti-PEG IgM production, is one of obstacles for development of PEGylated liposome and protein formulations, due to decreased efficiency and/or side effects such as anaphylaxis upon repeat administrations. We have shown in murine ABC models that splenectomy suppressed the level of anti-PEG IgM production induced by PEGylated liposomes, indicating that murine splenic B cells play an important role in its production. However, splenectomy did not completely inhibit production of anti-PEG IgM, suggesting that other cells may contribute to its production in the ABC phenomenon. In this study, we examined the contribution of hepatosplenic phagocytic cells to anti-PEG IgM production and clearance of PEGylated liposomes during the ABC phenomenon. Depletion of hepatosplenic phagocytic cells by pretreatment of mice with clodronate-containing non-PEGylated liposomes suppressed anti-PEG IgM production to a considerable degree, without a change in the number of splenic B cells, and attenuated the enhanced clearance of second dose of PEGylated liposomes. These results suggest that hepatosplenic phagocytic cells, in addition to splenic B cells, contribute to the production of anti-PEG IgM and the ABC phenomenon against PEGylated liposomes. The mechanism whereby splenic B cells interact with hepatosplenic phagocytic cells to produce anti-PEG IgM, upon administration of an initial dose of PEGylated liposomes remains to be elucidated."},"publication_date":"2020-07-10","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.323","starting_page":"102","ending_page":"109","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2020.04.011"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:54, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507460"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32376372","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=365548","label":"url"}],"paper_title":{"en":"Pegfilgrastim (PEG-G-CSF) induces anti-PEG IgM in a dose dependent manner and causes the accelerated blood clearance (ABC) phenomenon upon repeated administration in mice","ja":"Pegfilgrastim (PEG-G-CSF) induces anti-PEG IgM in a dose dependent manner and causes the accelerated blood clearance (ABC) phenomenon upon repeated administration in mice"},"authors":{"en":[{"name":"Elhewan Ali Emam Elsadek Emam Nehal"},{"name":"Lila Abu Ali Ahmed Selim Amr"},{"name":"Emam Abdallah Emam Sherif"},{"name":"Shimizu Taro"},{"name":"Takata Haruka"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Elhewan Ali Emam Elsadek Emam Nehal"},{"name":"Lila Abu Ali Ahmed Selim Amr"},{"name":"Emam Abdallah Emam Sherif"},{"name":"清水 太郎"},{"name":"髙田 春風"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Pegfilgrastimis a recombinant PEGylated human granulocyte colony-stimulating factor (G-CSF) analog filgrastim (trade names Neulasta® or G-Lasta®) that stimulates the production of white blood cells (neutrophils). It is employed as an alternative to filgrastim (G-CSF) for chemotherapy-induced neutropenia in patients due to its longer half-life. In clinical settings, PEG-G-CSF is administered to cancer patients via both the s.c. and i.v. routes. In a murine study, we showed that, regardless of administration route, initial doses of PEG-G-CSF above 0.06 mg/kg elicited anti-PEG immune response in a dose-dependent manner. I.v. administration elicited higher levels of anti-PEG IgM than the s.c. route. Initial doses of PEG-G-CSF (6 mg/kg) that were high enough to trigger production of anti-PEG IgM, did not trigger the accelerated clearance of a lower subsequent dose (0.06 mg/kg) that was similar to i.v. clinical doses of PEG-G-CSF, but when the subsequent dose of PEG-G-CSF was raised to (6 mg/kg), the initial dose triggered the accelerated clearance of the second dose via an anti-PEG IgM-mediated complement activation. Similar observations were noted when an increased PEG-OVA dose was given as the second dose, indicating that pre-existing and/or treatment-induced anti-PEG antibodies might compromise the therapeutic activity and/or reduce tolerance of other PEGylated formulations. To the best of our knowledge, this is the first report to suggest the induction of the ABC phenomenon upon repeated injections of pegfilgrastim. In the clinic, cancer patients, receiving multiple cycles of chemotherapy, receive multiple cycles of pegfilgrastim to avoid infections and substantial morbidity. The ABC phenomenon to pegfilgrastim appears to be the cause of loss of clinical benefit of sequential treatments with pegfilgrastim in patients.","ja":"Pegfilgrastimis a recombinant PEGylated human granulocyte colony-stimulating factor (G-CSF) analog filgrastim (trade names Neulasta® or G-Lasta®) that stimulates the production of white blood cells (neutrophils). It is employed as an alternative to filgrastim (G-CSF) for chemotherapy-induced neutropenia in patients due to its longer half-life. In clinical settings, PEG-G-CSF is administered to cancer patients via both the s.c. and i.v. routes. In a murine study, we showed that, regardless of administration route, initial doses of PEG-G-CSF above 0.06 mg/kg elicited anti-PEG immune response in a dose-dependent manner. I.v. administration elicited higher levels of anti-PEG IgM than the s.c. route. Initial doses of PEG-G-CSF (6 mg/kg) that were high enough to trigger production of anti-PEG IgM, did not trigger the accelerated clearance of a lower subsequent dose (0.06 mg/kg) that was similar to i.v. clinical doses of PEG-G-CSF, but when the subsequent dose of PEG-G-CSF was raised to (6 mg/kg), the initial dose triggered the accelerated clearance of the second dose via an anti-PEG IgM-mediated complement activation. Similar observations were noted when an increased PEG-OVA dose was given as the second dose, indicating that pre-existing and/or treatment-induced anti-PEG antibodies might compromise the therapeutic activity and/or reduce tolerance of other PEGylated formulations. To the best of our knowledge, this is the first report to suggest the induction of the ABC phenomenon upon repeated injections of pegfilgrastim. In the clinic, cancer patients, receiving multiple cycles of chemotherapy, receive multiple cycles of pegfilgrastim to avoid infections and substantial morbidity. The ABC phenomenon to pegfilgrastim appears to be the cause of loss of clinical benefit of sequential treatments with pegfilgrastim in patients."},"publication_date":"2020-07","publication_name":{"en":"European Journal of Pharmaceutics and Biopharmaceutics","ja":"European Journal of Pharmaceutics and Biopharmaceutics"},"volume":"Vol.152","starting_page":"56","ending_page":"62","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ejpb.2020.04.026"],"issn":["1873-3441"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:55, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507461"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=365767","label":"url"}],"paper_title":{"en":"An immediate hypersensitivity reaction induced by PEGylated recombinant factor VIII","ja":"An immediate hypersensitivity reaction induced by PEGylated recombinant factor VIII"},"authors":{"en":[{"name":"Oh Yukiko"},{"name":"Niijima Hitomi"},{"name":"Kawahara Yuta"},{"name":"Hayase Tomomi"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"},{"name":"Morimoto Akira"}],"ja":[{"name":"Oh Yukiko"},{"name":"Niijima Hitomi"},{"name":"Kawahara Yuta"},{"name":"Hayase Tomomi"},{"name":"清水 太郎"},{"name":"石田 竜弘"},{"name":"Morimoto Akira"}]},"publication_date":"2020-06-04","publication_name":{"en":"Haemophilia","ja":"Haemophilia"},"languages":["eng"],"referee":true,"identifiers":{"doi":["10.1111/hae.14048"],"issn":["1365-2516"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:56, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507462"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31344279","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85070929282&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=354296","label":"url"}],"paper_title":{"en":"Quantitative evaluation of the intratumoral distribution of platinum in oxaliplatin-treated rectal cancer: In situ visualization of platinum via synchrotron radiation X-ray fluorescence spectrometry","ja":"Quantitative evaluation of the intratumoral distribution of platinum in oxaliplatin-treated rectal cancer: In situ visualization of platinum via synchrotron radiation X-ray fluorescence spectrometry"},"authors":{"en":[{"name":"Koba Ryo"},{"name":"Fujita Hayato"},{"name":"Nishibori Maiko"},{"name":"Saeki Kiyoshi"},{"name":"Nagayoshi Kinuko"},{"name":"Sadakari Yoshihiko"},{"name":"Nagai Shuntaro"},{"name":"Sekizawa Oki"},{"name":"Nitta Kiyofumi"},{"name":"Manabe Tatsuya"},{"name":"Ueki Takashi"},{"name":"Ishida Tatsuhiro"},{"name":"Oda Yoshinao"},{"name":"Nakamura Masafumi"}],"ja":[{"name":"Koba Ryo"},{"name":"Fujita Hayato"},{"name":"Nishibori Maiko"},{"name":"Saeki Kiyoshi"},{"name":"Nagayoshi Kinuko"},{"name":"Sadakari Yoshihiko"},{"name":"Nagai Shuntaro"},{"name":"Sekizawa Oki"},{"name":"Nitta Kiyofumi"},{"name":"Manabe Tatsuya"},{"name":"Ueki Takashi"},{"name":"石田 竜弘"},{"name":"Oda Yoshinao"},{"name":"Nakamura Masafumi"}]},"description":{"en":"Oxaliplatin (l-OHP), a platinum-based drug, is a key chemotherapeutic agent for colorectal cancer (CRC), but drug resistance and toxic effects have been major limitations of its use. Synchrotron radiation X-ray fluorescence spectrometry (SR-XRF) is a rapid, nondestructive technique for monitoring the distribution of metals and trace elements in cells or tissue samples. We applied SR-XRF to visualize the distribution of platinum and other elements in 30 rectal cancer specimens resected from patients who received l-OHP-based preoperative chemotherapy and quantified platinum concentration in the tumor epithelium and stroma, respectively, using calibration curves. The platinum concentration in rectal cancer tissue ranged 2.85-11.44 ppm, and the detection limit of platinum was 1.848 ppm. In the tumor epithelium, the platinum concentration was significantly higher in areas of degeneration caused by chemotherapy than in nondegenerated area (p < 0.001). Conversely, in the tumor stroma, the platinum concentration was significantly higher in patients with limited therapeutic responses than in those with strong therapeutic responses (p < 0.001). Furthermore, multivariate analysis illustrated that higher platinum concentration in the tumor stroma was an independent predictive factor of limited histologic response (odds ratio; 19.99, 95% confidence interval; 2.04-196.37, p = 0.013). This is the first study to visualize and quantify the distribution of platinum in human cancer tissues using SR-XRF. These results suggest that SR-XRF analysis may contribute to predicting the therapeutic effect of l-OHP-based chemotherapy by quantifying the distribution of platinum.","ja":"Oxaliplatin (l-OHP), a platinum-based drug, is a key chemotherapeutic agent for colorectal cancer (CRC), but drug resistance and toxic effects have been major limitations of its use. Synchrotron radiation X-ray fluorescence spectrometry (SR-XRF) is a rapid, nondestructive technique for monitoring the distribution of metals and trace elements in cells or tissue samples. We applied SR-XRF to visualize the distribution of platinum and other elements in 30 rectal cancer specimens resected from patients who received l-OHP-based preoperative chemotherapy and quantified platinum concentration in the tumor epithelium and stroma, respectively, using calibration curves. The platinum concentration in rectal cancer tissue ranged 2.85-11.44 ppm, and the detection limit of platinum was 1.848 ppm. In the tumor epithelium, the platinum concentration was significantly higher in areas of degeneration caused by chemotherapy than in nondegenerated area (p < 0.001). Conversely, in the tumor stroma, the platinum concentration was significantly higher in patients with limited therapeutic responses than in those with strong therapeutic responses (p < 0.001). Furthermore, multivariate analysis illustrated that higher platinum concentration in the tumor stroma was an independent predictive factor of limited histologic response (odds ratio; 19.99, 95% confidence interval; 2.04-196.37, p = 0.013). This is the first study to visualize and quantify the distribution of platinum in human cancer tissues using SR-XRF. These results suggest that SR-XRF analysis may contribute to predicting the therapeutic effect of l-OHP-based chemotherapy by quantifying the distribution of platinum."},"publication_date":"2020-05-01","publication_name":{"en":"International Journal of Cancer","ja":"International Journal of Cancer"},"volume":"Vol.146","number":"No.9","starting_page":"2498","ending_page":"2509","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/ijc.32592"],"issn":["1097-0215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:57, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507463"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115605","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32283709","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85083281974&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=364894","label":"url"}],"paper_title":{"en":"A unique gene-silencing approach, using an intelligent RNA expression device (iRed), results in minimal immune stimulation when given by local intrapleural injection in malignant pleural mesothelioma","ja":"A unique gene-silencing approach, using an intelligent RNA expression device (iRed), results in minimal immune stimulation when given by local intrapleural injection in malignant pleural mesothelioma"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Saito-Tarashima Noriko"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Kinjoh Nozomi"},{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Minakawa Noriaki"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"田良島 典子"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"金城 望"},{"name":"清水 太郎"},{"name":"異島 優"},{"name":"南川 典昭"},{"name":"石田 竜弘"}]},"description":{"en":"We have recently introduced an intelligent RNA expression device (iRed), comprising the minimum essential components needed to transcribe short hairpin RNA (shRNA) in cells. Use of iRed efficiently produced shRNA molecules after transfection into cells and alleviated the innate immune stimulation following intravenous injection. To study the usefulness of iRed for local injection, the engineered iRed encoding luciferase shRNA (Luc iRed), complexed with cationic liposomes (Luc iRed/liposome-complexes), was intrapleurally injected into an orthotopic mesothelioma mouse model. Luc iRed/liposome-complexes markedly suppressed the expression of a luciferase marker gene in pleurally disseminated mesothelioma cells. The suppressive efficiency was correlated with the expression level of shRNA within the mesothelioma cells. In addition, intrapleural injection of iRed/liposome-complexes did not induce IL-6 production in the pleural space and consequently in the blood compartment, although plasmid DNA (pDNA) or dsDNA (the natural construct for iRed) in the formulation did. Local delivery of iRed could augment the in vivo gene silencing effect without eliciting pronounced innate immune stimulation. Our results might hold promise for widespread utilization of iRed as an RNAi-based therapeutic for intracelial malignant cancers.","ja":"We have recently introduced an intelligent RNA expression device (iRed), comprising the minimum essential components needed to transcribe short hairpin RNA (shRNA) in cells. Use of iRed efficiently produced shRNA molecules after transfection into cells and alleviated the innate immune stimulation following intravenous injection. To study the usefulness of iRed for local injection, the engineered iRed encoding luciferase shRNA (Luc iRed), complexed with cationic liposomes (Luc iRed/liposome-complexes), was intrapleurally injected into an orthotopic mesothelioma mouse model. Luc iRed/liposome-complexes markedly suppressed the expression of a luciferase marker gene in pleurally disseminated mesothelioma cells. The suppressive efficiency was correlated with the expression level of shRNA within the mesothelioma cells. In addition, intrapleural injection of iRed/liposome-complexes did not induce IL-6 production in the pleural space and consequently in the blood compartment, although plasmid DNA (pDNA) or dsDNA (the natural construct for iRed) in the formulation did. Local delivery of iRed could augment the in vivo gene silencing effect without eliciting pronounced innate immune stimulation. Our results might hold promise for widespread utilization of iRed as an RNAi-based therapeutic for intracelial malignant cancers."},"publication_date":"2020-04-01","publication_name":{"en":"Molecules","ja":"Molecules"},"volume":"Vol.25","number":"No.7","starting_page":"1725","ending_page":"1725","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/molecules25071725"],"issn":["1420-3049"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:58, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507464"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31794135","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85076101146&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=360737","label":"url"}],"paper_title":{"en":"Albumin domain mutants with enhanced Aβ binding capacity identified by phage display analysis for application in various peripheral Aβ elimination approaches of Alzheimer's disease treatment","ja":"Albumin domain mutants with enhanced Aβ binding capacity identified by phage display analysis for application in various peripheral Aβ elimination approaches of Alzheimer's disease treatment"},"authors":{"en":[{"name":"Ishima Yu"},{"name":"Minomo Ai"},{"name":"Victor Tuan Giam Chuang"},{"name":"Fukuda Tetsuya"},{"name":"Kusumoto Kohshi"},{"name":"Okuhira Keiichiro"},{"name":"Suwa Yoshiaki"},{"name":"Watanabe Hiroshi"},{"name":"Ishida Tatsuhiro"},{"name":"Morioka Hiroshi"},{"name":"Maruyama Toru"},{"name":"Otagiri Masaki"}],"ja":[{"name":"異島 優"},{"name":"Minomo Ai"},{"name":"Victor Tuan Giam Chuang"},{"name":"Fukuda Tetsuya"},{"name":"楠本 嵩志"},{"name":"奥平 桂一郎"},{"name":"Suwa Yoshiaki"},{"name":"Watanabe Hiroshi"},{"name":"石田 竜弘"},{"name":"Morioka Hiroshi"},{"name":"Maruyama Toru"},{"name":"Otagiri Masaki"}]},"description":{"en":"Deposition of amyloid protein, particularly Aβ , is a major contributor to the onset of Alzheimer's disease (AD). However, almost no deposition of Aβ in the peripheral tissues could be found. Human serum albumin (HSA), the most abundant protein in the blood, has been reported to inhibit amyloid formation through binding Aβ, which is believed to play an important role in the peripheral clearance of Aβ. We identified the Aβ binding site on HSA and developed HSA mutants with high binding capacities for Aβ using a phage display method. HSA fragment 187-385 (Domain II) was found to exhibit the highest binding capacity for Aβ compared with the other two HSA fragments. To elucidate the sequence that forms the binding site for Aβ on Domain II, a random screening of Domain II display phage biopanning was constructed. A number of mutants with higher Aβ binding capacities than the wild type were identified. These mutants exhibited stronger scavenging abilities than the wild type, as revealed via in vitro equilibrium dialysis of Aβ experiments. These findings provide useful basic data for developing a safer alternative therapy than Aβ vaccines and for application in plasma exchange as well as extracorporeal dialysis.","ja":"Deposition of amyloid protein, particularly Aβ , is a major contributor to the onset of Alzheimer's disease (AD). However, almost no deposition of Aβ in the peripheral tissues could be found. Human serum albumin (HSA), the most abundant protein in the blood, has been reported to inhibit amyloid formation through binding Aβ, which is believed to play an important role in the peripheral clearance of Aβ. We identified the Aβ binding site on HSA and developed HSA mutants with high binding capacities for Aβ using a phage display method. HSA fragment 187-385 (Domain II) was found to exhibit the highest binding capacity for Aβ compared with the other two HSA fragments. To elucidate the sequence that forms the binding site for Aβ on Domain II, a random screening of Domain II display phage biopanning was constructed. A number of mutants with higher Aβ binding capacities than the wild type were identified. These mutants exhibited stronger scavenging abilities than the wild type, as revealed via in vitro equilibrium dialysis of Aβ experiments. These findings provide useful basic data for developing a safer alternative therapy than Aβ vaccines and for application in plasma exchange as well as extracorporeal dialysis."},"publication_date":"2020-04","publication_name":{"en":"IUBMB life","ja":"IUBMB life"},"volume":"Vol.72","number":"No.4","starting_page":"641","ending_page":"651","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/iub.2203"],"issn":["1521-6551"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:59, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507467"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/114728","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=362596","label":"url"}],"paper_title":{"en":"Characteristics of unique endocytosis induced by weak current for cytoplasmic drug delivery","ja":"Characteristics of unique endocytosis induced by weak current for cytoplasmic drug delivery"},"authors":{"en":[{"name":"Torao Tasuku"},{"name":"Mimura Miyuki"},{"name":"Ohshima Yasufumi"},{"name":"Fujikawa Kohki"},{"name":"Hasan Mahadi"},{"name":"Shimokawa Tatsuharu"},{"name":"Yamazaki Naoshi"},{"name":"ANDO Hidenori"},{"name":"Ishida Tatsuhiro"},{"name":"Fukuta Tatsuya"},{"name":"Tanaka Tamotsu"},{"name":"Kogure Kentaro"}],"ja":[{"name":"虎尾 祐"},{"name":"三村 美夕紀"},{"name":"大島 康史"},{"name":"藤川 昂樹"},{"name":"Hasan Mahadi"},{"name":"下川 達張"},{"name":"山﨑 尚志"},{"name":"安藤 英紀"},{"name":"石田 竜弘"},{"name":"福田 達也"},{"name":"田中 保"},{"name":"小暮 健太朗"}]},"publication_date":"2020-02","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.576","starting_page":"119010","ending_page":"119010","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2019.119010"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:60, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507468"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31629787","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85073758566&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=360421","label":"url"}],"paper_title":{"en":"Cancer cell-type tropism is one of crucial determinants for the efficient systemic delivery of cancer cell-derived exosomes to tumor tissues","ja":"Cancer cell-type tropism is one of crucial determinants for the efficient systemic delivery of cancer cell-derived exosomes to tumor tissues"},"authors":{"en":[{"name":"Sherif Emam Abdallah Emam"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"ANDO Hidenori"},{"name":"Shimizu Taro"},{"name":"Okuhira Keiichiro"},{"name":"Ishima Yu"},{"name":"Mahdy M"},{"name":"Ghazy E"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Sherif Emam Abdallah Emam"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Nehal Emam Elsadek Emam Ali Elhewan"},{"name":"安藤 英紀"},{"name":"清水 太郎"},{"name":"奥平 桂一郎"},{"name":"異島 優"},{"name":"Mahdy M"},{"name":"Ghazy E"},{"name":"石田 竜弘"}]},"description":{"en":"Exosomes are gaining increasing attention as drug delivery vehicles due to their low toxicity and ability to functionally transfer biological cargos between cells. However, the therapeutic applicability of exosomes is partially hampered by a lack of cell-type specificity. In this study, therefore, we investigated the impact of cell-type tropism on the in vivo systemic delivery of exosomes to tumor tissues. Exosomes derived from murine colorectal cancer cells (C26) (C26-Exos) and murine melanoma cells (B16BL6) (B16BL6-Exos) were collected. In vitro cellular uptake of either autologous (C26) or allogeneic (B16BL6) exosomes by C26 tumor cells was determined. In vivo tumor accumulation of each type of exosomes in mice bearing C26 tumors was monitored with an in vivo imaging system (IVIS). In in vitro studies, autologous C26-Exos were more efficiently taken up by C26 cancer cells, compared to allogeneic B16BL6-Exos. For in vivo studies, exosomes were modified with surface polyethylene glycol (PEG) to improve their circulation lifetimes. Although both types of PEGylated exosomes accumulated in C26-tumor tissue, autologous exosomes were preferentially accumulated within C26-tumor tissue compared to allogeneic exosomes. The increased tumor accumulation of autologous PEGylated exosomes was accompanied by the preferential uptake of exosomes by not only C26-tumor cells but also tumor-associated immune cells. This study implies that cancer cell-type tropism is an important factor in the achievement of tumor cell targeting with cancer cell-derived exosomes.","ja":"Exosomes are gaining increasing attention as drug delivery vehicles due to their low toxicity and ability to functionally transfer biological cargos between cells. However, the therapeutic applicability of exosomes is partially hampered by a lack of cell-type specificity. In this study, therefore, we investigated the impact of cell-type tropism on the in vivo systemic delivery of exosomes to tumor tissues. Exosomes derived from murine colorectal cancer cells (C26) (C26-Exos) and murine melanoma cells (B16BL6) (B16BL6-Exos) were collected. In vitro cellular uptake of either autologous (C26) or allogeneic (B16BL6) exosomes by C26 tumor cells was determined. In vivo tumor accumulation of each type of exosomes in mice bearing C26 tumors was monitored with an in vivo imaging system (IVIS). In in vitro studies, autologous C26-Exos were more efficiently taken up by C26 cancer cells, compared to allogeneic B16BL6-Exos. For in vivo studies, exosomes were modified with surface polyethylene glycol (PEG) to improve their circulation lifetimes. Although both types of PEGylated exosomes accumulated in C26-tumor tissue, autologous exosomes were preferentially accumulated within C26-tumor tissue compared to allogeneic exosomes. The increased tumor accumulation of autologous PEGylated exosomes was accompanied by the preferential uptake of exosomes by not only C26-tumor cells but also tumor-associated immune cells. This study implies that cancer cell-type tropism is an important factor in the achievement of tumor cell targeting with cancer cell-derived exosomes."},"publication_date":"2019-12","publication_name":{"en":"European Journal of Pharmaceutics and Biopharmaceutics","ja":"European Journal of Pharmaceutics and Biopharmaceutics"},"volume":"Vol.145","starting_page":"27","ending_page":"34","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ejpb.2019.10.005"],"issn":["0939-6411"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:61, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507469"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115036","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31609087","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=359929","label":"url"}],"paper_title":{"en":"A novel intraperitoneal therapy for gastric cancer with DFP-10825, a unique RNAi therapeutic targeting thymidylate synthase, in peritoneally disseminated xenograft model","ja":"A novel intraperitoneal therapy for gastric cancer with DFP-10825, a unique RNAi therapeutic targeting thymidylate synthase, in peritoneally disseminated xenograft model"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Fukushima M"},{"name":"Eshima K"},{"name":"Hasui Taichi"},{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Huang C"},{"name":"Wada H"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"Fukushima M"},{"name":"Eshima K"},{"name":"蓮井 太一"},{"name":"清水 太郎"},{"name":"異島 優"},{"name":"Huang C"},{"name":"Wada H"},{"name":"石田 竜弘"}]},"description":{"en":"In advanced gastric cancer, peritoneal dissemination is a life-threatening mode of metastasis. Since the treatment options with conventional chemotherapy remain limited, any novel therapeutic strategy that could control such metastasis would improve the outcome of treatment. We recently developed a unique RNA interference therapeutic regimen (DFP-10825) consisting of short hairpin RNA against thymidylate synthase (TS shRNA) and cationic liposomes. The treatment with DFP-10825 has shown remarkable antitumor activity in peritoneally disseminated human ovarian cancer-bearing mice via intraperitoneal administration. In this study, we expanded DFP-10825 to the treatment of peritoneally disseminated gastric cancer. DFP-10825 was administered intraperitoneally into mice with intraperitoneally implanted human gastric cancer cells (MKN45 or NCI-N87). Antitumor activity and host survival benefits were monitored. Intraperitoneal distribution of fluorescence-labeled DFP-10825 was monitored in this MKN45 peritoneally disseminated mouse model. Intraperitoneal injection of DFP-10825 suppressed tumor growth in two peritoneally disseminated cancer models (MKN45 and NCI-N87) and increased the survival time of the MKN45 model without severe side effects. Throughout the treatment regimen, no significant body weight loss was associated with the administration of DFP-10825. Interestingly, after intraperitoneal injection, fluorescence-labeled DFP-10825 retained for more than 72 hours in the peritoneal cavity and selectively accumulated in disseminated tumors. Intraperitoneal injection of DFP-10825 demonstrated effective antitumor activity without systemic severe adverse effects via the selective delivery of RNAi molecules into disseminated tumors in the peritoneal cavity. Our current study indicates that DFP-10825 could become an alternative option to improve the outcomes of patients with peritoneally disseminated gastric cancer.","ja":"In advanced gastric cancer, peritoneal dissemination is a life-threatening mode of metastasis. Since the treatment options with conventional chemotherapy remain limited, any novel therapeutic strategy that could control such metastasis would improve the outcome of treatment. We recently developed a unique RNA interference therapeutic regimen (DFP-10825) consisting of short hairpin RNA against thymidylate synthase (TS shRNA) and cationic liposomes. The treatment with DFP-10825 has shown remarkable antitumor activity in peritoneally disseminated human ovarian cancer-bearing mice via intraperitoneal administration. In this study, we expanded DFP-10825 to the treatment of peritoneally disseminated gastric cancer. DFP-10825 was administered intraperitoneally into mice with intraperitoneally implanted human gastric cancer cells (MKN45 or NCI-N87). Antitumor activity and host survival benefits were monitored. Intraperitoneal distribution of fluorescence-labeled DFP-10825 was monitored in this MKN45 peritoneally disseminated mouse model. Intraperitoneal injection of DFP-10825 suppressed tumor growth in two peritoneally disseminated cancer models (MKN45 and NCI-N87) and increased the survival time of the MKN45 model without severe side effects. Throughout the treatment regimen, no significant body weight loss was associated with the administration of DFP-10825. Interestingly, after intraperitoneal injection, fluorescence-labeled DFP-10825 retained for more than 72 hours in the peritoneal cavity and selectively accumulated in disseminated tumors. Intraperitoneal injection of DFP-10825 demonstrated effective antitumor activity without systemic severe adverse effects via the selective delivery of RNAi molecules into disseminated tumors in the peritoneal cavity. Our current study indicates that DFP-10825 could become an alternative option to improve the outcomes of patients with peritoneally disseminated gastric cancer."},"publication_date":"2019-12","publication_name":{"en":"Cancer Medicine","ja":"Cancer Medicine"},"volume":"Vol.8","number":"No.17","starting_page":"7313","ending_page":"7321","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/cam4.2598"],"issn":["2045-7634"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:62, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507470"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=354919","label":"url"}],"paper_title":{"en":"PEG修飾リポソームに対する免疫応答","ja":"PEG修飾リポソームに対する免疫応答"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"publication_date":"2019-11-01","publication_name":{"en":"人工血液","ja":"人工血液"},"volume":"Vol.27","starting_page":"37","ending_page":"43","languages":["jpn"],"referee":true,"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:63, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507471"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31082432","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85065581511&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=352004","label":"url"}],"paper_title":{"en":"Cell-penetrating mechanism of intracellular targeting albumin: Contribution of macropinocytosis induction and endosomal escape","ja":"Cell-penetrating mechanism of intracellular targeting albumin: Contribution of macropinocytosis induction and endosomal escape"},"authors":{"en":[{"name":"Ichimizu S"},{"name":"Watanabe H"},{"name":"Maeda H"},{"name":"Hamasaki K"},{"name":"Ikegami K"},{"name":"Chuang V"},{"name":"Kinoshita Ryo"},{"name":"Nishida K"},{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"},{"name":"Seki T"},{"name":"Katsuki H"},{"name":"Futaki S"},{"name":"Otagiri M"},{"name":"Maruyama T"}],"ja":[{"name":"Ichimizu S"},{"name":"Watanabe H"},{"name":"Maeda H"},{"name":"Hamasaki K"},{"name":"Ikegami K"},{"name":"Chuang V"},{"name":"木下 遼"},{"name":"Nishida K"},{"name":"清水 太郎"},{"name":"異島 優"},{"name":"石田 竜弘"},{"name":"Seki T"},{"name":"Katsuki H"},{"name":"Futaki S"},{"name":"Otagiri M"},{"name":"Maruyama T"}]},"description":{"en":"We recently developed a cell-penetrating drug carrier composed of albumin (HSA) combined with palmitoyl-cyclic-(D-Arg). While it is possible that the palmitoyl-cyclic-(D-Arg)/HSA enters the cell mainly via macropinocytosis, the mechanism responsible for the induction of macropinocytosis and endosomal escape remain unknown. We report herein that palmitoyl-cyclic-(D-Arg)/HSA might interact with heparan sulfate proteoglycan and the chemokine receptor CXCR4 followed by multiple activations of the PKC/PI3K/JNK/mTOR signaling pathways to induce macropinocytosis. This result was further confirmed by a co-treatment with 70 kDa dextran, a macropinocytosis marker. Using liposomes that mimic endosomes, the leakage of 5,6-carboxyfluorescein from liposome was observed in the presence of palmitoyl-cyclic-(D-Arg)/HSA only in the case of the anionic late endosome-like liposomes but not the neutral early endosome-like liposomes. Heparin largely inhibited this leakage, suggesting the importance of electrostatic interactions between palmitoyl-cyclic-(D-Arg)/HSA and the late-endosomal membrane. Immunofluorescence staining and Western blotting data indicated that the intact HSA could be transferred from endosomes to the cytosol. These collective data suggest that the palmitoyl-cyclic-(D-Arg)/HSA is internalized via macropinocytosis and intact HSA is released from the late endosomes to the cytoplasm before the endosomes fuse with lysosomes. Palmitoyl-cyclic-(D-Arg)/HSA not only functions as an intracellular drug delivery carrier but also as an inducer of macropinocytosis.","ja":"We recently developed a cell-penetrating drug carrier composed of albumin (HSA) combined with palmitoyl-cyclic-(D-Arg). While it is possible that the palmitoyl-cyclic-(D-Arg)/HSA enters the cell mainly via macropinocytosis, the mechanism responsible for the induction of macropinocytosis and endosomal escape remain unknown. We report herein that palmitoyl-cyclic-(D-Arg)/HSA might interact with heparan sulfate proteoglycan and the chemokine receptor CXCR4 followed by multiple activations of the PKC/PI3K/JNK/mTOR signaling pathways to induce macropinocytosis. This result was further confirmed by a co-treatment with 70 kDa dextran, a macropinocytosis marker. Using liposomes that mimic endosomes, the leakage of 5,6-carboxyfluorescein from liposome was observed in the presence of palmitoyl-cyclic-(D-Arg)/HSA only in the case of the anionic late endosome-like liposomes but not the neutral early endosome-like liposomes. Heparin largely inhibited this leakage, suggesting the importance of electrostatic interactions between palmitoyl-cyclic-(D-Arg)/HSA and the late-endosomal membrane. Immunofluorescence staining and Western blotting data indicated that the intact HSA could be transferred from endosomes to the cytosol. These collective data suggest that the palmitoyl-cyclic-(D-Arg)/HSA is internalized via macropinocytosis and intact HSA is released from the late endosomes to the cytoplasm before the endosomes fuse with lysosomes. Palmitoyl-cyclic-(D-Arg)/HSA not only functions as an intracellular drug delivery carrier but also as an inducer of macropinocytosis."},"publication_date":"2019-06-28","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.304","starting_page":"156","ending_page":"163","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2019.05.015"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:64, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507472"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31015002","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85064496754&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=352003","label":"url"}],"paper_title":{"en":"A simplified method for manufacturing RNAi therapeutics for local administration","ja":"A simplified method for manufacturing RNAi therapeutics for local administration"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Fukushima M"},{"name":"Matsuoka Rie"},{"name":"Shimizu Taro"},{"name":"Okuhira Keiichiro"},{"name":"Ishima Yu"},{"name":"Huang C"},{"name":"Wada H"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Fukushima M"},{"name":"松岡 里英"},{"name":"清水 太郎"},{"name":"奥平 桂一郎"},{"name":"異島 優"},{"name":"Huang C"},{"name":"Wada H"},{"name":"石田 竜弘"}]},"description":{"en":"RNA interference (RNAi) is one of the most promising strategies for cancer therapeutics. The successful translation of RNAi therapeutics to a clinic setting requires a delivery system that is efficient and simple to upscale. In this study, we devised a simple industrial method to manufacture lipoplex, which includes short hairpin RNA against the expression of thymidylate synthase (TS shRNA) - a key molecule for DNA biosynthesis. An aqueous solution of TS shRNA was gently mixed with either a precursor of cationic liposome (Presome DF-1) or a cationic lipid mixture in an o/w emulsion. This solution was subsequently lyophilized under optimal conditions to obtain either FD-lipoplex-1 or FD-lipoplex-2, respectively. With this method, a lipoplex in activated form was obtained via a simple \"one-step\" hydration with saline. Both forms of FD-lipoplex showed physicochemical properties comparable to those of conventional lipoplex. FD-lipoplexes stably retained TS shRNA within their formulations in the presence of tumor ascites fluid. Intraperitoneal treatment with either FD-lipoplex-1 or FD-lipoplex-2 provided a therapeutic level of efficacy comparable to that of conventional lipoplex in the treatment of a peritoneal disseminated gastric cancer mouse model. Collectively, established freeze-drying-based methods for RNAi-therapeutic preparation could realistically be used in a clinical setting for the treatment of patients with peritoneal disseminated cancer.","ja":"RNA interference (RNAi) is one of the most promising strategies for cancer therapeutics. The successful translation of RNAi therapeutics to a clinic setting requires a delivery system that is efficient and simple to upscale. In this study, we devised a simple industrial method to manufacture lipoplex, which includes short hairpin RNA against the expression of thymidylate synthase (TS shRNA) - a key molecule for DNA biosynthesis. An aqueous solution of TS shRNA was gently mixed with either a precursor of cationic liposome (Presome DF-1) or a cationic lipid mixture in an o/w emulsion. This solution was subsequently lyophilized under optimal conditions to obtain either FD-lipoplex-1 or FD-lipoplex-2, respectively. With this method, a lipoplex in activated form was obtained via a simple \"one-step\" hydration with saline. Both forms of FD-lipoplex showed physicochemical properties comparable to those of conventional lipoplex. FD-lipoplexes stably retained TS shRNA within their formulations in the presence of tumor ascites fluid. Intraperitoneal treatment with either FD-lipoplex-1 or FD-lipoplex-2 provided a therapeutic level of efficacy comparable to that of conventional lipoplex in the treatment of a peritoneal disseminated gastric cancer mouse model. Collectively, established freeze-drying-based methods for RNAi-therapeutic preparation could realistically be used in a clinical setting for the treatment of patients with peritoneal disseminated cancer."},"publication_date":"2019-06-10","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.564","starting_page":"256","ending_page":"262","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2019.04.054"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:65, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507473"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31002935","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85064481198&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=352002","label":"url"}],"paper_title":{"en":"Long-term storage of PEGylated liposomal oxaliplatin with improved stability and long circulation times in vivo","ja":"Long-term storage of PEGylated liposomal oxaliplatin with improved stability and long circulation times in vivo"},"authors":{"en":[{"name":"Doi Yusuke"},{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"土井 祐輔"},{"name":"清水 太郎"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Liposomal anticancer drugs have been developed with improved clinical effects and reduced side effects. We have developed a PEGylated liposomal formulation of oxaliplatin that has anticancer effects in animal models of colorectal cancer with a favorable toxicity profile. To move this formulation into clinical development, a formulation that is stable during long term storage is needed, which has similar pharmacokinetics and therapeutic activity against solid tumors to the original formulation. In this study, we found that PEGylated liposomal oxaliplatin showed no changes in particle size after long term storage (12 months at 2-8 °C), but phospholipid degradation had occurred. Hence, the stored formulation had compromised membrane integrity, resulting in decreased in vivo circulation times of the liposomes. To improve the stability during long-term storage, a screening study to obtain an appropriate stabilizer was carried out. The buffer 2-morpholinoethansulfonic acid (MES) attenuated not only phospholipid degradation but also oxaliplatin degradation, unlike most other excipients. After 12 months storage at 2-8 °C in the presence of MES only slight degradation of phospholipids in PEGylated liposomal oxaliplatin occurred, resulting in similar in vivo pharmacokinetic profiles of the encapsulated oxaliplatin to the original formulation. Long term stability of PEGylated liposomal oxaliplatin was achieved by addition of MES, resulting in long circulation half-lives in vivo, a property which would be expected to lead to increased suppression of tumor growth and reduced side effects. Our formulation may now be suitable for clinical development.","ja":"Liposomal anticancer drugs have been developed with improved clinical effects and reduced side effects. We have developed a PEGylated liposomal formulation of oxaliplatin that has anticancer effects in animal models of colorectal cancer with a favorable toxicity profile. To move this formulation into clinical development, a formulation that is stable during long term storage is needed, which has similar pharmacokinetics and therapeutic activity against solid tumors to the original formulation. In this study, we found that PEGylated liposomal oxaliplatin showed no changes in particle size after long term storage (12 months at 2-8 °C), but phospholipid degradation had occurred. Hence, the stored formulation had compromised membrane integrity, resulting in decreased in vivo circulation times of the liposomes. To improve the stability during long-term storage, a screening study to obtain an appropriate stabilizer was carried out. The buffer 2-morpholinoethansulfonic acid (MES) attenuated not only phospholipid degradation but also oxaliplatin degradation, unlike most other excipients. After 12 months storage at 2-8 °C in the presence of MES only slight degradation of phospholipids in PEGylated liposomal oxaliplatin occurred, resulting in similar in vivo pharmacokinetic profiles of the encapsulated oxaliplatin to the original formulation. Long term stability of PEGylated liposomal oxaliplatin was achieved by addition of MES, resulting in long circulation half-lives in vivo, a property which would be expected to lead to increased suppression of tumor growth and reduced side effects. Our formulation may now be suitable for clinical development."},"publication_date":"2019-06-10","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.564","starting_page":"237","ending_page":"243","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2019.04.042"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:66, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507474"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31155576","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85067107514&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=352535","label":"url"}],"paper_title":{"en":"A photo-activatable peptide mimicking functions of apolipoprotein A-I","ja":"A photo-activatable peptide mimicking functions of apolipoprotein A-I"},"authors":{"en":[{"name":"Kawahara Haruka"},{"name":"Miyashita Naoki"},{"name":"Tachibana Kohki"},{"name":"Tsuda Yusuke"},{"name":"Morimoto Kyohei"},{"name":"Tsuji Kouhei"},{"name":"Shigenaga Akira"},{"name":"Otaka Akira"},{"name":"Ishida Tatsuhiro"},{"name":"Okuhira Keiichiro"}],"ja":[{"name":"川原 遥華"},{"name":"宮下 直樹"},{"name":"立花 洸季"},{"name":"津田 雄介"},{"name":"森本 恭平"},{"name":"辻 耕平"},{"name":"重永 章"},{"name":"大髙 章"},{"name":"石田 竜弘"},{"name":"奥平 桂一郎"}]},"description":{"en":"Apolipoprotein A-I (apoA-I) plays a critical role in high-density lipoprotein (HDL) biogenesis, function and structural dynamics. Peptides that mimic apoA-I have a short amphipathic α-helical structure that can functionally recapitulate many of the same biologic properties of full-length apoA-I in HDL. Hence, they might be expected to have clinical applications in the reduction of atherosclerosis. However, nonspecific cellular efflux of cholesterol induced by apoA-I mimetic peptides might cause side effects that are, as yet, unidentified. In this study, we developed a photo-activatable peptide, 2F*, which is an 18 amino acid peptide mimicking apoA-I bearing an internal photocleavable caging group that is designed to assume an α-helical structure in response to a light stimulus and trigger efflux of cholesterol from cells. Without light irradiation, 2F* peptide showed a low tendency for the formation of α-helices, and therefore did not associate with lipids and failed to induce efflux of cholesterol. In addition, 2F* did not cause hemolysis under our experimental condition. Mass spectrometry indicated that, after light exposure, the caging group detached from 2F* and it assumed the α-helical structure in the presence of lipids, and enhanced cholesterol efflux from cells. Photo-activatable peptides such as 2F* that control cholesterol efflux following light stimulus may be useful for future atherosclerosis-reducing therapies.","ja":"Apolipoprotein A-I (apoA-I) plays a critical role in high-density lipoprotein (HDL) biogenesis, function and structural dynamics. Peptides that mimic apoA-I have a short amphipathic α-helical structure that can functionally recapitulate many of the same biologic properties of full-length apoA-I in HDL. Hence, they might be expected to have clinical applications in the reduction of atherosclerosis. However, nonspecific cellular efflux of cholesterol induced by apoA-I mimetic peptides might cause side effects that are, as yet, unidentified. In this study, we developed a photo-activatable peptide, 2F*, which is an 18 amino acid peptide mimicking apoA-I bearing an internal photocleavable caging group that is designed to assume an α-helical structure in response to a light stimulus and trigger efflux of cholesterol from cells. Without light irradiation, 2F* peptide showed a low tendency for the formation of α-helices, and therefore did not associate with lipids and failed to induce efflux of cholesterol. In addition, 2F* did not cause hemolysis under our experimental condition. Mass spectrometry indicated that, after light exposure, the caging group detached from 2F* and it assumed the α-helical structure in the presence of lipids, and enhanced cholesterol efflux from cells. Photo-activatable peptides such as 2F* that control cholesterol efflux following light stimulus may be useful for future atherosclerosis-reducing therapies."},"publication_date":"2019-06-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.42","number":"No.6","starting_page":"1019","ending_page":"1024","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b19-00114"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:67, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507475"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115606","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31052207","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85065659717&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=351999","label":"url"}],"paper_title":{"en":"Distribution of Polysulfide in Human Biological Fluids and Their. Association with Amylase and Sperm Activities","ja":"Distribution of Polysulfide in Human Biological Fluids and Their. Association with Amylase and Sperm Activities"},"authors":{"en":[{"name":"Ikeda Mayumi"},{"name":"Ishima Yu"},{"name":"Chuang VTG"},{"name":"Sakai Maki"},{"name":"Osafune Hiroki"},{"name":"ANDO Hidenori"},{"name":"Shimizu Taro"},{"name":"Okuhira Keiichiro"},{"name":"Watanabe H"},{"name":"Maruyama T"},{"name":"Otagiri M"},{"name":"Akaike T"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"池田 真由美"},{"name":"異島 優"},{"name":"Chuang VTG"},{"name":"酒井 真紀"},{"name":"長船 裕輝"},{"name":"安藤 英紀"},{"name":"清水 太郎"},{"name":"奥平 桂一郎"},{"name":"Watanabe H"},{"name":"Maruyama T"},{"name":"Otagiri M"},{"name":"Akaike T"},{"name":"石田 竜弘"}]},"description":{"en":"Intracellular polysulfide could regulate the redox balance via its anti-oxidant activity. However, the existence of polysulfide in biological fluids still remains unknown. Recently, we developed a quantitative analytical method for polysulfide and discovered that polysulfide exists in plasma and responds to oxidative stress. In this study, we confirmed the presence of polysulfide in other biological fluids, such as semen and nasal discharge. The levels of polysulfide in these biological fluids from healthy volunteers ( = 9) with identical characteristics were compared. Additionally, the circadian rhythm of plasma polysulfide was also investigated. The polysulfide levels detected from nasal discharge and seminal fluid were approximately 400 and 600 μM, respectively. No correlation could be found between plasma polysulfide and the polysulfide levels of tear, saliva, and nasal discharge. On the other hand, seminal polysulfide was positively correlated with plasma polysulfide, and almost all polysulfide contained in semen was found in seminal fluid. Intriguingly, saliva and seminal polysulfide strongly correlated with salivary amylase and sperm activities, respectively. These results provide a foundation for scientific breakthroughs in various research areas like infertility and the digestive system process.","ja":"Intracellular polysulfide could regulate the redox balance via its anti-oxidant activity. However, the existence of polysulfide in biological fluids still remains unknown. Recently, we developed a quantitative analytical method for polysulfide and discovered that polysulfide exists in plasma and responds to oxidative stress. In this study, we confirmed the presence of polysulfide in other biological fluids, such as semen and nasal discharge. The levels of polysulfide in these biological fluids from healthy volunteers ( = 9) with identical characteristics were compared. Additionally, the circadian rhythm of plasma polysulfide was also investigated. The polysulfide levels detected from nasal discharge and seminal fluid were approximately 400 and 600 μM, respectively. No correlation could be found between plasma polysulfide and the polysulfide levels of tear, saliva, and nasal discharge. On the other hand, seminal polysulfide was positively correlated with plasma polysulfide, and almost all polysulfide contained in semen was found in seminal fluid. Intriguingly, saliva and seminal polysulfide strongly correlated with salivary amylase and sperm activities, respectively. These results provide a foundation for scientific breakthroughs in various research areas like infertility and the digestive system process."},"publication_date":"2019-04-30","publication_name":{"en":"Molecules","ja":"Molecules"},"volume":"Vol.24","number":"No.9","starting_page":"1689","ending_page":"1689","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/molecules24091689"],"issn":["1420-3049"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:68, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507476"},"force":{"see_also":[{"@id":"http://id.ndl.go.jp/bib/029638754","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1523669554920042240/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=350270","label":"url"}],"paper_title":{"en":"入学者選抜の評価を支援する分散評価システムの開発と導入 ―薬学部AO入試における書類審査での活用事例から―","ja":"入学者選抜の評価を支援する分散評価システムの開発と導入 ―薬学部AO入試における書類審査での活用事例から―"},"authors":{"en":[{"name":"Seki Yosuke"},{"name":"Ueno Yoshihiko"},{"name":"Sawada Maiko"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"関 陽介"},{"name":"植野 美彦"},{"name":"澤田 麻衣子"},{"name":"石田 竜弘"}]},"publication_date":"2019-03","publication_name":{"en":"The Journal of University Admissions Research","ja":"大学入試研究ジャーナル"},"number":"No.29","starting_page":"217","ending_page":"222","languages":["jpn"],"referee":true,"identifiers":{"issn":["1348-2629"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:69, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507477"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116302","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32123826","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=345876","label":"url"}],"paper_title":{"en":"S-Nitrosated alpha-1-acid glycoprotein exhibits antibacterial activity against multidrug-resistant bacteria strains and synergistically enhances the effect of antibiotics","ja":"S-Nitrosated alpha-1-acid glycoprotein exhibits antibacterial activity against multidrug-resistant bacteria strains and synergistically enhances the effect of antibiotics"},"authors":{"en":[{"name":"Ishima Yu"},{"name":"Watanabe Kaori"},{"name":"Chuang T. G. Victor"},{"name":"Takeda Iyo"},{"name":"Kuroda Teruo"},{"name":"Ogawa Wakano"},{"name":"Watanabe Hiroshi"},{"name":"Iwao Yasunori"},{"name":"Ishida Tatsuhiro"},{"name":"Otagiri Masaki"},{"name":"Maruyama Toru"}],"ja":[{"name":"異島 優"},{"name":"Watanabe Kaori"},{"name":"Chuang T. G. Victor"},{"name":"Takeda Iyo"},{"name":"Kuroda Teruo"},{"name":"Ogawa Wakano"},{"name":"Watanabe Hiroshi"},{"name":"Iwao Yasunori"},{"name":"石田 竜弘"},{"name":"Otagiri Masaki"},{"name":"Maruyama Toru"}]},"publication_date":"2019-03","publication_name":{"en":"FASEB BioAdvances","ja":"FASEB BioAdvances"},"volume":"Vol.1","number":"No.3","starting_page":"137","ending_page":"150","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1096/fba.1018"],"issn":["2573-9832"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:70, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507478"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/30280273","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85054175366&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=345958","label":"url"}],"paper_title":{"en":"A cell assay for detecting anti-PEG immune response against PEG-modified therapeutics","ja":"A cell assay for detecting anti-PEG immune response against PEG-modified therapeutics"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Awata Mizuki"},{"name":"Kubo Yukiyo"},{"name":"Mima Yu"},{"name":"Hashimoto Yosuke"},{"name":"ANDO Hidenori"},{"name":"Okuhira Keiichiro"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"粟田 瑞月"},{"name":"久保 幸代"},{"name":"美馬 優"},{"name":"橋本 洋佑"},{"name":"安藤 英紀"},{"name":"奥平 桂一郎"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Immunogenicity of PEGylated proteins and nanomedicines represents a potential impediment against their development and use in clinical settings. The purpose of this study is to develop a method for detecting anti-PEG immunity of PEGylated proteins and/or nanomedicines using flow cytometry. The binding of fluorescence-labeled mPEG-modified liposomes to HIK-G11 cells, PEG-specific hybridoma cells, or spleen cells was evaluated by flow cytometry for detecting immunogenicity of PEGylated therapeutics. The fluorescence-labeled methoxy PEG (mPEG)-modified liposomes were efficiently bound to HIK-G11 cells. Such staining with fluorescence-labeled mPEG-modified liposomes was significantly inhibited in the presence of either non-labeled mPEG-modified liposomes or mPEG-modified ovalbumin (OVA) but not polyglycerol-modified liposomes. In addition, we found that mPEG-modified liposomes, highly immunogenic, caused proliferation of PEG-specific cells, while hydroxyl PEG-modified liposomes, less immunogenic, scarcely caused. Furthermore, after intravenous injection of mPEG-modified liposomes, the percentage of PEG-specific cells in the splenocytes, as determined by flow cytometry, corresponded well with the production level of anti-PEG antibodies, as determined by ELISA. PEG-specific B cell assay we introduced may become a useful method to detect an anti-PEG immune response against PEGylated therapeutics and clarify the mechanism for anti-PEG immune responses.","ja":"Immunogenicity of PEGylated proteins and nanomedicines represents a potential impediment against their development and use in clinical settings. The purpose of this study is to develop a method for detecting anti-PEG immunity of PEGylated proteins and/or nanomedicines using flow cytometry. The binding of fluorescence-labeled mPEG-modified liposomes to HIK-G11 cells, PEG-specific hybridoma cells, or spleen cells was evaluated by flow cytometry for detecting immunogenicity of PEGylated therapeutics. The fluorescence-labeled methoxy PEG (mPEG)-modified liposomes were efficiently bound to HIK-G11 cells. Such staining with fluorescence-labeled mPEG-modified liposomes was significantly inhibited in the presence of either non-labeled mPEG-modified liposomes or mPEG-modified ovalbumin (OVA) but not polyglycerol-modified liposomes. In addition, we found that mPEG-modified liposomes, highly immunogenic, caused proliferation of PEG-specific cells, while hydroxyl PEG-modified liposomes, less immunogenic, scarcely caused. Furthermore, after intravenous injection of mPEG-modified liposomes, the percentage of PEG-specific cells in the splenocytes, as determined by flow cytometry, corresponded well with the production level of anti-PEG antibodies, as determined by ELISA. PEG-specific B cell assay we introduced may become a useful method to detect an anti-PEG immune response against PEGylated therapeutics and clarify the mechanism for anti-PEG immune responses."},"publication_date":"2018-11","publication_name":{"en":"Pharmaceutical Research","ja":"Pharmaceutical Research"},"volume":"Vol.35","number":"No.11","starting_page":"223","ending_page":"223","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s11095-018-2505-3"],"issn":["1573-904X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:71, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507479"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/30333124","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=345866","label":"url"}],"paper_title":{"en":"A novel platform for cancer vaccines: Antigen-selective delivery to splenic marginal zone B cells via repeated injections of PEGylated liposomes","ja":"A novel platform for cancer vaccines: Antigen-selective delivery to splenic marginal zone B cells via repeated injections of PEGylated liposomes"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Kawaguchi Yoshino"},{"name":"Shimazaki Yuna"},{"name":"Mima Yu"},{"name":"Hashimoto Yosuke"},{"name":"Okuhira Keiichiro"},{"name":"Storm G"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"川口 桂乃"},{"name":"島崎 優奈"},{"name":"美馬 優"},{"name":"橋本 洋佑"},{"name":"奥平 桂一郎"},{"name":"Storm G"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Treating cancer with vaccines has been a challenge. In this study, we introduce a novel Ag delivery platform for cancer vaccines that delivers an encapsulated Ag to splenic marginal zone B (MZ-B) cells via the aid of a PEGylated liposome (PL) system. Splenic MZ-B cells have recently attracted interest as alternative APCs. In mice, preimmunization with empty (no Ag encapsulation) PLs triggered the efficient delivery of a subsequent dose of Ag-containing PLs, injected 3 d later, to the spleen compared with a single dose of Ag-containing PLs. In addition, immunization with empty PLs allowed three subsequent sequential injections of OVA-PLs to efficiently induce a CTL response against OVA-expressing murine thymoma (EG7-OVA) cells and resulted in in vivo growth inhibition of subsequently inoculated EG7-OVA cells. However, these sequential treatments require repeated immunizations to achieve their antitumor effect. Therefore, to improve the antitumor effect of our novel vaccine system, an adjuvant, -galactosylceramide (GC), was incorporated into the OVA-PLs (GC/OVA-PLs). As expected, the incorporation of GC reduced the required number of immunizations with OVA-PLs to the point that a single immunization treatment with empty PLs and an injection of GC/OVA-PL efficiently triggered a potent CTL induction, resulting in a rejection of the development and a suppression of the growth of tumors that had already developed s.c. Results of this study indicate that a novel Ag delivery platform that grants efficient Ag delivery to splenic MZ-B cells shows promise as a therapeutic modality for conquering tumor growth and/or progression.","ja":"Treating cancer with vaccines has been a challenge. In this study, we introduce a novel Ag delivery platform for cancer vaccines that delivers an encapsulated Ag to splenic marginal zone B (MZ-B) cells via the aid of a PEGylated liposome (PL) system. Splenic MZ-B cells have recently attracted interest as alternative APCs. In mice, preimmunization with empty (no Ag encapsulation) PLs triggered the efficient delivery of a subsequent dose of Ag-containing PLs, injected 3 d later, to the spleen compared with a single dose of Ag-containing PLs. In addition, immunization with empty PLs allowed three subsequent sequential injections of OVA-PLs to efficiently induce a CTL response against OVA-expressing murine thymoma (EG7-OVA) cells and resulted in in vivo growth inhibition of subsequently inoculated EG7-OVA cells. However, these sequential treatments require repeated immunizations to achieve their antitumor effect. Therefore, to improve the antitumor effect of our novel vaccine system, an adjuvant, -galactosylceramide (GC), was incorporated into the OVA-PLs (GC/OVA-PLs). As expected, the incorporation of GC reduced the required number of immunizations with OVA-PLs to the point that a single immunization treatment with empty PLs and an injection of GC/OVA-PL efficiently triggered a potent CTL induction, resulting in a rejection of the development and a suppression of the growth of tumors that had already developed s.c. Results of this study indicate that a novel Ag delivery platform that grants efficient Ag delivery to splenic MZ-B cells shows promise as a therapeutic modality for conquering tumor growth and/or progression."},"publication_date":"2018-10-17","publication_name":{"en":"The Journal of Immunology","ja":"The Journal of Immunology"},"volume":"Vol.201","number":"No.10","starting_page":"2969","ending_page":"2976","languages":["eng"],"referee":true,"identifiers":{"doi":["10.4049/jimmunol.1701351"],"issn":["1550-6606"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:72, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507480"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115154","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/30349254","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=339620","label":"url"}],"paper_title":{"en":"Involvement of complement activation in the pulmonary vasoactivity of polystyrene nanoparticles in pigs: Unique surface properties underlying alternative pathway activation and instant opsonization","ja":"Involvement of complement activation in the pulmonary vasoactivity of polystyrene nanoparticles in pigs: Unique surface properties underlying alternative pathway activation and instant opsonization"},"authors":{"en":[{"name":"Mészáros T"},{"name":"Kozma G"},{"name":"Shimizu Taro"},{"name":"Miyahara Kohga"},{"name":"Turjeman K"},{"name":"Ishida Tatsuhiro"},{"name":"Barenholz Y"},{"name":"Urbanics R"},{"name":"Szebeni J"}],"ja":[{"name":"Mészáros T"},{"name":"Kozma G"},{"name":"清水 太郎"},{"name":"宮原 康嘉"},{"name":"Turjeman K"},{"name":"石田 竜弘"},{"name":"Barenholz Y"},{"name":"Urbanics R"},{"name":"Szebeni J"}]},"description":{"en":"It has been proposed that many hypersensitivity reactions to nanopharmaceuticals represent complement (C)-activation-related pseudoallergy (CARPA), and that pigs provide a sensitive animal model to study the phenomenon. However, a recent study suggested that pulmonary hypertension, the pivotal symptom of porcine CARPA, is not mediated by C in cases of polystyrene nanoparticle (PS-NP)-induced reactions. To characterize PS-NPs and reexamine the contribution of CARPA to their pulmonary reactivity in pigs. C activation by 200, 500, and 750 nm (diameter) PS-NPs and their opsonization were measured in human and pig sera, respectively, and correlated with hemodynamic effects of the same NPs in pigs in vivo. Physicochemical characterization of PS-NPs included size, ζ-potential, cryo-transmission electron microscopy, and hydrophobicity analyses. C activation in human serum was measured by ELISA and opsonization of PS-NPs in pig serum by Western blot and flow cytometry. Pulmonary vasoactivity of PS-NPs was quantified in the porcine CARPA model. PS-NPs are monodisperse, highly hydrophobic spheres with strong negative surface charge. In human serum, they caused size-dependent, significant rises in C3a, Bb, and sC5b-9, but not C4d. Exposure to pig serum led within minutes to deposition of C5b-9 and opsonic iC3b on the NPs, and opsonic iC3b fragments (C3dg, C3d) also appeared in serum. PS-NPs caused major hemodynamic changes in pigs, primarily pulmonary hypertension, on the same time scale (minutes) as iC3b fragmentation and opsonization proceeded. There was significant correlation between C activation by different PS-NPs in human serum and pulmonary hypertension in pigs. PS-NPs have extreme surface properties with no relevance to clinically used nanomedicines. They can activate C via the alternative pathway, entailing instantaneous opsonization of NPs in pig serum. Therefore, rather than being solely C-independent reactivity, the mechanism of PS-NP-induced hypersensitivity in pigs may involve C activation. These data are consistent with the \"double-hit\" concept of nanoparticle-induced hypersensitivity reactions involving both CARPA and C-independent pseudoallergy.","ja":"It has been proposed that many hypersensitivity reactions to nanopharmaceuticals represent complement (C)-activation-related pseudoallergy (CARPA), and that pigs provide a sensitive animal model to study the phenomenon. However, a recent study suggested that pulmonary hypertension, the pivotal symptom of porcine CARPA, is not mediated by C in cases of polystyrene nanoparticle (PS-NP)-induced reactions. To characterize PS-NPs and reexamine the contribution of CARPA to their pulmonary reactivity in pigs. C activation by 200, 500, and 750 nm (diameter) PS-NPs and their opsonization were measured in human and pig sera, respectively, and correlated with hemodynamic effects of the same NPs in pigs in vivo. Physicochemical characterization of PS-NPs included size, ζ-potential, cryo-transmission electron microscopy, and hydrophobicity analyses. C activation in human serum was measured by ELISA and opsonization of PS-NPs in pig serum by Western blot and flow cytometry. Pulmonary vasoactivity of PS-NPs was quantified in the porcine CARPA model. PS-NPs are monodisperse, highly hydrophobic spheres with strong negative surface charge. In human serum, they caused size-dependent, significant rises in C3a, Bb, and sC5b-9, but not C4d. Exposure to pig serum led within minutes to deposition of C5b-9 and opsonic iC3b on the NPs, and opsonic iC3b fragments (C3dg, C3d) also appeared in serum. PS-NPs caused major hemodynamic changes in pigs, primarily pulmonary hypertension, on the same time scale (minutes) as iC3b fragmentation and opsonization proceeded. There was significant correlation between C activation by different PS-NPs in human serum and pulmonary hypertension in pigs. PS-NPs have extreme surface properties with no relevance to clinically used nanomedicines. They can activate C via the alternative pathway, entailing instantaneous opsonization of NPs in pig serum. Therefore, rather than being solely C-independent reactivity, the mechanism of PS-NP-induced hypersensitivity in pigs may involve C activation. These data are consistent with the \"double-hit\" concept of nanoparticle-induced hypersensitivity reactions involving both CARPA and C-independent pseudoallergy."},"publication_date":"2018-10-11","publication_name":{"en":"International Journal of Nanomedicine","ja":"International Journal of Nanomedicine"},"volume":"Vol.13","starting_page":"6345","ending_page":"6357","languages":["eng"],"referee":true,"identifiers":{"doi":["10.2147/IJN.S161369"],"issn":["1178-2013"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:73, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507481"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/114955","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/30262875","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85054056121&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=345956","label":"url"}],"paper_title":{"en":"Liposome co-incubation with cancer cells secreted exosomes (extracellular vesicles) with different proteins expressions and different uptake pathways","ja":"Liposome co-incubation with cancer cells secreted exosomes (extracellular vesicles) with different proteins expressions and different uptake pathways"},"authors":{"en":[{"name":"Sherif Emam Abdallah Emam"},{"name":"ANDO Hidenori"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Shimizu Taro"},{"name":"Okuhira Keiichiro"},{"name":"Ishima Yu"},{"name":"Mahdy M"},{"name":"Ghazy F"},{"name":"Sagawa I"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Sherif Emam Abdallah Emam"},{"name":"安藤 英紀"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"清水 太郎"},{"name":"奥平 桂一郎"},{"name":"異島 優"},{"name":"Mahdy M"},{"name":"Ghazy F"},{"name":"Sagawa I"},{"name":"石田 竜弘"}]},"description":{"en":"We recently showed that in vitro incubation of cells with liposomes of varying compositions can increase exosome secretion and increase the yield of harvested exosomes (extracellular vesicles, EVs). This might foster their potential therapeutic implementations. In the current study, we investigated the surface proteins and the uptake of the harvested exosomes (EVs) to see if the incubation of cells with liposomes would change the biological properties of these exosomes (EVs). Interestingly, exosomes (EVs) induced by solid cationic liposomes lacked some major exosome marker proteins such as CD9, flotillin-1, annexin-A2 and EGF, and subsequently had lower levels of cellular uptake upon re-incubation with donor cancer cells. However, exosomes (EVs) induced under normal condition and by fluid cationic liposomes, displayed the entire spectrum of proteins, and exhibited higher uptake by the donor cancer cells. Although endocytosis was the major uptake pathway of exosomes (EVs) by tumor cells, endocytosis could occur via more than one mechanism. Higher exosome uptake was observed in donor B16BL6 cells than in allogeneic C26 cells, indicating that donor cells might interact specifically with their exosomes (EVs) and avidly internalize them. Taken together, these results suggest a technique for controlling the characteristics of secreted exosomes (EVs) by incubating donor cancer cells with liposomes of varying physiochemical properties.","ja":"We recently showed that in vitro incubation of cells with liposomes of varying compositions can increase exosome secretion and increase the yield of harvested exosomes (extracellular vesicles, EVs). This might foster their potential therapeutic implementations. In the current study, we investigated the surface proteins and the uptake of the harvested exosomes (EVs) to see if the incubation of cells with liposomes would change the biological properties of these exosomes (EVs). Interestingly, exosomes (EVs) induced by solid cationic liposomes lacked some major exosome marker proteins such as CD9, flotillin-1, annexin-A2 and EGF, and subsequently had lower levels of cellular uptake upon re-incubation with donor cancer cells. However, exosomes (EVs) induced under normal condition and by fluid cationic liposomes, displayed the entire spectrum of proteins, and exhibited higher uptake by the donor cancer cells. Although endocytosis was the major uptake pathway of exosomes (EVs) by tumor cells, endocytosis could occur via more than one mechanism. Higher exosome uptake was observed in donor B16BL6 cells than in allogeneic C26 cells, indicating that donor cells might interact specifically with their exosomes (EVs) and avidly internalize them. Taken together, these results suggest a technique for controlling the characteristics of secreted exosomes (EVs) by incubating donor cancer cells with liposomes of varying physiochemical properties."},"publication_date":"2018-09-27","publication_name":{"en":"Scientific Reports","ja":"Scientific Reports"},"volume":"Vol.8","number":"No.1","starting_page":"14493","ending_page":"14493","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/s41598-018-32861-w"],"issn":["2045-2322"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:74, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507482"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29962402","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85049360539&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=339527","label":"url"}],"paper_title":{"en":"Doxorubicin expands in vivo secretion of circulating exosome in mice","ja":"Doxorubicin expands in vivo secretion of circulating exosome in mice"},"authors":{"en":[{"name":"Sherif Emam Abdallah Emam"},{"name":"ANDO Hidenori"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Kobayashi Shinya"},{"name":"Shimizu Taro"},{"name":"Okuhira Keiichiro"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Sherif Emam Abdallah Emam"},{"name":"安藤 英紀"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"小林 真也"},{"name":"清水 太郎"},{"name":"奥平 桂一郎"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Modulation of tumor immunity is a known factor in the antitumor activity of many chemotherapeutic agents. Exosomes are extracellular nanometric vesicles that are released by almost all types of cells, which includes cancer cells. These vesicles play a crucial role in tumor immunity. Many in vitro studies have reproduced the aggressive secretion of exosomes following treatment with conventional anticancer drugs. Nevertheless, how chemotherapeutic agents including nanomedicines such as Doxil affect the in vivo secretion of exosomes is yet to be elucidated. In this study, the effect of intravenous injection of either free doxorubicin (DXR) or liposomal DXR formulation (Doxil) on exosome secretion was evaluated in BALB/c mice. Exosomes were isolated from serum by using an ExoQuick™ kit. Free DXR treatment markedly increased serum exosome levels in a post-injection time-dependent manner, while Doxil treatment did not. Exosomal size distribution and marker protein expressions (CD9, CD63, and TSG101) were studied. The physical/biological characteristics of treatment-induced exosomes were comparable to those of control mice. Interestingly, splenectomy significantly suppressed the copious exosomal secretions induced by free DXR. Collectively, our results indicate that conventional anticancer agents induce the secretion of circulating exosomes, presumably via stimulating immune cells of the spleen. As far as we know, this study represents the first report indicating that conventional chemotherapeutics may induce exosome secretion which might, in turn, contribute partly to the antitumor effect of chemotherapeutic agents.","ja":"Modulation of tumor immunity is a known factor in the antitumor activity of many chemotherapeutic agents. Exosomes are extracellular nanometric vesicles that are released by almost all types of cells, which includes cancer cells. These vesicles play a crucial role in tumor immunity. Many in vitro studies have reproduced the aggressive secretion of exosomes following treatment with conventional anticancer drugs. Nevertheless, how chemotherapeutic agents including nanomedicines such as Doxil affect the in vivo secretion of exosomes is yet to be elucidated. In this study, the effect of intravenous injection of either free doxorubicin (DXR) or liposomal DXR formulation (Doxil) on exosome secretion was evaluated in BALB/c mice. Exosomes were isolated from serum by using an ExoQuick™ kit. Free DXR treatment markedly increased serum exosome levels in a post-injection time-dependent manner, while Doxil treatment did not. Exosomal size distribution and marker protein expressions (CD9, CD63, and TSG101) were studied. The physical/biological characteristics of treatment-induced exosomes were comparable to those of control mice. Interestingly, splenectomy significantly suppressed the copious exosomal secretions induced by free DXR. Collectively, our results indicate that conventional anticancer agents induce the secretion of circulating exosomes, presumably via stimulating immune cells of the spleen. As far as we know, this study represents the first report indicating that conventional chemotherapeutics may induce exosome secretion which might, in turn, contribute partly to the antitumor effect of chemotherapeutic agents."},"publication_date":"2018-07-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.41","number":"No.7","starting_page":"1078","ending_page":"1083","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b18-00202"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:75, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507483"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29462689","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85042257067&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=336344","label":"url"}],"paper_title":{"en":"A hydroxyl PEG version of PEGylated liposomes and its impact on anti-PEG IgM induction and on the accelerated clearance of PEGylated liposomes","ja":"A hydroxyl PEG version of PEGylated liposomes and its impact on anti-PEG IgM induction and on the accelerated clearance of PEGylated liposomes"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Fujita Risako"},{"name":"Awata Mizuki"},{"name":"Kawanishi Munehira"},{"name":"Hashimoto Yosuke"},{"name":"Okuhira Keiichiro"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"藤田 理紗子"},{"name":"粟田 瑞月"},{"name":"川西 宗平"},{"name":"橋本 洋佑"},{"name":"奥平 桂一郎"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Surface decoration of liposomes with polyethylene glycol (PEG), PEGylation, is recognized as a method to bestow liposomes with a prolonged circulation time following intravenous administration. However, many reports have emphasized that a first dose of PEGylated liposomes (PL) elicits an anti-PEG IgM antibody response that can trigger a rapid systemic clearance of a second dose of PL via a phenomenon that is referred to as \"accelerated blood clearance (ABC).\" Such a phenomenon is usually observed with PL that has been modified with methoxy-PEG. In the current study, we introduced various functional groups, methoxy (OCH), amino (NH), carboxyl (COOH), and hydroxyl (OH), at the chain ends of PEG to investigate the effect on anti-PEG IgM induction. Among different PEG-modified liposomes, hydroxyl PEG-modified liposomes (PL-OH) efficiently attenuated the anti-PEG IgM response in vitro. In addition, PL-OH was less recognizable by anti-PEG IgM compared with other PLs. These findings raised the possibility that PL-OH could attenuate/abrogate elicitation of the ABC phenomenon. Nonetheless, upon repeated intravenous injection, PL-OH triggered the enhanced clearance of a subsequently injected second dose. Furthermore, in vitro studies have demonstrated that, as a complement activator, PL-OH is stronger than PL-OCH and induces further complement activation in the presence of anti-PEG IgM, which was the predominant contributor to the rapid clearance of a second dose of PL-OH. Our results suggest that the screening of complement activation by polymer-modified products in tandem with anti-polymer antibody production should be a prerequisite in the development of polymers that might enhance the therapeutic efficacy of nanocarriers.","ja":"Surface decoration of liposomes with polyethylene glycol (PEG), PEGylation, is recognized as a method to bestow liposomes with a prolonged circulation time following intravenous administration. However, many reports have emphasized that a first dose of PEGylated liposomes (PL) elicits an anti-PEG IgM antibody response that can trigger a rapid systemic clearance of a second dose of PL via a phenomenon that is referred to as \"accelerated blood clearance (ABC).\" Such a phenomenon is usually observed with PL that has been modified with methoxy-PEG. In the current study, we introduced various functional groups, methoxy (OCH), amino (NH), carboxyl (COOH), and hydroxyl (OH), at the chain ends of PEG to investigate the effect on anti-PEG IgM induction. Among different PEG-modified liposomes, hydroxyl PEG-modified liposomes (PL-OH) efficiently attenuated the anti-PEG IgM response in vitro. In addition, PL-OH was less recognizable by anti-PEG IgM compared with other PLs. These findings raised the possibility that PL-OH could attenuate/abrogate elicitation of the ABC phenomenon. Nonetheless, upon repeated intravenous injection, PL-OH triggered the enhanced clearance of a subsequently injected second dose. Furthermore, in vitro studies have demonstrated that, as a complement activator, PL-OH is stronger than PL-OCH and induces further complement activation in the presence of anti-PEG IgM, which was the predominant contributor to the rapid clearance of a second dose of PL-OH. Our results suggest that the screening of complement activation by polymer-modified products in tandem with anti-polymer antibody production should be a prerequisite in the development of polymers that might enhance the therapeutic efficacy of nanocarriers."},"publication_date":"2018-06","publication_name":{"en":"European Journal of Pharmaceutics and Biopharmaceutics","ja":"European Journal of Pharmaceutics and Biopharmaceutics"},"volume":"Vol.127","starting_page":"142","ending_page":"149","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ejpb.2018.02.019"],"issn":["1873-3441"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:76, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507484"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29709910","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85046668949&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=336279","label":"url"}],"paper_title":{"en":"A novel strategy to increase the yield of exosomes (extracellular vesicles) for an expansion of basic research","ja":"A novel strategy to increase the yield of exosomes (extracellular vesicles) for an expansion of basic research"},"authors":{"en":[{"name":"Sherif Emam Abdallah Emam"},{"name":"ANDO Hidenori"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Shimizu Taro"},{"name":"Ukawa Masami"},{"name":"Okuhira Keiichiro"},{"name":"Ishima Yu"},{"name":"Mahdy M A"},{"name":"Ghazy F S"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Sherif Emam Abdallah Emam"},{"name":"安藤 英紀"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"清水 太郎"},{"name":"鵜川 真実"},{"name":"奥平 桂一郎"},{"name":"異島 優"},{"name":"Mahdy M A"},{"name":"Ghazy F S"},{"name":"石田 竜弘"}]},"description":{"en":"Exosomes are tiny extracellular vesicles that are usually harvested in small quantities. Such small yield has been an obstacle for the expansion of the basic research regarding exosome analysis and applications in drug delivery. To increase exosome yield, we attempted to stimulate tumor cells via the addition of liposomes in vitro. Neutral, cationic-bare or PEGylated liposomes were incubated with four different tumor cell lines. The stimulatory effect of liposomal formulations on exosome secretion and cellular uptake propensity of the collected exosome by mother cells or different cells was evaluated. Both neutral and cationic-bare liposomes enhanced exosome secretion in a dose-dependent manner. Fluid cationic liposomes provided the strongest stimulation. Surprisingly, the PEGylation of bare liposomes diminished exosome secretion. Exosomes harvested in the presence of fluid cationic liposomes showed increased cellular uptake, but solid cationic liposomes did not. Our findings indicate that the physicochemical properties of liposomes determine whether they will act as a stimulant or as a depressant on exosome secretion from tumor cells. Liposomal stimulation may be a useful strategy to increase exosome yield, although further preparation to increase the purity of exosomes may be needed. In addition, fine-tuning of the biological properties of induced exosomes could be achieved via controlling the physicochemical properties of the stimulant liposomes.","ja":"Exosomes are tiny extracellular vesicles that are usually harvested in small quantities. Such small yield has been an obstacle for the expansion of the basic research regarding exosome analysis and applications in drug delivery. To increase exosome yield, we attempted to stimulate tumor cells via the addition of liposomes in vitro. Neutral, cationic-bare or PEGylated liposomes were incubated with four different tumor cell lines. The stimulatory effect of liposomal formulations on exosome secretion and cellular uptake propensity of the collected exosome by mother cells or different cells was evaluated. Both neutral and cationic-bare liposomes enhanced exosome secretion in a dose-dependent manner. Fluid cationic liposomes provided the strongest stimulation. Surprisingly, the PEGylation of bare liposomes diminished exosome secretion. Exosomes harvested in the presence of fluid cationic liposomes showed increased cellular uptake, but solid cationic liposomes did not. Our findings indicate that the physicochemical properties of liposomes determine whether they will act as a stimulant or as a depressant on exosome secretion from tumor cells. Liposomal stimulation may be a useful strategy to increase exosome yield, although further preparation to increase the purity of exosomes may be needed. In addition, fine-tuning of the biological properties of induced exosomes could be achieved via controlling the physicochemical properties of the stimulant liposomes."},"publication_date":"2018-05-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.41","number":"No.5","starting_page":"733","ending_page":"742","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b17-00919"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:77, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507485"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115087","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29688069","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85053734891&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=346483","label":"url"}],"paper_title":{"en":"Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions","ja":"Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions"},"authors":{"en":[{"name":"Minayoshi Yuki"},{"name":"Maeda Hitoshi"},{"name":"Yanagisawa Hiroki"},{"name":"Hamasaki Keisuke"},{"name":"Mizuta Yuki"},{"name":"Nishida Kento"},{"name":"Kinoshita Ryo"},{"name":"Enoki Yuki"},{"name":"Imafuku Tadasi"},{"name":"Chuang Victor Tuan Giam"},{"name":"Koga Tomoaki"},{"name":"Fujiwara Yukiko"},{"name":"Takeya Motohiro"},{"name":"Sonoda Kayoko"},{"name":"Wakayama Tomohiro"},{"name":"Taguchi Kazuaki"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"},{"name":"Iwakiri Yasuko"},{"name":"Tanaka Motohiko"},{"name":"Sasaki Yutaka"},{"name":"Watanabe Hiroshi"},{"name":"Otagiri Masako"},{"name":"Maruyama Toru"}],"ja":[{"name":"Minayoshi Yuki"},{"name":"Maeda Hitoshi"},{"name":"Yanagisawa Hiroki"},{"name":"Hamasaki Keisuke"},{"name":"Mizuta Yuki"},{"name":"Nishida Kento"},{"name":"木下 遼"},{"name":"Enoki Yuki"},{"name":"Imafuku Tadasi"},{"name":"Chuang Victor Tuan Giam"},{"name":"Koga Tomoaki"},{"name":"Fujiwara Yukiko"},{"name":"Takeya Motohiro"},{"name":"Sonoda Kayoko"},{"name":"Wakayama Tomohiro"},{"name":"Taguchi Kazuaki"},{"name":"異島 優"},{"name":"石田 竜弘"},{"name":"Iwakiri Yasuko"},{"name":"Tanaka Motohiko"},{"name":"Sasaki Yutaka"},{"name":"Watanabe Hiroshi"},{"name":"Otagiri Masako"},{"name":"Maruyama Toru"}]},"description":{"en":"Because of its multifaceted anti-inflammatory and immunomodulatory effects, delivering type-I interferon to Kupffer cells has the potential to function as a novel type of therapy for the treatment of various types of hepatitis. We report herein on the preparation of a Kupffer cell targeting type-I interferon, an albumin-IFNα2b fusion protein that contains highly mannosylated N-linked oligosaccharide chains, Man-HSA(D494N)-IFNα2b, attached by combining albumin fusion technology and site-directed mutagenesis. The presence of this unique oligosaccharide permits the protein to be efficiently, rapidly and preferentially distributed to Kupffer cells. Likewise IFNα2b, Man-HSA(D494N)-IFNα2b caused a significant induction in the mRNA levels of IL-10, IL-1Ra, PD-L1 in RAW264.7 cells and mouse isolated Kupffer cells, and these inductions were largely inhibited by blocking the interferon receptor. These data indicate that Man-HSA(D494N)-IFNα2b retained the biological activities of type-I interferon. Man-HSA(D494N)-IFNα2b significantly inhibited liver injury in Concanavalin A (Con-A)-induced hepatitis model mice, and consequently improved their survival rate. Moreover, the post-administration of Man-HSA(D494N)-IFNα2b at 2 h after the Con-A challenge also exerted hepato-protective effects. In conclusion, this proof-of-concept study demonstrates the therapeutic effectiveness and utility of Kupffer cell targeting type-I interferon against hepatitis via its anti-inflammatory and immunomodulatory actions.","ja":"Because of its multifaceted anti-inflammatory and immunomodulatory effects, delivering type-I interferon to Kupffer cells has the potential to function as a novel type of therapy for the treatment of various types of hepatitis. We report herein on the preparation of a Kupffer cell targeting type-I interferon, an albumin-IFNα2b fusion protein that contains highly mannosylated N-linked oligosaccharide chains, Man-HSA(D494N)-IFNα2b, attached by combining albumin fusion technology and site-directed mutagenesis. The presence of this unique oligosaccharide permits the protein to be efficiently, rapidly and preferentially distributed to Kupffer cells. Likewise IFNα2b, Man-HSA(D494N)-IFNα2b caused a significant induction in the mRNA levels of IL-10, IL-1Ra, PD-L1 in RAW264.7 cells and mouse isolated Kupffer cells, and these inductions were largely inhibited by blocking the interferon receptor. These data indicate that Man-HSA(D494N)-IFNα2b retained the biological activities of type-I interferon. Man-HSA(D494N)-IFNα2b significantly inhibited liver injury in Concanavalin A (Con-A)-induced hepatitis model mice, and consequently improved their survival rate. Moreover, the post-administration of Man-HSA(D494N)-IFNα2b at 2 h after the Con-A challenge also exerted hepato-protective effects. In conclusion, this proof-of-concept study demonstrates the therapeutic effectiveness and utility of Kupffer cell targeting type-I interferon against hepatitis via its anti-inflammatory and immunomodulatory actions."},"publication_date":"2018-04-24","publication_name":{"en":"Drug Delivery","ja":"Drug Delivery"},"volume":"Vol.25","number":"No.1","starting_page":"1067","ending_page":"1077","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1080/10717544.2018.1464083"],"issn":["1521-0464"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:78, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507486"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=339528","label":"url"}],"paper_title":{"en":"発酵ナノセルロース(NFBC)の大量生産とその医療応用","ja":"発酵ナノセルロース(NFBC)の大量生産とその医療応用"},"authors":{"en":[{"name":"田島 健次"},{"name":"小瀬 亮太"},{"name":"Ishida Tatsuhiro"},{"name":"松島 得雄"}],"ja":[{"name":"田島 健次"},{"name":"小瀬 亮太"},{"name":"石田 竜弘"},{"name":"松島 得雄"}]},"publication_date":"2018-04-12","publication_name":{"en":"BIO INDUSTRY","ja":"月刊バイオインダストリー"},"volume":"Vol.35","number":"No.4","starting_page":"55","ending_page":"63","languages":["jpn"],"referee":true,"identifiers":{"issn":["0910-6545"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:79, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507487"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115707","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29040960","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85042682163&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=334157","label":"url"}],"paper_title":{"en":"A Novel S-Sulfhydrated Human Serum Albumin Preparation Suppresses Melanin Synthesis","ja":"A Novel S-Sulfhydrated Human Serum Albumin Preparation Suppresses Melanin Synthesis"},"authors":{"en":[{"name":"Ikeda, M"},{"name":"Ishima Yu"},{"name":"Kinoshita, R"},{"name":"Chuang, V"},{"name":"Tasaka, N"},{"name":"Matsuo, N"},{"name":"Watanabe, H"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"},{"name":"Otagiri, M"},{"name":"Maruyama, T"}],"ja":[{"name":"池田 真由美"},{"name":"異島 優"},{"name":"木下 遼"},{"name":"Chuang, V"},{"name":"田坂 菜々美"},{"name":"松尾 菜々"},{"name":"Watanabe, H"},{"name":"清水 太郎"},{"name":"石田 竜弘"},{"name":"Otagiri, M"},{"name":"Maruyama, T"}]},"publication_date":"2018-04","publication_name":{"en":"Redox Biology","ja":"Redox Biology"},"volume":"Vol.14","starting_page":"354","ending_page":"360","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.redox.2017.10.007"],"issn":["2213-2317"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:80, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507488"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29287147","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85041697937&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=335639","label":"url"}],"paper_title":{"en":"Intratumoral visualization of oxaliplatin within a liposomal formulation using X-ray fluorescence spectrometry","ja":"Intratumoral visualization of oxaliplatin within a liposomal formulation using X-ray fluorescence spectrometry"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Tanaka Masao"},{"name":"Doi Yusuke"},{"name":"Terada Yasuko"},{"name":"Yagi Naoto"},{"name":"Shimizu Taro"},{"name":"Okuhira Keiichiro"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"田中 真生"},{"name":"土井 祐輔"},{"name":"Terada Yasuko"},{"name":"Yagi Naoto"},{"name":"清水 太郎"},{"name":"奥平 桂一郎"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Microsynchrotron radiation X-ray fluorescence spectrometry (-SR-XRF) is an X-ray procedure that utilizes synchrotron radiation as an excitation source. -SR-XRF is a rapid, nondestructive technique that allows mapping and quantification of metals and biologically important elements in cell or tissue samples. Generally, the intratumor distribution of nanocarrier-based therapeutics is assessed by tracing the distribution of a labeled nanocarrier within tumor tissue, rather than by tracing the encapsulated drug. Instead of targeting the delivery vehicle, we employed -SR-XRF to visualize the intratumoral microdistribution of oxaliplatin (l-OHP) encapsulated within PEGylated liposomes. Tumor-bearing mice were intravenously injected with either l-OHP-containing PEGylated liposomes (l-OHP liposomes) or free l-OHP. The intratumor distribution of l-OHP within tumor sections was determined by detecting the fluorescence of platinum atoms, which are the main elemental components of l-OHP. The l-OHP in the liposomal formulation was localized near the tumor vessels and accumulated in tumors at concentrations greater than those seen with the free form, which is consistent with the results of our previous study that focused on fluorescent labeling of PEGylated liposomes. In addition, repeated administration of l-OHP liposomes substantially enhanced the tumor accumulation and/or intratumor distribution of a subsequent dose of l-OHP liposomes, presumably via improvements in tumor vascular permeability, which is also consistent with our previous results. In conclusion, -SR-XRF imaging efficiently and directly traced the intratumor distribution of the active pharmaceutical ingredient l-OHP encapsulated in liposomes within tumor tissue. -SR-XRF imaging could be a powerful means for estimating tissue distribution and even predicting the pharmacological effect of nanocarrier-based anticancer metal compounds.","ja":"Microsynchrotron radiation X-ray fluorescence spectrometry (-SR-XRF) is an X-ray procedure that utilizes synchrotron radiation as an excitation source. -SR-XRF is a rapid, nondestructive technique that allows mapping and quantification of metals and biologically important elements in cell or tissue samples. Generally, the intratumor distribution of nanocarrier-based therapeutics is assessed by tracing the distribution of a labeled nanocarrier within tumor tissue, rather than by tracing the encapsulated drug. Instead of targeting the delivery vehicle, we employed -SR-XRF to visualize the intratumoral microdistribution of oxaliplatin (l-OHP) encapsulated within PEGylated liposomes. Tumor-bearing mice were intravenously injected with either l-OHP-containing PEGylated liposomes (l-OHP liposomes) or free l-OHP. The intratumor distribution of l-OHP within tumor sections was determined by detecting the fluorescence of platinum atoms, which are the main elemental components of l-OHP. The l-OHP in the liposomal formulation was localized near the tumor vessels and accumulated in tumors at concentrations greater than those seen with the free form, which is consistent with the results of our previous study that focused on fluorescent labeling of PEGylated liposomes. In addition, repeated administration of l-OHP liposomes substantially enhanced the tumor accumulation and/or intratumor distribution of a subsequent dose of l-OHP liposomes, presumably via improvements in tumor vascular permeability, which is also consistent with our previous results. In conclusion, -SR-XRF imaging efficiently and directly traced the intratumor distribution of the active pharmaceutical ingredient l-OHP encapsulated in liposomes within tumor tissue. -SR-XRF imaging could be a powerful means for estimating tissue distribution and even predicting the pharmacological effect of nanocarrier-based anticancer metal compounds."},"publication_date":"2018-02-05","publication_name":{"en":"Molecular Pharmaceutics","ja":"Molecular Pharmaceutics"},"volume":"Vol.15","number":"No.2","starting_page":"403","ending_page":"409","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acs.molpharmaceut.7b00762"],"issn":["1543-8392"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:81, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507489"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29217175","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85037534004&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=335200","label":"url"}],"paper_title":{"en":"Reactivity of IgM antibodies elicited by PEGylated liposomes or PEGylated lipoplexes against auto and foreign antigens","ja":"Reactivity of IgM antibodies elicited by PEGylated liposomes or PEGylated lipoplexes against auto and foreign antigens"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Kawanishi Munehira"},{"name":"Shimizu Taro"},{"name":"Okuhira Keiichiro"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"川西 宗平"},{"name":"清水 太郎"},{"name":"奥平 桂一郎"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Polyethylene glycol (PEG) is an attractive tool for the development of nanoparticle-based cancer therapy since it endows nanoparticles with extended-circulation properties. Nevertheless, recent reports have revealed that intravenous injection of either PEGylated liposomes (SLs) or PEGylated lipoplex (PLpx) could elicit an anti-PEG immunoglobulin (IgM) response in a T cell-independent (TI) manner that would substantially compromise the in vivo fate of PEGylated products upon repeated administration. In the same context, viral or bacterial infections trigger the production of polyreactive IgM that binds both self and foreign antigens. The polyreactivity of IgM elicited by SLs or PLpx, to bacteria and other polymers, however, is yet to be elucidated. In this study, the polyreactivity of IgM elicited by SLs or PLpx was challenged against different bacteria (TI antigens) and against synthetic polymer composed of repetitive structures (PVP-360 or FITC-dextran). Results demonstrated that anti-PEG IgM elicited by either SLs or PLpx showed no reactivity to various bacteria examined, while the IgM showed remarkable reactivity to both PVP-360 and FITC-dextran. In addition, interestingly, anti-PEG IgM elicited by either SLs or PLpx showed no antinuclear antibody-like immune reactivity, and, therefore, treatment with either SLs or PLpx was not expected to exacerbate autoimmune diseases such as systemic lupus erythematosus. Collectively, our findings could provide information supporting the safety of PEGylated nanoparticle-based pharmaceutics, particularly in patients with autoimmune diseases.","ja":"Polyethylene glycol (PEG) is an attractive tool for the development of nanoparticle-based cancer therapy since it endows nanoparticles with extended-circulation properties. Nevertheless, recent reports have revealed that intravenous injection of either PEGylated liposomes (SLs) or PEGylated lipoplex (PLpx) could elicit an anti-PEG immunoglobulin (IgM) response in a T cell-independent (TI) manner that would substantially compromise the in vivo fate of PEGylated products upon repeated administration. In the same context, viral or bacterial infections trigger the production of polyreactive IgM that binds both self and foreign antigens. The polyreactivity of IgM elicited by SLs or PLpx, to bacteria and other polymers, however, is yet to be elucidated. In this study, the polyreactivity of IgM elicited by SLs or PLpx was challenged against different bacteria (TI antigens) and against synthetic polymer composed of repetitive structures (PVP-360 or FITC-dextran). Results demonstrated that anti-PEG IgM elicited by either SLs or PLpx showed no reactivity to various bacteria examined, while the IgM showed remarkable reactivity to both PVP-360 and FITC-dextran. In addition, interestingly, anti-PEG IgM elicited by either SLs or PLpx showed no antinuclear antibody-like immune reactivity, and, therefore, treatment with either SLs or PLpx was not expected to exacerbate autoimmune diseases such as systemic lupus erythematosus. Collectively, our findings could provide information supporting the safety of PEGylated nanoparticle-based pharmaceutics, particularly in patients with autoimmune diseases."},"publication_date":"2018-01-28","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.270","starting_page":"114","ending_page":"119","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2017.12.002"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:82, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507490"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/112025","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29462674","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85042401633&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=339054","label":"url"}],"paper_title":{"en":"Lysophosphatidic acid in medicinal herbs enhances prostaglandin E2 and protects against indomethacin-induced gastric cell damage in vivo and in vitro","ja":"Lysophosphatidic acid in medicinal herbs enhances prostaglandin E2 and protects against indomethacin-induced gastric cell damage in vivo and in vitro"},"authors":{"en":[{"name":"Afroz Sheuli"},{"name":"Yagi Ayano"},{"name":"Fujikawa Kouki"},{"name":"Rahman Motiur M."},{"name":"Morito Katsuya"},{"name":"Fukuta Tatsuya"},{"name":"Watanabe Shiro"},{"name":"Toida Kazunori"},{"name":"Kiyokage Emi"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"},{"name":"Kogure Kentaro"},{"name":"Tokumura Akira"},{"name":"Tanaka Tamotsu"}],"ja":[{"name":"SHEULI AFROZ"},{"name":"屋宜 亜耶乃"},{"name":"藤川 昂樹"},{"name":"Md. Motiur Rahman"},{"name":"森戸 克弥"},{"name":"福田 達也"},{"name":"Watanabe Shiro"},{"name":"Toida Kazunori"},{"name":"Kiyokage Emi"},{"name":"清水 太郎"},{"name":"石田 竜弘"},{"name":"小暮 健太朗"},{"name":"德村 彰"},{"name":"田中 保"}]},"description":{"en":"Lysophosphatidic acid (LPA) is a bioactive phospholipid that induces diverse biological responses. Recently, we found that LPA ameliorates NSAIDs-induced gastric ulcer in mice. Here, we quantified LPA in 21 medicinal herbs used for treatment of gastrointestinal (GI) disorders. We found that half of them contained LPA at relatively high levels (40-240 μg/g) compared to soybean seed powder (4.6 μg/g), which we previously identified as an LPA-rich food. The LPA in peony (Paeonia lactiflora) root powder is highly concentrated in the lipid fraction that ameliorates indomethacin-induced gastric ulcer in mice. Synthetic 18:1 LPA, peony root LPA and peony root lipid enhanced prostaglandin E production in a gastric cancer cell line, MKN74 cells that express LPA abundantly. These materials also prevented indomethacin-induced cell death and stimulated the proliferation of MKN74 cells. We found that LPA was present in stomach fluids at 2.4 μM, which is an effective LPA concentration for inducing a cellular response in vitro. These results indicated that LPA is one of the active components of medicinal herbs for the treatment of GI disorder and that orally administered LPA-rich herbs may augment the protective actions of endogenous LPA on gastric mucosa.","ja":"Lysophosphatidic acid (LPA) is a bioactive phospholipid that induces diverse biological responses. Recently, we found that LPA ameliorates NSAIDs-induced gastric ulcer in mice. Here, we quantified LPA in 21 medicinal herbs used for treatment of gastrointestinal (GI) disorders. We found that half of them contained LPA at relatively high levels (40-240 μg/g) compared to soybean seed powder (4.6 μg/g), which we previously identified as an LPA-rich food. The LPA in peony (Paeonia lactiflora) root powder is highly concentrated in the lipid fraction that ameliorates indomethacin-induced gastric ulcer in mice. Synthetic 18:1 LPA, peony root LPA and peony root lipid enhanced prostaglandin E production in a gastric cancer cell line, MKN74 cells that express LPA abundantly. These materials also prevented indomethacin-induced cell death and stimulated the proliferation of MKN74 cells. We found that LPA was present in stomach fluids at 2.4 μM, which is an effective LPA concentration for inducing a cellular response in vitro. These results indicated that LPA is one of the active components of medicinal herbs for the treatment of GI disorder and that orally administered LPA-rich herbs may augment the protective actions of endogenous LPA on gastric mucosa."},"publication_date":"2018-01-25","publication_name":{"en":"Prostaglandins & Other Lipid Mediators","ja":"Prostaglandins & Other Lipid Mediators"},"volume":"Vol.135","starting_page":"36","ending_page":"44","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.prostaglandins.2018.01.003"],"issn":["1098-8823"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:83, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507491"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29122608","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85032951371&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=335211","label":"url"}],"paper_title":{"en":"Thioredoxin-Albumin Fusion Protein Prevents Copper enhanced Zinc-induced Neurotoxicity via Its Antioxidative activity","ja":"Thioredoxin-Albumin Fusion Protein Prevents Copper enhanced Zinc-induced Neurotoxicity via Its Antioxidative activity"},"authors":{"en":[{"name":"Tanaka K"},{"name":"Shimoda M"},{"name":"Chuang V"},{"name":"Nishida K"},{"name":"Kawahara M"},{"name":"Ishida Tatsuhiro"},{"name":"Otagiri M"},{"name":"Maruyama T"},{"name":"Ishima Yu"}],"ja":[{"name":"Tanaka K"},{"name":"Shimoda M"},{"name":"Chuang V"},{"name":"Nishida K"},{"name":"Kawahara M"},{"name":"石田 竜弘"},{"name":"Otagiri M"},{"name":"Maruyama T"},{"name":"異島 優"}]},"description":{"en":"Zinc (Zn) is a co-factor for a vast number of enzymes, and functions as a regulator for immune mechanism and protein synthesis. However, excessive Zn release induced in pathological situations such as stroke or transient global ischemia is toxic. Previously, we demonstrated that the interaction of Zn and copper (Cu) is involved in the pathogenesis of Alzheimer's disease and vascular dementia. Furthermore, oxidative stress has been shown to play a significant role in the pathogenesis of various metal ions induced neuronal death. Thioredoxin-Albumin fusion (HSA-Trx) is a derivative of thioredoxin (Trx), an antioxidative protein, with improved plasma retention and stability of Trx. In this study, we examined the effect of HSA-Trx on Cu/Zn-induced neurotoxicity. Firstly, HSA-Trx was found to clearly suppress Cu/Zn-induced neuronal cell death in mouse hypothalamic neuronal cells (GT1-7 cells). Moreover, HSA-Trx markedly suppressed Cu/Zn-induced ROS production and the expression of oxidative stress related genes, such as heme oxygenase-1. In contrast, HSA-Trx did not affect the intracellular levels of both Cu and Zn after Cu/Zn treatment. Finally, HSA-Trx was found to significantly suppress endoplasmic reticulum (ER) stress response induced by Cu/Zn treatment in a dose dependent manner. These results suggest that HSA-Trx counteracted Cu/Zn-induced neurotoxicity by suppressing the production of ROS via interfering the related gene expressions, in addition to the highly possible radical scavenging activity of the fusion protein. Based on these findings, HSA-Trx has great potential as a promising therapeutic agent for the treatment of refractory neurological diseases.","ja":"Zinc (Zn) is a co-factor for a vast number of enzymes, and functions as a regulator for immune mechanism and protein synthesis. However, excessive Zn release induced in pathological situations such as stroke or transient global ischemia is toxic. Previously, we demonstrated that the interaction of Zn and copper (Cu) is involved in the pathogenesis of Alzheimer's disease and vascular dementia. Furthermore, oxidative stress has been shown to play a significant role in the pathogenesis of various metal ions induced neuronal death. Thioredoxin-Albumin fusion (HSA-Trx) is a derivative of thioredoxin (Trx), an antioxidative protein, with improved plasma retention and stability of Trx. In this study, we examined the effect of HSA-Trx on Cu/Zn-induced neurotoxicity. Firstly, HSA-Trx was found to clearly suppress Cu/Zn-induced neuronal cell death in mouse hypothalamic neuronal cells (GT1-7 cells). Moreover, HSA-Trx markedly suppressed Cu/Zn-induced ROS production and the expression of oxidative stress related genes, such as heme oxygenase-1. In contrast, HSA-Trx did not affect the intracellular levels of both Cu and Zn after Cu/Zn treatment. Finally, HSA-Trx was found to significantly suppress endoplasmic reticulum (ER) stress response induced by Cu/Zn treatment in a dose dependent manner. These results suggest that HSA-Trx counteracted Cu/Zn-induced neurotoxicity by suppressing the production of ROS via interfering the related gene expressions, in addition to the highly possible radical scavenging activity of the fusion protein. Based on these findings, HSA-Trx has great potential as a promising therapeutic agent for the treatment of refractory neurological diseases."},"publication_date":"2018-01-15","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.535","number":"No.1-2","starting_page":"140","ending_page":"147","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2017.11.012"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:84, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507492"},"force":{"see_also":[{"@id":"https://cir.nii.ac.jp/crid/1390001205741139840/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=335241","label":"url"}],"paper_title":{"en":"放射光施設(SPring-8)における蛍光X線分析法を用いたオキサリプラチン腫瘍内分布解析","ja":"放射光施設(SPring-8)における蛍光X線分析法を用いたオキサリプラチン腫瘍内分布解析"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"石田 竜弘"}]},"publication_date":"2018-01","publication_name":{"en":"Journal of Pharmaceutical Science and Technology, Japan","ja":"薬剤学"},"volume":"Vol.78","number":"No.1","starting_page":"28","ending_page":"33","languages":["jpn"],"referee":true,"identifiers":{"doi":["10.14843/jpstj.78.28"],"issn":["0372-7629"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:85, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507493"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29054682","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85032786660&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=334214","label":"url"}],"paper_title":{"en":"Liposomalization of oxaliplatin induces skin accumulation of it, but negligible skin toxicity","ja":"Liposomalization of oxaliplatin induces skin accumulation of it, but negligible skin toxicity"},"authors":{"en":[{"name":"Nishida Kentaro"},{"name":"Kashiwagi Misaki"},{"name":"Shiba Shunsuke"},{"name":"Muroki Kiwamu"},{"name":"Ohishi Akihiro"},{"name":"Doi Yusuke"},{"name":"ANDO Hidenori"},{"name":"Ishida Tatsuhiro"},{"name":"Nagasawa Kazuki"}],"ja":[{"name":"Nishida Kentaro"},{"name":"Kashiwagi Misaki"},{"name":"Shiba Shunsuke"},{"name":"Muroki Kiwamu"},{"name":"Ohishi Akihiro"},{"name":"土井 祐輔"},{"name":"安藤 英紀"},{"name":"石田 竜弘"},{"name":"Nagasawa Kazuki"}]},"description":{"en":"Liposomalization causes alteration of the pharmacokinetics of encapsulated drugs, and allows delivery to tumor tissues through passive targeting via an enhanced permeation and retention (EPR) effect. PEGylated liposomal doxorubicin (Doxil(®), Lipo-DXR), a representative liposomal drug, is well-known to reduce cardiotoxicity and increase the anti-tumor activity of DXR, but to induce the hand-foot syndrome (HFS) as a result of skin DXR accumulation, which is one of its severe adverse effects. We have developed a new liposomal preparation of oxaliplatin (l-OHP), an important anti-tumor drug for treatment of colorectal cancer, using PEGylated liposomes (Lipo-l-OHP), and showed that Lipo-l-OHP exhibits increased anti-tumor activity in tumor-bearing mice compared to the original preparation of l-OHP. However, whether Lipo-l-OHP causes HFS-like skin toxicity similar to Lipo-DXR remains to be determined. Administration of Lipo-l-OHP promoted accumulation of platinum in rat hind paws, however, it caused negligible morphological and histological alterations on the plantar surface of the paws. Administration of DiI-labeled empty PEGylated liposomes gave almost the same distribution profile of dyes into the dermis of hind paws with DXR as in the case of Lipo-DXR. Treatment with Lipo-l-OHP, Lipo-DXR, DiI-labeled empty PEGylated liposomes or empty PEGylated liposomes caused migration of CD68(+) macrophages into the dermis of hind paws. These findings suggest that the skin toxicity on administration of liposomalized drugs is reflected in the proinflammatory characteristics of encapsulated drugs, and indicate that Lipo-l-OHP with a higher anti-cancer effect and no HFS may be an outstanding l-OHP preparation leading to an improved quality of life of cancer patients.","ja":"Liposomalization causes alteration of the pharmacokinetics of encapsulated drugs, and allows delivery to tumor tissues through passive targeting via an enhanced permeation and retention (EPR) effect. PEGylated liposomal doxorubicin (Doxil(®), Lipo-DXR), a representative liposomal drug, is well-known to reduce cardiotoxicity and increase the anti-tumor activity of DXR, but to induce the hand-foot syndrome (HFS) as a result of skin DXR accumulation, which is one of its severe adverse effects. We have developed a new liposomal preparation of oxaliplatin (l-OHP), an important anti-tumor drug for treatment of colorectal cancer, using PEGylated liposomes (Lipo-l-OHP), and showed that Lipo-l-OHP exhibits increased anti-tumor activity in tumor-bearing mice compared to the original preparation of l-OHP. However, whether Lipo-l-OHP causes HFS-like skin toxicity similar to Lipo-DXR remains to be determined. Administration of Lipo-l-OHP promoted accumulation of platinum in rat hind paws, however, it caused negligible morphological and histological alterations on the plantar surface of the paws. Administration of DiI-labeled empty PEGylated liposomes gave almost the same distribution profile of dyes into the dermis of hind paws with DXR as in the case of Lipo-DXR. Treatment with Lipo-l-OHP, Lipo-DXR, DiI-labeled empty PEGylated liposomes or empty PEGylated liposomes caused migration of CD68(+) macrophages into the dermis of hind paws. These findings suggest that the skin toxicity on administration of liposomalized drugs is reflected in the proinflammatory characteristics of encapsulated drugs, and indicate that Lipo-l-OHP with a higher anti-cancer effect and no HFS may be an outstanding l-OHP preparation leading to an improved quality of life of cancer patients."},"publication_date":"2017-12-15","publication_name":{"en":"Toxicology and Applied Pharmacology","ja":"Toxicology and Applied Pharmacology"},"volume":"Vol.337","starting_page":"76","ending_page":"84","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.taap.2017.10.006"],"issn":["1096-0333"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:86, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507494"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28414103","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=324411","label":"url"}],"paper_title":{"en":"Apoptosis induction of Poly-S-nitrosated human serum albumin in resistant solid tumor under hypoxia can be restored by phosphodiesterase 5 inhibition","ja":"Apoptosis induction of Poly-S-nitrosated human serum albumin in resistant solid tumor under hypoxia can be restored by phosphodiesterase 5 inhibition"},"authors":{"en":[{"name":"Ikeda Mayumi"},{"name":"Ishima Yu"},{"name":"Chuang Victor"},{"name":"Ikeda Tsuyoshi"},{"name":"Kinoshita Ryo"},{"name":"Watanabe Hiroshi"},{"name":"Ishida Tatsuhiro"},{"name":"Otagiri Masaki"},{"name":"Maruyama Toru"}],"ja":[{"name":"池田 真由美"},{"name":"異島 優"},{"name":"Chuang Victor"},{"name":"Ikeda Tsuyoshi"},{"name":"木下 遼"},{"name":"Watanabe Hiroshi"},{"name":"石田 竜弘"},{"name":"Otagiri Masaki"},{"name":"Maruyama Toru"}]},"description":{"en":"Poly-S-nitrosated human serum albumin (Poly-SNO-HSA) delivered and accumulated nitric oxide (NO) in tumors and induces apoptosis. Tumor hypoxia is strongly associated with malignant progression and tumor resistance to therapy. In this study, we examined the cytotoxic effect of Poly-SNO-HSA under hypoxia on the murine colon 26 adenocarcinoma (C26) cells in vitro and in vivo. Under hypoxia, at about 4 times LD50 dose of Poly-SNO-HSA in vitro, the reactive oxygen species production was hindered but apoptotic cells were induced via cGMP pathway as the effect was suppressed by a soluble guanylate cyclase inhibitor, NS2028. The apoptosis induction effect of low dose Poly-SNO-HSA on C26 cells in vitro under hypoxia can be restored by a phosphodiesterase 5 (PDE5) inhibitor, vardenafil. In C26-bearing mice, Poly-SNO-HSA/vardenafil combination treatment significantly suppressed the tumor volume compared with Poly-SNO-HSA or vardenafil treatment alone. Furthermore, the core tumor tissues showed increased expression of caspase-3 than the non-core tissue. The expression of caspase-3 appeared to overlap with the hypoxic zone of tumor tissues. Similar results were also obtained when the experiments were repeated using Epimedium extract, a natural herbal supplement with PDE5 inhibition activity. In conclusion, Poly-SNO-HSA/PDE5 inhibitors combination therapy is a promising approach for enhancing the anticancer therapeutic effects of Poly-SNO-HSA against not only anti-cancer drug resistance but also hypoxic stress related solid tumor resistance.","ja":"Poly-S-nitrosated human serum albumin (Poly-SNO-HSA) delivered and accumulated nitric oxide (NO) in tumors and induces apoptosis. Tumor hypoxia is strongly associated with malignant progression and tumor resistance to therapy. In this study, we examined the cytotoxic effect of Poly-SNO-HSA under hypoxia on the murine colon 26 adenocarcinoma (C26) cells in vitro and in vivo. Under hypoxia, at about 4 times LD50 dose of Poly-SNO-HSA in vitro, the reactive oxygen species production was hindered but apoptotic cells were induced via cGMP pathway as the effect was suppressed by a soluble guanylate cyclase inhibitor, NS2028. The apoptosis induction effect of low dose Poly-SNO-HSA on C26 cells in vitro under hypoxia can be restored by a phosphodiesterase 5 (PDE5) inhibitor, vardenafil. In C26-bearing mice, Poly-SNO-HSA/vardenafil combination treatment significantly suppressed the tumor volume compared with Poly-SNO-HSA or vardenafil treatment alone. Furthermore, the core tumor tissues showed increased expression of caspase-3 than the non-core tissue. The expression of caspase-3 appeared to overlap with the hypoxic zone of tumor tissues. Similar results were also obtained when the experiments were repeated using Epimedium extract, a natural herbal supplement with PDE5 inhibition activity. In conclusion, Poly-SNO-HSA/PDE5 inhibitors combination therapy is a promising approach for enhancing the anticancer therapeutic effects of Poly-SNO-HSA against not only anti-cancer drug resistance but also hypoxic stress related solid tumor resistance."},"publication_date":"2017-09-30","publication_name":{"en":"Nitric Oxide: Biology and Chemistry","ja":"Nitric Oxide: Biology and Chemistry"},"volume":"Vol.69","starting_page":"28","ending_page":"34","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.niox.2017.04.005"],"issn":["1089-8611"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:87, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507495"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28651144","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85021192830&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=325199","label":"url"}],"paper_title":{"en":"Improved anticancer effects of albumin-bound paclitaxel nanoparticle via augmentation of EPR effect and albumin-protein interactions using S-Nitrosated Human Serum Albumin Dimer","ja":"Improved anticancer effects of albumin-bound paclitaxel nanoparticle via augmentation of EPR effect and albumin-protein interactions using S-Nitrosated Human Serum Albumin Dimer"},"authors":{"en":[{"name":"Kinoshita, Ryo"},{"name":"Ishima Yu"},{"name":"Chuang T.G. Victor"},{"name":"Nakamura, Hideaki"},{"name":"Fang, Jun"},{"name":"Watanabe, Hiroshi"},{"name":"Shimizu Taro"},{"name":"Okuhira Keiichiro"},{"name":"Ishida Tatsuhiro"},{"name":"Maeda, Hiroshi"},{"name":"Otagiri, Masaki"},{"name":"Maruyama, Toru"}],"ja":[{"name":"木下 遼"},{"name":"異島 優"},{"name":"Chuang T.G. Victor"},{"name":"Nakamura, Hideaki"},{"name":"Fang, Jun"},{"name":"Watanabe, Hiroshi"},{"name":"清水 太郎"},{"name":"奥平 桂一郎"},{"name":"石田 竜弘"},{"name":"Maeda, Hiroshi"},{"name":"Otagiri, Masaki"},{"name":"Maruyama, Toru"}]},"description":{"en":"In the latest trend of anticancer chemotherapy research, there were many macromolecular anticancer drugs developed based on enhanced permeability and retention (EPR) effect, such as albumin bound paclitaxel nanoparticle (nab- PTX, also called Abraxane). However, cancers with low vascular permeability posed a challenge for these EPR based therapeutic systems. Augmenting the intrinsic EPR effect with an intrinsic vascular modulator such as nitric oxide (NO) could be a promising strategy. S-nitrosated human serum albumin dimer (SNO-HSA Dimer) shown promising activity previously was evaluated for the synergistic effect when used as a pretreatment agent in nab-PTX therapy against various tumor models. In the high vascular permeability C26 murine colon cancer subcutaneous inoculation model, SNO-HSA Dimer enhanced tumor selectivity of nab-PTX, and attenuated myelosuppression. SNO-HSA Dimer also augmented the tumor growth inhibition of nab-PTX in low vascular permeability B16 murine melanoma subcutaneous inoculation model. Furthermore, nab-PTX therapy combined with SNO-HSA Dimer showed higher antitumor activity and improved survival rate of SUIT2 human pancreatic cancer orthotopic model. In conclusion, SNO-HSA Dimer could enhance the therapeutic effect of nab-PTX even in low vascular permeability or intractable pancreatic cancers. The possible underlying mechanisms of action of SNO-HSA Dimer were discussed.","ja":"In the latest trend of anticancer chemotherapy research, there were many macromolecular anticancer drugs developed based on enhanced permeability and retention (EPR) effect, such as albumin bound paclitaxel nanoparticle (nab- PTX, also called Abraxane). However, cancers with low vascular permeability posed a challenge for these EPR based therapeutic systems. Augmenting the intrinsic EPR effect with an intrinsic vascular modulator such as nitric oxide (NO) could be a promising strategy. S-nitrosated human serum albumin dimer (SNO-HSA Dimer) shown promising activity previously was evaluated for the synergistic effect when used as a pretreatment agent in nab-PTX therapy against various tumor models. In the high vascular permeability C26 murine colon cancer subcutaneous inoculation model, SNO-HSA Dimer enhanced tumor selectivity of nab-PTX, and attenuated myelosuppression. SNO-HSA Dimer also augmented the tumor growth inhibition of nab-PTX in low vascular permeability B16 murine melanoma subcutaneous inoculation model. Furthermore, nab-PTX therapy combined with SNO-HSA Dimer showed higher antitumor activity and improved survival rate of SUIT2 human pancreatic cancer orthotopic model. In conclusion, SNO-HSA Dimer could enhance the therapeutic effect of nab-PTX even in low vascular permeability or intractable pancreatic cancers. The possible underlying mechanisms of action of SNO-HSA Dimer were discussed."},"publication_date":"2017-09","publication_name":{"en":"Biomaterials","ja":"Biomaterials"},"volume":"Vol.140","starting_page":"162","ending_page":"169","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.biomaterials.2017.06.021"],"issn":["1878-5905"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:88, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507496"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115035","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27838412","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85007010070&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=321160","label":"url"}],"paper_title":{"en":"Metronomic S-1 dosing and thymidylate synthase silencing have synergistic antitumor efficacy in a colorectal cancer xenograft model.","ja":"Metronomic S-1 dosing and thymidylate synthase silencing have synergistic antitumor efficacy in a colorectal cancer xenograft model."},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Moriyoshi Naoto"},{"name":"Fukushima Masakazu"},{"name":"Huang Cheng-long"},{"name":"Wada Hiromi"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"森吉 直人"},{"name":"Fukushima Masakazu"},{"name":"Huang Cheng-long"},{"name":"Wada Hiromi"},{"name":"石田 竜弘"}]},"description":{"en":"Metronomic chemotherapy is currently considered an emerging therapeutic option in clinical oncology. S-1, an oral formulation of Tegafur (TF), a prodrug of 5-fluorouracil (5-FU), is designed to improve the antitumor activity of 5-FU in tandem with reducing its toxicity. Clinically, metronomic S-1 dosing has been approved for the standard first- and second-line treatment of metastatic or advanced stage of colorectal (CRC). However, expression of intratumor thymidylate synthase (TS), a significant gene in cellular proliferation, is associated with poor outcome to 5-FU-based chemotherapeutic regimens. In this study, therefore, we examined the effect of a combination of TS silencing by an RNA interfering molecule, chemically synthesized short hairpin RNA against TS (shTS), and 5-FU on the growth of human colorectal cancer cell (DLD-1) both in vitro and in vivo. The combined treatment of both shTS with 5-FU substantially inhibited cell proliferation in vitro. For in vivo treatments, the combined treatment of metronomic S-1 dosing with intravenously injected polyethylene glycol (PEG)-coated shTS-lipoplex significantly suppressed tumor growth, compared to a single treatment of either S-1 or PEG-coated shTS-lipoplex. In addition, the combined treatment increased the proportion of apoptotic cells in the DLD-1 tumor tissue. Our results suggest that metronomic S-1 dosing combined with TS silencing might represent an emerging therapeutic strategy for the treatment of patients with advanced CRC.","ja":"Metronomic chemotherapy is currently considered an emerging therapeutic option in clinical oncology. S-1, an oral formulation of Tegafur (TF), a prodrug of 5-fluorouracil (5-FU), is designed to improve the antitumor activity of 5-FU in tandem with reducing its toxicity. Clinically, metronomic S-1 dosing has been approved for the standard first- and second-line treatment of metastatic or advanced stage of colorectal (CRC). However, expression of intratumor thymidylate synthase (TS), a significant gene in cellular proliferation, is associated with poor outcome to 5-FU-based chemotherapeutic regimens. In this study, therefore, we examined the effect of a combination of TS silencing by an RNA interfering molecule, chemically synthesized short hairpin RNA against TS (shTS), and 5-FU on the growth of human colorectal cancer cell (DLD-1) both in vitro and in vivo. The combined treatment of both shTS with 5-FU substantially inhibited cell proliferation in vitro. For in vivo treatments, the combined treatment of metronomic S-1 dosing with intravenously injected polyethylene glycol (PEG)-coated shTS-lipoplex significantly suppressed tumor growth, compared to a single treatment of either S-1 or PEG-coated shTS-lipoplex. In addition, the combined treatment increased the proportion of apoptotic cells in the DLD-1 tumor tissue. Our results suggest that metronomic S-1 dosing combined with TS silencing might represent an emerging therapeutic strategy for the treatment of patients with advanced CRC."},"publication_date":"2017-08-01","publication_name":{"en":"Cancer Letters","ja":"Cancer Letters"},"volume":"Vol.400","starting_page":"223","ending_page":"231","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.canlet.2016.11.005"],"issn":["0304-3835"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:89, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507497"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/112372","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28643902","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=325157","label":"url"}],"paper_title":{"en":"Modulation of antitumor immunity contributes to the enhanced therapeutic efficacy of liposomal oxaliplatin in mouse model","ja":"Modulation of antitumor immunity contributes to the enhanced therapeutic efficacy of liposomal oxaliplatin in mouse model"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Nishio Miho"},{"name":"Doi Yusuke"},{"name":"ANDO Hidenori"},{"name":"Ukawa Masami"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"西尾 美穂"},{"name":"土井 祐輔"},{"name":"安藤 英紀"},{"name":"鵜川 真実"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"description":{"en":"Immune modulation of the tumor microenvironment has been reported to participate in the therapeutic efficacy of many chemotherapeutic agents. Recently, we reported that liposomal encapsulation of oxaliplatin (l-OHP) within PEGylated liposomes conferred a superior antitumor efficacy to free l-OHP in murine colorectal carcinoma-bearing mice through permitting preferential accumulation of the encapsulated drug within tumor tissue. However, the contribution of the immune-modulatory properties of liposomal l-OHP and/or free l-OHP to the overall antitumor efficacy was not elucidated. In the present study, therefore, we investigated the effect of liposomal encapsulation of l-OHP within PEGylated liposomes on the antitumor immunity in both immunocompetent and immunodeficient mice. Liposomal l-OHP significantly suppressed the growth of tumors implanted in immunocompetent mice, but not in immunodeficient mice. In immunocompetent mice, liposomal l-OHP increased the tumor MHC-1 level and preserved antitumor immunity through decreasing the number of immune suppressor cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, which collectively suppress CD8(+) T cell-mediated tumor cells killing. In contrast, free l-OHP ruined antitumor immunity. These results suggest that the antitumor efficacy of liposomal l-OHP is attributed, on the one hand, to its immunomodulatory effect on tumor immune microenvironment that is superior to that of free l-OHP, and on the other hand, to its direct cytotoxic effect on tumor cells.","ja":"Immune modulation of the tumor microenvironment has been reported to participate in the therapeutic efficacy of many chemotherapeutic agents. Recently, we reported that liposomal encapsulation of oxaliplatin (l-OHP) within PEGylated liposomes conferred a superior antitumor efficacy to free l-OHP in murine colorectal carcinoma-bearing mice through permitting preferential accumulation of the encapsulated drug within tumor tissue. However, the contribution of the immune-modulatory properties of liposomal l-OHP and/or free l-OHP to the overall antitumor efficacy was not elucidated. In the present study, therefore, we investigated the effect of liposomal encapsulation of l-OHP within PEGylated liposomes on the antitumor immunity in both immunocompetent and immunodeficient mice. Liposomal l-OHP significantly suppressed the growth of tumors implanted in immunocompetent mice, but not in immunodeficient mice. In immunocompetent mice, liposomal l-OHP increased the tumor MHC-1 level and preserved antitumor immunity through decreasing the number of immune suppressor cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, which collectively suppress CD8(+) T cell-mediated tumor cells killing. In contrast, free l-OHP ruined antitumor immunity. These results suggest that the antitumor efficacy of liposomal l-OHP is attributed, on the one hand, to its immunomodulatory effect on tumor immune microenvironment that is superior to that of free l-OHP, and on the other hand, to its direct cytotoxic effect on tumor cells."},"publication_date":"2017-07-14","publication_name":{"en":"Cancer Science","ja":"Cancer Science"},"volume":"Vol.108","number":"No.9","starting_page":"1864","ending_page":"1869","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1111/cas.13305"],"issn":["1349-7006"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:90, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507498"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28461099","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=324412","label":"url"}],"paper_title":{"en":"Co-administration of liposomal l-OHP and PEGylated TS shRNA-lipoplex: A novel approach to enhance anti-tumor efficacy and reduce the immunogenic response to RNAi molecules","ja":"Co-administration of liposomal l-OHP and PEGylated TS shRNA-lipoplex: A novel approach to enhance anti-tumor efficacy and reduce the immunogenic response to RNAi molecules"},"authors":{"en":[{"name":"Eman Alaaeldin"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"ANDO Hidenori"},{"name":"Fukushima, M"},{"name":"Huang, C"},{"name":"Wada, H"},{"name":"Sarhan, H.A"},{"name":"Khaled, K.A"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Eman Alaaeldin"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"安藤 英紀"},{"name":"Fukushima, M"},{"name":"Huang, C"},{"name":"Wada, H"},{"name":"Sarhan, H.A"},{"name":"Khaled, K.A"},{"name":"石田 竜弘"}]},"description":{"en":"Many therapeutic strategies have been applied in efforts to conquer the development and/or progression of cancer. The combination of chemotherapy and an RNAi-based approach has proven to be an efficient anticancer therapy. However, the feasibility of such a therapeutic strategy has been substantially restricted either by the failure to achieve the efficient delivery of RNAi molecules to tumor tissue or by the immunostimulatory response triggered by RNAi molecules. In this study, therefore, we intended to investigate the efficacy of using liposomal oxaliplatin (liposomal l-OHP) to guarantee the efficient delivery of RNAi molecules, namely shRNA against thymidylate synthase (TS shRNA) complexed with cationic liposome (TS shRNA-lipoplex), to solid tumors, and to suppress the immunostimulatory effect of RNAi molecules, TS shRNA, following intravenous administration. Herein, we describe how liposomal l-OHP enhanced the intra-tumor accumulation of TS shRNA-lipoplex and significantly reduced the immunostimulatory response triggered by TS shRNA. Consequently, such enhanced accumulation of TS shRNA-lipoplex along with the cytotoxic effect of liposomal l-OHP led to a remarkable tumor growth suppression (compared to mono-therapy) following systemic administration. Our results, therefore, may have important implications for the provision of a safer and more applicable combination therapy of RNAi molecules and anti-cancer agents that can produce a more reliable anti-tumor effect.","ja":"Many therapeutic strategies have been applied in efforts to conquer the development and/or progression of cancer. The combination of chemotherapy and an RNAi-based approach has proven to be an efficient anticancer therapy. However, the feasibility of such a therapeutic strategy has been substantially restricted either by the failure to achieve the efficient delivery of RNAi molecules to tumor tissue or by the immunostimulatory response triggered by RNAi molecules. In this study, therefore, we intended to investigate the efficacy of using liposomal oxaliplatin (liposomal l-OHP) to guarantee the efficient delivery of RNAi molecules, namely shRNA against thymidylate synthase (TS shRNA) complexed with cationic liposome (TS shRNA-lipoplex), to solid tumors, and to suppress the immunostimulatory effect of RNAi molecules, TS shRNA, following intravenous administration. Herein, we describe how liposomal l-OHP enhanced the intra-tumor accumulation of TS shRNA-lipoplex and significantly reduced the immunostimulatory response triggered by TS shRNA. Consequently, such enhanced accumulation of TS shRNA-lipoplex along with the cytotoxic effect of liposomal l-OHP led to a remarkable tumor growth suppression (compared to mono-therapy) following systemic administration. Our results, therefore, may have important implications for the provision of a safer and more applicable combination therapy of RNAi molecules and anti-cancer agents that can produce a more reliable anti-tumor effect."},"publication_date":"2017-06-10","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.255","starting_page":"210","ending_page":"217","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2017.04.040"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:91, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507499"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28411626","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85017155399&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=324410","label":"url"}],"paper_title":{"en":"Quantitative determination of polysulfide in albumins, plasma proteins and biological fluid samples using a novel combined assays approach","ja":"Quantitative determination of polysulfide in albumins, plasma proteins and biological fluid samples using a novel combined assays approach"},"authors":{"en":[{"name":"Ikeda, Mayumi"},{"name":"Ishima Yu"},{"name":"Shibata, Akitomo"},{"name":"Chuang T.G. Victor"},{"name":"Sawa, Tomohiro"},{"name":"Ihara, Hideshi"},{"name":"Watanabe, Hiroshi"},{"name":"Xian, Ming"},{"name":"Ouchi, Yuya"},{"name":"Shimizu Taro"},{"name":"ANDO Hidenori"},{"name":"Ukawa Masami"},{"name":"Ishida Tatsuhiro"},{"name":"Akaike, T"},{"name":"Otagiri, M"},{"name":"Maruyama, T"}],"ja":[{"name":"池田 真由美"},{"name":"異島 優"},{"name":"Shibata, Akitomo"},{"name":"Chuang T.G. Victor"},{"name":"Sawa, Tomohiro"},{"name":"Ihara, Hideshi"},{"name":"Watanabe, Hiroshi"},{"name":"Xian, Ming"},{"name":"Ouchi, Yuya"},{"name":"清水 太郎"},{"name":"安藤 英紀"},{"name":"鵜川 真実"},{"name":"石田 竜弘"},{"name":"Akaike, T"},{"name":"Otagiri, M"},{"name":"Maruyama, T"}]},"description":{"en":"Hydrogen sulfide (H2S) signaling involves polysulfide (RSSnSR') formation on various proteins. However, the current lack of sensitive polysulfide detection assays poses methodological challenges for understanding sulfane sulfur homeostasis and signaling. We developed a novel combined assay by modifying Sulfide Antioxidant Buffer (SAOB) to produce an \"Elimination Method of Sulfide from Polysulfide\" (EMSP) treatment solution that liberates sulfide, followed with methylene blue (MB) sulfide detection assay. The combined EMSP-MB sulfide detection assay performed on low molecular weight sulfur species showed that sulfide was produced from trisulfide compounds such as glutathione trisulfide and diallyl trisulfide, but not from the thiol compounds such as cysteine, cystine and glutathione. In the case of plasma proteins, this novel combined detection assay revealed that approximately 14.7, 1.7, 3.9, 3.7 sulfide mol/mol released from human serum albumin, 1-anti-trypsin, 1-acid glycoprotein and ovalbumin, respectively, suggesting that serum albumin is a major pool of polysulfide in human blood circulation. Taken together with the results of albumins of different species, the liberated sulfide has a good correlation with cysteine instead of methionine, indicating the site of incorporation of polysulfide is cysteine. With this novel sulfide detention assay, approximately 8,000, 120 and 1100 M of polysulfide concentrations was quantitated in human healthy plasma, saliva and tear, respectively. Our promising polysulfide specific detection assay can be a very important tool because quantitative determination of polysulfide sheds light on the functional consequence of protein-bound cysteine polysulfide and expands the research area of reactive oxygen to reactive polysulfide species.","ja":"Hydrogen sulfide (H2S) signaling involves polysulfide (RSSnSR') formation on various proteins. However, the current lack of sensitive polysulfide detection assays poses methodological challenges for understanding sulfane sulfur homeostasis and signaling. We developed a novel combined assay by modifying Sulfide Antioxidant Buffer (SAOB) to produce an \"Elimination Method of Sulfide from Polysulfide\" (EMSP) treatment solution that liberates sulfide, followed with methylene blue (MB) sulfide detection assay. The combined EMSP-MB sulfide detection assay performed on low molecular weight sulfur species showed that sulfide was produced from trisulfide compounds such as glutathione trisulfide and diallyl trisulfide, but not from the thiol compounds such as cysteine, cystine and glutathione. In the case of plasma proteins, this novel combined detection assay revealed that approximately 14.7, 1.7, 3.9, 3.7 sulfide mol/mol released from human serum albumin, 1-anti-trypsin, 1-acid glycoprotein and ovalbumin, respectively, suggesting that serum albumin is a major pool of polysulfide in human blood circulation. Taken together with the results of albumins of different species, the liberated sulfide has a good correlation with cysteine instead of methionine, indicating the site of incorporation of polysulfide is cysteine. With this novel sulfide detention assay, approximately 8,000, 120 and 1100 M of polysulfide concentrations was quantitated in human healthy plasma, saliva and tear, respectively. Our promising polysulfide specific detection assay can be a very important tool because quantitative determination of polysulfide sheds light on the functional consequence of protein-bound cysteine polysulfide and expands the research area of reactive oxygen to reactive polysulfide species."},"publication_date":"2017-05-29","publication_name":{"en":"Analytica Chimica Acta","ja":"Analytica Chimica Acta"},"volume":"Vol.969","starting_page":"18","ending_page":"25","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.aca.2017.03.027"],"issn":["1873-4324"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:92, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507500"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28458352","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85019212162&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=324408","label":"url"}],"paper_title":{"en":"Preparation of an ultrafine rebamipide ophthalmic suspension with high transparency","ja":"Preparation of an ultrafine rebamipide ophthalmic suspension with high transparency"},"authors":{"en":[{"name":"Matsuda, Takakuni"},{"name":"Hiraoka, Shogo"},{"name":"Urashima, Hiroki"},{"name":"Ogura, Ako"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"松田 貴邦"},{"name":"Hiraoka, Shogo"},{"name":"Urashima, Hiroki"},{"name":"Ogura, Ako"},{"name":"石田 竜弘"}]},"description":{"en":"A 2% commercially available, milky-white, rebamipide micro-particle suspension is used to treat dry eyes, and it causes short-term blurring of the patient's vision. In the current study, to improve the transparency of a rebamipide suspension, we attempted to obtain a clear rebamipide suspension by transforming the rebamipide particles to an ultrafine state. In the initial few efforts, various rebamipide suspensions were prepared using a neutralizing crystallization method with additives, but the suspensions retained their opaque quality. However, as a consequence of several critical improvements in the neutralizing crystallization methods such as selection of additives for crystallization, process parameters during crystallization, the dispersion method, and dialysis, we obtained an ultrafine rebamipide suspension (2%) that was highly transparent (transmittance at 640 nm: 59%). The particle size and transparency demonstrated the fewest level of changes at 25°C after 3 years, compared to initial levels. During that period, no obvious particle sedimentation was observed. The administration of this ultrafine rebamipide suspension (2%) increased the conjunctival mucin, which was comparable to the commercially available micro-particle suspension (2%). The corneal and conjunctival concentration of rebamipide following ocular administration of the ultrafine suspension was slightly higher than that of the micro-particle suspension. The ultrafine rebamipide suspension (eye-drop formulation) with a highly transparent ophthalmic clearness should improve a patient's QOL by preventing even a shortened period of blurred vision.","ja":"A 2% commercially available, milky-white, rebamipide micro-particle suspension is used to treat dry eyes, and it causes short-term blurring of the patient's vision. In the current study, to improve the transparency of a rebamipide suspension, we attempted to obtain a clear rebamipide suspension by transforming the rebamipide particles to an ultrafine state. In the initial few efforts, various rebamipide suspensions were prepared using a neutralizing crystallization method with additives, but the suspensions retained their opaque quality. However, as a consequence of several critical improvements in the neutralizing crystallization methods such as selection of additives for crystallization, process parameters during crystallization, the dispersion method, and dialysis, we obtained an ultrafine rebamipide suspension (2%) that was highly transparent (transmittance at 640 nm: 59%). The particle size and transparency demonstrated the fewest level of changes at 25°C after 3 years, compared to initial levels. During that period, no obvious particle sedimentation was observed. The administration of this ultrafine rebamipide suspension (2%) increased the conjunctival mucin, which was comparable to the commercially available micro-particle suspension (2%). The corneal and conjunctival concentration of rebamipide following ocular administration of the ultrafine suspension was slightly higher than that of the micro-particle suspension. The ultrafine rebamipide suspension (eye-drop formulation) with a highly transparent ophthalmic clearness should improve a patient's QOL by preventing even a shortened period of blurred vision."},"publication_date":"2017-05-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.40","number":"No.5","starting_page":"665","ending_page":"674","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b16-00962"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:93, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507501"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28179196","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85011965687&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=324409","label":"url"}],"paper_title":{"en":"Ganglioside inserted into PEGylated liposome attenuates anti-PEG immunity","ja":"Ganglioside inserted into PEGylated liposome attenuates anti-PEG immunity"},"authors":{"en":[{"name":"Mima Yu"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Shimizu Taro"},{"name":"Ukawa Masami"},{"name":"ANDO Hidenori"},{"name":"Kurata Yasuko"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"美馬 優"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"清水 太郎"},{"name":"鵜川 真実"},{"name":"安藤 英紀"},{"name":"藏田 靖子"},{"name":"石田 竜弘"}]},"description":{"en":"Despite the clinical introduction of a vast number of polyethylene glycol (PEG)-conjugated therapeutics, conjugated PEG is also known for an unfortunate inclination toward immunogenicity. Immunogenicity of PEG, manifested by the robust production of anti-PEG IgM, is known to compromise the therapeutic efficacy and/or reduce the tolerance of PEGylated therapeutics. In the present study, we inserted ganglioside into the membrane of PEGylated liposome (PL) to prepare ganglioside-modified PEGylated liposomes (G-PL), and investigated its efficacy in attenuating the anti-PEG IgM response against PL. A single intravenous injection of G-PL significantly attenuated the anti-PEG IgM production, compared with that of naïve PL. In addition, pretreatment with G-PL substantially alleviated the anti-PEG IgM response elicited by a subsequent dose of PL, presumably via inducing B cell tolerance, and as a consequence, this modification abrogated/attenuated the incidence of the rapid clearance of subsequently administrated PL. These results indicate that incorporating gangliosides in PEGylated liposome membrane not only prevents the immunogenicity of PEG but also induces the tolerance of B cells to subsequent doses of the immunogenic PL. Consequently, liposomal membrane modification with ganglioside might represent a promising approach to attenuating the immunogenicity of PEGylated liposomes while preserving their therapeutic efficacy, particularly upon repeated administration.","ja":"Despite the clinical introduction of a vast number of polyethylene glycol (PEG)-conjugated therapeutics, conjugated PEG is also known for an unfortunate inclination toward immunogenicity. Immunogenicity of PEG, manifested by the robust production of anti-PEG IgM, is known to compromise the therapeutic efficacy and/or reduce the tolerance of PEGylated therapeutics. In the present study, we inserted ganglioside into the membrane of PEGylated liposome (PL) to prepare ganglioside-modified PEGylated liposomes (G-PL), and investigated its efficacy in attenuating the anti-PEG IgM response against PL. A single intravenous injection of G-PL significantly attenuated the anti-PEG IgM production, compared with that of naïve PL. In addition, pretreatment with G-PL substantially alleviated the anti-PEG IgM response elicited by a subsequent dose of PL, presumably via inducing B cell tolerance, and as a consequence, this modification abrogated/attenuated the incidence of the rapid clearance of subsequently administrated PL. These results indicate that incorporating gangliosides in PEGylated liposome membrane not only prevents the immunogenicity of PEG but also induces the tolerance of B cells to subsequent doses of the immunogenic PL. Consequently, liposomal membrane modification with ganglioside might represent a promising approach to attenuating the immunogenicity of PEGylated liposomes while preserving their therapeutic efficacy, particularly upon repeated administration."},"publication_date":"2017-03-28","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.250","starting_page":"20","ending_page":"26","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2017.01.040"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:94, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507502"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115155","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27822036","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=320421","label":"url"}],"paper_title":{"en":"Improvement of intratumor microdistribution of PEGylated liposome via tumor priming by metronomic S-1 dosing","ja":"Improvement of intratumor microdistribution of PEGylated liposome via tumor priming by metronomic S-1 dosing"},"authors":{"en":[{"name":"Doi Yusuke"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Matsumoto Haruna"},{"name":"Okada Tomoko"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"土井 祐輔"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"松本 春菜"},{"name":"岡田 知子"},{"name":"清水 太郎"},{"name":"石田 竜弘"}]},"description":{"en":"The efficient delivery of nanocarrier-based cancer therapeutics into tumor tissue is problematic. Structural abnormalities, tumor vasculature heterogeneity, and elevated intratumor pressure impose barriers against the preferential accumulation of nanocarrier-based cancer therapeutics within tumor tissues and, consequently, compromise their therapeutic efficacy. Recently, we have reported that metronomic S-1, orally available tegafur formulation, dosing synergistically augmented the therapeutic efficacy of oxaliplatin (l-OHP)-containing PEGylated liposome without increasing the toxicity in animal model. However, the exact mechanism behind such synergistic effect was not fully elucidated. In this study, therefore, we tried to shed the light on the contributions of metronomic S-1 dosing to the enhanced accumulation and/or spatial distribution of PEGylated liposome within tumor tissue. Tumor priming with metronomic S-1 treatment induced a potent apoptotic response against both angiogenic endothelial cells and tumor cells adjacent to tumor blood vessels, resulting in enhanced tumor blood flow via transient normalization of tumor vasculature, along with alleviation of intratumor pressure. Such a change in the tumor microenvironment imparted by S-1 treatment allows efficient delivery of PEGylated liposome to tumor tissue and permits their deep penetration/distribution into the tumor mass. Such a priming effect of S-1 dosing can be exploited as a promising strategy to enhance the therapeutic efficacy of nanocarrier-based cancer therapeutics suffering from inadequate/heterogeneous delivery to tumor tissues.","ja":"The efficient delivery of nanocarrier-based cancer therapeutics into tumor tissue is problematic. Structural abnormalities, tumor vasculature heterogeneity, and elevated intratumor pressure impose barriers against the preferential accumulation of nanocarrier-based cancer therapeutics within tumor tissues and, consequently, compromise their therapeutic efficacy. Recently, we have reported that metronomic S-1, orally available tegafur formulation, dosing synergistically augmented the therapeutic efficacy of oxaliplatin (l-OHP)-containing PEGylated liposome without increasing the toxicity in animal model. However, the exact mechanism behind such synergistic effect was not fully elucidated. In this study, therefore, we tried to shed the light on the contributions of metronomic S-1 dosing to the enhanced accumulation and/or spatial distribution of PEGylated liposome within tumor tissue. Tumor priming with metronomic S-1 treatment induced a potent apoptotic response against both angiogenic endothelial cells and tumor cells adjacent to tumor blood vessels, resulting in enhanced tumor blood flow via transient normalization of tumor vasculature, along with alleviation of intratumor pressure. Such a change in the tumor microenvironment imparted by S-1 treatment allows efficient delivery of PEGylated liposome to tumor tissue and permits their deep penetration/distribution into the tumor mass. Such a priming effect of S-1 dosing can be exploited as a promising strategy to enhance the therapeutic efficacy of nanocarrier-based cancer therapeutics suffering from inadequate/heterogeneous delivery to tumor tissues."},"publication_date":"2016-10-25","publication_name":{"en":"International Journal of Nanomedicine","ja":"International Journal of Nanomedicine"},"volume":"Vol.11","starting_page":"5573","ending_page":"5582","languages":["eng"],"referee":true,"identifiers":{"doi":["10.2147/IJN.S119069"],"issn":["1178-2013"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:95, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507503"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27666483","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84989831563&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=325118","label":"url"}],"paper_title":{"en":"Human serum albumin hydropersulfide is a potent reactive oxygen species scavenger in oxidative stress conditions such as chronic kidney disease","ja":"Human serum albumin hydropersulfide is a potent reactive oxygen species scavenger in oxidative stress conditions such as chronic kidney disease"},"authors":{"en":[{"name":"Shibata Akitomo"},{"name":"Ishima Yu"},{"name":"Ikeda Mayumi"},{"name":"Sato Hirokazu"},{"name":"Imafuku Tadashi"},{"name":"Chuang T. G. Victor"},{"name":"Ouchi Yuya"},{"name":"Abe Takaya"},{"name":"Watanabe Hiroshi"},{"name":"Ishida Tatsuhiro"},{"name":"Otagiri Masaki"},{"name":"Maruyama Toru"}],"ja":[{"name":"Shibata Akitomo"},{"name":"異島 優"},{"name":"池田 真由美"},{"name":"Sato Hirokazu"},{"name":"Imafuku Tadashi"},{"name":"Chuang T. G. Victor"},{"name":"Ouchi Yuya"},{"name":"Abe Takaya"},{"name":"Watanabe Hiroshi"},{"name":"石田 竜弘"},{"name":"Otagiri Masaki"},{"name":"Maruyama Toru"}]},"description":{"en":"Recently, hydropersulfide (RSSH) was found to exist in mammalian tissues and fluids. Cysteine hydropersulfide can be found in free cysteine residues as well as in proteins, and it has potent antioxidative activity. Human serum albumin (HSA) is the most abundant protein in mammalian serum. HSA possesses a free thiol group in Cys-34 that could be a site for hydropersulfide formation. HSA hydropersulfide of high purity as a positive control was prepared by treatment of HSA with Na2S. The presence of HSA hydropersulfide was confirmed by spectroscopy and ESI-TOFMS analysis where molecular weights of HSA hydropersulfide by increments of approximately 32 Da (Sulfur atom) were detected. The fluorescent probe results showed that Alexa Fluor 680 conjugated maleimide (Red-Mal) was a suitable assay and bromotrimethylammoniumbimane bromide appeared to be a selective reagent for hydropersulfide. The effect of oxidative stress related disease on the existence of albumin hydropersulfides was examined in rat 5/6 nephrectomy model of chronic kidney disease (CKD). Interestingly, the level of hydropersulfides in rat 5/6 nephrectomy model serum was decreased by a uremic toxin that increases oxidative stress in rat 5/6 nephrectomy model. Furthermore, we demonstrated that the levels of HSA hydropersulfide in human subjects were reduced in CKD but restored by hemodialysis using Red-Mal assay. We conclude that HSA hydropersulfide could potentially play an important role in biological anti-oxidative defense, and it is a promising diagnostic and therapeutic marker of oxidative diseases.","ja":"Recently, hydropersulfide (RSSH) was found to exist in mammalian tissues and fluids. Cysteine hydropersulfide can be found in free cysteine residues as well as in proteins, and it has potent antioxidative activity. Human serum albumin (HSA) is the most abundant protein in mammalian serum. HSA possesses a free thiol group in Cys-34 that could be a site for hydropersulfide formation. HSA hydropersulfide of high purity as a positive control was prepared by treatment of HSA with Na2S. The presence of HSA hydropersulfide was confirmed by spectroscopy and ESI-TOFMS analysis where molecular weights of HSA hydropersulfide by increments of approximately 32 Da (Sulfur atom) were detected. The fluorescent probe results showed that Alexa Fluor 680 conjugated maleimide (Red-Mal) was a suitable assay and bromotrimethylammoniumbimane bromide appeared to be a selective reagent for hydropersulfide. The effect of oxidative stress related disease on the existence of albumin hydropersulfides was examined in rat 5/6 nephrectomy model of chronic kidney disease (CKD). Interestingly, the level of hydropersulfides in rat 5/6 nephrectomy model serum was decreased by a uremic toxin that increases oxidative stress in rat 5/6 nephrectomy model. Furthermore, we demonstrated that the levels of HSA hydropersulfide in human subjects were reduced in CKD but restored by hemodialysis using Red-Mal assay. We conclude that HSA hydropersulfide could potentially play an important role in biological anti-oxidative defense, and it is a promising diagnostic and therapeutic marker of oxidative diseases."},"publication_date":"2016-10-21","publication_name":{"en":"Biochemical and Biophysical Research Communications","ja":"Biochemical and Biophysical Research Communications"},"volume":"Vol.479","number":"No.3","starting_page":"578","ending_page":"583","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.bbrc.2016.09.113"],"issn":["0006-291X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:96, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507504"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115599","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27740765","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=320933","label":"url"}],"paper_title":{"en":"Systemically administered RNAi molecule sensitizes malignant pleural mesothelioma cells to pemetrexed therapy","ja":"Systemically administered RNAi molecule sensitizes malignant pleural mesothelioma cells to pemetrexed therapy"},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Fukushima, M."},{"name":"Huang, C."},{"name":"Wada, H"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Fukushima, M."},{"name":"Huang, C."},{"name":"Wada, H"},{"name":"石田 竜弘"}]},"description":{"en":"Pemetrexed (PMX) is a key drug for the management of malignant pleural mesothelioma (MPM). However, its therapeutic efficacy is cruelly restricted in many clinical settings by the overexpression of thymidylate synthase (TS) gene. Recently, we emphasized the efficacy of locally administered shRNA designed against TS gene in enhancing the cytotoxic effect of PMX against orthotopically implanted MPM cells in tumor xenograft tumor model. Herein, we explored the efficiency of systemic, rather than local, delivery of TS RNAi molecule in sensitizing MPM cells to the cytotoxic effect of PMX. We here designed a PEG-coated TS shRNA-lipoplex (PEG-coated TS shRNA-lipoplex) for systemic injection. PEG modification efficiently delivered TS shRNA in the lipoplex to tumor tissue following intravenous administration as indicated by a significant suppression of TS expression level in tumor tissue. In addition, the combined treatment of PMX with systemic injection of PEG-coated TS shRNA-lipoplex exerted a potent antitumor activity in a s.c. xenograft tumor model, compared to a single treatment with either PMX or PEG-coated TS shRNA-lipoplex. Metastasis, or the spread, of mesothelioma substantially dedicates the effectiveness of treatment options. The systemic, in addition to local, delivery of tumor targeted anti-TS RNAi system we propose in this study might be an effective option to extend the clinical utility of PMX in treating malignant mesothelioma.","ja":"Pemetrexed (PMX) is a key drug for the management of malignant pleural mesothelioma (MPM). However, its therapeutic efficacy is cruelly restricted in many clinical settings by the overexpression of thymidylate synthase (TS) gene. Recently, we emphasized the efficacy of locally administered shRNA designed against TS gene in enhancing the cytotoxic effect of PMX against orthotopically implanted MPM cells in tumor xenograft tumor model. Herein, we explored the efficiency of systemic, rather than local, delivery of TS RNAi molecule in sensitizing MPM cells to the cytotoxic effect of PMX. We here designed a PEG-coated TS shRNA-lipoplex (PEG-coated TS shRNA-lipoplex) for systemic injection. PEG modification efficiently delivered TS shRNA in the lipoplex to tumor tissue following intravenous administration as indicated by a significant suppression of TS expression level in tumor tissue. In addition, the combined treatment of PMX with systemic injection of PEG-coated TS shRNA-lipoplex exerted a potent antitumor activity in a s.c. xenograft tumor model, compared to a single treatment with either PMX or PEG-coated TS shRNA-lipoplex. Metastasis, or the spread, of mesothelioma substantially dedicates the effectiveness of treatment options. The systemic, in addition to local, delivery of tumor targeted anti-TS RNAi system we propose in this study might be an effective option to extend the clinical utility of PMX in treating malignant mesothelioma."},"publication_date":"2016-10-14","publication_name":{"en":"Molecular Pharmaceutics","ja":"Molecular Pharmaceutics"},"volume":"Vol.13","number":"No.11","starting_page":"3955","ending_page":"3963","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acs.molpharmaceut.6b00728"],"issn":["1543-8392"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:97, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507505"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27582335","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84984698994&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=314203","label":"url"}],"paper_title":{"en":"Hydrodynamic tail vein injection as a simple tool for yielding extended transgene expression in solid tumors.","ja":"Hydrodynamic tail vein injection as a simple tool for yielding extended transgene expression in solid tumors."},"authors":{"en":[{"name":"Takayama Takuma"},{"name":"Ukawa Masami"},{"name":"Kanazawa Yuki"},{"name":"ANDO Hidenori"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"髙山 拓磨"},{"name":"鵜川 真実"},{"name":"金沢 有希"},{"name":"安藤 英紀"},{"name":"清水 太郎"},{"name":"石田 竜弘"}]},"description":{"en":"Hydrodynamic tail vein injection was considered an in vivo transfection method that yields a higher level of gene expression mainly in the liver. This method has been applied to cancer gene therapy targeting both hepatic and non-hepatic cancers. However, intratumor transgene expression in non-hepatic tumors has not been well studied. In this study, we showed an extended transgene expression of -galactosidase (LacZ), a nonsecretory protein, in a subcutaneously implanted murine solid tumor following the hydrodynamic injection of plasmid DNA (LacZ pDNA). Our result may indicate that the hydrodynamic injection method is a powerful tool that can be used to gain transgene expression not only in the liver but also in solid tumors.","ja":"Hydrodynamic tail vein injection was considered an in vivo transfection method that yields a higher level of gene expression mainly in the liver. This method has been applied to cancer gene therapy targeting both hepatic and non-hepatic cancers. However, intratumor transgene expression in non-hepatic tumors has not been well studied. In this study, we showed an extended transgene expression of -galactosidase (LacZ), a nonsecretory protein, in a subcutaneously implanted murine solid tumor following the hydrodynamic injection of plasmid DNA (LacZ pDNA). Our result may indicate that the hydrodynamic injection method is a powerful tool that can be used to gain transgene expression not only in the liver but also in solid tumors."},"publication_date":"2016-09-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.39","number":"No.9","starting_page":"1555","ending_page":"1558","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b16-00283"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:98, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507506"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115101","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26945484","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=310610","label":"url"}],"paper_title":{"en":"Lidocaine self-sacrificially improves the skin permeation of the acidic and poorly water-soluble drug etodolac via its transformation into an ionic liquid","ja":"Lidocaine self-sacrificially improves the skin permeation of the acidic and poorly water-soluble drug etodolac via its transformation into an ionic liquid"},"authors":{"en":[{"name":"Miwa, Y"},{"name":"Hamamoto H"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Miwa, Y"},{"name":"Hamamoto H"},{"name":"石田 竜弘"}]},"description":{"en":"Poor transdermal penetration of active pharmaceutical ingredients (APIs) impairs both bioavailability and therapeutic benefits and is a major challenge in the development of transdermal drug delivery systems. Here, we transformed a poorly water-soluble drug, etodolac, into an ionic liquid in order to improve its hydrophobicity, hydrophilicity and skin permeability. The ionic liquid was prepared by mixing etodolac with lidocaine (1:1, mol/mol). Both the free drug and the transformed ionic liquid were characterized by differential scanning colorimetry (DSC), infrared spectroscopy (IR), and saturation concentration measurements. In addition, in vitro skin-permeation testing was carried out via an ionic liquid-containing patch (Etoreat patch). The lidocaine and etodolac in ionic liquid form led to a relatively lower melting point than either lidocaine or etodolac alone, and this improved the lipophilicity/hydrophilicity of etodolac. In vitro skin-permeation testing demonstrated that the Etoreat patch significantly increased the skin permeation of etodolac (9.3-fold) compared with an etodolac alone patch, although an Etoreat patch did not increase the skin permeation of lidocaine, which was consistent with the results when using a lidocaine alone patch. Lidocaine appeared to self-sacrificially improve the skin permeation of etodolac via its transformation into an ionic liquid. The data suggest that ionic liquids composed of approved drugs may substantially expand the formulation preparation method to meet the challenges of drugs which are characterized by poor rates of transdermal absorption.","ja":"Poor transdermal penetration of active pharmaceutical ingredients (APIs) impairs both bioavailability and therapeutic benefits and is a major challenge in the development of transdermal drug delivery systems. Here, we transformed a poorly water-soluble drug, etodolac, into an ionic liquid in order to improve its hydrophobicity, hydrophilicity and skin permeability. The ionic liquid was prepared by mixing etodolac with lidocaine (1:1, mol/mol). Both the free drug and the transformed ionic liquid were characterized by differential scanning colorimetry (DSC), infrared spectroscopy (IR), and saturation concentration measurements. In addition, in vitro skin-permeation testing was carried out via an ionic liquid-containing patch (Etoreat patch). The lidocaine and etodolac in ionic liquid form led to a relatively lower melting point than either lidocaine or etodolac alone, and this improved the lipophilicity/hydrophilicity of etodolac. In vitro skin-permeation testing demonstrated that the Etoreat patch significantly increased the skin permeation of etodolac (9.3-fold) compared with an etodolac alone patch, although an Etoreat patch did not increase the skin permeation of lidocaine, which was consistent with the results when using a lidocaine alone patch. Lidocaine appeared to self-sacrificially improve the skin permeation of etodolac via its transformation into an ionic liquid. The data suggest that ionic liquids composed of approved drugs may substantially expand the formulation preparation method to meet the challenges of drugs which are characterized by poor rates of transdermal absorption."},"publication_date":"2016-05","publication_name":{"en":"European Journal of Pharmaceutics and Biopharmaceutics","ja":"European Journal of Pharmaceutics and Biopharmaceutics"},"volume":"Vol.102","starting_page":"92","ending_page":"100","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ejpb.2016.03.003"],"issn":["1873-3441"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:99, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507507"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26847426","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=306286","label":"url"}],"paper_title":{"en":"Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model","ja":"Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model"},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Katoh Chihiro"},{"name":"Fukushima M"},{"name":"Huang C"},{"name":"Wada H"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"加藤 千尋"},{"name":"Fukushima M"},{"name":"Huang C"},{"name":"Wada H"},{"name":"石田 竜弘"}]},"description":{"en":"Malignant pleural mesothelioma (MPM) is an incurable cancer with an increasing incidence. Currently, pemetrexed (PMX)-based chemotherapy is the mainstay of chemotherapy for MPM, however, the outcome of PMX-based chemotherapy in patients with MPM is dismal. RNA interference (RNAi) technology has been considered as an effective tool to substantially enhance the therapeutic efficacy of chemotherapeutic agents in many preclinical and clinical settings. In this study, therefore, we investigated whether non-viral anti-thymidylate synthase RNAi embedded liposome (TS shRNA lipoplex) would effectively guide the downregulation of TS in human malignant mesothelioma MSTO-211H cells. Consequently, it enhanced the antitumor effect of PMX both in vitro and in vivo. TS shRNA effectively enhanced the in vitro cell growth inhibition upon treatment with PMX via downregulating TS expression in the MSTO-211H cell line. In in vivo orthotopic tumor model, the combined treatment of PMX and TS shRNA lipoplex efficiently combated the progression of orthotopic thoracic tumors and as a result prolonged mouse survival, compared to each single treatment. Our findings emphasize the pivotal relevance of RNAi as an effective tool for increasing the therapeutic efficacy of PMX, a cornerstone in the treatment regimens of MPM, and thereby, raising the possibility for the development of a novel therapeutic strategy, combination therapy of TS-shRNA and PMX, that can surpass many of the currently applied, but less effective, therapeutic regimens against lethal MPM.","ja":"Malignant pleural mesothelioma (MPM) is an incurable cancer with an increasing incidence. Currently, pemetrexed (PMX)-based chemotherapy is the mainstay of chemotherapy for MPM, however, the outcome of PMX-based chemotherapy in patients with MPM is dismal. RNA interference (RNAi) technology has been considered as an effective tool to substantially enhance the therapeutic efficacy of chemotherapeutic agents in many preclinical and clinical settings. In this study, therefore, we investigated whether non-viral anti-thymidylate synthase RNAi embedded liposome (TS shRNA lipoplex) would effectively guide the downregulation of TS in human malignant mesothelioma MSTO-211H cells. Consequently, it enhanced the antitumor effect of PMX both in vitro and in vivo. TS shRNA effectively enhanced the in vitro cell growth inhibition upon treatment with PMX via downregulating TS expression in the MSTO-211H cell line. In in vivo orthotopic tumor model, the combined treatment of PMX and TS shRNA lipoplex efficiently combated the progression of orthotopic thoracic tumors and as a result prolonged mouse survival, compared to each single treatment. Our findings emphasize the pivotal relevance of RNAi as an effective tool for increasing the therapeutic efficacy of PMX, a cornerstone in the treatment regimens of MPM, and thereby, raising the possibility for the development of a novel therapeutic strategy, combination therapy of TS-shRNA and PMX, that can surpass many of the currently applied, but less effective, therapeutic regimens against lethal MPM."},"publication_date":"2016-04","publication_name":{"en":"International Journal of Oncology","ja":"International Journal of Oncology"},"volume":"Vol.48","number":"No.4","starting_page":"1399","ending_page":"1407","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3892/ijo.2016.3367"],"issn":["1791-2423"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:100, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507508"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26830481","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84958964867&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=305484","label":"url"}],"paper_title":{"en":"Hepatic tumor metastases cause enhanced PEGylated liposome uptake by Kupffer cells","ja":"Hepatic tumor metastases cause enhanced PEGylated liposome uptake by Kupffer cells"},"authors":{"en":[{"name":"Ukawa Masami"},{"name":"Fujiwara Yukako"},{"name":"ANDO Hidenori"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"鵜川 真実"},{"name":"藤原 由佳子"},{"name":"安藤 英紀"},{"name":"清水 太郎"},{"name":"石田 竜弘"}]},"description":{"en":"Kupffer cells in livers bearing tumor metastases were found to have promoted tumor invasion and exacerbated the metastasis. This implies that the function of Kupffer cells might differ between animals bearing hepatic metastases and those that are healthy. Kupffer cells are considered responsible for the accumulation of liposomes in the liver. In this study, we hypothesized that the alteration in the function of Kupffer cells by hepatic metastasis would also affect the biodistribution of liposomes following intravenous administration. The hepatic accumulation and the blood concentration of PEGylated liposomes were compared between healthy mice and tumor-bearing mice. We noted that hepatic accumulation and elimination from the blood were significantly accelerated in tumor-bearing mice, indicating that our hypothesis was correct. In the tumor-bearing mice, the proportion of Kupffer cells taking up liposomes was significantly increased. Intravenous injection of oxaliplatin (l-OHP) containing PEGylated liposomes decreased the fraction of Kupffer cells, but this administration caused no injury to the hepatocytes. These results suggest that PEGylated liposomes containing l-OHP may have the potential to treat metastatic hepatic cancer-not only via the direct killing of the cancer cells but also via a reduction in tumor-supportive Kupffer cells.","ja":"Kupffer cells in livers bearing tumor metastases were found to have promoted tumor invasion and exacerbated the metastasis. This implies that the function of Kupffer cells might differ between animals bearing hepatic metastases and those that are healthy. Kupffer cells are considered responsible for the accumulation of liposomes in the liver. In this study, we hypothesized that the alteration in the function of Kupffer cells by hepatic metastasis would also affect the biodistribution of liposomes following intravenous administration. The hepatic accumulation and the blood concentration of PEGylated liposomes were compared between healthy mice and tumor-bearing mice. We noted that hepatic accumulation and elimination from the blood were significantly accelerated in tumor-bearing mice, indicating that our hypothesis was correct. In the tumor-bearing mice, the proportion of Kupffer cells taking up liposomes was significantly increased. Intravenous injection of oxaliplatin (l-OHP) containing PEGylated liposomes decreased the fraction of Kupffer cells, but this administration caused no injury to the hepatocytes. These results suggest that PEGylated liposomes containing l-OHP may have the potential to treat metastatic hepatic cancer-not only via the direct killing of the cancer cells but also via a reduction in tumor-supportive Kupffer cells."},"publication_date":"2016-02-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.39","number":"No.2","starting_page":"215","ending_page":"220","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b15-00611"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:101, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507509"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/110894","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26730811","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84953792236&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=305323","label":"url"}],"paper_title":{"en":"Gene silencing using 4'-thioDNA as an artificial template to synthesize short-hairpin RNA without inducing a detectable innate immune response","ja":"Gene silencing using 4'-thioDNA as an artificial template to synthesize short-hairpin RNA without inducing a detectable innate immune response"},"authors":{"en":[{"name":"Saito-Tarashima Noriko"},{"name":"ANDO Hidenori"},{"name":"Kojima Takamitsu"},{"name":"Kinjo Nozomi"},{"name":"Hashimoto Yosuke"},{"name":"Furukawa Kazuhiro"},{"name":"Ishida Tatsuhiro"},{"name":"Minakawa Noriaki"}],"ja":[{"name":"田良島 典子"},{"name":"安藤 英紀"},{"name":"小島 孝允"},{"name":"金城 望"},{"name":"橋本 洋佑"},{"name":"古川 和寛"},{"name":"石田 竜弘"},{"name":"南川 典昭"}]},"description":{"en":"The development of a versatile technique to induce RNA interference (RNAi) without immune stimulation in vivo is of interest as existing approaches to trigger RNAi, such as small interfering RNA (siRNA) and plasmid DNA (pDNA) expressing short hairpin RNA (shRNA), present drawbacks arising from innate immune stimulation. To overcome them, an intelligent shRNA expression device (iRed) designed to induce RNAi was developed. The minimum sequence of iRed encodes only the U6 promoter and shRNA. A series of iRed comprises a polymerase chain reaction (PCR)-amplified 4'-thioDNA in which any one type of adenine (A), guanine (G), cytosine (C), or thymine (T) nucleotide unit was substituted by each cognate 4'-thio derivatives, i.e., dSA iRed, dSG iRed, dSC iRed, and ST iRed respectively. Each modified iRed acted as a template to transcribe shRNA with RNAi activity. The highest shRNA yield was generated using dSC iRed that exerted gene silencing activity in an orthotopic mouse model of mesothelioma. Reducing the minimal structure required to transcribe shRNA and the presence of the 4'-thiomodification synergistically function to abrogate innate immune response induced by dsDNA. The iRed will introduce a new approach to induce RNAi without inducing a detectable innate immune response.","ja":"The development of a versatile technique to induce RNA interference (RNAi) without immune stimulation in vivo is of interest as existing approaches to trigger RNAi, such as small interfering RNA (siRNA) and plasmid DNA (pDNA) expressing short hairpin RNA (shRNA), present drawbacks arising from innate immune stimulation. To overcome them, an intelligent shRNA expression device (iRed) designed to induce RNAi was developed. The minimum sequence of iRed encodes only the U6 promoter and shRNA. A series of iRed comprises a polymerase chain reaction (PCR)-amplified 4'-thioDNA in which any one type of adenine (A), guanine (G), cytosine (C), or thymine (T) nucleotide unit was substituted by each cognate 4'-thio derivatives, i.e., dSA iRed, dSG iRed, dSC iRed, and ST iRed respectively. Each modified iRed acted as a template to transcribe shRNA with RNAi activity. The highest shRNA yield was generated using dSC iRed that exerted gene silencing activity in an orthotopic mouse model of mesothelioma. Reducing the minimal structure required to transcribe shRNA and the presence of the 4'-thiomodification synergistically function to abrogate innate immune response induced by dsDNA. The iRed will introduce a new approach to induce RNAi without inducing a detectable innate immune response."},"publication_date":"2016-02","publication_name":{"en":"Molecular Therapy. Nucleic Acids","ja":"Molecular Therapy. Nucleic Acids"},"volume":"Vol.5","starting_page":"e274","ending_page":"e274","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/mtna.2015.48"],"issn":["2162-2531"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:102, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507510"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26415830","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=304493","label":"url"}],"paper_title":{"en":"Encapsulation in a rapid-release liposomal formulation enhances the anti-tumor efficacy of pemetrexed in a murine solid mesothelioma-xenograft model","ja":"Encapsulation in a rapid-release liposomal formulation enhances the anti-tumor efficacy of pemetrexed in a murine solid mesothelioma-xenograft model"},"authors":{"en":[{"name":"Essam Eldin N"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Kawazoe Kazuyoshi"},{"name":"Elnahas H M"},{"name":"Mahdy M A"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Essam Eldin N"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"川添 和義"},{"name":"Elnahas H M"},{"name":"Mahdy M A"},{"name":"石田 竜弘"}]},"description":{"en":"We recently developed a PEG-coated liposome encapsulating the anti-folate drug pemetrexed (PMX). Such liposomal formulations have shown potent cytotoxic effects against malignant pleural mesothelioma (MPM) cells in vitro. In the present study, we investigated the pharmacokinetics, bio-distribution and in vivo anti-tumor efficacy of two liposomal PMX formulations with different drug release rates in a murine mesothelioma-xenograft model. Liposomes with different PMX release rates were prepared via manipulating liposomal membrane fluidity through incorporating either a solid-phase (HSPC) or a fluid-phase (POPC) phospholipid. Both liposomal PMX formulations showed prolonged plasma pharmacokinetics and were accumulated to a similar extent in tumors and other tissues, presumably, due to surface modification with polyethylene glycol (PEG). In a murine mesothelioma-xenograft model, interestingly, PMX encapsulated in a fast-release POPC liposome produced superior tumor growth suppression compared with either free PMX or PMX encapsulated in a slow-release HSPC liposome. Such in vivo anti-tumor efficacy was accomplished mainly by a potent induction of apoptosis within tumor tissue by the released PMX from POPC liposomes. Our results clearly emphasize the therapeutic efficacy of liposomal PMX over free PMX in conquering aggressive solid tumors such as malignant mesothelioma. A guarantee of the targeted delivery of PMX to tumor cells helps overcome some of the major shortcomings encountered with the use of free PMX.","ja":"We recently developed a PEG-coated liposome encapsulating the anti-folate drug pemetrexed (PMX). Such liposomal formulations have shown potent cytotoxic effects against malignant pleural mesothelioma (MPM) cells in vitro. In the present study, we investigated the pharmacokinetics, bio-distribution and in vivo anti-tumor efficacy of two liposomal PMX formulations with different drug release rates in a murine mesothelioma-xenograft model. Liposomes with different PMX release rates were prepared via manipulating liposomal membrane fluidity through incorporating either a solid-phase (HSPC) or a fluid-phase (POPC) phospholipid. Both liposomal PMX formulations showed prolonged plasma pharmacokinetics and were accumulated to a similar extent in tumors and other tissues, presumably, due to surface modification with polyethylene glycol (PEG). In a murine mesothelioma-xenograft model, interestingly, PMX encapsulated in a fast-release POPC liposome produced superior tumor growth suppression compared with either free PMX or PMX encapsulated in a slow-release HSPC liposome. Such in vivo anti-tumor efficacy was accomplished mainly by a potent induction of apoptosis within tumor tissue by the released PMX from POPC liposomes. Our results clearly emphasize the therapeutic efficacy of liposomal PMX over free PMX in conquering aggressive solid tumors such as malignant mesothelioma. A guarantee of the targeted delivery of PMX to tumor cells helps overcome some of the major shortcomings encountered with the use of free PMX."},"publication_date":"2016-01-01","publication_name":{"en":"European Journal of Pharmaceutical Sciences","ja":"European Journal of Pharmaceutical Sciences"},"volume":"Vol.81","starting_page":"60","ending_page":"66","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ejps.2015.09.015"],"issn":["1879-0720"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:103, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507511"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26548975","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84946716430&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=305316","label":"url"}],"paper_title":{"en":"Intra-tumor distribution of PEGylated liposome upon repeated injection: No possession by prior dose","ja":"Intra-tumor distribution of PEGylated liposome upon repeated injection: No possession by prior dose"},"authors":{"en":[{"name":"Nakamura Hiroyuki"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Nishio Miho"},{"name":"Tanaka Masao"},{"name":"ANDO Hidenori"},{"name":"Kiwada Hiroshi"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"中村 浩之"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"西尾 美穂"},{"name":"田中 真生"},{"name":"安藤 英紀"},{"name":"際田 弘志"},{"name":"石田 竜弘"}]},"description":{"en":"Liposomes have proven to be a viable means for the delivery of chemotherapeutic agents to solid tumors. However, significant variability has been detected in their intra-tumor accumulation and distribution, resulting in compromised therapeutic outcomes. We recently examined the intra-tumor accumulation and distribution of weekly sequentially administered oxaliplatin (l-OHP)-containing PEGylated liposomes. In that study, the first and second doses of l-OHP-containing PEGylated liposomes were distributed diversely and broadly within tumor tissues, resulting in a potent anti-tumor efficacy. However, little is known about the mechanism underlying such a diverse and broad liposome distribution. Therefore, in the present study, we investigated the influence of dosage interval on the intra-tumor accumulation and distribution of \"empty\" PEGylated liposomes. Intra-tumor distribution of sequentially administered \"empty\" PEGylated liposomes was altered in a dosing interval-dependent manner. In addition, the intra-tumor distribution pattern was closely related to the chronological alteration of tumor blood flow as well as vascular permeability in the growing tumor tissue. These results suggest that the sequential administrations of PEGylated liposomes in well-spaced intervals might allow the distribution to different areas and enhance the total bulk accumulation within tumor tissue, resulting in better therapeutic efficacy of the encapsulated payload. This study may provide useful information for a better design of therapeutic regimens involving multiple administrations of nanocarrier drug delivery systems.","ja":"Liposomes have proven to be a viable means for the delivery of chemotherapeutic agents to solid tumors. However, significant variability has been detected in their intra-tumor accumulation and distribution, resulting in compromised therapeutic outcomes. We recently examined the intra-tumor accumulation and distribution of weekly sequentially administered oxaliplatin (l-OHP)-containing PEGylated liposomes. In that study, the first and second doses of l-OHP-containing PEGylated liposomes were distributed diversely and broadly within tumor tissues, resulting in a potent anti-tumor efficacy. However, little is known about the mechanism underlying such a diverse and broad liposome distribution. Therefore, in the present study, we investigated the influence of dosage interval on the intra-tumor accumulation and distribution of \"empty\" PEGylated liposomes. Intra-tumor distribution of sequentially administered \"empty\" PEGylated liposomes was altered in a dosing interval-dependent manner. In addition, the intra-tumor distribution pattern was closely related to the chronological alteration of tumor blood flow as well as vascular permeability in the growing tumor tissue. These results suggest that the sequential administrations of PEGylated liposomes in well-spaced intervals might allow the distribution to different areas and enhance the total bulk accumulation within tumor tissue, resulting in better therapeutic efficacy of the encapsulated payload. This study may provide useful information for a better design of therapeutic regimens involving multiple administrations of nanocarrier drug delivery systems."},"publication_date":"2015-12-28","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.220","starting_page":"406","ending_page":"413","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2015.11.002"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:104, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507512"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26476173","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84944717805&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=304996","label":"url"}],"paper_title":{"en":"Advanced therapeutic approach for the treatment of malignant pleural mesothelioma via the intrapleural administration of liposomal pemetrexed","ja":"Advanced therapeutic approach for the treatment of malignant pleural mesothelioma via the intrapleural administration of liposomal pemetrexed"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Kobayashi Sakiko"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Essam Eldin N"},{"name":"Katoh Chihiro"},{"name":"Shimizu Taro"},{"name":"Ukawa Masami"},{"name":"Kawazoe Kazuyoshi"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"小林 早紀子"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Essam Eldin N"},{"name":"加藤 千尋"},{"name":"清水 太郎"},{"name":"鵜川 真実"},{"name":"川添 和義"},{"name":"石田 竜弘"}]},"description":{"en":"Malignant pleural mesothelioma (MPM) is an aggressive cancer that proliferates in the pleural cavity. Pemetrexed (PMX) in combination with cisplatin is currently the approved standard care for MPM, but a dismal response rate persists. Recently, we prepared various liposomal PMX formulations using different lipid compositions and evaluated their in vitro cytotoxicity against human mesothelioma cells (MSTO-211H). In the present study, we investigated the in vivo therapeutic effect of our liposomal PMX formulations using an orthotopic MPM tumor mouse model. PMX encapsulated within either cholesterol-containing (PMX/Chol CL) or cholesterol-free (PMX/Non-Chol CL) cationic liposome was intrapleurally injected into tumor-bearing mice. PMX encapsulated in cholesterol-free liposomes (PMX/Non-Chol CL) drastically inhibited the tumor growth in the pleural cavity, while free PMX and PMX encapsulated in cholesterol-containing liposomes (PMX/Chol CL) barely inhibited the tumor growth. The enhanced in vivo anti-tumor efficacy of PMX/Non-Chol CL was credited, on the one hand, for prolonging the retention of cationic liposomes in the pleural cavity via their electrostatic interaction with the negatively charged membranes of tumor cells, but on the other hand, it was charged with contributing to a higher drug release from the \"fluid\" liposomal membrane following intrapleural administration. This therapeutic strategy of direct intrapleural administration of liposomal PMX, along with the great advances in CL-guided therapeutics, might be a promising therapeutic approach to conquering the poor prognosis for MPM.","ja":"Malignant pleural mesothelioma (MPM) is an aggressive cancer that proliferates in the pleural cavity. Pemetrexed (PMX) in combination with cisplatin is currently the approved standard care for MPM, but a dismal response rate persists. Recently, we prepared various liposomal PMX formulations using different lipid compositions and evaluated their in vitro cytotoxicity against human mesothelioma cells (MSTO-211H). In the present study, we investigated the in vivo therapeutic effect of our liposomal PMX formulations using an orthotopic MPM tumor mouse model. PMX encapsulated within either cholesterol-containing (PMX/Chol CL) or cholesterol-free (PMX/Non-Chol CL) cationic liposome was intrapleurally injected into tumor-bearing mice. PMX encapsulated in cholesterol-free liposomes (PMX/Non-Chol CL) drastically inhibited the tumor growth in the pleural cavity, while free PMX and PMX encapsulated in cholesterol-containing liposomes (PMX/Chol CL) barely inhibited the tumor growth. The enhanced in vivo anti-tumor efficacy of PMX/Non-Chol CL was credited, on the one hand, for prolonging the retention of cationic liposomes in the pleural cavity via their electrostatic interaction with the negatively charged membranes of tumor cells, but on the other hand, it was charged with contributing to a higher drug release from the \"fluid\" liposomal membrane following intrapleural administration. This therapeutic strategy of direct intrapleural administration of liposomal PMX, along with the great advances in CL-guided therapeutics, might be a promising therapeutic approach to conquering the poor prognosis for MPM."},"publication_date":"2015-12-28","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.220","starting_page":"29","ending_page":"36","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2015.10.019"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:105, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507513"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26095176","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84937974851&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=295059","label":"url"}],"paper_title":{"en":"Anti-PEG IgM and complement system are required for the association of second doses of PEGylated liposomes with splenic marginal zone B cells","ja":"Anti-PEG IgM and complement system are required for the association of second doses of PEGylated liposomes with splenic marginal zone B cells"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Mima Yu"},{"name":"Hashimoto Yosuke"},{"name":"Ukawa Masami"},{"name":"ANDO Hidenori"},{"name":"Kiwada Hiroshi"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"美馬 優"},{"name":"橋本 洋佑"},{"name":"鵜川 真実"},{"name":"安藤 英紀"},{"name":"際田 弘志"},{"name":"石田 竜弘"}]},"description":{"en":"The accelerated blood clearance (ABC) phenomenon makes it crucial to use PEGylated liposomes and micelles to deliver drugs. The ABC phenomenon is an immune response against an initial dose of PEGylated liposome, which causes subsequent doses to be rapidly cleared by macrophages in the liver. We recently found that in the early phase of the ABC phenomenon, subsequent doses of PEGylated liposomes were associated with splenic marginal zone (MZ)-B cells and were transported from the MZ to the follicle (FO). In this study, we investigated the underlying mechanisms behind the association of subsequent doses of PEGylated liposomes with MZ-B cells in the spleen. Serum factors, anti-PEG IgM and complement system, were crucial to the association of PEGylated liposomes with MZ-B cells, while the sensitization of MZ-B cells by the first dose of PEGylated liposomes was not significant. It was the complement receptors (CRs) on the MZ-B cells, rather than either the PEG-specific B-cell receptors or the IgM Fc receptors, that were the main contributors to the association between PEGylated liposomes and MZ-B cells. It appeared that anti-PEG IgM would bind to PEGylated liposomes and causes subsequent complement activation, resulting in the formation of immune complexes of PEGylated liposome-anti-PEG IgM-complement. The MZ-B cells then recognized these immune complexes via their CRs. Such an association via CRs might have triggered the transport of the immune complex by MZ-B cells to the FO in the spleen. The information obtained in this study might be useful in the development of an efficient antigen delivery system to usher PEGylated nanoparticles into FO dendritic cells.","ja":"The accelerated blood clearance (ABC) phenomenon makes it crucial to use PEGylated liposomes and micelles to deliver drugs. The ABC phenomenon is an immune response against an initial dose of PEGylated liposome, which causes subsequent doses to be rapidly cleared by macrophages in the liver. We recently found that in the early phase of the ABC phenomenon, subsequent doses of PEGylated liposomes were associated with splenic marginal zone (MZ)-B cells and were transported from the MZ to the follicle (FO). In this study, we investigated the underlying mechanisms behind the association of subsequent doses of PEGylated liposomes with MZ-B cells in the spleen. Serum factors, anti-PEG IgM and complement system, were crucial to the association of PEGylated liposomes with MZ-B cells, while the sensitization of MZ-B cells by the first dose of PEGylated liposomes was not significant. It was the complement receptors (CRs) on the MZ-B cells, rather than either the PEG-specific B-cell receptors or the IgM Fc receptors, that were the main contributors to the association between PEGylated liposomes and MZ-B cells. It appeared that anti-PEG IgM would bind to PEGylated liposomes and causes subsequent complement activation, resulting in the formation of immune complexes of PEGylated liposome-anti-PEG IgM-complement. The MZ-B cells then recognized these immune complexes via their CRs. Such an association via CRs might have triggered the transport of the immune complex by MZ-B cells to the FO in the spleen. The information obtained in this study might be useful in the development of an efficient antigen delivery system to usher PEGylated nanoparticles into FO dendritic cells."},"publication_date":"2015-10","publication_name":{"en":"Immunobiology","ja":"Immunobiology"},"volume":"Vol.220","number":"No.10","starting_page":"1151","ending_page":"1160","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.imbio.2015.06.005"],"issn":["1878-3279"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:106, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507514"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/25196743","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84939520973&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=285506","label":"url"}],"paper_title":{"en":"Comprehensive analysis of PEGylated liposome-asscociated proteins relating to the accelerated blood clearance phenomenon by combination with shotgun analysis and conventional methods","ja":"Comprehensive analysis of PEGylated liposome-asscociated proteins relating to the accelerated blood clearance phenomenon by combination with shotgun analysis and conventional methods"},"authors":{"en":[{"name":"Kawanishi Munehira"},{"name":"Hashimoto Yosuke"},{"name":"Shimizu Taro"},{"name":"Sagawa Ikuko"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"川西 宗平"},{"name":"橋本 洋佑"},{"name":"清水 太郎"},{"name":"Sagawa Ikuko"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"PEGylated liposome, sterically stabilized by polyethylene glycol (PEG), results in reduced recognition of the liposome by the mononuclear phagocyte system. Recently, we reported regarding the accelerated blood clearance (ABC) phenomenon that PEGylated liposome is cleared very rapidly from blood circulation upon repeated injection. Anti-PEG IgM production and subsequent complement activation were crucial in causing the ABC phenomenon. However, there still remains the possibility that unknown plasma factors might affect the fate of PEGylated liposome that is subjected to the ABC phenomenon. A label-free approach to shotgun analysis is a great tool for characterizing proteins in a biological system. In this study, therefore, a shotgun analysis was employed to identify plasma protein bound on PEGylated liposome after the ABC phenomenon was induced in the mouse model. The analysis revealed that immunoglobulin and complement components (C1 and C3) are the major proteins. Subsequent analysis with enzyme-linked immunosorbent assay and Western blotting showed that the immunoglobulin was IgM and that the complement system was mainly activated via an anti-PEG IgM-mediated classical pathway. These results support our earlier assumptions-anti-PEG IgM and complement activation were the major causes of the ABC phenomenon. Our proposed analytical strategy would be expected to provide useful information for the development and design of the nanocarrier drug delivery system.","ja":"PEGylated liposome, sterically stabilized by polyethylene glycol (PEG), results in reduced recognition of the liposome by the mononuclear phagocyte system. Recently, we reported regarding the accelerated blood clearance (ABC) phenomenon that PEGylated liposome is cleared very rapidly from blood circulation upon repeated injection. Anti-PEG IgM production and subsequent complement activation were crucial in causing the ABC phenomenon. However, there still remains the possibility that unknown plasma factors might affect the fate of PEGylated liposome that is subjected to the ABC phenomenon. A label-free approach to shotgun analysis is a great tool for characterizing proteins in a biological system. In this study, therefore, a shotgun analysis was employed to identify plasma protein bound on PEGylated liposome after the ABC phenomenon was induced in the mouse model. The analysis revealed that immunoglobulin and complement components (C1 and C3) are the major proteins. Subsequent analysis with enzyme-linked immunosorbent assay and Western blotting showed that the immunoglobulin was IgM and that the complement system was mainly activated via an anti-PEG IgM-mediated classical pathway. These results support our earlier assumptions-anti-PEG IgM and complement activation were the major causes of the ABC phenomenon. Our proposed analytical strategy would be expected to provide useful information for the development and design of the nanocarrier drug delivery system."},"publication_date":"2015-07","publication_name":{"en":"Biotechnology and Applied Biochemistry","ja":"Biotechnology and Applied Biochemistry"},"volume":"Vol.62","number":"No.4","starting_page":"547","ending_page":"555","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/bab.1291"],"issn":["1470-8744"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:107, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507515"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26070445","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84936758421&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=295313","label":"url"}],"paper_title":{"en":"Anti-PEG IgM is a major contributor to the accelerated blood clearance of polyethylene glycol-conjugated protein","ja":"Anti-PEG IgM is a major contributor to the accelerated blood clearance of polyethylene glycol-conjugated protein"},"authors":{"en":[{"name":"Mima Yu"},{"name":"Hashimoto Yosuke"},{"name":"Shimizu Taro"},{"name":"Kiwada Hiroshi"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"美馬 優"},{"name":"橋本 洋佑"},{"name":"清水 太郎"},{"name":"際田 弘志"},{"name":"石田 竜弘"}]},"description":{"en":"Limited therapeutic efficacy of polyethylene glycol-conjugated (PEGylated) protein drugs has been recently reported in animals and human following repeat injections. Since there are reports that an accelerated blood clearance (ABC) phenomenon is caused by repeated injection of PEGylated liposome, there is an assumption that PEGylated proteins lose their long circulating property when they are injected repeatedly due to the induction of anti-PEG antibody. Although induction of anti-PEG antibody by PEGylated protein has been reported, there is little evidence of accelerated blood clearance of PEGylated protein upon repeated injection. Herein, we investigated the blood concentration of PEGylated ovalbumin (PEG-OVA), a model PEGylated protein, upon its repeated injection. A single intravenous administration of PEG-OVA elicited an anti-PEG IgM response but not anti-PEG IgG response, while the administration did not elicit antibody against OVA. At 24 h postinjection of test PEG-OVA, although control mice showed 41.6% dose of PEG-OVA in blood, the mice pretreated with PEG-OVA showed rapid clearance of test PEG-OVA from blood and undetectable level of PEG-OVA. Interestingly, the anti-PEG IgM induced by PEGylated liposome did not affect the blood concentration of subsequent dose of PEG-OVA. Our result suggests that anti-PEG IgM is a major contributor to the accelerated blood clearance of PEG-conjugated protein, but the presence of anti-PEG IgM in blood circulation does not necessarily affect circulating property of entire PEGylated materials.","ja":"Limited therapeutic efficacy of polyethylene glycol-conjugated (PEGylated) protein drugs has been recently reported in animals and human following repeat injections. Since there are reports that an accelerated blood clearance (ABC) phenomenon is caused by repeated injection of PEGylated liposome, there is an assumption that PEGylated proteins lose their long circulating property when they are injected repeatedly due to the induction of anti-PEG antibody. Although induction of anti-PEG antibody by PEGylated protein has been reported, there is little evidence of accelerated blood clearance of PEGylated protein upon repeated injection. Herein, we investigated the blood concentration of PEGylated ovalbumin (PEG-OVA), a model PEGylated protein, upon its repeated injection. A single intravenous administration of PEG-OVA elicited an anti-PEG IgM response but not anti-PEG IgG response, while the administration did not elicit antibody against OVA. At 24 h postinjection of test PEG-OVA, although control mice showed 41.6% dose of PEG-OVA in blood, the mice pretreated with PEG-OVA showed rapid clearance of test PEG-OVA from blood and undetectable level of PEG-OVA. Interestingly, the anti-PEG IgM induced by PEGylated liposome did not affect the blood concentration of subsequent dose of PEG-OVA. Our result suggests that anti-PEG IgM is a major contributor to the accelerated blood clearance of PEG-conjugated protein, but the presence of anti-PEG IgM in blood circulation does not necessarily affect circulating property of entire PEGylated materials."},"publication_date":"2015-06-24","publication_name":{"en":"Molecular Pharmaceutics","ja":"Molecular Pharmaceutics"},"volume":"Vol.12","number":"No.7","starting_page":"2429","ending_page":"2435","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acs.molpharmaceut.5b00144"],"issn":["1543-8392"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:108, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507516"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26053864","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84934957265&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=294909","label":"url"}],"paper_title":{"en":"Synthesis of DNA fragments containing 2-deoxy-4-selenonucleoside units using DNA polymerases: comparison of dNTPs with O, S and Se at the 4-position in replication Org","ja":"Synthesis of DNA fragments containing 2-deoxy-4-selenonucleoside units using DNA polymerases: comparison of dNTPs with O, S and Se at the 4-position in replication Org"},"authors":{"en":[{"name":"Saito-Tarashima Noriko"},{"name":"Sumitomo Tatsuya"},{"name":"ANDO Hidenori"},{"name":"Furukawa Kazuhiro"},{"name":"Ishida Tatsuhiro"},{"name":"Minakawa Noriaki"}],"ja":[{"name":"田良島 典子"},{"name":"Sumitomo Tatsuya"},{"name":"安藤 英紀"},{"name":"古川 和寛"},{"name":"石田 竜弘"},{"name":"南川 典昭"}]},"description":{"en":"4'-SelenoDNA fragments were synthesized for the first time using 4'-selenothymidine triphosphate (SeTTP) by taking advantage of its bioequivalence against DNA polymerases. DNA fragments each with a homologous element (O, S or Se) at the 4'-position of the thymidine units were effectively amplified using KOD Dash DNA polymerase.","ja":"4'-SelenoDNA fragments were synthesized for the first time using 4'-selenothymidine triphosphate (SeTTP) by taking advantage of its bioequivalence against DNA polymerases. DNA fragments each with a homologous element (O, S or Se) at the 4'-position of the thymidine units were effectively amplified using KOD Dash DNA polymerase."},"publication_date":"2015-05-20","publication_name":{"en":"Organic & Biomolecular Chemistry","ja":"Organic & Biomolecular Chemistry"},"volume":"Vol.13","number":"No.25","starting_page":"6949","ending_page":"6952","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1039/c5ob00941c"],"issn":["1477-0539"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:109, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507517"},"force":{"see_also":[{"@id":"http://ci.nii.ac.jp/naid/130004872284/","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/25757923","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390282679608052736/","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84937217183&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=288683","label":"url"}],"paper_title":{"en":"Relationship between the concentration of anti-polyethylene glycol (PEG) in immunoglobulin M (IgM) and the intensity of the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes in mice","ja":"Relationship between the concentration of anti-polyethylene glycol (PEG) in immunoglobulin M (IgM) and the intensity of the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes in mice"},"authors":{"en":[{"name":"Hashimoto Yosuke"},{"name":"Shimizu Taro"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"橋本 洋佑"},{"name":"清水 太郎"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"PEGylation, which is the surface modification of nanocarriers with polyethylene glycol (PEG), has increased the circulation time and reduced the immunogenic responses to nanocarriers. However, many reports have demonstrated that the intravenous injection of sterically stabilized PEGylated liposome (SL) causes an accelerated blood clearance (ABC) of subsequent doses via anti-PEG immunoglobulin M (IgM)-mediated complement activation. In the present study, the relationships between serum anti-PEG IgM concentration, the intensity of complement activation and the hepatic clearance of SL were quantitatively investigated for their role in the ABC phenomenon. Interestingly, with increasing serum anti-PEG IgM concentrations, the intensity of complement activation increased linearly, while the intensity of the hepatic clearance of SL was increased and then saturated. In addition, only 15-17% of anti-PEG IgM in blood circulation induced by SL at different doses was associated with a second dose SL. The present results indicate that it is the hepatic uptake of SL that is the limiting step in the ABC phenomenon, rather than the association of anti-PEG IgM to the SL and a subsequent complement activation.","ja":"PEGylation, which is the surface modification of nanocarriers with polyethylene glycol (PEG), has increased the circulation time and reduced the immunogenic responses to nanocarriers. However, many reports have demonstrated that the intravenous injection of sterically stabilized PEGylated liposome (SL) causes an accelerated blood clearance (ABC) of subsequent doses via anti-PEG immunoglobulin M (IgM)-mediated complement activation. In the present study, the relationships between serum anti-PEG IgM concentration, the intensity of complement activation and the hepatic clearance of SL were quantitatively investigated for their role in the ABC phenomenon. Interestingly, with increasing serum anti-PEG IgM concentrations, the intensity of complement activation increased linearly, while the intensity of the hepatic clearance of SL was increased and then saturated. In addition, only 15-17% of anti-PEG IgM in blood circulation induced by SL at different doses was associated with a second dose SL. The present results indicate that it is the hepatic uptake of SL that is the limiting step in the ABC phenomenon, rather than the association of anti-PEG IgM to the SL and a subsequent complement activation."},"publication_date":"2015-03-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.38","number":"No.3","starting_page":"417","ending_page":"424","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b14-00653"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:110, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507518"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/25757929","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84936159744&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=288682","label":"url"}],"paper_title":{"en":"Liposomal pemetrexed: Formulation, characterization and in vitro cytotoxicity studies for effective management of malignant pleural mesothelioma","ja":"Liposomal pemetrexed: Formulation, characterization and in vitro cytotoxicity studies for effective management of malignant pleural mesothelioma"},"authors":{"en":[{"name":"Essam Eldin N"},{"name":"Elnahas H M"},{"name":"Mahdy M A"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Essam Eldin N"},{"name":"Elnahas H M"},{"name":"Mahdy M A"},{"name":"石田 竜弘"}]},"description":{"en":"Pemetrexed (PMX) is a newly developed multi-targeted anti-folate with promising clinical activity in many solid tumors including malignant pleural mesothelioma (MPM). However, PMX does not show sufficient anti-tumor activity in vivo when used alone either due to inefficient delivery of adequate concentrations to tumor tissue or dose-limiting side effects. In order to overcome these problems and to achieve potent anti-tumor activity, PMX was encapsulated into a liposomal delivery system. In the present study, various formulations of liposomal PMX were prepared. The effect of formulation parameters on the encapsulation efficiency of PMX within liposomes was evaluated. In addition, the influence of drug release rate on the in vitro cytotoxicity was investigated. Encapsulation of PMX within liposomes was remarkably increased by the incorporation of cholesterol within liposomal membranes and by increasing the total lipid concentration. Encapsulation efficiency was found to be unaffected by the type of phospholipid used or the inclusion of a cation lipid, DC-6-14. Interestingly, encapsulation of PMX within \"fluid\" liposomes was found to allow efficient release of PMX from liposomes resulting in a potent in vitro cytotoxicity against MPM MSTO-211H cell line. On the other hand, entrapment of PMX within \"solid\" liposomes substantially hindered PMX release from liposomes, and thus PMX failed to exert any in vitro cytotoxicity. These results suggest that encapsulation of PMX within \"fluid\" liposomes might represent a novel strategy to enhance the therapeutic efficacy of PMX while minimizing the side effect encountered by the non selective delivery of free PMX to various body tissues.","ja":"Pemetrexed (PMX) is a newly developed multi-targeted anti-folate with promising clinical activity in many solid tumors including malignant pleural mesothelioma (MPM). However, PMX does not show sufficient anti-tumor activity in vivo when used alone either due to inefficient delivery of adequate concentrations to tumor tissue or dose-limiting side effects. In order to overcome these problems and to achieve potent anti-tumor activity, PMX was encapsulated into a liposomal delivery system. In the present study, various formulations of liposomal PMX were prepared. The effect of formulation parameters on the encapsulation efficiency of PMX within liposomes was evaluated. In addition, the influence of drug release rate on the in vitro cytotoxicity was investigated. Encapsulation of PMX within liposomes was remarkably increased by the incorporation of cholesterol within liposomal membranes and by increasing the total lipid concentration. Encapsulation efficiency was found to be unaffected by the type of phospholipid used or the inclusion of a cation lipid, DC-6-14. Interestingly, encapsulation of PMX within \"fluid\" liposomes was found to allow efficient release of PMX from liposomes resulting in a potent in vitro cytotoxicity against MPM MSTO-211H cell line. On the other hand, entrapment of PMX within \"solid\" liposomes substantially hindered PMX release from liposomes, and thus PMX failed to exert any in vitro cytotoxicity. These results suggest that encapsulation of PMX within \"fluid\" liposomes might represent a novel strategy to enhance the therapeutic efficacy of PMX while minimizing the side effect encountered by the non selective delivery of free PMX to various body tissues."},"publication_date":"2015-03-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.38","number":"No.3","starting_page":"461","ending_page":"469","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b14-00769"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:111, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507519"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/25280884","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84907897464&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=286135","label":"url"}],"paper_title":{"en":"Influence of dose and animal species on accelerated blood clearance of PEGylated liposomal doxorubicin","ja":"Influence of dose and animal species on accelerated blood clearance of PEGylated liposomal doxorubicin"},"authors":{"en":[{"name":"Suzuki Takuya"},{"name":"Ichihara Masako"},{"name":"Hyodo Kenji"},{"name":"Yamamoto Eiichi"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"},{"name":"Kikuchi Hiroshi"},{"name":"Ishihara Hiroshi"}],"ja":[{"name":"鈴木 卓也"},{"name":"市原 理子"},{"name":"Hyodo Kenji"},{"name":"Yamamoto Eiichi"},{"name":"石田 竜弘"},{"name":"際田 弘志"},{"name":"Kikuchi Hiroshi"},{"name":"Ishihara Hiroshi"}]},"description":{"en":"We recently demonstrated that Doxil loses its long-circulating properties when injected repeatedly at doses below 2 mg/m(2) in dogs. In studies using other animal species, PEGylated liposomal doxorubicin has been reported not to induce the accelerated blood clearance (ABC) phenomenon. We investigated the issue of whether Doxil can elicit the ABC phenomenon in several species. In minipigs, the ABC phenomenon was induced at 2 mg/m(2). In other animal species, the ABC phenomenon was not observed at higher doses (>2 mg/m(2)), but was observed at much lower doses (0.2 mg/m(2)). The pharmacokinetic profile of a second dose of Doxil reflected the circulating anti-PEG IgM level induced by the first dose. The ABC phenomenon was not observed at the clinically recommended DXR dose (20 mg/m(2)) in any animal species. These results indicate that Doxil can cause the ABC phenomenon in all animals tested, the extent of induction was dependent on the first dose of Doxil, and a higher Doxil dose lessened the ABC phenomenon. The current study results suggest that a careful study design including selection of animal species is important for preclinical studies using PEGylated liposomal formulations even if they contain anticancer drugs that suppress the host immune response.","ja":"We recently demonstrated that Doxil loses its long-circulating properties when injected repeatedly at doses below 2 mg/m(2) in dogs. In studies using other animal species, PEGylated liposomal doxorubicin has been reported not to induce the accelerated blood clearance (ABC) phenomenon. We investigated the issue of whether Doxil can elicit the ABC phenomenon in several species. In minipigs, the ABC phenomenon was induced at 2 mg/m(2). In other animal species, the ABC phenomenon was not observed at higher doses (>2 mg/m(2)), but was observed at much lower doses (0.2 mg/m(2)). The pharmacokinetic profile of a second dose of Doxil reflected the circulating anti-PEG IgM level induced by the first dose. The ABC phenomenon was not observed at the clinically recommended DXR dose (20 mg/m(2)) in any animal species. These results indicate that Doxil can cause the ABC phenomenon in all animals tested, the extent of induction was dependent on the first dose of Doxil, and a higher Doxil dose lessened the ABC phenomenon. The current study results suggest that a careful study design including selection of animal species is important for preclinical studies using PEGylated liposomal formulations even if they contain anticancer drugs that suppress the host immune response."},"publication_date":"2014-12-10","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.476","starting_page":"205","ending_page":"212","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2014.09.047"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:112, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507520"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/25314258","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84915745333&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=294446","label":"url"}],"paper_title":{"en":"Chemistry, properties, and in vitro and in vivo applications of 2'-O-methoxyethyl-4'-thioRNA, a novel hybrid type of chemically modified RNA.","ja":"Chemistry, properties, and in vitro and in vivo applications of 2'-O-methoxyethyl-4'-thioRNA, a novel hybrid type of chemically modified RNA."},"authors":{"en":[{"name":"Saito Yota"},{"name":"Hashimoto Yosuke"},{"name":"Arai Mai"},{"name":"Saito-Tarashima Noriko"},{"name":"Miyazawa Tadashi"},{"name":"Miki Kazuya"},{"name":"Takahashi Mayumi"},{"name":"Furukawa Kazuhiro"},{"name":"Yamazaki Naoshi"},{"name":"Matsuda Akira"},{"name":"Ishida Tatsuhiro"},{"name":"Minakawa Noriaki"}],"ja":[{"name":"Saito Yota"},{"name":"橋本 洋佑"},{"name":"Arai Mai"},{"name":"田良島 典子"},{"name":"Miyazawa Tadashi"},{"name":"Miki Kazuya"},{"name":"Takahashi Mayumi"},{"name":"古川 和寛"},{"name":"山﨑 尚志"},{"name":"Matsuda Akira"},{"name":"石田 竜弘"},{"name":"南川 典昭"}]},"description":{"en":"We report the synthesis, properties, and in vitro and in vivo applications of 2'-O-methoxyethyl-4'-thioRNA (MOE-SRNA), a novel type of hybrid chemically modified RNA. In its hybridization with complementary RNA, MOE-SRNA showed a moderate improvement of Tm value (+3.4 °C relative to an RNA:RNA duplex). However, the results of a comprehensive comparison of the nuclease stability of MOE-SRNA relative to 2'-O-methoxyethylRNA (MOERNA), 2'-O-methyl-4'-thioRNA (Me-SRNA), 2'-O-methylRNA (MeRNA), 4'-thioRNA (SRNA), and natural RNA revealed that MOE-SRNA had the highest stability (t1/2 >48 h in human plasma). Because of the favorable properties of MOE-SRNA, we evaluated its in vitro and in vivo potencies as an anti-microRNA oligonucleotide against miR-21. Although the in vitro potency of MOE-SRNA was moderate, its in vivo potency was significant for the suppression of tumor growth (similar to that of MOERNA).","ja":"We report the synthesis, properties, and in vitro and in vivo applications of 2'-O-methoxyethyl-4'-thioRNA (MOE-SRNA), a novel type of hybrid chemically modified RNA. In its hybridization with complementary RNA, MOE-SRNA showed a moderate improvement of Tm value (+3.4 °C relative to an RNA:RNA duplex). However, the results of a comprehensive comparison of the nuclease stability of MOE-SRNA relative to 2'-O-methoxyethylRNA (MOERNA), 2'-O-methyl-4'-thioRNA (Me-SRNA), 2'-O-methylRNA (MeRNA), 4'-thioRNA (SRNA), and natural RNA revealed that MOE-SRNA had the highest stability (t1/2 >48 h in human plasma). Because of the favorable properties of MOE-SRNA, we evaluated its in vitro and in vivo potencies as an anti-microRNA oligonucleotide against miR-21. Although the in vitro potency of MOE-SRNA was moderate, its in vivo potency was significant for the suppression of tumor growth (similar to that of MOERNA)."},"publication_date":"2014-11-24","publication_name":{"en":"ChemBioChem","ja":"ChemBioChem"},"volume":"Vol.15","number":"No.17","starting_page":"2535","ending_page":"2540","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/cbic.201402398"],"issn":["1439-7633"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:113, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507521"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24727075","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84899502162&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=277004","label":"url"}],"paper_title":{"en":"B cell-intrinsic toll-like receptor 7 is responsible for the enhanced anti-PEG IgM production following injection of siRNA-containing PEGylated lipoplex in mice","ja":"B cell-intrinsic toll-like receptor 7 is responsible for the enhanced anti-PEG IgM production following injection of siRNA-containing PEGylated lipoplex in mice"},"authors":{"en":[{"name":"Hashimoto Yosuke"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"橋本 洋佑"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"清水 太郎"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Recently, we reported that immunostimulatory siRNA-containing PEGylated lipoplex (PEGylated siRNA-lipoplex) activates the immune system, resulting in the enhanced production of anti-PEG IgM. However, the enhancing mechanism upon anti-PEG IgM production has not been fully elucidated. In this study, we employed toll-like receptor 7 knock out (TLR7 KO) mice, and showed how PEGylated siRNA-lipoplex activates the innate immune system through TLR7 and consequently enhances anti-PEG IgM production. In addition, we showed that SCID mice reconstituted with TLR7-deficient B cells failed to enhance anti-PEG IgM production following the injection of PEGylated siRNA-lipoplex, but that SCID mice reconstituted with wild type B cells did enhance anti-PEG IgM production. These results suggest that immune activation via B cell-intrinsic TLR7, but not other TLR7-expressing cells, contributes predominantly to an enhanced anti-PEG IgM production in response to the intravenous injection of PEGylated siRNA-lipoplexes. A strategy to evade B cell-intrinsic TLR7 activation by siRNA, such as chemical modification, may overcome immunological barriers to PEGylated liposome-based siRNA therapeutics.","ja":"Recently, we reported that immunostimulatory siRNA-containing PEGylated lipoplex (PEGylated siRNA-lipoplex) activates the immune system, resulting in the enhanced production of anti-PEG IgM. However, the enhancing mechanism upon anti-PEG IgM production has not been fully elucidated. In this study, we employed toll-like receptor 7 knock out (TLR7 KO) mice, and showed how PEGylated siRNA-lipoplex activates the innate immune system through TLR7 and consequently enhances anti-PEG IgM production. In addition, we showed that SCID mice reconstituted with TLR7-deficient B cells failed to enhance anti-PEG IgM production following the injection of PEGylated siRNA-lipoplex, but that SCID mice reconstituted with wild type B cells did enhance anti-PEG IgM production. These results suggest that immune activation via B cell-intrinsic TLR7, but not other TLR7-expressing cells, contributes predominantly to an enhanced anti-PEG IgM production in response to the intravenous injection of PEGylated siRNA-lipoplexes. A strategy to evade B cell-intrinsic TLR7 activation by siRNA, such as chemical modification, may overcome immunological barriers to PEGylated liposome-based siRNA therapeutics."},"publication_date":"2014-06-28","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.184","starting_page":"1","ending_page":"8","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2014.04.003"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:114, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507522"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24694537","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84902086530&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=275910","label":"url"}],"paper_title":{"en":"Activation of TLR9 by incorporated pDNA within PEG-coated lipoplex enhances anti-PEG IgM production","ja":"Activation of TLR9 by incorporated pDNA within PEG-coated lipoplex enhances anti-PEG IgM production"},"authors":{"en":[{"name":"Hashimoto Yosuke"},{"name":"Uehara Yumi"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"橋本 洋佑"},{"name":"上原 友美"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Cationic liposome represents a promising alternative to viral vectors for the delivery of therapeutic genes. For in vivo use, surface modification of the liposome with polyethylene glycol (PEG) is frequently applied to achieve gene-expression in the targeted tissue. However, we have reported that PEG-coated liposomes have induced anti-PEG IgM, which has caused subsequent doses of PEG-coated liposome to be rapidly cleared from blood circulation, and the complexation of pDNA electrostatically associated with liposome surface has enhanced this antibody response. In this study, we investigated how a Toll-like receptor (TLR) might enhance anti-PEG IgM production. PEG-coated pDNA-lipoplex (PDCL) was injected into either wild type, MyD88 (all TLR adaptor protein, independent of TLR3) knock out (KO) or TLR9 KO mice, and the anti-PEG IgM production levels were detected. Attenuated anti-PEG IgM production following the injection of PDCL was observed in both MyD88 and TLR9 KO mice compared to wild type mice, probably due to the abolished induction of cytokines in both MyD88 and TLR9 KO mice. Our results suggest that TLR, exclusively TLR9, signaling plays a potential role in the enhanced anti-PEG IgM production following the injection of PDCL. This result may have important implications for the design and development of an efficient PEG-coated non-viral gene vector.","ja":"Cationic liposome represents a promising alternative to viral vectors for the delivery of therapeutic genes. For in vivo use, surface modification of the liposome with polyethylene glycol (PEG) is frequently applied to achieve gene-expression in the targeted tissue. However, we have reported that PEG-coated liposomes have induced anti-PEG IgM, which has caused subsequent doses of PEG-coated liposome to be rapidly cleared from blood circulation, and the complexation of pDNA electrostatically associated with liposome surface has enhanced this antibody response. In this study, we investigated how a Toll-like receptor (TLR) might enhance anti-PEG IgM production. PEG-coated pDNA-lipoplex (PDCL) was injected into either wild type, MyD88 (all TLR adaptor protein, independent of TLR3) knock out (KO) or TLR9 KO mice, and the anti-PEG IgM production levels were detected. Attenuated anti-PEG IgM production following the injection of PDCL was observed in both MyD88 and TLR9 KO mice compared to wild type mice, probably due to the abolished induction of cytokines in both MyD88 and TLR9 KO mice. Our results suggest that TLR, exclusively TLR9, signaling plays a potential role in the enhanced anti-PEG IgM production following the injection of PDCL. This result may have important implications for the design and development of an efficient PEG-coated non-viral gene vector."},"publication_date":"2014-06","publication_name":{"en":"Gene Therapy","ja":"Gene Therapy"},"volume":"Vol.21","number":"No.6","starting_page":"593","ending_page":"598","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/gt.2014.32"],"issn":["1476-5462"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:115, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507523"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24632081","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84897940686&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=276217","label":"url"}],"paper_title":{"en":"Generation, characterization and in vivo biological activity of two distinct monoclonal anti-PEG IgMs","ja":"Generation, characterization and in vivo biological activity of two distinct monoclonal anti-PEG IgMs"},"authors":{"en":[{"name":"Hashimoto Yosuke"},{"name":"Shimizu Taro"},{"name":"Mima Yu"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"橋本 洋佑"},{"name":"清水 太郎"},{"name":"美馬 優"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"PEGylation, the attachment of polyethylene glycol (PEG) to nanocarriers and proteins, is a widely accepted approach to improving the in vivo efficacy of the non-PEGylated products. However, both PEGylated liposomes and PEGylated proteins reportedly trigger the production of specific antibodies, mainly IgM, against the PEG moiety, which possibly leads to a reduction in safety and therapeutic efficacy of the PEGylated products. In the present study, two monoclonal anti-PEG IgMs--HIK-M09 via immunization with an intravenous injection of PEGylated liposomes (SLs) and HIK-M11 via immunization with a subcutaneous administration of PEGylated ovalbumin (PEG-OVA) were successfully generated. The generated IgMs showed efficient reactivity to mPEG2000 conjugated to 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine (DSPE), PEGylated liposome (SL) and PEG-OVA. It appears that HIK-M09 recognizes ethoxy (OCH2CH2) repeat units along with a terminal motif of PEG, while HIK-M11 recognizes only ethoxy repeat units of PEG. Such unique properties allow HIK-M09 to bind with dense PEG. In addition, their impact on the in vivo clearance of the PEGylated products was investigated. It was found that the generated ant-PEG IgMs induced a clearance of SL as they were intravenously administered with SL. Interestingly, the HIK-M11, generated by PEG-OVA, induced the clearance of both SL and PEG-OVA, while the HIK-M09, generated by SL, induced the clearance of SL only. We here revealed that the presence of serum anti-PEG IgM and the subsequent binding of anti-PEG IgM to the PEGylated products are not necessarily related to the enhanced clearance of the products. It appears that subsequent complement activation following anti-PEG IgM binding is the most important step in dictating the in vivo fate of PEGylated products. This study may have implications for the design, development and clinical application of PEGylated products and therapeutics.","ja":"PEGylation, the attachment of polyethylene glycol (PEG) to nanocarriers and proteins, is a widely accepted approach to improving the in vivo efficacy of the non-PEGylated products. However, both PEGylated liposomes and PEGylated proteins reportedly trigger the production of specific antibodies, mainly IgM, against the PEG moiety, which possibly leads to a reduction in safety and therapeutic efficacy of the PEGylated products. In the present study, two monoclonal anti-PEG IgMs--HIK-M09 via immunization with an intravenous injection of PEGylated liposomes (SLs) and HIK-M11 via immunization with a subcutaneous administration of PEGylated ovalbumin (PEG-OVA) were successfully generated. The generated IgMs showed efficient reactivity to mPEG2000 conjugated to 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine (DSPE), PEGylated liposome (SL) and PEG-OVA. It appears that HIK-M09 recognizes ethoxy (OCH2CH2) repeat units along with a terminal motif of PEG, while HIK-M11 recognizes only ethoxy repeat units of PEG. Such unique properties allow HIK-M09 to bind with dense PEG. In addition, their impact on the in vivo clearance of the PEGylated products was investigated. It was found that the generated ant-PEG IgMs induced a clearance of SL as they were intravenously administered with SL. Interestingly, the HIK-M11, generated by PEG-OVA, induced the clearance of both SL and PEG-OVA, while the HIK-M09, generated by SL, induced the clearance of SL only. We here revealed that the presence of serum anti-PEG IgM and the subsequent binding of anti-PEG IgM to the PEGylated products are not necessarily related to the enhanced clearance of the products. It appears that subsequent complement activation following anti-PEG IgM binding is the most important step in dictating the in vivo fate of PEGylated products. This study may have implications for the design, development and clinical application of PEGylated products and therapeutics."},"publication_date":"2014-05-15","publication_name":{"en":"Toxicology and Applied Pharmacology","ja":"Toxicology and Applied Pharmacology"},"volume":"Vol.277","number":"No.1","starting_page":"30","ending_page":"38","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.taap.2014.03.002"],"issn":["0041-008X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:116, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507524"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24694614","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84898751899&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=274520","label":"url"}],"paper_title":{"en":"Novel Submicronized Rebamipide Liquid with Moderate Viscosity: Significant Effects on Oral Mucositis in Animal Models","ja":"Novel Submicronized Rebamipide Liquid with Moderate Viscosity: Significant Effects on Oral Mucositis in Animal Models"},"authors":{"en":[{"name":"Nakashima Takako"},{"name":"Sako N"},{"name":"Matsuda Takakuni"},{"name":"Uematsu N"},{"name":"Sakurai K"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"中島 貴子"},{"name":"Sako N"},{"name":"松田 貴邦"},{"name":"Uematsu N"},{"name":"Sakurai K"},{"name":"石田 竜弘"}]},"description":{"en":"This study aimed at developing a novel rebamipide liquid for an effective treatment of oral mucositis. The healing effects of a variety of liquids comprising submicronized rebamipide crystals were investigated using a rat cauterization-induced oral ulcer model. Whereas 2% rebamipide liquid comprising micro-crystals did not exhibit significant curative effect, 2% rebamipide liquids comprising submicronized crystals with moderate viscosities exhibited healing effects following intra-oral administration. The 2% and 4% optimized rebamipide liquids showed significant healing effects in the rat oral ulcer model (p<0.01). In addition, in the rat radiation-induced glossitis model, whereby the injury was caused to the tongue by exposing only around the rat's snout to a 15 Gy of X-irradiation, the 2% optimized rebamipide liquid significantly reduced the percent area of ulcerated injury (p<0.05). In conclusion, the submicronized rebamipide liquid with moderate viscosity following intra-oral administration showed better both healing effect in the rat oral ulcer model and preventive effect in the rat irradiation-induced glossitis model.","ja":"This study aimed at developing a novel rebamipide liquid for an effective treatment of oral mucositis. The healing effects of a variety of liquids comprising submicronized rebamipide crystals were investigated using a rat cauterization-induced oral ulcer model. Whereas 2% rebamipide liquid comprising micro-crystals did not exhibit significant curative effect, 2% rebamipide liquids comprising submicronized crystals with moderate viscosities exhibited healing effects following intra-oral administration. The 2% and 4% optimized rebamipide liquids showed significant healing effects in the rat oral ulcer model (p<0.01). In addition, in the rat radiation-induced glossitis model, whereby the injury was caused to the tongue by exposing only around the rat's snout to a 15 Gy of X-irradiation, the 2% optimized rebamipide liquid significantly reduced the percent area of ulcerated injury (p<0.05). In conclusion, the submicronized rebamipide liquid with moderate viscosity following intra-oral administration showed better both healing effect in the rat oral ulcer model and preventive effect in the rat irradiation-induced glossitis model."},"publication_date":"2014-04-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.37","number":"No.4","starting_page":"671","ending_page":"678","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b13-01006"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:117, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507525"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24361534","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84901597347&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=273830","label":"url"}],"paper_title":{"en":"Sequential treatment of oxaliplatin-containing PEGylated liposome together with S-1 improves intratumor distribution of subsequent doses of oxaliplatin-containing PEGylated liposome","ja":"Sequential treatment of oxaliplatin-containing PEGylated liposome together with S-1 improves intratumor distribution of subsequent doses of oxaliplatin-containing PEGylated liposome"},"authors":{"en":[{"name":"Nakamura Hiroyuki"},{"name":"Doi Yusuke"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Nagao Ai"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"中村 浩之"},{"name":"土井 祐輔"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"長尾 愛"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"We recently reported that combination therapy with metronomic S-1 dosing and oxaliplatin (l-OHP)-containing PEGylated liposomes improved antitumor activity in a murine colorectal tumor model. However, little is known about the mechanism underlying such improved therapeutic efficacy. Here we investigated the impact of combined treatment on biodistribution, tumor accumulation and intratumor distribution of test PEGylated liposomes and on the structure of tumor vasculature in a solid tumor. The combined treatment clearly enhanced tumor accumulation and intratumor distribution of a subsequent test dose of PEGylated liposome as a result of on the one hand prolonging blood circulation of test liposome and on the other hand the alteration in tumor microenvironment. The l-OHP-containing PEGylated liposomes contributed predominantly to the enhanced tumor accumulation and altered tumor distribution of test liposome. On the other hand, metronomic S-1 dosing contributed to the altered tumor distribution but not the tumor accumulation of test liposome. The antitumor effect of the combined treatment, reflected by the proportion of apoptotic cells in the tumor, was approximately equally accounted for by each of the two treatments, leading to a roughly additive effect. In conclusion, 1-OHP-containing PEGylated liposome together with S-1 enhanced intratumor influx, leading to improved antitumor activity of subsequently injected 1-OHP-containing PEGylated liposomes and/or S-1. This strategy we propose, which is clinically applicable, may overcome the problems related to the use of EPR effect-based nanocarrier systems.","ja":"We recently reported that combination therapy with metronomic S-1 dosing and oxaliplatin (l-OHP)-containing PEGylated liposomes improved antitumor activity in a murine colorectal tumor model. However, little is known about the mechanism underlying such improved therapeutic efficacy. Here we investigated the impact of combined treatment on biodistribution, tumor accumulation and intratumor distribution of test PEGylated liposomes and on the structure of tumor vasculature in a solid tumor. The combined treatment clearly enhanced tumor accumulation and intratumor distribution of a subsequent test dose of PEGylated liposome as a result of on the one hand prolonging blood circulation of test liposome and on the other hand the alteration in tumor microenvironment. The l-OHP-containing PEGylated liposomes contributed predominantly to the enhanced tumor accumulation and altered tumor distribution of test liposome. On the other hand, metronomic S-1 dosing contributed to the altered tumor distribution but not the tumor accumulation of test liposome. The antitumor effect of the combined treatment, reflected by the proportion of apoptotic cells in the tumor, was approximately equally accounted for by each of the two treatments, leading to a roughly additive effect. In conclusion, 1-OHP-containing PEGylated liposome together with S-1 enhanced intratumor influx, leading to improved antitumor activity of subsequently injected 1-OHP-containing PEGylated liposomes and/or S-1. This strategy we propose, which is clinically applicable, may overcome the problems related to the use of EPR effect-based nanocarrier systems."},"publication_date":"2014-02","publication_name":{"en":"European Journal of Pharmaceutics and Biopharmaceutics","ja":"European Journal of Pharmaceutics and Biopharmaceutics"},"volume":"Vol.87","number":"No.1","starting_page":"142","ending_page":"151","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ejpb.2013.12.007"],"issn":["1873-3441"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:118, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507526"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24347396","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84895929589&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=273437","label":"url"}],"paper_title":{"en":"Application of polyglycerol-coating to pDNA lipoplex for the evasion of the accelerated blood clearance (ABC) phenomenon in nucleic acid delivery.","ja":"Application of polyglycerol-coating to pDNA lipoplex for the evasion of the accelerated blood clearance (ABC) phenomenon in nucleic acid delivery."},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Uehara Yumi"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"上原 友美"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Cationic liposomes (CLs) have shown promise as nonviral delivery systems. To achieve in vivo stability and long circulation, most liposomes are modified with hydrophilic polymer polyethylene glycol (PEG). However, we have reported that repeated administration of PEG-coated CLs containing plasmid DNA (pDNA; PEGylated lipoplexes) induces what is referred to as \"the accelerated blood clearance (ABC) phenomenon\" and, consequently, subsequently administered lipoplexes lose their prolonged circulation characteristics. Anti-PEG IgM produced in response to the first dose of PEG-coated pDNA-lipoplexes (PEG-DCL) has proven to be a major cause of the ABC phenomenon. In this study, to evade and/or attenuate this unexpected immune response, we modified the surface of a lipoplex with polyglycerol (PG)-derived lipid. The PG-coated pDNA-lipoplex (PG-DCL) attenuated the production of anti-polymer IgM, whereas PEG-coated pDNA-lipoplex (PEG-DCL) did not. In addition, a second dose of PG-DCL maintained the accumulation level in the tumor tissue of a tumor-bearing mouse model, comparable to that of the first dose, whereas the tumor accumulation level of a second dose of PEG-DCL was significantly compromised, compared with the first dose of PEG-DCL. Our results indicate that surface modification of lipoplex with PG represents a viable means for the attenuation, and/or evasion, of the ABC phenomenon that is encountered upon repeated administrations of nucleic acids containing PEG-coated nanocarriers.","ja":"Cationic liposomes (CLs) have shown promise as nonviral delivery systems. To achieve in vivo stability and long circulation, most liposomes are modified with hydrophilic polymer polyethylene glycol (PEG). However, we have reported that repeated administration of PEG-coated CLs containing plasmid DNA (pDNA; PEGylated lipoplexes) induces what is referred to as \"the accelerated blood clearance (ABC) phenomenon\" and, consequently, subsequently administered lipoplexes lose their prolonged circulation characteristics. Anti-PEG IgM produced in response to the first dose of PEG-coated pDNA-lipoplexes (PEG-DCL) has proven to be a major cause of the ABC phenomenon. In this study, to evade and/or attenuate this unexpected immune response, we modified the surface of a lipoplex with polyglycerol (PG)-derived lipid. The PG-coated pDNA-lipoplex (PG-DCL) attenuated the production of anti-polymer IgM, whereas PEG-coated pDNA-lipoplex (PEG-DCL) did not. In addition, a second dose of PG-DCL maintained the accumulation level in the tumor tissue of a tumor-bearing mouse model, comparable to that of the first dose, whereas the tumor accumulation level of a second dose of PEG-DCL was significantly compromised, compared with the first dose of PEG-DCL. Our results indicate that surface modification of lipoplex with PG represents a viable means for the attenuation, and/or evasion, of the ABC phenomenon that is encountered upon repeated administrations of nucleic acids containing PEG-coated nanocarriers."},"publication_date":"2014-01","publication_name":{"en":"Journal of Pharmaceutical Sciences","ja":"Journal of Pharmaceutical Sciences"},"volume":"Vol.103","number":"No.2","starting_page":"557","ending_page":"566","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/jps.23823"],"issn":["1520-6017"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:119, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507527"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24189428","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=268437","label":"url"}],"paper_title":{"en":"Ex-Vivo/In-Vitro Anti-Polyethylene Glycol (PEG) IgM Production From Murine Splenic B Cells Stimulated by PEGylated Liposome","ja":"Ex-Vivo/In-Vitro Anti-Polyethylene Glycol (PEG) IgM Production From Murine Splenic B Cells Stimulated by PEGylated Liposome"},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Ichihara Masako"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"市原 理子"},{"name":"清水 太郎"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"We have reported that PEGylated liposomes lose their long-circulating properties when injected twice into the same animal within a certain interval (the accelerated blood clearance (ABC) phenomenon). We assumed that this phenomenon was triggered via the abundant secretion of anti-polyethylene glycol (PEG) immunoglobulin M (IgM) in response to the first dose of PEGylated liposomes and that the spleen played an important role in the production of anti-PEG IgM. However, no direct evidence has yet confirmed this suspicion. In the current study, we verified, both in vitro and ex vivo, that spleen cells are indeed responsible for the production of anti-PEG IgM in response to PEGylated liposomes. In this study, spleen cells obtained from either naïve mice or mice pre-treated with PEGylated liposomes induced the production of anti-PEG IgM in a dose- and time-dependent manner, upon incubation with PEGylated liposomes. In addition, we confirmed that among the different fractions of splenic B cells, IgM-positive B cells, rather than CD45R-positive or CD19-positive splenic B cells, which are presumed to be the marginal zone B (MZB) cells, are the major cells producing anti-PEG IgM in the response to stimulation by PEGylated liposomes. These results may provide new insights into the mechanisms underlying the anti-PEG IgM production in response to the stimulation by PEGylated liposomes.","ja":"We have reported that PEGylated liposomes lose their long-circulating properties when injected twice into the same animal within a certain interval (the accelerated blood clearance (ABC) phenomenon). We assumed that this phenomenon was triggered via the abundant secretion of anti-polyethylene glycol (PEG) immunoglobulin M (IgM) in response to the first dose of PEGylated liposomes and that the spleen played an important role in the production of anti-PEG IgM. However, no direct evidence has yet confirmed this suspicion. In the current study, we verified, both in vitro and ex vivo, that spleen cells are indeed responsible for the production of anti-PEG IgM in response to PEGylated liposomes. In this study, spleen cells obtained from either naïve mice or mice pre-treated with PEGylated liposomes induced the production of anti-PEG IgM in a dose- and time-dependent manner, upon incubation with PEGylated liposomes. In addition, we confirmed that among the different fractions of splenic B cells, IgM-positive B cells, rather than CD45R-positive or CD19-positive splenic B cells, which are presumed to be the marginal zone B (MZB) cells, are the major cells producing anti-PEG IgM in the response to stimulation by PEGylated liposomes. These results may provide new insights into the mechanisms underlying the anti-PEG IgM production in response to the stimulation by PEGylated liposomes."},"publication_date":"2013-11-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.36","number":"No.11","starting_page":"1842","ending_page":"1848","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b13-00562"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:120, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507528"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24060545","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=272247","label":"url"}],"paper_title":{"en":"Establishment of an X-ray irradiation-induced glossitis model in rats: biphasic elevation of proinflammatory cytokines and chemokines","ja":"Establishment of an X-ray irradiation-induced glossitis model in rats: biphasic elevation of proinflammatory cytokines and chemokines"},"authors":{"en":[{"name":"Nakashima Takako"},{"name":"Uematsu N"},{"name":"Shibamori M"},{"name":"Sakurai K"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"中島 貴子"},{"name":"Uematsu N"},{"name":"Shibamori M"},{"name":"Sakurai K"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Oral mucositis is a frequent and serious side effect in patients who receive radiotherapy for head and neck cancer. The purpose of this study was to develop a noninvasive and quantitative model of oral mucositis in rats, investigate the pathophysiology, and evaluate the efficacy of pharmacological interventions. Rats received a single dose of 15 Gy of X-rays to the snout after shielding of the remainder of the rat body with lead plates to protect the body from irradiation (day 0). After irradiation, the macroscopic area of tongue injury gradually increased. The total area of injury and the ulcer-like area reached a maximum on day 7 and then gradually decreased until disappearance on day 28. Expression of proinflammatory cytokines and chemokines occurred transiently within 1-4 hours after irradiation and returned to a normal level at 24 hours. This expression was again observed from days 3 to 5 and increased significantly on day 7, which approximately coincided with the histologic severity of tissue damage. Subcutaneous administration of palifermin at 3 mg/kg per day for 3 consecutive days before irradiation completely prevented ulcer formation in this model. In conclusion, we established a novel model of glossitis in rats, induced by X-ray irradiation, in which biphasic elevations of expression of proinflammatory cytokines and chemokines could be monitored. This model is considered useful to investigate the pathophysiology of oral mucositis and evaluate the preventive effect of pharmacological interventions on oral mucositis induced by X-ray irradiation.","ja":"Oral mucositis is a frequent and serious side effect in patients who receive radiotherapy for head and neck cancer. The purpose of this study was to develop a noninvasive and quantitative model of oral mucositis in rats, investigate the pathophysiology, and evaluate the efficacy of pharmacological interventions. Rats received a single dose of 15 Gy of X-rays to the snout after shielding of the remainder of the rat body with lead plates to protect the body from irradiation (day 0). After irradiation, the macroscopic area of tongue injury gradually increased. The total area of injury and the ulcer-like area reached a maximum on day 7 and then gradually decreased until disappearance on day 28. Expression of proinflammatory cytokines and chemokines occurred transiently within 1-4 hours after irradiation and returned to a normal level at 24 hours. This expression was again observed from days 3 to 5 and increased significantly on day 7, which approximately coincided with the histologic severity of tissue damage. Subcutaneous administration of palifermin at 3 mg/kg per day for 3 consecutive days before irradiation completely prevented ulcer formation in this model. In conclusion, we established a novel model of glossitis in rats, induced by X-ray irradiation, in which biphasic elevations of expression of proinflammatory cytokines and chemokines could be monitored. This model is considered useful to investigate the pathophysiology of oral mucositis and evaluate the preventive effect of pharmacological interventions on oral mucositis induced by X-ray irradiation."},"publication_date":"2013-09-23","publication_name":{"en":"The Journal of Pharmacology and Experimental Therapeutics","ja":"The Journal of Pharmacology and Experimental Therapeutics"},"volume":"Vol.347","number":"No.3","starting_page":"660","ending_page":"668","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1124/jpet.113.208405"],"issn":["1521-0103"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:121, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507529"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23928149","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=265533","label":"url"}],"paper_title":{"en":"Use of polyglycerol (PG), instead of polyethylene glycol (PEG), prevents induction of the accelerated blood clearance phenomenon against long-circulating liposomes upon repeated administration","ja":"Use of polyglycerol (PG), instead of polyethylene glycol (PEG), prevents induction of the accelerated blood clearance phenomenon against long-circulating liposomes upon repeated administration"},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Nawata Kousuke"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"名和田 幸介"},{"name":"清水 太郎"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"The accelerated blood clearance (ABC) phenomenon accounts for the rapid systemic clearance of PEGylated nanocarriers upon repeated administrations. IgM production against the polyethylene glycol (PEG) coating in PEGylated liposomes is now known to be responsible for such unexpected pharmacokinetical alterations. The ABC phenomenon poses a remarkable clinical challenge by reducing the therapeutic efficacy of encapsulated drugs and causing harmful effects due to the altered tissue distribution pattern of the drugs. In this study, we investigated the in vivo performance of liposomes modified with polyglycerol (PG) upon repeated injection, and the in vivo therapeutic efficacy of such liposomes when they encapsulated a cytotoxic agent, doxorubicin (DXR). Repeated injection of PEG-coated liposomes in rats induced the ABC phenomenon, while repeated injection of PG-coated liposomes did not. In addition, DXR-containing PG-coated liposomes showed antitumor activity that was superior to that of free DXR and similar to that of DXR-containing PEG-coated liposomes upon repeated administration. These results indicate that polyglycerol (PG) might represent a promising alternative to PEG via enhancing the in vivo performance of liposomes by not eliciting the ABC phenomenon upon repeated administration.","ja":"The accelerated blood clearance (ABC) phenomenon accounts for the rapid systemic clearance of PEGylated nanocarriers upon repeated administrations. IgM production against the polyethylene glycol (PEG) coating in PEGylated liposomes is now known to be responsible for such unexpected pharmacokinetical alterations. The ABC phenomenon poses a remarkable clinical challenge by reducing the therapeutic efficacy of encapsulated drugs and causing harmful effects due to the altered tissue distribution pattern of the drugs. In this study, we investigated the in vivo performance of liposomes modified with polyglycerol (PG) upon repeated injection, and the in vivo therapeutic efficacy of such liposomes when they encapsulated a cytotoxic agent, doxorubicin (DXR). Repeated injection of PEG-coated liposomes in rats induced the ABC phenomenon, while repeated injection of PG-coated liposomes did not. In addition, DXR-containing PG-coated liposomes showed antitumor activity that was superior to that of free DXR and similar to that of DXR-containing PEG-coated liposomes upon repeated administration. These results indicate that polyglycerol (PG) might represent a promising alternative to PEG via enhancing the in vivo performance of liposomes by not eliciting the ABC phenomenon upon repeated administration."},"publication_date":"2013-08-05","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.456","number":"No.1","starting_page":"235","ending_page":"242","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2013.07.059"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:122, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507530"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23673556","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=263269","label":"url"}],"paper_title":{"en":"The co-delivery of oxaliplatin abrogates the immunogenic response to PEGylated siRNA-lipoplex.","ja":"The co-delivery of oxaliplatin abrogates the immunogenic response to PEGylated siRNA-lipoplex."},"authors":{"en":[{"name":"Alaaeldin E"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Moriyoshi Naoto"},{"name":"Sarahan H"},{"name":"Khaled A"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Alaaeldin E"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"森吉 直人"},{"name":"Sarahan H"},{"name":"Khaled A"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"In vivo application of siRNA/PEGylated cationic liposome complex (lipoplex) is impeded by two main obstacles: cytokine responses and anti-PEG IgM responses to PEGylated siRNA-lipoplex. Here, we investigated whether co-administration of oxaliplatin (l-OHP) abrogates the cytokine release and anti-PEG IgM production by PEGylated siRNA-lipoplex. Free l-OHP was administered either simultaneously or 30 min prior to PEGylated siRNA-lipoplex administration, and cytokine response and anti-PEG IgM production were evaluated. In addition, the effect of the liposomal encapsulation of l-OHP on the immunogenic response of PEGylated siRNA-lipoplex was investigated. Simultaneous co-administration of free l-OHP with PEGylated siRNA-lipoplex caused a significant reduction in anti-PEG IgM production, along with an increase in the cytokine response. Free l-OHP injected prior to the lipoplex injection, however, successfully reduced cytokine release and anti-PEG IgM response. Platination of siRNA by simultaneously administered free l-OHP might facilitate the dissociation of double-stranded siRNA to single-stranded siRNA, resulting in the inducement of a potent immuno-stimulation of siRNA via endosomal toll-like receptors (TLRs). On the other hand, encapsulation of l-OHP into the siRNA-lipoplex resulted in a reduction of both anti-PEG IgM production and cytokine responses. Our results suggest that, besides the expected therapeutic efficacy of co-administration, encapsulation of l-OHP into the PEGylated siRNA-lipoplex has great potential for minimizing the immunostimulation of PEGylated siRNA-lipoplex, resulting in a safe, applicable, and compliant treatment regimen for sequential clinical administration.","ja":"In vivo application of siRNA/PEGylated cationic liposome complex (lipoplex) is impeded by two main obstacles: cytokine responses and anti-PEG IgM responses to PEGylated siRNA-lipoplex. Here, we investigated whether co-administration of oxaliplatin (l-OHP) abrogates the cytokine release and anti-PEG IgM production by PEGylated siRNA-lipoplex. Free l-OHP was administered either simultaneously or 30 min prior to PEGylated siRNA-lipoplex administration, and cytokine response and anti-PEG IgM production were evaluated. In addition, the effect of the liposomal encapsulation of l-OHP on the immunogenic response of PEGylated siRNA-lipoplex was investigated. Simultaneous co-administration of free l-OHP with PEGylated siRNA-lipoplex caused a significant reduction in anti-PEG IgM production, along with an increase in the cytokine response. Free l-OHP injected prior to the lipoplex injection, however, successfully reduced cytokine release and anti-PEG IgM response. Platination of siRNA by simultaneously administered free l-OHP might facilitate the dissociation of double-stranded siRNA to single-stranded siRNA, resulting in the inducement of a potent immuno-stimulation of siRNA via endosomal toll-like receptors (TLRs). On the other hand, encapsulation of l-OHP into the siRNA-lipoplex resulted in a reduction of both anti-PEG IgM production and cytokine responses. Our results suggest that, besides the expected therapeutic efficacy of co-administration, encapsulation of l-OHP into the PEGylated siRNA-lipoplex has great potential for minimizing the immunostimulation of PEGylated siRNA-lipoplex, resulting in a safe, applicable, and compliant treatment regimen for sequential clinical administration."},"publication_date":"2013-05-15","publication_name":{"en":"Pharmaceutical Research","ja":"Pharmaceutical Research"},"volume":"Vol.30","number":"No.9","starting_page":"2344","ending_page":"2354","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s11095-013-1078-4"],"issn":["1573-904X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:123, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507531"},"force":{"see_also":[{"@id":"http://id.ndl.go.jp/bib/024312005","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390001206129003136/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=258898","label":"url"}],"paper_title":{"en":"Development of siRNA Delivery Strategy by Active Control of Tumor Microenvironment","ja":"腫瘍内微小環境の能動的制御に基づくsiRNAデリバリー技術の開発とがん治療への展開"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Efficient systemic siRNA delivery to cells in the target tissue is a current critical challenge in the drug delivery field. Several studies have demonstrated that nanoparticles such as polyethylene glycol (PEG)-coated siRNA-lipoplexes may enhance the systemic delivery of siRNA to tumor. However, the disordered tumor microenvironment still poses a potential impediment with respect to the efficient delivery of PEG-coated siRNA-lipoplexes. We recently showed that metronomic S-1 dosing (daily oral administration) enhanced the accumulation of PEG-coated liposome containing anticancer drug in solid tumor tissue and thereby increased therapeutic efficacy in tumor-bearing mouse model. To extend this work, we tried to investigate the effect of metronomic S-1 dosing on the intratumoral accumulation of PEG-coated siRNA-lipoplex and, thereby, their therapeutic efficacy in solid tumor-bearing mouse model. Results showed that metronomic S-1 dosing improved systemic delivery of intravenously injected PEG-coated siRNA-lipoplexes into solid tumor tissue. In addition, the combined therapy of S-1 and PEG-coated siRNA-lipoplexes showed potent tumor growth suppressive effect. Our proposed strategy may pose a promising therapeutic one to conquer cancer progression with siRNA.<br>","ja":"Efficient systemic siRNA delivery to cells in the target tissue is a current critical challenge in the drug delivery field. Several studies have demonstrated that nanoparticles such as polyethylene glycol (PEG)-coated siRNA-lipoplexes may enhance the systemic delivery of siRNA to tumor. However, the disordered tumor microenvironment still poses a potential impediment with respect to the efficient delivery of PEG-coated siRNA-lipoplexes. We recently showed that metronomic S-1 dosing (daily oral administration) enhanced the accumulation of PEG-coated liposome containing anticancer drug in solid tumor tissue and thereby increased therapeutic efficacy in tumor-bearing mouse model. To extend this work, we tried to investigate the effect of metronomic S-1 dosing on the intratumoral accumulation of PEG-coated siRNA-lipoplex and, thereby, their therapeutic efficacy in solid tumor-bearing mouse model. Results showed that metronomic S-1 dosing improved systemic delivery of intravenously injected PEG-coated siRNA-lipoplexes into solid tumor tissue. In addition, the combined therapy of S-1 and PEG-coated siRNA-lipoplexes showed potent tumor growth suppressive effect. Our proposed strategy may pose a promising therapeutic one to conquer cancer progression with siRNA.<br>"},"publication_date":"2013-03-01","publication_name":{"en":"Journal of the Pharmaceutical Society of Japan","ja":"薬学雑誌"},"volume":"Vol.133","number":"No.3","starting_page":"379","ending_page":"386","languages":["jpn"],"referee":true,"identifiers":{"doi":["10.1248/yakushi.12-00239-5"],"issn":["0031-6903"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:124, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507532"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/22995937","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=254013","label":"url"}],"paper_title":{"en":"Transport of PEGylated liposomes from the splenic marginal zone to the follicle in the induction phase of the accelerated blood clearance phenomenon.","ja":"Transport of PEGylated liposomes from the splenic marginal zone to the follicle in the induction phase of the accelerated blood clearance phenomenon."},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"清水 太郎"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"The accelerated blood clearance (ABC) phenomenon has been reported to enhance the clearance of PEGylated liposomes from the blood circulation when the liposomes are injected into the same animal repeatedly. We have shown that anti-PEG IgM production from splenic B cells is crucial in the ABC phenomenon. In this study, we describe the crucial role of marginal zone (MZ) B cells in the anti-PEG IgM production and recognition of PEGylated liposomes in the induction phase of ABC phenomenon. Suppression of the anti-PEG IgM production was correlated with the disappearance of IgM(high) cells in the MZ, particularly MZ-B cells, following cyclophosphamide (CPA)-treatment, confirming that splenic MZ-B cells are responsible for anti-PEG IgM production. The MZ-B cells stimulated by a first dose of PEGylated liposomes internalized the second dose of PEGylated liposomes in a PEG modification-dependent manner and transported the liposomes into the follicle (FO) region. To the best of our knowledge, this is the first report showing that PEGylated liposome is recognized by MZ-B cells and transported to the FO region like blood-borne antigens or immune complexes. It is likely that PEGylated liposomes are recognized as a TI-2 antigen by the first line of defense against life-threatening infections by blood-borne organisms. Our study may have implications for immunogenicity of synthesized polymer-grafted therapeutics including nanocarriers, nucleic acids and proteins.","ja":"The accelerated blood clearance (ABC) phenomenon has been reported to enhance the clearance of PEGylated liposomes from the blood circulation when the liposomes are injected into the same animal repeatedly. We have shown that anti-PEG IgM production from splenic B cells is crucial in the ABC phenomenon. In this study, we describe the crucial role of marginal zone (MZ) B cells in the anti-PEG IgM production and recognition of PEGylated liposomes in the induction phase of ABC phenomenon. Suppression of the anti-PEG IgM production was correlated with the disappearance of IgM(high) cells in the MZ, particularly MZ-B cells, following cyclophosphamide (CPA)-treatment, confirming that splenic MZ-B cells are responsible for anti-PEG IgM production. The MZ-B cells stimulated by a first dose of PEGylated liposomes internalized the second dose of PEGylated liposomes in a PEG modification-dependent manner and transported the liposomes into the follicle (FO) region. To the best of our knowledge, this is the first report showing that PEGylated liposome is recognized by MZ-B cells and transported to the FO region like blood-borne antigens or immune complexes. It is likely that PEGylated liposomes are recognized as a TI-2 antigen by the first line of defense against life-threatening infections by blood-borne organisms. Our study may have implications for immunogenicity of synthesized polymer-grafted therapeutics including nanocarriers, nucleic acids and proteins."},"publication_date":"2013-03","publication_name":{"en":"Immunobiology","ja":"Immunobiology"},"volume":"Vol.218","number":"No.5","starting_page":"725","ending_page":"732","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.imbio.2012.08.274"],"issn":["1878-3279"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:125, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507533"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23419947","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=259586","label":"url"}],"paper_title":{"en":"Suppression of immune response by antigen-decorated liposomes encapsulating model agents: A novel strategy for the treatment of allergy.","ja":"Suppression of immune response by antigen-decorated liposomes encapsulating model agents: A novel strategy for the treatment of allergy."},"authors":{"en":[{"name":"Ichikawa K"},{"name":"Asai T"},{"name":"Shimizu K"},{"name":"Yonezawa S"},{"name":"Urakami T"},{"name":"Miyauchi H"},{"name":"Kawashima H"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"},{"name":"Oku N"}],"ja":[{"name":"Ichikawa K"},{"name":"Asai T"},{"name":"Shimizu K"},{"name":"Yonezawa S"},{"name":"Urakami T"},{"name":"Miyauchi H"},{"name":"Kawashima H"},{"name":"石田 竜弘"},{"name":"際田 弘志"},{"name":"Oku N"}]},"description":{"en":"A specific antigen-sensitized animal has antigen-specific immune cells that recognize the antigen. Therefore, an antigen-modified drug carrier would be recognized by the immune cells. When such a carrier encapsulates certain drugs, these drugs should be specifically delivered to the immune cells. To examine this strategy, ovalbumin (OVA) was used as model antigen, and mice were presensitized with 100 μg of OVA with Alum. For preparing OVA-modified liposomes (OVA-lipo), OVA was incubated with DSPE-PEG-NHS and resulting DSPE-PEG-OVA was inserted into liposomes. OVA-specific IgG was produced 6-fold higher by intravenous injection of OVA-lipo thrice (10 μg as OVA in each injection) in OVA-sensitized mice, than that by the injection of control liposomes, suggesting that OVA-lipo was recognized by the antigen-specific immune cells. Moreover, intra-splenic accumulation of OVA-lipo was observed in OVA-sensitized mice, but not in naive mice. To achieve the delivery of a drug to specific immune cells, OVA-lipo encapsulated low dose of doxorubicin (DOX) as a model drug (20 μg DOX/mouse, Ca. 1 mg/kg) was injected in the sensitized mice. The injection of OVA-lipo encapsulating DOX suppressed the production of IgE against OVA, suggesting that the specific delivery of the drug to immune cells responsible for OVA recognition was achieved and that these immune cells were removed by the drug treatment. This strategy would be useful for the fundamental treatment of allergy by the use of immunosuppressing agents.","ja":"A specific antigen-sensitized animal has antigen-specific immune cells that recognize the antigen. Therefore, an antigen-modified drug carrier would be recognized by the immune cells. When such a carrier encapsulates certain drugs, these drugs should be specifically delivered to the immune cells. To examine this strategy, ovalbumin (OVA) was used as model antigen, and mice were presensitized with 100 μg of OVA with Alum. For preparing OVA-modified liposomes (OVA-lipo), OVA was incubated with DSPE-PEG-NHS and resulting DSPE-PEG-OVA was inserted into liposomes. OVA-specific IgG was produced 6-fold higher by intravenous injection of OVA-lipo thrice (10 μg as OVA in each injection) in OVA-sensitized mice, than that by the injection of control liposomes, suggesting that OVA-lipo was recognized by the antigen-specific immune cells. Moreover, intra-splenic accumulation of OVA-lipo was observed in OVA-sensitized mice, but not in naive mice. To achieve the delivery of a drug to specific immune cells, OVA-lipo encapsulated low dose of doxorubicin (DOX) as a model drug (20 μg DOX/mouse, Ca. 1 mg/kg) was injected in the sensitized mice. The injection of OVA-lipo encapsulating DOX suppressed the production of IgE against OVA, suggesting that the specific delivery of the drug to immune cells responsible for OVA recognition was achieved and that these immune cells were removed by the drug treatment. This strategy would be useful for the fundamental treatment of allergy by the use of immunosuppressing agents."},"publication_date":"2013-02-16","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.167","number":"No.3","starting_page":"284","ending_page":"289","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2013.02.002"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:126, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507534"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23174409","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84872804670&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=258822","label":"url"}],"paper_title":{"en":"Abrogation of the accelerated blood clearance phenomenon by SOXL regimen: Promise for clinical application.","ja":"Abrogation of the accelerated blood clearance phenomenon by SOXL regimen: Promise for clinical application."},"authors":{"en":[{"name":"Nagao Ai"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"長尾 愛"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"We recently proposed an S-1 combined with oxaliplatin (SOXL) regimen, a combination treatment consisting of oral metronomic S-1 dosing and intravenous administration of oxaliplatin (l-OHP) containing PEGylated liposomes, which showed potent antitumor activity in vivo. PEGylated liposomes induce what is referred to as the \"accelerated blood clearance (ABC) phenomenon\" upon repeated administration and consequently lose their long-circulating characteristics. This phenomenon seems to pose an impediment for the clinical application and use of PEGylated liposomal formulations. In the present study, l-OHP-containing PEGylated liposomes in the SOXL regimen significantly attenuated the ABC phenomenon in a dose-dependent manner through suppression of the anti-PEG IgM response, which allowed an enhanced hepatic uptake of subsequently injected test PEGylated liposomes. In tumor-bearing mice, the abrogation of the ABC phenomenon restored intratumor accumulation of subsequently injected PEGylated liposomes. Consequently, the therapeutic efficacy of the SOXL regimen over the combination of the free form of the drugs was credited not only with the selective delivery of drugs to the tumor tissue but also with ensuring an adequate accumulation of subsequent doses within the tumor tissue. The SOXL regimen we proposed may hold promise as a safe and effective treatment regimen for advanced colorectal cancer.","ja":"We recently proposed an S-1 combined with oxaliplatin (SOXL) regimen, a combination treatment consisting of oral metronomic S-1 dosing and intravenous administration of oxaliplatin (l-OHP) containing PEGylated liposomes, which showed potent antitumor activity in vivo. PEGylated liposomes induce what is referred to as the \"accelerated blood clearance (ABC) phenomenon\" upon repeated administration and consequently lose their long-circulating characteristics. This phenomenon seems to pose an impediment for the clinical application and use of PEGylated liposomal formulations. In the present study, l-OHP-containing PEGylated liposomes in the SOXL regimen significantly attenuated the ABC phenomenon in a dose-dependent manner through suppression of the anti-PEG IgM response, which allowed an enhanced hepatic uptake of subsequently injected test PEGylated liposomes. In tumor-bearing mice, the abrogation of the ABC phenomenon restored intratumor accumulation of subsequently injected PEGylated liposomes. Consequently, the therapeutic efficacy of the SOXL regimen over the combination of the free form of the drugs was credited not only with the selective delivery of drugs to the tumor tissue but also with ensuring an adequate accumulation of subsequent doses within the tumor tissue. The SOXL regimen we proposed may hold promise as a safe and effective treatment regimen for advanced colorectal cancer."},"publication_date":"2013-01-30","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.441","number":"No.1-2","starting_page":"395","ending_page":"401","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2012.11.015"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:127, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507536"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/22850293","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=250266","label":"url"}],"paper_title":{"en":"Accelerated blood clearance of PEGylated liposomes containing doxorubicin upon repeated administration to dogs.","ja":"Accelerated blood clearance of PEGylated liposomes containing doxorubicin upon repeated administration to dogs."},"authors":{"en":[{"name":"Suzuki Takuya"},{"name":"Ichihara Masako"},{"name":"Hyodo Kenji"},{"name":"Yamamoto Eiichi"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"},{"name":"Ishihara Hiroshi"},{"name":"Kikuchi Hiroshi"}],"ja":[{"name":"鈴木 卓也"},{"name":"市原 理子"},{"name":"Hyodo Kenji"},{"name":"Yamamoto Eiichi"},{"name":"石田 竜弘"},{"name":"際田 弘志"},{"name":"Ishihara Hiroshi"},{"name":"Kikuchi Hiroshi"}]},"description":{"en":"The accelerated blood clearance phenomenon involving anti-PEG IgM production has been recognized as an important issue for the design and development of PEGylated liposomes. Here, we show that empty PEGylated liposomes and Doxil, PEGylated liposomes containing doxorubicin, both caused anti-PEG IgM production and thereby a rapid clearance of the second and/or third dose of Doxil in Beagle dogs in a lipid-dose, inverse-dependent manner. It appears that the pharmacokinetic profile of the second and third administration of Doxil reflected the presence of anti-PEG IgM circulating in the blood. Doxil plus an excess amount of empty PEGylated liposomes rather enhanced the production of anti-PEG IgM compared to Doxil of the same doxorubicin dose. During sequential administration, increasing the lipid dose of Doxil in each dose by the addition of empty PEGylated liposomes strongly attenuated the magnitude of the ABC phenomenon during the effectuation phase of a second and third dose of Doxil. Our results suggest that the pre-clinical study of anti-cancer drug-containing PEGylated liposomes with dogs must be carefully designed and performed with monitoring of the anti-PEG IgM and liposomal drugs circulating in the blood.","ja":"The accelerated blood clearance phenomenon involving anti-PEG IgM production has been recognized as an important issue for the design and development of PEGylated liposomes. Here, we show that empty PEGylated liposomes and Doxil, PEGylated liposomes containing doxorubicin, both caused anti-PEG IgM production and thereby a rapid clearance of the second and/or third dose of Doxil in Beagle dogs in a lipid-dose, inverse-dependent manner. It appears that the pharmacokinetic profile of the second and third administration of Doxil reflected the presence of anti-PEG IgM circulating in the blood. Doxil plus an excess amount of empty PEGylated liposomes rather enhanced the production of anti-PEG IgM compared to Doxil of the same doxorubicin dose. During sequential administration, increasing the lipid dose of Doxil in each dose by the addition of empty PEGylated liposomes strongly attenuated the magnitude of the ABC phenomenon during the effectuation phase of a second and third dose of Doxil. Our results suggest that the pre-clinical study of anti-cancer drug-containing PEGylated liposomes with dogs must be carefully designed and performed with monitoring of the anti-PEG IgM and liposomal drugs circulating in the blood."},"publication_date":"2012-10-15","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.436","number":"No.1-2","starting_page":"636","ending_page":"643","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2012.07.049"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:128, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507537"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/22944302","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=254191","label":"url"}],"paper_title":{"en":"Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: a possible mechanism and the potential for clinical application.","ja":"Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: a possible mechanism and the potential for clinical application."},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Essam Eldin N"},{"name":"Ichihara Masako"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Essam Eldin N"},{"name":"市原 理子"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"We previously developed a PEG-coated cationic liposome that enabled dual targeting delivery of oxaliplatin (l-OHP) to both tumor endothelial cells and tumor cells in a solid tumor. The targeted liposomal l-OHP formulation consequently elicited potent antitumor efficacy in a murine solid tumor model after 3 sequential injections. However, the probable mechanism(s) for this enhanced antitumor activity has not been fully elucidated. In the present study, therefore, the changes in tumor microenvironment induced by sequential administration of liposomal l-OHP were investigated, with emphasis on its impact to the intratumoral localization of the subsequently injected dose. In addition, the potential for anti-PEG IgM production upon repeated administration of liposomal l-OHP-containing PEGylated lipid was clearly revealed. Two sequential injections of liposomal l-OHP induced superior apoptotic activity in tumor tissue and thus resulted in broader intratumor distribution of the subsequent test dose of PEG-coated cationic liposomes, compared with a single injection of liposomal l-OHP. In addition, it was confirmed that repeated administration of liposomal l-OHP did not induce a significant anti-PEG IgM response, indicating that l-OHP encapsulated in PEG-coated liposomes was efficient in abrogating the ABC phenomenon. These results suggest that sequential treatment strategies with liposomal cytotoxic agents might be superior to mono-treatment strategies in achieving alterations in the tumor microenvironment and maintaining/restoring the pharmacokinetics of the formulation, and, therefore, would result in substantial therapeutic efficacy.","ja":"We previously developed a PEG-coated cationic liposome that enabled dual targeting delivery of oxaliplatin (l-OHP) to both tumor endothelial cells and tumor cells in a solid tumor. The targeted liposomal l-OHP formulation consequently elicited potent antitumor efficacy in a murine solid tumor model after 3 sequential injections. However, the probable mechanism(s) for this enhanced antitumor activity has not been fully elucidated. In the present study, therefore, the changes in tumor microenvironment induced by sequential administration of liposomal l-OHP were investigated, with emphasis on its impact to the intratumoral localization of the subsequently injected dose. In addition, the potential for anti-PEG IgM production upon repeated administration of liposomal l-OHP-containing PEGylated lipid was clearly revealed. Two sequential injections of liposomal l-OHP induced superior apoptotic activity in tumor tissue and thus resulted in broader intratumor distribution of the subsequent test dose of PEG-coated cationic liposomes, compared with a single injection of liposomal l-OHP. In addition, it was confirmed that repeated administration of liposomal l-OHP did not induce a significant anti-PEG IgM response, indicating that l-OHP encapsulated in PEG-coated liposomes was efficient in abrogating the ABC phenomenon. These results suggest that sequential treatment strategies with liposomal cytotoxic agents might be superior to mono-treatment strategies in achieving alterations in the tumor microenvironment and maintaining/restoring the pharmacokinetics of the formulation, and, therefore, would result in substantial therapeutic efficacy."},"publication_date":"2012-08-24","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.438","number":"No.1-2","starting_page":"176","ending_page":"183","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2012.08.030"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:129, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507535"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/22863934","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390001204632293632/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=247686","label":"url"}],"paper_title":{"en":"Intravenous administration of polyethylene glycol-coated (PEGylated) proteins and PEGylated adenovirus elicits an anti-PEG immunoglobulin M response.","ja":"Intravenous administration of polyethylene glycol-coated (PEGylated) proteins and PEGylated adenovirus elicits an anti-PEG immunoglobulin M response."},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Ichihara Masako"},{"name":"Yoshioka Yasuo"},{"name":"Ishida Tatsuhiro"},{"name":"Nakagawa Shinsaku"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"清水 太郎"},{"name":"市原 理子"},{"name":"Yoshioka Yasuo"},{"name":"石田 竜弘"},{"name":"Nakagawa Shinsaku"},{"name":"際田 弘志"}]},"description":{"en":"A single intravenous administration of polyethylene glycol-coated (PEGylated) bovine serum albumin (BSA) and ovalbumin (OVA) elicited an anti-PEG immunoglobulin M (IgM) response, similar to that from PEGylated liposomes, although the administration did not elicit specific neutralizing antibodies to BSA and OVA. A cross-reactivity was observed between anti-PEG IgMs elicited by PEG-BSA and PEGylated liposomes. The anti-PEG IgM level induced by PEGylated proteins (BSA and OVA) reached the maximum at day 5 following intravenous injection. This production pattern was consistent with that induced by PEGylated liposomes. Splenectomy suppressed the anti-PEG IgM response against PEG-BSA and PEGylated liposomes. These observations relating PEG-BSA and PEGylated liposomes indicate that PEGylated proteins might promote the immune responses against PEG with a mechanism similar to that of PEGylated liposomes. In addition, a single intravenous administration of PEGylated adenovirus (PEG-Ad) also elicited an anti-PEG IgM response in a PEG-modification ratio dependent manner. To the best of our knowledge, this is the first report showing that an intravenous administration can elicit an anti-PEG IgM response against PEGylated substances. It appears that anti-PEG IgMs can be produced by the systemic administration of a PEGylated substance and may limit the efficacy of PEGylated substances such as proteins, Ad vector and nanoparticles, due to a cross-reactivity seen in some patients. The immunogenicity of PEGylated substances is usually tested against those very substances, rather than against covalently attached PEG. Our study suggests that the PEG immunogenicity of PEGylated therapeutic agents and particles merits further investigation.","ja":"A single intravenous administration of polyethylene glycol-coated (PEGylated) bovine serum albumin (BSA) and ovalbumin (OVA) elicited an anti-PEG immunoglobulin M (IgM) response, similar to that from PEGylated liposomes, although the administration did not elicit specific neutralizing antibodies to BSA and OVA. A cross-reactivity was observed between anti-PEG IgMs elicited by PEG-BSA and PEGylated liposomes. The anti-PEG IgM level induced by PEGylated proteins (BSA and OVA) reached the maximum at day 5 following intravenous injection. This production pattern was consistent with that induced by PEGylated liposomes. Splenectomy suppressed the anti-PEG IgM response against PEG-BSA and PEGylated liposomes. These observations relating PEG-BSA and PEGylated liposomes indicate that PEGylated proteins might promote the immune responses against PEG with a mechanism similar to that of PEGylated liposomes. In addition, a single intravenous administration of PEGylated adenovirus (PEG-Ad) also elicited an anti-PEG IgM response in a PEG-modification ratio dependent manner. To the best of our knowledge, this is the first report showing that an intravenous administration can elicit an anti-PEG IgM response against PEGylated substances. It appears that anti-PEG IgMs can be produced by the systemic administration of a PEGylated substance and may limit the efficacy of PEGylated substances such as proteins, Ad vector and nanoparticles, due to a cross-reactivity seen in some patients. The immunogenicity of PEGylated substances is usually tested against those very substances, rather than against covalently attached PEG. Our study suggests that the PEG immunogenicity of PEGylated therapeutic agents and particles merits further investigation."},"publication_date":"2012-08-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.35","number":"No.8","starting_page":"1336","ending_page":"1342","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.b12-00276"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:130, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507538"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/22554766","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=246848","label":"url"}],"paper_title":{"en":"Tumor type dependent vascular permeability constitutes a potential impediment to the therapeutic efficacy of liposomal oxaliplatin.","ja":"Tumor type dependent vascular permeability constitutes a potential impediment to the therapeutic efficacy of liposomal oxaliplatin."},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Matsumoto Haruna"},{"name":"Doi Yusuke"},{"name":"Nakamura Hiroyuki"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"松本 春菜"},{"name":"土井 祐輔"},{"name":"中村 浩之"},{"name":"石田 竜弘"},{"name":"際田 弘志"},{"name":"際田 弘志"}]},"description":{"en":"The delivery of anticancer agents to solid tumors is problematic. Nanomolecular drug carriers represent an attractive alternative strategy for efficient anticancer drug delivery to tumor tissue, because they appear to target tumors and have limited toxicity in normal tissue. However, inadequate and heterogeneous distribution of nanocarriers in tumor tissue is a major impediment for their efficient use in clinical cancer therapy. In the present study, we examined the effect of tumor type on the intratumor accumulation and distribution of polyethylene glycol (PEG)-coated liposomes using in vivo mouse models of three cancer cell lines: colon adenocarcinoma (C26), Lewis lung carcinoma (LLC), and B16BL6 melanoma (B16BL6). The tumor growth inhibition and the apoptotic response of oxaliplatin (l-OHP) encapsulated in the PEG-coated liposomes were tumor type dependent and correlated with a tendency toward tumor accumulation and intratumor distribution of PEG-coated liposome, in contrast to in vitro cytotoxicity of l-OHP. A potent antitumor effect observed in both C26 and LLC tumor-bearing mice was attributed to the enhanced extravasation with subsequent preferential accumulation of PEG-coated liposomes through tumor vasculature with high permeability. Our results suggest that the permeability of tumor vasculature constitutes a potential impediment to tumor localization and thereby to the antitumor efficacy of PEG-coated liposomal anticancer drugs.","ja":"The delivery of anticancer agents to solid tumors is problematic. Nanomolecular drug carriers represent an attractive alternative strategy for efficient anticancer drug delivery to tumor tissue, because they appear to target tumors and have limited toxicity in normal tissue. However, inadequate and heterogeneous distribution of nanocarriers in tumor tissue is a major impediment for their efficient use in clinical cancer therapy. In the present study, we examined the effect of tumor type on the intratumor accumulation and distribution of polyethylene glycol (PEG)-coated liposomes using in vivo mouse models of three cancer cell lines: colon adenocarcinoma (C26), Lewis lung carcinoma (LLC), and B16BL6 melanoma (B16BL6). The tumor growth inhibition and the apoptotic response of oxaliplatin (l-OHP) encapsulated in the PEG-coated liposomes were tumor type dependent and correlated with a tendency toward tumor accumulation and intratumor distribution of PEG-coated liposome, in contrast to in vitro cytotoxicity of l-OHP. A potent antitumor effect observed in both C26 and LLC tumor-bearing mice was attributed to the enhanced extravasation with subsequent preferential accumulation of PEG-coated liposomes through tumor vasculature with high permeability. Our results suggest that the permeability of tumor vasculature constitutes a potential impediment to tumor localization and thereby to the antitumor efficacy of PEG-coated liposomal anticancer drugs."},"publication_date":"2012-04-25","publication_name":{"en":"European Journal of Pharmaceutics and Biopharmaceutics","ja":"European Journal of Pharmaceutics and Biopharmaceutics"},"volume":"Vol.81","number":"No.3","starting_page":"524","ending_page":"531","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ejpb.2012.04.010"],"issn":["1873-3441"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:131, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507539"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/22525078","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=246651","label":"url"}],"paper_title":{"en":"Agitation during lipoplex formation harmonizes the interaction of siRNA to cationic liposomes.","ja":"Agitation during lipoplex formation harmonizes the interaction of siRNA to cationic liposomes."},"authors":{"en":[{"name":"Barichello Jose"},{"name":"Kizuki Shinji"},{"name":"Tagami Tatsuaki"},{"name":"Luiz Alberto Lira Soares"},{"name":"Kikuchi Hiroshi"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Barichello Jose"},{"name":"城 慎二"},{"name":"田上 辰秋"},{"name":"Luiz Alberto Lira Soares"},{"name":"Kikuchi Hiroshi"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"We recently demonstrated that agitation during lipoplex formation (vorLTsiR) improves the gene knockdown effect of siRNA because the resultant decrease in lipoplex size leads to an enhanced uptake by cells. In furthering this line of research, the present study was focused on the interaction of siRNA to cationic liposomes during lipoplex preparation. A fluorescence resonance energy transfer (FRET) study indicated that the application of agitation in the presence of siRNA effectively reorganized positively charged lipids (DC-6-14 and DOPE) in an order that effectively promoted further electrostatic interaction between the negatively charged phosphate backbone of siRNA and the positively charged lipids in the cationic liposome membrane. A circular dichroism (CD) study indicated that the agitation did not bring about a change in the A-form helix of siRNA, therefore the interactions between the lateral anionic groups of siRNA - responsible for the characteristic bands of the A-form helix - and cationic liposomes were effectively promoted. Factorial design coupled with response surface methodology was used to statistically analyze the influence of vortex speed and time and siRNA dose on the in vitro gene knockdown effects of siRNA-lipoplex that were spontaneously formulated (spoLTsiR) along with that formulated under agitation (vorLTsiR). The analysis indicated that vortex speed plays the most important role in enhancing the gene knockdown effect of siRNA among the three variables, although all three are important. It was concluded that the high energy transmitted by applying agitation during lipoplex formation harmonized the interaction of siRNA to positively charged lipids (DC-6-14 and DOPE) in cationic liposomes, resulting in a superior gene knockdown efficacy of vorLTsiR compared to spoLTsiR. Our study suggests that the preparation procedure is one of the critical factors in producing the enhanced gene knockdown effect of siRNA.","ja":"We recently demonstrated that agitation during lipoplex formation (vorLTsiR) improves the gene knockdown effect of siRNA because the resultant decrease in lipoplex size leads to an enhanced uptake by cells. In furthering this line of research, the present study was focused on the interaction of siRNA to cationic liposomes during lipoplex preparation. A fluorescence resonance energy transfer (FRET) study indicated that the application of agitation in the presence of siRNA effectively reorganized positively charged lipids (DC-6-14 and DOPE) in an order that effectively promoted further electrostatic interaction between the negatively charged phosphate backbone of siRNA and the positively charged lipids in the cationic liposome membrane. A circular dichroism (CD) study indicated that the agitation did not bring about a change in the A-form helix of siRNA, therefore the interactions between the lateral anionic groups of siRNA - responsible for the characteristic bands of the A-form helix - and cationic liposomes were effectively promoted. Factorial design coupled with response surface methodology was used to statistically analyze the influence of vortex speed and time and siRNA dose on the in vitro gene knockdown effects of siRNA-lipoplex that were spontaneously formulated (spoLTsiR) along with that formulated under agitation (vorLTsiR). The analysis indicated that vortex speed plays the most important role in enhancing the gene knockdown effect of siRNA among the three variables, although all three are important. It was concluded that the high energy transmitted by applying agitation during lipoplex formation harmonized the interaction of siRNA to positively charged lipids (DC-6-14 and DOPE) in cationic liposomes, resulting in a superior gene knockdown efficacy of vorLTsiR compared to spoLTsiR. Our study suggests that the preparation procedure is one of the critical factors in producing the enhanced gene knockdown effect of siRNA."},"publication_date":"2012-04-12","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.430","number":"No.1-2","starting_page":"359","ending_page":"365","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2012.04.006"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:132, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507540"},"force":{"see_also":[{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84864774906&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=243690","label":"url"}],"paper_title":{"en":"Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model","ja":"Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model"},"authors":{"en":[{"name":"Tagami Tatsuaki"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Matsunaga Mariko"},{"name":"Moriyoshi Naoto"},{"name":"Nakamura Hiroyuki"},{"name":"Nakamura Kazuya"},{"name":"Suzuki Takuya"},{"name":"Doi Yusuke"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"田上 辰秋"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"松永 真理子"},{"name":"森吉 直人"},{"name":"中村 浩之"},{"name":"中村 和也"},{"name":"鈴木 卓也"},{"name":"土井 祐輔"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"publication_date":"2012-04-01","publication_name":{"en":"Drug Delivery and Translational Research","ja":"Drug Delivery and Translational Research"},"volume":"Vol.2","number":"No.2","starting_page":"77","ending_page":"86","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s13346-012-0059-1"],"issn":["2190-3948"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:133, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507541"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/22310465","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=244305","label":"url"}],"paper_title":{"en":"Combination therapy with metronomic S-1 dosing and oxaliplatin-containing PEG-coated cationic liposomes in a murine colorectal tumor model: Synergy or antagonism?","ja":"Combination therapy with metronomic S-1 dosing and oxaliplatin-containing PEG-coated cationic liposomes in a murine colorectal tumor model: Synergy or antagonism?"},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Okada Tomoko"},{"name":"Doi Yusuke"},{"name":"Ichihara Masako"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"岡田 知子"},{"name":"土井 祐輔"},{"name":"市原 理子"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Combination therapy with 2 or more drugs with different mechanisms of action has been considered a promising strategy for the effective treatment of advanced and metastatic cancers. However, the rational design of combination therapy represents a potential prerequisite for its effectiveness. Recently, we showed that the combination of oral metronomic S-1 dosing with oxaliplatin (l-OHP)-containing PEG-coated \"neutral\" liposomes exerted excellent antitumor activity. In addition, we recently designed a PEG-coated \"cationic\" liposome for dual-targeting delivery of l-OHP to tumor endothelial cells and tumor cells in a solid tumor. This targeted liposomal l-OHP formulation showed efficient antitumor activity in a murine tumor model, compared with l-OHP-containing PEG-coated \"neutral\" liposomes. In the present study, we investigated the issue of whether metronomic S-1 dosing with l-OHP-containing PEG-coated \"cationic\" liposomes creates synergy. Unfortunately, metronomic S-1 dosing resulted in impaired delivery of PEG-coated \"cationic\" liposomes into tumor tissue, presumably by decreasing the binding sites on tumor blood vessels available for the liposomes. The anticipated cytotoxic synergistic effect of the combination treatment was not achieved. Instead, the combination treatment showed lower antitumor efficacy than l-OHP-containing PEG-coated \"cationic\" liposomes alone. These results suggest that the combined treatment of S-1 and l-OHP-containing PEG-coated \"cationic\" liposomes seems to be antagonistic rather than synergistic.","ja":"Combination therapy with 2 or more drugs with different mechanisms of action has been considered a promising strategy for the effective treatment of advanced and metastatic cancers. However, the rational design of combination therapy represents a potential prerequisite for its effectiveness. Recently, we showed that the combination of oral metronomic S-1 dosing with oxaliplatin (l-OHP)-containing PEG-coated \"neutral\" liposomes exerted excellent antitumor activity. In addition, we recently designed a PEG-coated \"cationic\" liposome for dual-targeting delivery of l-OHP to tumor endothelial cells and tumor cells in a solid tumor. This targeted liposomal l-OHP formulation showed efficient antitumor activity in a murine tumor model, compared with l-OHP-containing PEG-coated \"neutral\" liposomes. In the present study, we investigated the issue of whether metronomic S-1 dosing with l-OHP-containing PEG-coated \"cationic\" liposomes creates synergy. Unfortunately, metronomic S-1 dosing resulted in impaired delivery of PEG-coated \"cationic\" liposomes into tumor tissue, presumably by decreasing the binding sites on tumor blood vessels available for the liposomes. The anticipated cytotoxic synergistic effect of the combination treatment was not achieved. Instead, the combination treatment showed lower antitumor efficacy than l-OHP-containing PEG-coated \"cationic\" liposomes alone. These results suggest that the combined treatment of S-1 and l-OHP-containing PEG-coated \"cationic\" liposomes seems to be antagonistic rather than synergistic."},"publication_date":"2012-01-30","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.426","starting_page":"263","ending_page":"270","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2012.01.046"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:134, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507542"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/22101286","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=242617","label":"url"}],"paper_title":{"en":"Anti-angiogenic therapy via cationic liposome-mediated systemic siRNA delivery.","ja":"Anti-angiogenic therapy via cationic liposome-mediated systemic siRNA delivery."},"authors":{"en":[{"name":"Tagami Tatsuaki"},{"name":"Suzuki Takuya"},{"name":"Matsunaga Mariko"},{"name":"Nakamura Kazuya"},{"name":"Moriyoshi Naoto"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"田上 辰秋"},{"name":"鈴木 卓也"},{"name":"松永 真理子"},{"name":"中村 和也"},{"name":"森吉 直人"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"siRNA has been touted as a therapeutic molecule against genetic diseases, which include cancers. But several challenging issues remain in order to achieve efficient systemic siRNA delivery and a sufficient therapeutic effect for siRNA in vivo. Cationic liposome shows promise as a carrier for nucleic acids, as it can selectively bind to angiogenic tumor blood vessels. In this way, anti-angiogenic therapy via cationic liposome-mediated systemic siRNA delivery could be achieved in cancer therapy. In the present study, we proved our assumption by preparing various kinds of polyethylene glycol (PEG)-coated siRNA/cationic liposome complexes (siRNA-lipoplexes) and screening the avidity of these siRNA-lipoplexes upon angiogenic tumor blood vessels by means of a murine dorsal air sac (DAS) model. The lipoplex, having a lipid composition of DC-6-14/POPC/CHOL/DOPE/mPEG(2000)-DSPE=20/30/30/20/5 (molar ratio) and a charge ratio of cationic liposome and siRNA=3.81 (+/-), showed a higher binding index to newly formed blood vessels. Systemic injection with the lipoplex containing siRNA for the Argonaute2 gene (apoptosis-inducible siRNA) resulted in significant anti-tumor effect without severe side effects in mice with Lewis lung carcinoma. Our results indicate that the PEGylated cationic liposome-mediated systemic delivery of cytotoxic siRNA achieves anti-angiogenesis, resulting in the suppression of tumor growth.","ja":"siRNA has been touted as a therapeutic molecule against genetic diseases, which include cancers. But several challenging issues remain in order to achieve efficient systemic siRNA delivery and a sufficient therapeutic effect for siRNA in vivo. Cationic liposome shows promise as a carrier for nucleic acids, as it can selectively bind to angiogenic tumor blood vessels. In this way, anti-angiogenic therapy via cationic liposome-mediated systemic siRNA delivery could be achieved in cancer therapy. In the present study, we proved our assumption by preparing various kinds of polyethylene glycol (PEG)-coated siRNA/cationic liposome complexes (siRNA-lipoplexes) and screening the avidity of these siRNA-lipoplexes upon angiogenic tumor blood vessels by means of a murine dorsal air sac (DAS) model. The lipoplex, having a lipid composition of DC-6-14/POPC/CHOL/DOPE/mPEG(2000)-DSPE=20/30/30/20/5 (molar ratio) and a charge ratio of cationic liposome and siRNA=3.81 (+/-), showed a higher binding index to newly formed blood vessels. Systemic injection with the lipoplex containing siRNA for the Argonaute2 gene (apoptosis-inducible siRNA) resulted in significant anti-tumor effect without severe side effects in mice with Lewis lung carcinoma. Our results indicate that the PEGylated cationic liposome-mediated systemic delivery of cytotoxic siRNA achieves anti-angiogenesis, resulting in the suppression of tumor growth."},"publication_date":"2012-01-17","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.422","number":"No.1-2","starting_page":"280","ending_page":"289","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2011.10.059"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:135, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507543"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/21878904","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=231566","label":"url"}],"paper_title":{"en":"A double-modulation strategy in cancer treatment with a chemotherapeutic agent and siRNA.","ja":"A double-modulation strategy in cancer treatment with a chemotherapeutic agent and siRNA."},"authors":{"en":[{"name":"Nakamura Kazuya"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Matsunaga Mariko"},{"name":"Doi Yusuke"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"中村 和也"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"松永 真理子"},{"name":"土井 祐輔"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"5-Fluorouracil (5-FU) is broadly considered the drug of choice for treating human colorectal cancer (CRC). However, 5-FU resistance, mainly caused by the overexpression of antiapoptotic proteins such as Bcl-2, often leads ultimately to treatment failure. We here investigated the effect of Bcl-2 gene silencing, using small interfering RNA (siRNA) (siBcl-2), on the efficacy of 5-FU in CRC. Transfection of siBcl-2 by a Lipofectamine2000/siRNA lipoplex effectively downregulated Bcl-2 expression in the DLD-1 cell line (a CRC), resulting in significant cell growth inhibition in vitro upon treatment with 5-FU. For in vivo treatments, S-1, an oral formulation of Tegafur (TF), a prodrug of 5-FU, was used to mimic 5-FU infusion. The combined treatment of polyethylene glycol (PEG)-coated siBcl-2-lipoplex and S-1 showed superior tumor growth suppression in a DLD-1 xenograft model, compared to each single treatment. Surprisingly, daily S-1 treatment enhanced the accumulation of PEG-coated siBcl-2-lipoplex in tumor tissue. We propose a novel double modulation strategy in cancer treatment, in which chemotherapy enhances intratumoral siRNA delivery and the delivered siRNA enhances the chemosensitivity of tumors. Combination of siRNA-containing nanocarriers with chemotherapy may compensate for the limited delivery of siRNA to tumor tissue. In addition, such modulation strategy may be considered a promising therapeutic approach to successfully managing 5-FU-resistant tumors.","ja":"5-Fluorouracil (5-FU) is broadly considered the drug of choice for treating human colorectal cancer (CRC). However, 5-FU resistance, mainly caused by the overexpression of antiapoptotic proteins such as Bcl-2, often leads ultimately to treatment failure. We here investigated the effect of Bcl-2 gene silencing, using small interfering RNA (siRNA) (siBcl-2), on the efficacy of 5-FU in CRC. Transfection of siBcl-2 by a Lipofectamine2000/siRNA lipoplex effectively downregulated Bcl-2 expression in the DLD-1 cell line (a CRC), resulting in significant cell growth inhibition in vitro upon treatment with 5-FU. For in vivo treatments, S-1, an oral formulation of Tegafur (TF), a prodrug of 5-FU, was used to mimic 5-FU infusion. The combined treatment of polyethylene glycol (PEG)-coated siBcl-2-lipoplex and S-1 showed superior tumor growth suppression in a DLD-1 xenograft model, compared to each single treatment. Surprisingly, daily S-1 treatment enhanced the accumulation of PEG-coated siBcl-2-lipoplex in tumor tissue. We propose a novel double modulation strategy in cancer treatment, in which chemotherapy enhances intratumoral siRNA delivery and the delivered siRNA enhances the chemosensitivity of tumors. Combination of siRNA-containing nanocarriers with chemotherapy may compensate for the limited delivery of siRNA to tumor tissue. In addition, such modulation strategy may be considered a promising therapeutic approach to successfully managing 5-FU-resistant tumors."},"publication_date":"2011-08-30","publication_name":{"en":"Molecular Therapy","ja":"Molecular Therapy"},"volume":"Vol.19","number":"No.11","starting_page":"2040","ending_page":"2047","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/mt.2011.174"],"issn":["1525-0024"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:136, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507544"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=226170","label":"url"}],"paper_title":{"en":"Argonaute2 is a potential target for siRNA-based cancer therapy for HT1080 human fibrosarcoma.","ja":"Argonaute2 is a potential target for siRNA-based cancer therapy for HT1080 human fibrosarcoma."},"authors":{"en":[{"name":"Tagami Tatsuaki"},{"name":"Suzuki Takuya"},{"name":"Hirose Kiyomi"},{"name":"Barichello Jose"},{"name":"Yamazaki Naoshi"},{"name":"Asai Tomohiro"},{"name":"Oku Naoto"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"田上 辰秋"},{"name":"鈴木 卓也"},{"name":"Hirose Kiyomi"},{"name":"Barichello Jose"},{"name":"山﨑 尚志"},{"name":"Asai Tomohiro"},{"name":"Oku Naoto"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"publication_date":"2011-08","publication_name":{"en":"Drug Delivery and Translational Research","ja":"Drug Delivery and Translational Research"},"volume":"Vol.1","number":"No.4","starting_page":"277","ending_page":"288","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s13346-011-0025-3"],"issn":["2190-393X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:137, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507545"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/21682565","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=223982","label":"url"}],"paper_title":{"en":"Immunoliposomal drug delivery system targeting lectin-like oxidized low density lipoprotein receptor 1 for carotid plaque lesion in rats.","ja":"Immunoliposomal drug delivery system targeting lectin-like oxidized low density lipoprotein receptor 1 for carotid plaque lesion in rats."},"authors":{"en":[{"name":"Saito Atsushi"},{"name":"Shimizu Hiroaki"},{"name":"Doi Yusuke"},{"name":"Ishida Tatsuhiro"},{"name":"Fujimura Miki"},{"name":"Inoue Takashi"},{"name":"Kiwada Hiroshi"},{"name":"Tominaga Teiji"}],"ja":[{"name":"Saito Atsushi"},{"name":"Shimizu Hiroaki"},{"name":"土井 祐輔"},{"name":"石田 竜弘"},{"name":"Fujimura Miki"},{"name":"Inoue Takashi"},{"name":"際田 弘志"},{"name":"Tominaga Teiji"}]},"description":{"en":"Targeted drug delivery with immunoliposomes has been applied to various in vivo animal models and is newly focused as a novel therapeutic target. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX1) is a potent regulator of systemic atherosclerosis, and the authors focused on its effect on carotid plaques. The authors developed a LOX1-targeted liposomal rho-kinase inhibitor and examined the therapeutic effect on carotid intimal hypertrophy in rats. LOX1-targeted rho-kinase inhibitor fasudil-containing liposomes, composed of hydrogenated soy phosphatidylcholine/cholesterol/PEG(2000)-DSPE, were prepared by conjugating anti-LOX1 antibodies on the surface and by remote loading of fasudil. Carotid intimal hypertrophy was induced by balloon injury, and the drugs were intravenously administered on Day 3 postinjury. The rats were divided into 4 groups: nontreatment, treatment with intravenous fasudil (2 mg), treatment with liposomal fasudil (2 mg), and treatment with LOX1-targeted liposomal fasudil (2 mg). The authors compared intimal hypertrophy, atherosclerotic factor, and matrix metalloproteinase-9 expression among groups. DiI-labeled LOX1-targeted liposomes were prominently observed in the lesions on Day 7 after the surgery. The intimal thickness was significantly reduced in the LOX1-targeted liposomal fasudil-treated group (mean 81.6 ± 13.9 m) compared with the other groups (no treatment 105.4 ± 16.8 m; fasudil treatment 102.4 ± 20.0 m; and liposomal fasudil treatment 102.8 ± 22.2 m; p = 0.046). Matrix metalloproteinase-9 expression was also significantly reduced in the LOX1-targeted liposomal fasudil group. Liposomes conjugated with anti-LOX1 antibody effectively reached carotid artery lesions, and liposomal rho-kinase significantly inhibited intimal hypertrophy. The new liposomal drug delivery system targeting LOX1 may become a therapeutic strategy for atherosclerotic diseases.","ja":"Targeted drug delivery with immunoliposomes has been applied to various in vivo animal models and is newly focused as a novel therapeutic target. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX1) is a potent regulator of systemic atherosclerosis, and the authors focused on its effect on carotid plaques. The authors developed a LOX1-targeted liposomal rho-kinase inhibitor and examined the therapeutic effect on carotid intimal hypertrophy in rats. LOX1-targeted rho-kinase inhibitor fasudil-containing liposomes, composed of hydrogenated soy phosphatidylcholine/cholesterol/PEG(2000)-DSPE, were prepared by conjugating anti-LOX1 antibodies on the surface and by remote loading of fasudil. Carotid intimal hypertrophy was induced by balloon injury, and the drugs were intravenously administered on Day 3 postinjury. The rats were divided into 4 groups: nontreatment, treatment with intravenous fasudil (2 mg), treatment with liposomal fasudil (2 mg), and treatment with LOX1-targeted liposomal fasudil (2 mg). The authors compared intimal hypertrophy, atherosclerotic factor, and matrix metalloproteinase-9 expression among groups. DiI-labeled LOX1-targeted liposomes were prominently observed in the lesions on Day 7 after the surgery. The intimal thickness was significantly reduced in the LOX1-targeted liposomal fasudil-treated group (mean 81.6 ± 13.9 m) compared with the other groups (no treatment 105.4 ± 16.8 m; fasudil treatment 102.4 ± 20.0 m; and liposomal fasudil treatment 102.8 ± 22.2 m; p = 0.046). Matrix metalloproteinase-9 expression was also significantly reduced in the LOX1-targeted liposomal fasudil group. Liposomes conjugated with anti-LOX1 antibody effectively reached carotid artery lesions, and liposomal rho-kinase significantly inhibited intimal hypertrophy. The new liposomal drug delivery system targeting LOX1 may become a therapeutic strategy for atherosclerotic diseases."},"publication_date":"2011-06-17","publication_name":{"en":"Journal of Neurosurgery","ja":"Journal of Neurosurgery"},"volume":"Vol.115","number":"No.4","starting_page":"720","ending_page":"727","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3171/2011.5.JNS10227"],"issn":["1933-0693"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:138, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507546"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/21392562","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=223980","label":"url"}],"paper_title":{"en":"Agitation during lipoplex formation improves the gene knockdown effect of siRNA.","ja":"Agitation during lipoplex formation improves the gene knockdown effect of siRNA."},"authors":{"en":[{"name":"Barichello Jose"},{"name":"Kizuki Shinji"},{"name":"Tagami Tatsuaki"},{"name":"Asai Tomohiro"},{"name":"Ishida Tatsuhiro"},{"name":"Kikuchi Hiroshi"},{"name":"Oku Naoto"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Barichello Jose"},{"name":"城 慎二"},{"name":"田上 辰秋"},{"name":"Asai Tomohiro"},{"name":"石田 竜弘"},{"name":"Kikuchi Hiroshi"},{"name":"Oku Naoto"},{"name":"際田 弘志"}]},"description":{"en":"The successful delivery of therapeutic siRNA to the designated target cells and their availability at the intracellular site of action are crucial requirements for successful RNAi therapy. In the present study, we focused on the siRNA-lipoplex preparation procedure and its effect on the gene-knockdown efficiency of siRNA in vitro. Agitation (vortex-mixing) during siRNA-lipoplex (vor-LTsiR) preparation and its effect on the gene-knockdown efficiency of stably expressed cell GFP was investigated, and their efficiency was compared with that of spontaneously formed lipoplex (spo-LTsiR). A dramatic difference in size between lipoplexes was observed at the N/P ratio of 7.62 (siRNA dose of 30 nM), even though both lipoplexes were positively charged. With the siRNA dose of 30 nM, vor-LTsiR accomplished a 50% gene-knockdown, while spo-LTsiR managed a similar knockdown effect at the 120 nM level, suggesting that the preparation procedure remarkably affects the gene-knockdown efficacy of siRNA. The uptake of vor-LTsiR was mainly via clathrin-mediated endocytosis, whereas that of spo-LTsiR was via membrane fusion. In addition, by inhibiting clathrin-mediated endocytosis, the gene-knockdown efficiency was significantly lowered. The size of the lipoplex, promoted by the preparation procedure, is likely to define the entry pathway, resulting in an increased amount of siRNA internalized in cells and an enhanced gene-knockdown efficacy. The results of the present study definitively show that a proper siRNA-lipoplex preparation procedure makes a significant contribution to the efficiency of cellular uptake, and thereby, to the gene-knockdown efficiency of siRNA.","ja":"The successful delivery of therapeutic siRNA to the designated target cells and their availability at the intracellular site of action are crucial requirements for successful RNAi therapy. In the present study, we focused on the siRNA-lipoplex preparation procedure and its effect on the gene-knockdown efficiency of siRNA in vitro. Agitation (vortex-mixing) during siRNA-lipoplex (vor-LTsiR) preparation and its effect on the gene-knockdown efficiency of stably expressed cell GFP was investigated, and their efficiency was compared with that of spontaneously formed lipoplex (spo-LTsiR). A dramatic difference in size between lipoplexes was observed at the N/P ratio of 7.62 (siRNA dose of 30 nM), even though both lipoplexes were positively charged. With the siRNA dose of 30 nM, vor-LTsiR accomplished a 50% gene-knockdown, while spo-LTsiR managed a similar knockdown effect at the 120 nM level, suggesting that the preparation procedure remarkably affects the gene-knockdown efficacy of siRNA. The uptake of vor-LTsiR was mainly via clathrin-mediated endocytosis, whereas that of spo-LTsiR was via membrane fusion. In addition, by inhibiting clathrin-mediated endocytosis, the gene-knockdown efficiency was significantly lowered. The size of the lipoplex, promoted by the preparation procedure, is likely to define the entry pathway, resulting in an increased amount of siRNA internalized in cells and an enhanced gene-knockdown efficacy. The results of the present study definitively show that a proper siRNA-lipoplex preparation procedure makes a significant contribution to the efficiency of cellular uptake, and thereby, to the gene-knockdown efficiency of siRNA."},"publication_date":"2011-03-08","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.410","number":"No.1-2","starting_page":"153","ending_page":"160","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2011.03.001"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:139, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507547"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=220438","label":"url"}],"paper_title":{"en":"Anti-PEG IgM response against PEGylated liposomes in mice and rats.","ja":"Anti-PEG IgM response against PEGylated liposomes in mice and rats."},"authors":{"en":[{"name":"Ichihara Masako"},{"name":"Shimizu Taro"},{"name":"Imoto Ami"},{"name":"Hashiguchi Yuki"},{"name":"Uehara Yumi"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"市原 理子"},{"name":"清水 太郎"},{"name":"井本 亜美"},{"name":"橋口 優紀"},{"name":"上原 友美"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"publication_date":"2011-03","publication_name":{"en":"Pharmaceutics","ja":"Pharmaceutics"},"volume":"Vol.3","number":"No.1","starting_page":"1","ending_page":"11","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3390/pharmaceutics3010001"],"issn":["1999-4923"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:140, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507548"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/21223988","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=220437","label":"url"}],"paper_title":{"en":"Anti-PEG IgM production by siRNA encapsulated in a PEGylated lipid nanocarrier is dependent on the sequence of the siRNA.","ja":"Anti-PEG IgM production by siRNA encapsulated in a PEGylated lipid nanocarrier is dependent on the sequence of the siRNA."},"authors":{"en":[{"name":"Tagami Tatsuaki"},{"name":"Uehara Yumi"},{"name":"Moriyoshi Naoto"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"田上 辰秋"},{"name":"上原 友美"},{"name":"森吉 直人"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"We recently reported that the prolonged circulation property of PEGylated cationic liposomes containing nucleic acids disappears, if the second dose is injected within a few days later, due to the production of anti-PEG IgM. This accelerated blood clearance is a concern for treating diseases which require repeated treatment with a PEGylated formulation containing nucleic acids. In this study, we investigated the effect of encapsulation of siRNA in a recently introduced PEGylated lipid nanocarrier for which the term \"wrapsome\" (PEGylated wrapsome, PEG-WS) was proposed as well as the sequence of the encapsulated siRNA on anti-PEG IgM production. siRNA encapsulated in PEG-WS produced little anti-PEG IgM relative to siRNA in conventional PEGylated lipoplexes. The sequence of siRNA in the PEG-WL dramatically affected the anti-PEG IgM production; a potent immune stimulatory siRNA induced a higher anti-PEG IgM production. Such enhanced effect was abrogated by incorporation of 2'-O-methyl (2'-OMe) uridine into the sequence of siRNA, probably via inhibiting cytokine induction such as IL-6 and TNF-. Our results strongly indicate that the use of an encapsulation-type lipid nanocarrier with a low immuno-stimulatory siRNA may allow repeated dosing of siRNA containing PEGylated formulations without the induction of a strong immune reaction against PEG and thus may advance synthetic siRNA into a broad range of therapeutic applications.","ja":"We recently reported that the prolonged circulation property of PEGylated cationic liposomes containing nucleic acids disappears, if the second dose is injected within a few days later, due to the production of anti-PEG IgM. This accelerated blood clearance is a concern for treating diseases which require repeated treatment with a PEGylated formulation containing nucleic acids. In this study, we investigated the effect of encapsulation of siRNA in a recently introduced PEGylated lipid nanocarrier for which the term \"wrapsome\" (PEGylated wrapsome, PEG-WS) was proposed as well as the sequence of the encapsulated siRNA on anti-PEG IgM production. siRNA encapsulated in PEG-WS produced little anti-PEG IgM relative to siRNA in conventional PEGylated lipoplexes. The sequence of siRNA in the PEG-WL dramatically affected the anti-PEG IgM production; a potent immune stimulatory siRNA induced a higher anti-PEG IgM production. Such enhanced effect was abrogated by incorporation of 2'-O-methyl (2'-OMe) uridine into the sequence of siRNA, probably via inhibiting cytokine induction such as IL-6 and TNF-. Our results strongly indicate that the use of an encapsulation-type lipid nanocarrier with a low immuno-stimulatory siRNA may allow repeated dosing of siRNA containing PEGylated formulations without the induction of a strong immune reaction against PEG and thus may advance synthetic siRNA into a broad range of therapeutic applications."},"publication_date":"2011-01-09","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.151","number":"No.2","starting_page":"149","ending_page":"154","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2010.12.013"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:141, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507549"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/20731663","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=211643","label":"url"}],"paper_title":{"en":"Combination therapy of metronomic S-1 dosing with oxaliplatin-containing PEG-coated liposome improves antitumor activity in a murine colorectal tumor model.","ja":"Combination therapy of metronomic S-1 dosing with oxaliplatin-containing PEG-coated liposome improves antitumor activity in a murine colorectal tumor model."},"authors":{"en":[{"name":"Doi Yusuke"},{"name":"Okada Tomoko"},{"name":"Matsumoto Haruna"},{"name":"Ichihara Masako"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"土井 祐輔"},{"name":"岡田 知子"},{"name":"松本 春菜"},{"name":"市原 理子"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Metronomic chemotherapy has been advocated recently as a novel chemotherapeutic regimen. Polyethylene glycol (PEG)-coated liposomes are well known to accumulate in solid tumors by virtue of the highly permeable angiogenic blood vessels characteristic for growing tumor tissue, the so-called \"enhanced permeability and retention (EPR) effect\". To expand the range of applications and investigate the clinical value of the combination strategy, the therapeutic benefit of metronomic S-1 dosing in combination with oxaliplatin (l-OHP)-containing PEG-coated liposomes was evaluated in a murine colon carcinoma-bearing mice model. S-1 is an oral fluoropyrimidine formulation and metronomic S-1 dosing is a promising alternative to infused 5-FU in colorectal cancer therapy. Therefore, the combination of S-1 with l-OHP may be an alternative to FOLFOX (infusional 5-FU/leucovorin (LV) in combination with l-OHP), which is a first-line therapeutic regimen of a colorectal carcinoma. The combination of oral metronomic S-1 dosing with intravenous administration of liposomal l-OHP formulation exerted excellent antitumor activity without severe overlapping side-effects, compared with either metronomic S-1 dosing, free l-OHP or liposomal l-OHP formulation alone or metronomic S-1 dosing plus free l-OHP. We confirmed that the synergistic antitumor effect is due to prolonged retention of l-OHP in the tumor on account of the PEG-coated liposomes, presumably via alteration of the tumor microenvironment caused by the metronomic S-1 treatment. The combination regimen proposed here may be a breakthrough in treatment of intractable solid tumors and an alternative to FOLFOX in advanced colorectal cancer therapy with acceptable tolerance and preservation of quality of life (QOL).","ja":"Metronomic chemotherapy has been advocated recently as a novel chemotherapeutic regimen. Polyethylene glycol (PEG)-coated liposomes are well known to accumulate in solid tumors by virtue of the highly permeable angiogenic blood vessels characteristic for growing tumor tissue, the so-called \"enhanced permeability and retention (EPR) effect\". To expand the range of applications and investigate the clinical value of the combination strategy, the therapeutic benefit of metronomic S-1 dosing in combination with oxaliplatin (l-OHP)-containing PEG-coated liposomes was evaluated in a murine colon carcinoma-bearing mice model. S-1 is an oral fluoropyrimidine formulation and metronomic S-1 dosing is a promising alternative to infused 5-FU in colorectal cancer therapy. Therefore, the combination of S-1 with l-OHP may be an alternative to FOLFOX (infusional 5-FU/leucovorin (LV) in combination with l-OHP), which is a first-line therapeutic regimen of a colorectal carcinoma. The combination of oral metronomic S-1 dosing with intravenous administration of liposomal l-OHP formulation exerted excellent antitumor activity without severe overlapping side-effects, compared with either metronomic S-1 dosing, free l-OHP or liposomal l-OHP formulation alone or metronomic S-1 dosing plus free l-OHP. We confirmed that the synergistic antitumor effect is due to prolonged retention of l-OHP in the tumor on account of the PEG-coated liposomes, presumably via alteration of the tumor microenvironment caused by the metronomic S-1 treatment. The combination regimen proposed here may be a breakthrough in treatment of intractable solid tumors and an alternative to FOLFOX in advanced colorectal cancer therapy with acceptable tolerance and preservation of quality of life (QOL)."},"publication_date":"2010-11","publication_name":{"en":"Cancer Science","ja":"Cancer Science"},"volume":"Vol.101","number":"No.11","starting_page":"2470","ending_page":"2475","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1111/j.1349-7006.2010.01678.x"],"issn":["1349-7006"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:142, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507550"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/20795699","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=214096","label":"url"}],"paper_title":{"en":"Evasion of the accelerated blood clearance phenomenon by coating of nanoparticles with various hydrophilic polymers.","ja":"Evasion of the accelerated blood clearance phenomenon by coating of nanoparticles with various hydrophilic polymers."},"authors":{"en":[{"name":"Ishihara T"},{"name":"Maeda T"},{"name":"Sakamoto H"},{"name":"Takasaki N"},{"name":"Shigyo M"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"},{"name":"Mizushima Y"},{"name":"Mizushima T"}],"ja":[{"name":"Ishihara T"},{"name":"Maeda T"},{"name":"Sakamoto H"},{"name":"Takasaki N"},{"name":"Shigyo M"},{"name":"石田 竜弘"},{"name":"際田 弘志"},{"name":"Mizushima Y"},{"name":"Mizushima T"}]},"description":{"en":"The accelerated blood clearance (ABC) phenomenon is induced upon repeated injections of poly(ethylene glycol) (PEG)-coated colloidal carriers. It is essential to suppress this phenomenon in a clinical setting because the pharmacokinetics must be reproducible. In this study, we evaluated the induction of the ABC phenomenon using nanoparticles coated with various hydrophilic polymers instead of PEG. Nanoparticles encapsulating prostaglandin E1 were prepared by the solvent diffusion method from a blend of poly(lactic acid) (PLA) and block copolymers consisting of various hydrophilic polymers and PLA. Coating of nanoparticles with poly(N-vinyl-2-pyrrolidone) (PVP), poly(4-acryloylmorpholine), or poly(N,N-dimethylacrylamide) led to extended residence of the nanoparticles in blood circulation in rats, although they had a shorter half-life than the PEG-coated nanoparticles. The ABC phenomenon was not induced upon repeated injection of PVP-coated nanoparticles at various time intervals, dosages, or frequencies, whereas it was elicited by PEG-coated nanoparticles. In addition, anti-PVP IgM antibody, which is estimated to be one of the crucial factors for induction of the ABC phenomenon, was not produced after injection of PVP-coated nanoparticles. These results suggest that the use of PVP, instead of PEG, as a coating material for colloidal carriers can evade the ABC phenomenon.","ja":"The accelerated blood clearance (ABC) phenomenon is induced upon repeated injections of poly(ethylene glycol) (PEG)-coated colloidal carriers. It is essential to suppress this phenomenon in a clinical setting because the pharmacokinetics must be reproducible. In this study, we evaluated the induction of the ABC phenomenon using nanoparticles coated with various hydrophilic polymers instead of PEG. Nanoparticles encapsulating prostaglandin E1 were prepared by the solvent diffusion method from a blend of poly(lactic acid) (PLA) and block copolymers consisting of various hydrophilic polymers and PLA. Coating of nanoparticles with poly(N-vinyl-2-pyrrolidone) (PVP), poly(4-acryloylmorpholine), or poly(N,N-dimethylacrylamide) led to extended residence of the nanoparticles in blood circulation in rats, although they had a shorter half-life than the PEG-coated nanoparticles. The ABC phenomenon was not induced upon repeated injection of PVP-coated nanoparticles at various time intervals, dosages, or frequencies, whereas it was elicited by PEG-coated nanoparticles. In addition, anti-PVP IgM antibody, which is estimated to be one of the crucial factors for induction of the ABC phenomenon, was not produced after injection of PVP-coated nanoparticles. These results suggest that the use of PVP, instead of PEG, as a coating material for colloidal carriers can evade the ABC phenomenon."},"publication_date":"2010-10-11","publication_name":{"en":"Biomacromolecules","ja":"Biomacromolecules"},"volume":"Vol.11","number":"No.10","starting_page":"2700","ending_page":"2706","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/bm100754e"],"issn":["1526-4602"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:143, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507551"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/20823571","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=209474","label":"url"}],"paper_title":{"en":"Optimized PEGylated adenovirus vector reduces the anti-vector humoral immune response against adenovirus and induces a therapeutic effect against metastatic lung cancer.","ja":"Optimized PEGylated adenovirus vector reduces the anti-vector humoral immune response against adenovirus and induces a therapeutic effect against metastatic lung cancer."},"authors":{"en":[{"name":"Eto Y"},{"name":"Yoshioka Y"},{"name":"Ishida Tatsuhiro"},{"name":"Yao X"},{"name":"Morishige T"},{"name":"Narimatsu S"},{"name":"Mizuguchi H"},{"name":"Mukai Y"},{"name":"Okada N"},{"name":"Kiwada Hiroshi"},{"name":"Nakagawa S"}],"ja":[{"name":"Eto Y"},{"name":"Yoshioka Y"},{"name":"石田 竜弘"},{"name":"Yao X"},{"name":"Morishige T"},{"name":"Narimatsu S"},{"name":"Mizuguchi H"},{"name":"Mukai Y"},{"name":"Okada N"},{"name":"際田 弘志"},{"name":"Nakagawa S"}]},"description":{"en":"Application of adenovirus vectors (Adv) in metastatic cancer treatment is limited. We previously demonstrated that covalent conjugation of polyethleneglycol (PEG) to Adv enhances therapeutic effects and decreases toxic side-effects after systemic administration, but the level of immune response to PEGylated Adv (PEG-Ad) was not examined. Here, we examined the effect of PEGylation of Adv on the production of anti-Adv antibodies and antitumor response. We constructed a set of PEG-Ad using 5-kDa PEG, with modification rates of 30%, 45% and 90%. After systemic administration of Advs to rats, we examined the level of anti-Adv immunoglobulin (Ig)G and IgM in serum. The levels of anti-Adv IgG and anti-Adv IgM in rats treated with unmodified Adv were higher than those in control group. Rats treated with PEG-Ad that had a 90% modification rate showed lower level of anti-Adv IgG and anti-Adv IgM than those treated with unmodified Adv, whereas rats treated with PEG-Ad that had a 30% or 45% modification rate showed a similar level of anti-Adv IgG and IgM to those treated with unmodified Adv. Systemic administration of PEG-Ad that had a 90% modification rate, and expressed tumor necrosis factor-alpha, significantly reduced the number of metastatic colonies in the lung compared to unmodified Adv, with negligible side effects. These results suggest that systemic administration of PEG-Ad with an appropriate PEG modification rate has the potential to reduce the production of antibodies against Adv and increase the therapeutic response against metastatic cancer.","ja":"Application of adenovirus vectors (Adv) in metastatic cancer treatment is limited. We previously demonstrated that covalent conjugation of polyethleneglycol (PEG) to Adv enhances therapeutic effects and decreases toxic side-effects after systemic administration, but the level of immune response to PEGylated Adv (PEG-Ad) was not examined. Here, we examined the effect of PEGylation of Adv on the production of anti-Adv antibodies and antitumor response. We constructed a set of PEG-Ad using 5-kDa PEG, with modification rates of 30%, 45% and 90%. After systemic administration of Advs to rats, we examined the level of anti-Adv immunoglobulin (Ig)G and IgM in serum. The levels of anti-Adv IgG and anti-Adv IgM in rats treated with unmodified Adv were higher than those in control group. Rats treated with PEG-Ad that had a 90% modification rate showed lower level of anti-Adv IgG and anti-Adv IgM than those treated with unmodified Adv, whereas rats treated with PEG-Ad that had a 30% or 45% modification rate showed a similar level of anti-Adv IgG and IgM to those treated with unmodified Adv. Systemic administration of PEG-Ad that had a 90% modification rate, and expressed tumor necrosis factor-alpha, significantly reduced the number of metastatic colonies in the lung compared to unmodified Adv, with negligible side effects. These results suggest that systemic administration of PEG-Ad with an appropriate PEG modification rate has the potential to reduce the production of antibodies against Adv and increase the therapeutic response against metastatic cancer."},"publication_date":"2010-09-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.33","number":"No.9","starting_page":"1540","ending_page":"1544","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.33.1540"],"issn":["1347-5215"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:144, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507552"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/20460820","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=204379","label":"url"}],"paper_title":{"en":"Co-administration of tacrolimus suppresses pharmacokinetic modulation of multiple subcutaneously administrated human interferon-alpha in beagle dogs.","ja":"Co-administration of tacrolimus suppresses pharmacokinetic modulation of multiple subcutaneously administrated human interferon-alpha in beagle dogs."},"authors":{"en":[{"name":"Yamazaki Hiroyuki"},{"name":"Miyake Masateru"},{"name":"Kamada Naoki"},{"name":"Nishibayashi Toru"},{"name":"Mukai Tadashi"},{"name":"Odomi Masaaki"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"山﨑 浩之"},{"name":"Miyake Masateru"},{"name":"Kamada Naoki"},{"name":"Nishibayashi Toru"},{"name":"Mukai Tadashi"},{"name":"Odomi Masaaki"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Specific antibody production is an important issue in crossover pharmacokinetic (PK) studies of protein-based formulations. We recently reported that intravenous co-administration of tacrolimus with multiple human interferon-alpha (h-IFN) administrations successfully suppressed the production of anti-h-IFN antibodies in rats. Since crossover PK studies are preferentially carried out using larger animals such as dogs or monkeys that are capable of accepting the same dosage formulations as those for clinical use, we extended our study of co-administration of tacrolimus with multiple h-IFN administrations to beagle dogs in the present study. Beagle dogs were subcutaneously administered 0.5 million IU/kg of h-IFN once a week for 4 weeks. In some experiments, tacrolimus at 0.01 or 0.1 mg/kg was intravenously co-administered at the same time as the h-IFN administration. Co-administration of the lower dose of tacrolimus (0.01 mg/kg) failed to suppress the anti-h-IFN IgG responses, while co-administration of the higher dose (0.1 mg/kg) successfully suppressed these responses. Moreover, co-administration of tacrolimus had little effect on the serum creatinine concentrations, suggesting that multiple administrations of tacrolimus at the concentrations examined did not cause severe renal disorders. Taken together, the present data confirm that co-administration of tacrolimus is a promising way to assess crossover PK studies of human or humanized proteinic formulations in beagle dogs.","ja":"Specific antibody production is an important issue in crossover pharmacokinetic (PK) studies of protein-based formulations. We recently reported that intravenous co-administration of tacrolimus with multiple human interferon-alpha (h-IFN) administrations successfully suppressed the production of anti-h-IFN antibodies in rats. Since crossover PK studies are preferentially carried out using larger animals such as dogs or monkeys that are capable of accepting the same dosage formulations as those for clinical use, we extended our study of co-administration of tacrolimus with multiple h-IFN administrations to beagle dogs in the present study. Beagle dogs were subcutaneously administered 0.5 million IU/kg of h-IFN once a week for 4 weeks. In some experiments, tacrolimus at 0.01 or 0.1 mg/kg was intravenously co-administered at the same time as the h-IFN administration. Co-administration of the lower dose of tacrolimus (0.01 mg/kg) failed to suppress the anti-h-IFN IgG responses, while co-administration of the higher dose (0.1 mg/kg) successfully suppressed these responses. Moreover, co-administration of tacrolimus had little effect on the serum creatinine concentrations, suggesting that multiple administrations of tacrolimus at the concentrations examined did not cause severe renal disorders. Taken together, the present data confirm that co-administration of tacrolimus is a promising way to assess crossover PK studies of human or humanized proteinic formulations in beagle dogs."},"publication_date":"2010-05-07","publication_name":{"en":"Drug Metabolism and Pharmacokinetics","ja":"Drug Metabolism and Pharmacokinetics"},"volume":"Vol.25","number":"No.2","starting_page":"149","ending_page":"154","languages":["eng"],"referee":true,"identifiers":{"doi":["10.2133/dmpk.25.149"],"issn":["1880-0920"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:145, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507553"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/20227473","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=208434","label":"url"}],"paper_title":{"en":"T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes.","ja":"T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes."},"authors":{"en":[{"name":"Koide H"},{"name":"Asai T"},{"name":"Hatanaka K"},{"name":"Akai S"},{"name":"Ishii T"},{"name":"Kenjo E"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"},{"name":"Tsukada H"},{"name":"Oku N"}],"ja":[{"name":"Koide H"},{"name":"Asai T"},{"name":"Hatanaka K"},{"name":"Akai S"},{"name":"Ishii T"},{"name":"Kenjo E"},{"name":"石田 竜弘"},{"name":"際田 弘志"},{"name":"Tsukada H"},{"name":"Oku N"}]},"description":{"en":"Repeated injection of polyethyleneglycol-modified (PEGylated) liposomes causes a rapid clearance of them from the bloodstream, this phenomenon is called accelerated blood clearance (ABC). In the present study, we focused on the immune system responsible for the ABC phenomenon. PEGylated liposomes were preadministered to BALB/c mice and [(3)H]-labeled ones were then administered to them 3 days after the preadministration. Consistent with our previous results, the preadministration with PEGylated liposomes triggered the rapid clearance of [(3)H]-labeled PEGylated liposomes from the bloodstream, but that with PEGylated liposomes encapsulating doxorubicin (Dox) did not. In addition, we found that the ABC phenomenon was observed when a mixture of free Dox and PEGylated liposomes was preadministered. These data indicate that immune cells responsible for the ABC phenomenon might be selectively damaged by the Dox encapsulated in PEGylated liposomes. The ABC phenomenon was also observed in BALB/c nu/nu mice, but not in BALB/c SCID mice. The amount of anti-PEG IgM antibody induced by the stimulation with the PEGylated liposomes was significantly increased in the BALB/c nu/nu mice, but not in the BALB/c SCID ones. These data indicate that a T cell-independent B cell response would play a significant role in the ABC phenomenon. Furthermore, the present study suggests that PEGylated liposomes might be recognized by B cells as a thymus-independent type 2 (TI-2) antigen. The present study provides important information for the future development of liposomal medicines.","ja":"Repeated injection of polyethyleneglycol-modified (PEGylated) liposomes causes a rapid clearance of them from the bloodstream, this phenomenon is called accelerated blood clearance (ABC). In the present study, we focused on the immune system responsible for the ABC phenomenon. PEGylated liposomes were preadministered to BALB/c mice and [(3)H]-labeled ones were then administered to them 3 days after the preadministration. Consistent with our previous results, the preadministration with PEGylated liposomes triggered the rapid clearance of [(3)H]-labeled PEGylated liposomes from the bloodstream, but that with PEGylated liposomes encapsulating doxorubicin (Dox) did not. In addition, we found that the ABC phenomenon was observed when a mixture of free Dox and PEGylated liposomes was preadministered. These data indicate that immune cells responsible for the ABC phenomenon might be selectively damaged by the Dox encapsulated in PEGylated liposomes. The ABC phenomenon was also observed in BALB/c nu/nu mice, but not in BALB/c SCID mice. The amount of anti-PEG IgM antibody induced by the stimulation with the PEGylated liposomes was significantly increased in the BALB/c nu/nu mice, but not in the BALB/c SCID ones. These data indicate that a T cell-independent B cell response would play a significant role in the ABC phenomenon. Furthermore, the present study suggests that PEGylated liposomes might be recognized by B cells as a thymus-independent type 2 (TI-2) antigen. The present study provides important information for the future development of liposomal medicines."},"publication_date":"2010-03-21","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.392","number":"No.1-2","starting_page":"218","ending_page":"223","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2010.03.022"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:146, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507554"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19850094","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=204384","label":"url"}],"paper_title":{"en":"CpG motifs in pDNA-sequences increase anti-PEG IgM production induced by PEG-coated pDNA-lipoplexes.","ja":"CpG motifs in pDNA-sequences increase anti-PEG IgM production induced by PEG-coated pDNA-lipoplexes."},"authors":{"en":[{"name":"Tagami Tatsuaki"},{"name":"Nakamura Kazuya"},{"name":"Shimizu Taro"},{"name":"Yamazaki Naoshi"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"田上 辰秋"},{"name":"中村 和也"},{"name":"清水 太郎"},{"name":"山﨑 尚志"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Gene therapy is largely dependent on the development of efficient delivery vehicles. To prolong their circulating time, PEGylation of the surface of a delivery vehicle is frequently applied. However, we have reported previously that anti-PEG IgM produced by intravenous injection of PEG-coated liposome is responsible for enhanced clearance of second dose PEG-coated liposomes, which is known as the \"accelerated blood clearance (ABC) phenomenon.\" A similar phenomenon has been observed with PEG-coated pDNA-lipoplexes (PDCLs) upon their repeated injection. But the effect of the sequence of pDNA in PDCLs on inducing the ABC phenomenon has not been thoroughly investigated. Here, we focus on CpG motifs in pDNA, which are known to have a potent immune-stimulatory activity. PDCLs with non-CpG pDNA (PNDCL) diminished the anti-PEG IgM response, resulting in significant accumulation of a second dose in tumor tissue, comparable to that of a single injection, but not in enhanced accumulation in liver. In addition, PDCL induced proliferation of IgM(+) splenic cells including B cells. These results suggest that the CpG motif is a major cause of the induction of the ABC phenomenon when PDCLs are repeatedly injected. Immunogenicity is a relevant point of concern for non-viral delivery systems. Our results indicate that the use of non-CpG pDNA may allow meaningful repeated dosing of pDNA formulations without the induction of a strong immune reaction and thus may have important implications for therapeutic use of liposomal formulations of nucleic acids.","ja":"Gene therapy is largely dependent on the development of efficient delivery vehicles. To prolong their circulating time, PEGylation of the surface of a delivery vehicle is frequently applied. However, we have reported previously that anti-PEG IgM produced by intravenous injection of PEG-coated liposome is responsible for enhanced clearance of second dose PEG-coated liposomes, which is known as the \"accelerated blood clearance (ABC) phenomenon.\" A similar phenomenon has been observed with PEG-coated pDNA-lipoplexes (PDCLs) upon their repeated injection. But the effect of the sequence of pDNA in PDCLs on inducing the ABC phenomenon has not been thoroughly investigated. Here, we focus on CpG motifs in pDNA, which are known to have a potent immune-stimulatory activity. PDCLs with non-CpG pDNA (PNDCL) diminished the anti-PEG IgM response, resulting in significant accumulation of a second dose in tumor tissue, comparable to that of a single injection, but not in enhanced accumulation in liver. In addition, PDCL induced proliferation of IgM(+) splenic cells including B cells. These results suggest that the CpG motif is a major cause of the induction of the ABC phenomenon when PDCLs are repeatedly injected. Immunogenicity is a relevant point of concern for non-viral delivery systems. Our results indicate that the use of non-CpG pDNA may allow meaningful repeated dosing of pDNA formulations without the induction of a strong immune reaction and thus may have important implications for therapeutic use of liposomal formulations of nucleic acids."},"publication_date":"2010-03-03","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.142","number":"No.2","starting_page":"160","ending_page":"166","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2009.10.017"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:147, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507555"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19861140","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=204381","label":"url"}],"paper_title":{"en":"Sequential administration with oxaliplatin-containing PEG-coated cationic liposomes promotes a significant delivery of subsequent dose into murine solid tumor.","ja":"Sequential administration with oxaliplatin-containing PEG-coated cationic liposomes promotes a significant delivery of subsequent dose into murine solid tumor."},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Doi Yusuke"},{"name":"Nakamura Kazuya"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"土井 祐輔"},{"name":"中村 和也"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Recently, we designed a PEG-coated cationic liposome to achieve dual targeting delivery of l-OHP to both tumor endothelial cells and tumor cells in a solid tumor. The targeted liposomal l-OHP formulation showed an efficient antitumor activity in a murine tumor model after three sequential liposomal l-OHP injections. This led us to assume that prior dosing with liposomes might enhance the intra-tumoral accumulation of a subsequent dose, and hence improve the therapeutic efficacy of entrapped l-OHP. The present study shows that while a single liposomal l-OHP injection does not enhance tumor accumulation of subsequent test-PEG-coated cationic liposomes, two sequential injections of liposomal l-OHP do. Cumulative cytotoxic effects of l-OHP delivered by PEG-coated cationic liposomes led to deep diffusion of a subsequent dose of liposomal l-OHP in solid tumor presumably as a result of the enlarged intra-tumoral interstitial space. Our study suggests that sequential injections of a targeted liposomal anticancer drug is of significant clinical and practical importance in enhancing the delivery of adequate quantities of anticancer agents into intractable solid tumors, and thereby may achieve a significant anticancer efficacy.","ja":"Recently, we designed a PEG-coated cationic liposome to achieve dual targeting delivery of l-OHP to both tumor endothelial cells and tumor cells in a solid tumor. The targeted liposomal l-OHP formulation showed an efficient antitumor activity in a murine tumor model after three sequential liposomal l-OHP injections. This led us to assume that prior dosing with liposomes might enhance the intra-tumoral accumulation of a subsequent dose, and hence improve the therapeutic efficacy of entrapped l-OHP. The present study shows that while a single liposomal l-OHP injection does not enhance tumor accumulation of subsequent test-PEG-coated cationic liposomes, two sequential injections of liposomal l-OHP do. Cumulative cytotoxic effects of l-OHP delivered by PEG-coated cationic liposomes led to deep diffusion of a subsequent dose of liposomal l-OHP in solid tumor presumably as a result of the enlarged intra-tumoral interstitial space. Our study suggests that sequential injections of a targeted liposomal anticancer drug is of significant clinical and practical importance in enhancing the delivery of adequate quantities of anticancer agents into intractable solid tumors, and thereby may achieve a significant anticancer efficacy."},"publication_date":"2010-03-03","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.142","number":"No.2","starting_page":"167","ending_page":"173","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2009.10.020"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:148, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507556"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19633820","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=193615","label":"url"}],"paper_title":{"en":"Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles.","ja":"Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles."},"authors":{"en":[{"name":"Ishihara Tsutomu"},{"name":"Takeda Miho"},{"name":"Sakamoto Haruka"},{"name":"Kimoto Ayumi"},{"name":"Kobayashi Chisa"},{"name":"Takasaki Naoko"},{"name":"Yuki Kanae"},{"name":"Tanaka Ken-ichiro"},{"name":"Takenaga Mitsuko"},{"name":"Igarashi Rie"},{"name":"Maeda Taishi"},{"name":"Yamakawa Naoki"},{"name":"Okamoto Yoshinari"},{"name":"Otsuka Masami"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"},{"name":"Mizushima Yutaka"},{"name":"Mizushima Tohru"}],"ja":[{"name":"Ishihara Tsutomu"},{"name":"Takeda Miho"},{"name":"Sakamoto Haruka"},{"name":"Kimoto Ayumi"},{"name":"Kobayashi Chisa"},{"name":"Takasaki Naoko"},{"name":"Yuki Kanae"},{"name":"Tanaka Ken-ichiro"},{"name":"Takenaga Mitsuko"},{"name":"Igarashi Rie"},{"name":"Maeda Taishi"},{"name":"Yamakawa Naoki"},{"name":"Okamoto Yoshinari"},{"name":"Otsuka Masami"},{"name":"石田 竜弘"},{"name":"際田 弘志"},{"name":"Mizushima Yutaka"},{"name":"Mizushima Tohru"}]},"description":{"en":"We recently developed prostaglandin E(1) (PGE(1))-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats. The plasma levels of PGE(1) and anti-PEG IgM antibody were determined by EIA and ELISA, respectively. Second injections of NP-L20 were cleared much more rapidly from the circulation than first injections, showing that the ABC phenomenon was induced. This ABC phenomenon, and the accompanying induction of anti-PEG IgM antibody production, was optimal at a time interval of 7 days between the first and second injections. Compared to NP-L20, NP-L33s that were prepared with PLA (Mw = 28,100) and have a smaller particle size induced production of anti-PEG IgM antibody to a lesser extent. NP-L20 but not NP-L33s gave rise to the ABC phenomenon with a time interval of 14 days. NP-L33s showed a better sustained-release profile of PGE(1) than NP-L20. This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE(1).","ja":"We recently developed prostaglandin E(1) (PGE(1))-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats. The plasma levels of PGE(1) and anti-PEG IgM antibody were determined by EIA and ELISA, respectively. Second injections of NP-L20 were cleared much more rapidly from the circulation than first injections, showing that the ABC phenomenon was induced. This ABC phenomenon, and the accompanying induction of anti-PEG IgM antibody production, was optimal at a time interval of 7 days between the first and second injections. Compared to NP-L20, NP-L33s that were prepared with PLA (Mw = 28,100) and have a smaller particle size induced production of anti-PEG IgM antibody to a lesser extent. NP-L20 but not NP-L33s gave rise to the ABC phenomenon with a time interval of 14 days. NP-L33s showed a better sustained-release profile of PGE(1) than NP-L20. This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE(1)."},"publication_date":"2009-10-01","publication_name":{"en":"Pharmaceutical Research","ja":"Pharmaceutical Research"},"volume":"Vol.26","number":"No.10","starting_page":"2270","ending_page":"2279","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s11095-009-9943-x"],"issn":["1573-904X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:149, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507557"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19415469","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=189435","label":"url"}],"paper_title":{"en":"Effect of co-administration of tacrolimus on the pharmacokinetics of multiple subcutaneous administered interferon-alpha in rats.","ja":"Effect of co-administration of tacrolimus on the pharmacokinetics of multiple subcutaneous administered interferon-alpha in rats."},"authors":{"en":[{"name":"Yamazaki Hiroyuki"},{"name":"Miyake Masateru"},{"name":"Nishibayashi Toru"},{"name":"Mukai Tadashi"},{"name":"Odomi Masaaki"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Yamazaki Hiroyuki"},{"name":"Miyake Masateru"},{"name":"Nishibayashi Toru"},{"name":"Mukai Tadashi"},{"name":"Odomi Masaaki"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Repeated administration of exogenous proteinic compounds triggers the production of specific antibodies. This reaction is limits not only pharmacokinetic studies in animal but also development of human or humanized proteins as drugs. We investigated the effect of co-administration of tacrolimus on pharmacokinetic of human interferon-alpha (h-IFN) following multiple subcutaneous administration in rats. h-IFN was administered at a dose of 5 million IU/kg. For some experiments, tacrolimus was also either subcutaneously or intravenously injected in rats at a dose of 0.001 or 0.5 mg/kg as well as with administration of h-IFN. Multiple administration of h-IFN without co-administration of tacrolimus induced IgG response at 2 or 3 weeks following first administration in the short dosing interval (daily, once per 3 days, or once per a week), irrespective of the dosing interval. Both intravenous and subcutaneous administration of tacrolimus (0.5 mg/kg) with multiple h-IFN injections successfully suppressed IgG response against h-IFN. Interestingly, in lower doses (0.001 mg/kg), intravenous co-administration of tacrolimus showed much stronger suppressive effect than subcutaneous co-administration. Intravenous co-administration of tacrolimus (0.001 mg/kg) may be a promising way to assess crossover pharmacokinetic study of human or humanized proteinic formulations with multiple dosing schedules in an experimental animal.","ja":"Repeated administration of exogenous proteinic compounds triggers the production of specific antibodies. This reaction is limits not only pharmacokinetic studies in animal but also development of human or humanized proteins as drugs. We investigated the effect of co-administration of tacrolimus on pharmacokinetic of human interferon-alpha (h-IFN) following multiple subcutaneous administration in rats. h-IFN was administered at a dose of 5 million IU/kg. For some experiments, tacrolimus was also either subcutaneously or intravenously injected in rats at a dose of 0.001 or 0.5 mg/kg as well as with administration of h-IFN. Multiple administration of h-IFN without co-administration of tacrolimus induced IgG response at 2 or 3 weeks following first administration in the short dosing interval (daily, once per 3 days, or once per a week), irrespective of the dosing interval. Both intravenous and subcutaneous administration of tacrolimus (0.5 mg/kg) with multiple h-IFN injections successfully suppressed IgG response against h-IFN. Interestingly, in lower doses (0.001 mg/kg), intravenous co-administration of tacrolimus showed much stronger suppressive effect than subcutaneous co-administration. Intravenous co-administration of tacrolimus (0.001 mg/kg) may be a promising way to assess crossover pharmacokinetic study of human or humanized proteinic formulations with multiple dosing schedules in an experimental animal."},"publication_date":"2009-08","publication_name":{"en":"Pharmaceutical Research","ja":"Pharmaceutical Research"},"volume":"Vol.26","number":"No.8","starting_page":"1832","ending_page":"1837","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s11095-009-9892-4"],"issn":["1573-904X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:150, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507558"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19361546","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180546","label":"url"}],"paper_title":{"en":"Effect of siRNA in PEG-coated siRNA-lipoplex on the anti-PEG IgM production.","ja":"Effect of siRNA in PEG-coated siRNA-lipoplex on the anti-PEG IgM production."},"authors":{"en":[{"name":"Tagami Tatsuaki"},{"name":"Nakamura Kazuya"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"田上 辰秋"},{"name":"中村 和也"},{"name":"清水 太郎"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"For efficient delivery of small interfering RNA (siRNA) in vivo, it is important to control the blood circulation of the delivery vehicle. Surface modification of the siRNA/cationic liposome complex (siRNA-lipoplex) with polyethylene glycol (PEG) is expected to enhance circulation time in blood. However, we have recently reported that anti-PEG IgM production after the first injection of PEG-coated liposome is responsible for a reduction in the blood circulation of the second dose of the liposome, which is known as the accelerated blood clearance (ABC) phenomenon. It is unknown whether a PEG-coated siRNA-lipoplex (PSCL) can cause the ABC phenomenon and anti-PEG IgM production. In this study, an anti-PEG IgM response to PSCL was detected and was inversely related to the PSCL dose. Interestingly, the anti-PEG IgM response was significantly lower for PSCL than it was for PEG-coated naked cationic liposomes (PCL). The studies with splenectomized mice and nude mice indicated that anti-PEG IgM production was closely related to an interaction of PSCL and PCL with the spleen, which is associated with a T cell-independent mechanism. In addition, PSCL induced apoptosis on IgM-expressing splenic cells more strongly than PCL did, which suggests that accumulation in the spleen and the apoptotic effect of PEG-coated substances on splenic B cells could affect the potency of anti-PEG IgM production.","ja":"For efficient delivery of small interfering RNA (siRNA) in vivo, it is important to control the blood circulation of the delivery vehicle. Surface modification of the siRNA/cationic liposome complex (siRNA-lipoplex) with polyethylene glycol (PEG) is expected to enhance circulation time in blood. However, we have recently reported that anti-PEG IgM production after the first injection of PEG-coated liposome is responsible for a reduction in the blood circulation of the second dose of the liposome, which is known as the accelerated blood clearance (ABC) phenomenon. It is unknown whether a PEG-coated siRNA-lipoplex (PSCL) can cause the ABC phenomenon and anti-PEG IgM production. In this study, an anti-PEG IgM response to PSCL was detected and was inversely related to the PSCL dose. Interestingly, the anti-PEG IgM response was significantly lower for PSCL than it was for PEG-coated naked cationic liposomes (PCL). The studies with splenectomized mice and nude mice indicated that anti-PEG IgM production was closely related to an interaction of PSCL and PCL with the spleen, which is associated with a T cell-independent mechanism. In addition, PSCL induced apoptosis on IgM-expressing splenic cells more strongly than PCL did, which suggests that accumulation in the spleen and the apoptotic effect of PEG-coated substances on splenic B cells could affect the potency of anti-PEG IgM production."},"publication_date":"2009-04-08","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.137","number":"No.3","starting_page":"234","ending_page":"240","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2009.04.006"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:151, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507559"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19095022","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180364","label":"url"}],"paper_title":{"en":"Synergistic antitumor activity of metronomic dosing of cyclophosphamide in combination with doxorubicin-containing PEGylated liposomes in a murine solid tumor model.","ja":"Synergistic antitumor activity of metronomic dosing of cyclophosphamide in combination with doxorubicin-containing PEGylated liposomes in a murine solid tumor model."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Shiraga Emi"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"白髪 恵美"},{"name":"際田 弘志"}]},"description":{"en":"Cyclophosphamide (CPA) and doxorubicin (DXR)-containing sterically stabilized liposomes (DXR-SL) have a proven clinical activity. We propose that a metronomic CPA dosing schedule enhances accumulation of DXR-SL in solid tumors, because it causes apoptosis in the endothelial cells of the growing tumor vasculature and thereby may increase the permeability of the tumor microvessels. To establish the validity of this hypothesis we investigated the therapeutic benefits of metronomic CPA dosing (p.o.) combined with DXR-SL (i.v.) in a Lewis lung carcinoma, subcutaneously growing in C57BL/6 mouse. The metronomic CPA dosing clearly promoted accumulation and subsequent deep diffusion of SL in the solid tumor as a result of rather a transient increase in the density of CD31(+)-microvessels, which shows high permeability to SL. It appears that the enhancing effect of metronomic CPA dosing is strongly dependent on the dose of CPA as well as on the time at which the treatment was initiated. Our study indicates that the use of metronomic chemotherapy combined with nanocarriers may be of significant clinical and practical importance in treating intractable solid tumors.","ja":"Cyclophosphamide (CPA) and doxorubicin (DXR)-containing sterically stabilized liposomes (DXR-SL) have a proven clinical activity. We propose that a metronomic CPA dosing schedule enhances accumulation of DXR-SL in solid tumors, because it causes apoptosis in the endothelial cells of the growing tumor vasculature and thereby may increase the permeability of the tumor microvessels. To establish the validity of this hypothesis we investigated the therapeutic benefits of metronomic CPA dosing (p.o.) combined with DXR-SL (i.v.) in a Lewis lung carcinoma, subcutaneously growing in C57BL/6 mouse. The metronomic CPA dosing clearly promoted accumulation and subsequent deep diffusion of SL in the solid tumor as a result of rather a transient increase in the density of CD31(+)-microvessels, which shows high permeability to SL. It appears that the enhancing effect of metronomic CPA dosing is strongly dependent on the dose of CPA as well as on the time at which the treatment was initiated. Our study indicates that the use of metronomic chemotherapy combined with nanocarriers may be of significant clinical and practical importance in treating intractable solid tumors."},"publication_date":"2009-03-19","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.134","number":"No.3","starting_page":"194","ending_page":"200","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2008.11.019"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:152, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507560"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19285528","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=188879","label":"url"}],"paper_title":{"en":"Oxaliplatin encapsulated in PEG-coated cationic liposomes induces significant tumor growth suppression via a dual-targeting approach in a murine solid tumor model.","ja":"Oxaliplatin encapsulated in PEG-coated cationic liposomes induces significant tumor growth suppression via a dual-targeting approach in a murine solid tumor model."},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Kizuki Shinji"},{"name":"Doi Yusuke"},{"name":"Suzuki Takuya"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"城 慎二"},{"name":"土井 祐輔"},{"name":"鈴木 卓也"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"We recently designed a PEG-coated cationic liposome targeted to angiogenic vessels and showed, in a murine dorsal air sac model, potent anti-angiogenic activity of an oxaliplatin (l-OHP) formulation of this liposome. In the present study, we extended the l-OHP formulation to a murine tumor-xenograft model. Following three injections, l-OHP containing PEG-coated cationic liposomes showed substantial tumor growth suppression and increased survival time of tumor-bearing mice without apparent side effects, compared with other l-OHP containing PEG-coated neutral liposomes and free l-OHP. In vivo imaging showed a preferential tumor accumulation and a broader distribution of PEG-coated cationic liposomes, compared with PEG-coated neutral liposomes. In addition, PEG-coated cationic liposomes delivered larger amounts of l-OHP into the tumor tissue than other l-OHP formulations, correlating with its antitumor efficiency. In vitro studies indicated that PEG-coated cationic liposomes were internalized not only by tumor cells but also by endothelial cells, and consequently its l-OHP formulation displayed higher cytotoxicity towards both cell types as compared with l-OHP containing PEG-coated neutral liposomes. In summary, l-OHP containing PEG-coated cationic liposomes induced significant tumor growth suppression, presumably by delivering encapsulated l-OHP into both tumor endothelial cells and tumor cells. Such dual targeting approach, i.e. vascular-targeting and tumor-targeting with a single liposomal l-OHP formulation, may have great potential for overcoming some major limitations in conventional chemotherapy.","ja":"We recently designed a PEG-coated cationic liposome targeted to angiogenic vessels and showed, in a murine dorsal air sac model, potent anti-angiogenic activity of an oxaliplatin (l-OHP) formulation of this liposome. In the present study, we extended the l-OHP formulation to a murine tumor-xenograft model. Following three injections, l-OHP containing PEG-coated cationic liposomes showed substantial tumor growth suppression and increased survival time of tumor-bearing mice without apparent side effects, compared with other l-OHP containing PEG-coated neutral liposomes and free l-OHP. In vivo imaging showed a preferential tumor accumulation and a broader distribution of PEG-coated cationic liposomes, compared with PEG-coated neutral liposomes. In addition, PEG-coated cationic liposomes delivered larger amounts of l-OHP into the tumor tissue than other l-OHP formulations, correlating with its antitumor efficiency. In vitro studies indicated that PEG-coated cationic liposomes were internalized not only by tumor cells but also by endothelial cells, and consequently its l-OHP formulation displayed higher cytotoxicity towards both cell types as compared with l-OHP containing PEG-coated neutral liposomes. In summary, l-OHP containing PEG-coated cationic liposomes induced significant tumor growth suppression, presumably by delivering encapsulated l-OHP into both tumor endothelial cells and tumor cells. Such dual targeting approach, i.e. vascular-targeting and tumor-targeting with a single liposomal l-OHP formulation, may have great potential for overcoming some major limitations in conventional chemotherapy."},"publication_date":"2009-03-12","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.137","number":"No.1","starting_page":"8","ending_page":"14","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2009.02.023"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:153, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507561"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19252277","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=186417","label":"url"}],"paper_title":{"en":"Gene expression analysis during platelet-like particle production in phorbol myristate acetate-treated MEG-01 cells.","ja":"Gene expression analysis during platelet-like particle production in phorbol myristate acetate-treated MEG-01 cells."},"authors":{"en":[{"name":"Isakari Yoshimasa"},{"name":"Sogo Shinji"},{"name":"Ishida Tatsuhiro"},{"name":"Kawakami Takuma"},{"name":"Ono Toshihide"},{"name":"Taki Takao"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"飯盛 良正"},{"name":"Sogo Shinji"},{"name":"石田 竜弘"},{"name":"Kawakami Takuma"},{"name":"Ono Toshihide"},{"name":"Taki Takao"},{"name":"際田 弘志"}]},"description":{"en":"A comprehensive gene-expression analysis during platelet (PLT) production from megakaryocytes may give important information on genes involved in the PLT production process. However, the low abundance of primary megakaryocytes makes the gene expression analysis difficult. Therefore, we employed MEG-01 cells, a human megakaryocytic cell line, and confirmed that the cell line produces PLT-like particles by treatment with phorbol myristate acetate (PMA). After treatment of MEG-01 cells with PMA for 8 or 24 h, comprehensive gene expression analysis was carried out using a microarray and Reverse Transcription-Polymerase Chain Reaction (RT-PCR). From the microarray analysis, 141 genes were up-regulated (>2-fold) and 164 genes were down-regulated (<1/2-fold). However, known PLT-related genes were not included in the up- or down-regulated genes. On the other hand, RT-PCR analysis detected increased expression of beta1-tubulin, CD62P, gpIbalpha and gpIII, which are related to PLT function and megakaryocyte differentiation, following PMA treatment for 24 h. These results indicate that the MEG-01 cell may be an alternative model system to study the process of human PLT production from megakaryocytes. The gene-expression analysis might be a powerful tool for identifying genes related to PLT production, if the experimental conditions are optimized.","ja":"A comprehensive gene-expression analysis during platelet (PLT) production from megakaryocytes may give important information on genes involved in the PLT production process. However, the low abundance of primary megakaryocytes makes the gene expression analysis difficult. Therefore, we employed MEG-01 cells, a human megakaryocytic cell line, and confirmed that the cell line produces PLT-like particles by treatment with phorbol myristate acetate (PMA). After treatment of MEG-01 cells with PMA for 8 or 24 h, comprehensive gene expression analysis was carried out using a microarray and Reverse Transcription-Polymerase Chain Reaction (RT-PCR). From the microarray analysis, 141 genes were up-regulated (>2-fold) and 164 genes were down-regulated (<1/2-fold). However, known PLT-related genes were not included in the up- or down-regulated genes. On the other hand, RT-PCR analysis detected increased expression of beta1-tubulin, CD62P, gpIbalpha and gpIII, which are related to PLT function and megakaryocyte differentiation, following PMA treatment for 24 h. These results indicate that the MEG-01 cell may be an alternative model system to study the process of human PLT production from megakaryocytes. The gene-expression analysis might be a powerful tool for identifying genes related to PLT production, if the experimental conditions are optimized."},"publication_date":"2009-03","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.32","number":"No.3","starting_page":"354","ending_page":"358","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.32.354"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:154, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507562"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19010364","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180362","label":"url"}],"paper_title":{"en":"Oxaliplatin targeting to angiogenic vessels by PEGylated cationic liposomes suppresses the angiogenesis in a dorsal air sac mouse model.","ja":"Oxaliplatin targeting to angiogenic vessels by PEGylated cationic liposomes suppresses the angiogenesis in a dorsal air sac mouse model."},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Suzuki Takuya"},{"name":"Doi Yusuke"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"鈴木 卓也"},{"name":"土井 祐輔"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatinum, l-OHP) is a third-generation platinum analogue with proven anti-tumor activity against many tumor cell lines, however it does not show sufficient anti-tumor activity in vivo when used alone. In order to overcome this problem and to achieve an anti-angiogenic therapy with l-OHP, the drug was encapsulated into PEG-coated cationic liposomes, which were designed to target the newly formed vessels, and its anti-angiogenic activity was evaluated in an in vivo mouse dorsal air sac (DAS) assay. For the DAS assay, chambers filled with tumor cells were implanted underneath the dorsal skin. l-OHP encapsulated in PEG-coated cationic liposomes (5 mg/kg mice) was intravenously injected once on day 1, 2, 3 or 4 after chamber implantation. On the fifth day after chamber implantation, animals were sacrificed and tumor-angiogenesis was evaluated. Liposome-encapsulated l-OHP completely suppressed angiogenesis in the skin when it was administered day 3 after chamber implantation. Under similar experimental conditions, neither l-OHP encapsulated in PEG-coated neutral liposomes, nor free l-OHP, nor \"empty\" (no drug containing) PEG-coated cationic liposomes showed such strong suppressive effect. The present study suggests that the liposomal formulation of l-OHP, which targeted to angiogenic vessels, has a remarkable in vivo anti-angiogenic activity and the formulation may become a promising novel approach to achieve anti-angiogenic therapy.","ja":"Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatinum, l-OHP) is a third-generation platinum analogue with proven anti-tumor activity against many tumor cell lines, however it does not show sufficient anti-tumor activity in vivo when used alone. In order to overcome this problem and to achieve an anti-angiogenic therapy with l-OHP, the drug was encapsulated into PEG-coated cationic liposomes, which were designed to target the newly formed vessels, and its anti-angiogenic activity was evaluated in an in vivo mouse dorsal air sac (DAS) assay. For the DAS assay, chambers filled with tumor cells were implanted underneath the dorsal skin. l-OHP encapsulated in PEG-coated cationic liposomes (5 mg/kg mice) was intravenously injected once on day 1, 2, 3 or 4 after chamber implantation. On the fifth day after chamber implantation, animals were sacrificed and tumor-angiogenesis was evaluated. Liposome-encapsulated l-OHP completely suppressed angiogenesis in the skin when it was administered day 3 after chamber implantation. Under similar experimental conditions, neither l-OHP encapsulated in PEG-coated neutral liposomes, nor free l-OHP, nor \"empty\" (no drug containing) PEG-coated cationic liposomes showed such strong suppressive effect. The present study suggests that the liposomal formulation of l-OHP, which targeted to angiogenic vessels, has a remarkable in vivo anti-angiogenic activity and the formulation may become a promising novel approach to achieve anti-angiogenic therapy."},"publication_date":"2009-02-20","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.134","number":"No.1","starting_page":"18","ending_page":"25","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2008.10.018"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:155, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507563"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/18581204","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180289","label":"url"}],"paper_title":{"en":"Global gene expression profiling in cultured cells is strongly influenced by treatment with siRNA-cationic liposome complexes.","ja":"Global gene expression profiling in cultured cells is strongly influenced by treatment with siRNA-cationic liposome complexes."},"authors":{"en":[{"name":"Tagami Tatsuaki"},{"name":"Hirose Kiyomi"},{"name":"Barichello Jose"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"田上 辰秋"},{"name":"廣瀬 聖実"},{"name":"Barichello Jose"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"The purpose of this study is to determine if the treatment with siRNA-lipoplexes significantly influences on global gene expression in the treated cells. We investigated global gene expression in a HT1080 cell line by a cDNA microarray. We also evaluated the effect of lipofection on global gene expression by determining the change of the expression of an exogenous gene, green fluorescence protein (GFP), and also determined treatment-related cytotoxicity. Treatment of the cells with either siRNA-lipoplexes or cationic liposomes altered the expression of approximately 2,500 genes. When lipoplexes containing non-specific siRNAs were used, GFP expression was enhanced. In this case the effect was independent on the dose and type of siRNA in the formulation. By contrast, when lipoplexes containing a specific siRNA against GFP was used, GFP expression was markedly diminished. These results clearly indicate that an efficient reduction of a targeted gene expression by a specific siRNA is accompanied by a significant alteration of the expression of numerous non-targeted genes. In addition, treatment-related cytotoxicity increased with siRNA- and cationic lipid-doses, but was not dependent on siRNA type. Non-specific effects of siRNA-lipoplexes may either enhance, attenuate or even fully mask the desired outcomes of siRNA-based biochemical studies and therapies.","ja":"The purpose of this study is to determine if the treatment with siRNA-lipoplexes significantly influences on global gene expression in the treated cells. We investigated global gene expression in a HT1080 cell line by a cDNA microarray. We also evaluated the effect of lipofection on global gene expression by determining the change of the expression of an exogenous gene, green fluorescence protein (GFP), and also determined treatment-related cytotoxicity. Treatment of the cells with either siRNA-lipoplexes or cationic liposomes altered the expression of approximately 2,500 genes. When lipoplexes containing non-specific siRNAs were used, GFP expression was enhanced. In this case the effect was independent on the dose and type of siRNA in the formulation. By contrast, when lipoplexes containing a specific siRNA against GFP was used, GFP expression was markedly diminished. These results clearly indicate that an efficient reduction of a targeted gene expression by a specific siRNA is accompanied by a significant alteration of the expression of numerous non-targeted genes. In addition, treatment-related cytotoxicity increased with siRNA- and cationic lipid-doses, but was not dependent on siRNA type. Non-specific effects of siRNA-lipoplexes may either enhance, attenuate or even fully mask the desired outcomes of siRNA-based biochemical studies and therapies."},"publication_date":"2008-06-26","publication_name":{"en":"Pharmaceutical Research","ja":"Pharmaceutical Research"},"volume":"Vol.25","number":"No.11","starting_page":"2497","ending_page":"2504","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s11095-008-9663-7"],"issn":["0724-8741"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:156, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507564"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/18586076","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180287","label":"url"}],"paper_title":{"en":"Particle size-dependent triggering of accelerated blood clearance phenomenon.","ja":"Particle size-dependent triggering of accelerated blood clearance phenomenon."},"authors":{"en":[{"name":"Koide Hiroyuki"},{"name":"Asai Tomohiro"},{"name":"Hatanaka Kentaro"},{"name":"Urakami Takeo"},{"name":"Ishii Takayuki"},{"name":"Kenjo Eriya"},{"name":"Nishihara Masamichi"},{"name":"Yokoyama Masayuki"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"},{"name":"Oku Naoto"}],"ja":[{"name":"Koide Hiroyuki"},{"name":"Asai Tomohiro"},{"name":"Hatanaka Kentaro"},{"name":"Urakami Takeo"},{"name":"Ishii Takayuki"},{"name":"Kenjo Eriya"},{"name":"Nishihara Masamichi"},{"name":"Yokoyama Masayuki"},{"name":"石田 竜弘"},{"name":"際田 弘志"},{"name":"Oku Naoto"}]},"description":{"en":"A repeat-injection of polyethylene glycol-modified liposomes (PEGylated liposomes) causes a rapid clearance of them from the blood circulation in certain cases that is referred to as the accelerated blood clearance (ABC) phenomenon. In the present study, we examined whether polymeric micelles trigger ABC phenomenon or not. As a preconditioning treatment, polymeric micelles (9.7, 31.5, or 50.2 nm in diameter) or PEGylated liposomes (119, 261 or 795 nm) were preadministered into BALB/c mice. Three days after the preadministration [(3)H]-labeled PEGylated liposomes (127 nm) as a test dose were administered into the mice to determine the biodistribution of PEGylated liposomes. At 24h after the test dose was given, accelerated clearance of PEGylated liposomes from the bloodstream and significant accumulation in the liver was observed in the mice preadministered with 50.2-795 nm nanoassemblies (PEGylated liposomes or polymeric micelles). In contrast, such phenomenon was not observed with 9.7-31.5 nm polymeric micelles. The enhanced blood clearance and hepatic uptake of the test dose (ABC phenomenon) were related to the size of triggering nanoassemblies. Our study provides important information for developing both drug and gene delivery systems by means of nanocarriers.","ja":"A repeat-injection of polyethylene glycol-modified liposomes (PEGylated liposomes) causes a rapid clearance of them from the blood circulation in certain cases that is referred to as the accelerated blood clearance (ABC) phenomenon. In the present study, we examined whether polymeric micelles trigger ABC phenomenon or not. As a preconditioning treatment, polymeric micelles (9.7, 31.5, or 50.2 nm in diameter) or PEGylated liposomes (119, 261 or 795 nm) were preadministered into BALB/c mice. Three days after the preadministration [(3)H]-labeled PEGylated liposomes (127 nm) as a test dose were administered into the mice to determine the biodistribution of PEGylated liposomes. At 24h after the test dose was given, accelerated clearance of PEGylated liposomes from the bloodstream and significant accumulation in the liver was observed in the mice preadministered with 50.2-795 nm nanoassemblies (PEGylated liposomes or polymeric micelles). In contrast, such phenomenon was not observed with 9.7-31.5 nm polymeric micelles. The enhanced blood clearance and hepatic uptake of the test dose (ABC phenomenon) were related to the size of triggering nanoassemblies. Our study provides important information for developing both drug and gene delivery systems by means of nanocarriers."},"publication_date":"2008-06-07","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.362","number":"No.1-2","starting_page":"197","ending_page":"200","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2008.06.004"],"issn":["1873-3476"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:157, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507565"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/18155369","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180267","label":"url"}],"paper_title":{"en":"A metronomic schedule of cyclophosphamide combined with PEGylated liposomal doxorubicin has a highly antitumor effect in an experimental pulmonary metastatic mouse model.","ja":"A metronomic schedule of cyclophosphamide combined with PEGylated liposomal doxorubicin has a highly antitumor effect in an experimental pulmonary metastatic mouse model."},"authors":{"en":[{"name":"Shiraga Emi"},{"name":"Barichello Jose"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"白髪 恵美"},{"name":"Barichello Jose"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Metronomic chemotherapy is a novel approach to the control of advanced cancer, as it appears to preferentially inhibit endothelial cell activity in the growing vasculature of tumors. Doxorubicin-containing sterically stabilized liposomes (DXR-SL) accumulate in large amounts in tumor tissue, resulting in enhanced antitumor effects of the encapsulated DXR. In the present study, it was hypothesized that metronomic chemotherapy may further augment the accumulation of DXR-SL, improving its therapeutic efficacy. This study tests the antitumor efficacy for the combination of a metronomic cyclophosphamide (CPA)-dosing schedule with sequential intravenous injections of DXR-SL in the treatment of lung metastatic B16BL6 melanoma-bearing mice. Three dosing schedules for the combination of metronomic CPA injections (s.c. 170 mg/kg every 6 days) plus either a low or a high dose of DXR-SL (i.v. 1 or 5 mg/kg every 6 days) were set: Schedule I, DXR-SL was given 3 days before the first CPA treatment; Schedule II, DXR-SL and CPA were given simultaneously; and, Schedule III, DXR-SL was given 3 days after the first CPA treatment. Lung weight and median survival time (MST) were evaluated. As expected, both the dosing schedule as well as the dose of DXR-SL improved therapeutic efficacy. Schedule I with the low DXR dose and Schedule II with the low or high DXR dose significantly increased MST, compared with regular metronomic CPA therapy. Under the dosing schedules (Schedule I with the low DXR dose and Schedule II with the high DXR), there was a strong relationship between increased MST and decreased lung weight. However, Schedule I with high DXR dose resulted in significantly lower lung weights, but did not increase MST, suggesting that chemotherapy may result in increased toxicity in some conditions. Although treatment regimens require optimization, the results of the present study may prove useful in further explorations of combining metronomic chemotherapy with liposomal anticancer drugs in the treatment of solid tumors.","ja":"Metronomic chemotherapy is a novel approach to the control of advanced cancer, as it appears to preferentially inhibit endothelial cell activity in the growing vasculature of tumors. Doxorubicin-containing sterically stabilized liposomes (DXR-SL) accumulate in large amounts in tumor tissue, resulting in enhanced antitumor effects of the encapsulated DXR. In the present study, it was hypothesized that metronomic chemotherapy may further augment the accumulation of DXR-SL, improving its therapeutic efficacy. This study tests the antitumor efficacy for the combination of a metronomic cyclophosphamide (CPA)-dosing schedule with sequential intravenous injections of DXR-SL in the treatment of lung metastatic B16BL6 melanoma-bearing mice. Three dosing schedules for the combination of metronomic CPA injections (s.c. 170 mg/kg every 6 days) plus either a low or a high dose of DXR-SL (i.v. 1 or 5 mg/kg every 6 days) were set: Schedule I, DXR-SL was given 3 days before the first CPA treatment; Schedule II, DXR-SL and CPA were given simultaneously; and, Schedule III, DXR-SL was given 3 days after the first CPA treatment. Lung weight and median survival time (MST) were evaluated. As expected, both the dosing schedule as well as the dose of DXR-SL improved therapeutic efficacy. Schedule I with the low DXR dose and Schedule II with the low or high DXR dose significantly increased MST, compared with regular metronomic CPA therapy. Under the dosing schedules (Schedule I with the low DXR dose and Schedule II with the high DXR), there was a strong relationship between increased MST and decreased lung weight. However, Schedule I with high DXR dose resulted in significantly lower lung weights, but did not increase MST, suggesting that chemotherapy may result in increased toxicity in some conditions. Although treatment regimens require optimization, the results of the present study may prove useful in further explorations of combining metronomic chemotherapy with liposomal anticancer drugs in the treatment of solid tumors."},"publication_date":"2008-04-02","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.353","number":"No.1-2","starting_page":"65","ending_page":"73","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2007.11.020"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:158, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507566"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/18379042","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180269","label":"url"}],"paper_title":{"en":"Lactoferrin inhibits platelet production from human megakaryocytes in vitro.","ja":"Lactoferrin inhibits platelet production from human megakaryocytes in vitro."},"authors":{"en":[{"name":"Matsumura-Takeda Kuniko"},{"name":"Ishida Tatsuhiro"},{"name":"Sogo Shinji"},{"name":"Isakari Yoshimasa"},{"name":"Taki Takao"},{"name":"Sudo Toshiki"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"武田 久仁子"},{"name":"石田 竜弘"},{"name":"Sogo Shinji"},{"name":"飯盛 良正"},{"name":"Taki Takao"},{"name":"Sudo Toshiki"},{"name":"際田 弘志"}]},"description":{"en":"The mechanism of megakaryopoiesis, proplatelet formation (PPF) and platelet (PLT) production is not fully elucidated. Lactoferrin (LF) has been reported to have many biological functions including cell proliferation and differentiation, and the LF receptor is present on megakaryocytic cells. In the present study, we examined the effect of human LF (hLF) on PLT production from primary megakaryocytes (MKs). At first, we developed a PLT production system derived from human CD34+ cells by thrombopoietin (TPO) stimulation. Because the number of proplatelets, PLTs and CD41+ MKs was remarkably increased after day 5, we employed the TPO-induced CD34+ cells on day 5. Then, the effect of hLF on PLT production from human primary MKs was examined. In the range of 3-30 micrg/ml, hLF significantly inhibited PLT production up to about 60%. However, it did not significantly change the intensity of CD41 expression in MKs and the ploidy of MKs. In addition, it did not inhibit MK progenitors. These results suggest that LF directly inhibits PLT production from matured MKs, but does not inhibit megakaryopoiesis, including proliferation/maturation processes.","ja":"The mechanism of megakaryopoiesis, proplatelet formation (PPF) and platelet (PLT) production is not fully elucidated. Lactoferrin (LF) has been reported to have many biological functions including cell proliferation and differentiation, and the LF receptor is present on megakaryocytic cells. In the present study, we examined the effect of human LF (hLF) on PLT production from primary megakaryocytes (MKs). At first, we developed a PLT production system derived from human CD34+ cells by thrombopoietin (TPO) stimulation. Because the number of proplatelets, PLTs and CD41+ MKs was remarkably increased after day 5, we employed the TPO-induced CD34+ cells on day 5. Then, the effect of hLF on PLT production from human primary MKs was examined. In the range of 3-30 micrg/ml, hLF significantly inhibited PLT production up to about 60%. However, it did not significantly change the intensity of CD41 expression in MKs and the ploidy of MKs. In addition, it did not inhibit MK progenitors. These results suggest that LF directly inhibits PLT production from matured MKs, but does not inhibit megakaryopoiesis, including proliferation/maturation processes."},"publication_date":"2008-04","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.31","number":"No.4","starting_page":"569","ending_page":"573","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.31.569"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:159, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507567"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/18160170","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180268","label":"url"}],"paper_title":{"en":"The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats.","ja":"The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kashima Shuntarou"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"鹿島 俊太郎"},{"name":"際田 弘志"}]},"description":{"en":"We earlier reported that PEGylated liposomes lose their long-circulating property when they are administered twice in the same animal within certain intervals. We recently proposed that anti-PEG IgM elicited by the first dose PEGylated liposomes selectively binds to the surface of a second dose, subsequently leading to substantial complement activation and complement-receptor mediated uptake of the second dose by hepatic Kupffer cells. In this study we found, by using a single-pass liver perfusion technique, that the first dose does not increase the intrinsic phagocytic activity of the Kupffer cells. It was also found that only serum obtained from rats that had received a first dose is able to enhance the hepatic uptake of test dose. The conditioned-serum-dependent hepatic uptake was completely abolished by pre-treatment of the serum at 56 degrees C for 30 min, which inhibits the complement activity. Conclusively, our results strongly support our earlier proposal that complement activation caused by anti-PEG IgM elicited by the first dose is a major cause of the initiation of the accelerated blood clearance of a subsequent dose PEGylated liposome in the ABC phenomenon.","ja":"We earlier reported that PEGylated liposomes lose their long-circulating property when they are administered twice in the same animal within certain intervals. We recently proposed that anti-PEG IgM elicited by the first dose PEGylated liposomes selectively binds to the surface of a second dose, subsequently leading to substantial complement activation and complement-receptor mediated uptake of the second dose by hepatic Kupffer cells. In this study we found, by using a single-pass liver perfusion technique, that the first dose does not increase the intrinsic phagocytic activity of the Kupffer cells. It was also found that only serum obtained from rats that had received a first dose is able to enhance the hepatic uptake of test dose. The conditioned-serum-dependent hepatic uptake was completely abolished by pre-treatment of the serum at 56 degrees C for 30 min, which inhibits the complement activity. Conclusively, our results strongly support our earlier proposal that complement activation caused by anti-PEG IgM elicited by the first dose is a major cause of the initiation of the accelerated blood clearance of a subsequent dose PEGylated liposome in the ABC phenomenon."},"publication_date":"2008-03-03","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.126","number":"No.2","starting_page":"162","ending_page":"165","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2007.11.009"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:160, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507568"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/18343610","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180270","label":"url"}],"paper_title":{"en":"Combined effect of liposomalization and addition of glycerol on the transdermal delivery of isosorbide 5-nitrate in rat skin.","ja":"Combined effect of liposomalization and addition of glycerol on the transdermal delivery of isosorbide 5-nitrate in rat skin."},"authors":{"en":[{"name":"Barichello José Mario"},{"name":"Yamakawa Noriko"},{"name":"Kisyuku Masatoshi"},{"name":"Handa Hiroshi"},{"name":"Shibata Taiki"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Barichello José Mario"},{"name":"山川 典子"},{"name":"木宿 昌俊"},{"name":"半田 寛"},{"name":"柴田 大樹"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"In this report, we investigated the combined effect of drug liposomalization and addition of glycerol on the transdermal delivery of isosorbide 5-nitrate (ISN) in rat abdominal skin in vitro. Occlusive application of both liposomal and aqueous ISN solution, with and without addition of 5% glycerol, showed that drug liposomalization and addition of glycerol has far-reaching implications for ISN permeation and accumulation in 4 and 8 weeks old rat abdominal skin. Using 8 weeks old rat abdominal skin, the optimal concentration of glycerol to be added to liposomal ISN was found to be 5%. The ISN mean values permeated through and accumulated in stripped 8 weeks old rat abdominal skin from those formulations described above were not significant different, which might indicate the combined effect of glycerol and liposomal ISN resides solely in the stratum corneum (SC). Based on previous reports, the enhancement effect of glycerol might be due to an increase in the SC hydration, and perhaps due to subtle changes in the lipid organization caused by penetration of liposomal lipids within the SC intercellular spaces. These data might provide evidence that glycerol action on SC is useful to facilitate skin permeation and accumulation of drugs formulated in liposome.","ja":"In this report, we investigated the combined effect of drug liposomalization and addition of glycerol on the transdermal delivery of isosorbide 5-nitrate (ISN) in rat abdominal skin in vitro. Occlusive application of both liposomal and aqueous ISN solution, with and without addition of 5% glycerol, showed that drug liposomalization and addition of glycerol has far-reaching implications for ISN permeation and accumulation in 4 and 8 weeks old rat abdominal skin. Using 8 weeks old rat abdominal skin, the optimal concentration of glycerol to be added to liposomal ISN was found to be 5%. The ISN mean values permeated through and accumulated in stripped 8 weeks old rat abdominal skin from those formulations described above were not significant different, which might indicate the combined effect of glycerol and liposomal ISN resides solely in the stratum corneum (SC). Based on previous reports, the enhancement effect of glycerol might be due to an increase in the SC hydration, and perhaps due to subtle changes in the lipid organization caused by penetration of liposomal lipids within the SC intercellular spaces. These data might provide evidence that glycerol action on SC is useful to facilitate skin permeation and accumulation of drugs formulated in liposome."},"publication_date":"2008-02-06","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.357","number":"No.1-2","starting_page":"199","ending_page":"205","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2008.01.052"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:161, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507569"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/18222171","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180285","label":"url"}],"paper_title":{"en":"Disappearance of the angiogenic potential of endothelial cells caused by Argonaute2 knockdown.","ja":"Disappearance of the angiogenic potential of endothelial cells caused by Argonaute2 knockdown."},"authors":{"en":[{"name":"Asai T"},{"name":"Suzuki Y"},{"name":"Matsushita S"},{"name":"Yonezawa S"},{"name":"Yokota J"},{"name":"Katanasaka Y"},{"name":"Ishida Tatsuhiro"},{"name":"Dewa T"},{"name":"Kiwada Hiroshi"},{"name":"Nango N"},{"name":"Oku N"}],"ja":[{"name":"Asai T"},{"name":"Suzuki Y"},{"name":"Matsushita S"},{"name":"Yonezawa S"},{"name":"Yokota J"},{"name":"Katanasaka Y"},{"name":"石田 竜弘"},{"name":"Dewa T"},{"name":"際田 弘志"},{"name":"Nango N"},{"name":"Oku N"}]},"description":{"en":"Argonaute2 (Ago2), a component protein of RNA-induced silencing complex, plays a central role in RNA interference. We focused on the involvement of Ago2 in angiogenesis. Human umbilical vein endothelial cells (HUVECs) stimulated with several growth factors such as vascular endothelial growth factor were used for angiogenesis assays. We applied polycation liposomes for transfection of small interfering RNA (siRNA) to determine the biological effects of siRNA for Ago2 (siAgo2) on HUVECs. The proliferation study indicated that siAgo2 significantly suppressed the growth of HUVECs compared with control siRNA. TUNEL staining showed a certain population of HUVECs treated with siAgo2 underwent apoptosis. Furthermore, the treatment with siAgo2 suppressed the tube formation of HUVECs and significantly reduced the length of the tubes. These present data demonstrate that siAgo2 inhibited indispensable events of angiogenesis in vitro. This is the first report suggesting that Ago2 is required for angiogenesis.","ja":"Argonaute2 (Ago2), a component protein of RNA-induced silencing complex, plays a central role in RNA interference. We focused on the involvement of Ago2 in angiogenesis. Human umbilical vein endothelial cells (HUVECs) stimulated with several growth factors such as vascular endothelial growth factor were used for angiogenesis assays. We applied polycation liposomes for transfection of small interfering RNA (siRNA) to determine the biological effects of siRNA for Ago2 (siAgo2) on HUVECs. The proliferation study indicated that siAgo2 significantly suppressed the growth of HUVECs compared with control siRNA. TUNEL staining showed a certain population of HUVECs treated with siAgo2 underwent apoptosis. Furthermore, the treatment with siAgo2 suppressed the tube formation of HUVECs and significantly reduced the length of the tubes. These present data demonstrate that siAgo2 inhibited indispensable events of angiogenesis in vitro. This is the first report suggesting that Ago2 is required for angiogenesis."},"publication_date":"2008-01-28","publication_name":{"en":"Biochemical and Biophysical Research Communications","ja":"Biochemical and Biophysical Research Communications"},"volume":"Vol.368","number":"No.2","starting_page":"243","ending_page":"248","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.bbrc.2008.01.074"],"issn":["1090-2104"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:162, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507570"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/17610982","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180284","label":"url"}],"paper_title":{"en":"PEGylated liposomes elicit an anti-PEG IgM response in a T-cells independent manner.","ja":"PEGylated liposomes elicit an anti-PEG IgM response in a T-cells independent manner."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Xinyu Wang"},{"name":"Shimizu Taro"},{"name":"Nawata Kousuke"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"王 新宇"},{"name":"清水 太郎"},{"name":"名和田 幸介"},{"name":"際田 弘志"}]},"description":{"en":"We recently reported that intravenous injections of \"empty\" PEGylated liposomes without encapsulated or surface coupled proteins elicit a PEG-specific IgM response in rats. In the present study, simultaneous weak anti-PEG IgG and strong anti-PEG IgM responses were detected following intravenous injections of \"empty\" PEGylated liposomes. The pattern of immune response appears to differ from the classic primary response against T cell-dependent (TD) antigens. The anti-PEG IgM response was detected in T-cell deficient nude BALB/c mice following intravenous injection of \"empty\" PEGylated liposomes, suggesting that \"empty\" PEGylated liposomes initiate the immune response against PEG in a T cell-independent manner. In vitro splenic lymphocytes-proliferation assay indicated that TNP-LPS, a typical type 1 T cell-independent (TI) antigen (TI-1 antigen), significantly primed the proliferation, while TNP-Ficoll, a typical type 2 TI antigen (TI-2 antigen), and \"empty\" PEGylated liposomes did not prime any proliferation under these experimental conditions. In addition, in splenic marginal zone (MZ) B-cell-depleted rats, the anti-PEG IgM response was diminished, while the immune reactions against TNP-BSA (a TD antigen) and TNP-LPS (TI-1 antigen) were not diminished. These results demonstrate that \"empty\" PEGylated liposomes may promote the immune response against PEG as a result of priming the activation of MZ B cells, as TI-2 antigen promotes a specific IgM response. In conclusion, although the mechanistic details behind the immune reaction against \"empty\" PEGylated liposomes are not yet clear, the liposomes elicit an anti-PEG IgM response in a T cell-independent manner and appear to be a TI-2 antigen, and splenic MZ B cells may be essential for the immune response against \"empty\" PEGylated liposomes.","ja":"We recently reported that intravenous injections of \"empty\" PEGylated liposomes without encapsulated or surface coupled proteins elicit a PEG-specific IgM response in rats. In the present study, simultaneous weak anti-PEG IgG and strong anti-PEG IgM responses were detected following intravenous injections of \"empty\" PEGylated liposomes. The pattern of immune response appears to differ from the classic primary response against T cell-dependent (TD) antigens. The anti-PEG IgM response was detected in T-cell deficient nude BALB/c mice following intravenous injection of \"empty\" PEGylated liposomes, suggesting that \"empty\" PEGylated liposomes initiate the immune response against PEG in a T cell-independent manner. In vitro splenic lymphocytes-proliferation assay indicated that TNP-LPS, a typical type 1 T cell-independent (TI) antigen (TI-1 antigen), significantly primed the proliferation, while TNP-Ficoll, a typical type 2 TI antigen (TI-2 antigen), and \"empty\" PEGylated liposomes did not prime any proliferation under these experimental conditions. In addition, in splenic marginal zone (MZ) B-cell-depleted rats, the anti-PEG IgM response was diminished, while the immune reactions against TNP-BSA (a TD antigen) and TNP-LPS (TI-1 antigen) were not diminished. These results demonstrate that \"empty\" PEGylated liposomes may promote the immune response against PEG as a result of priming the activation of MZ B cells, as TI-2 antigen promotes a specific IgM response. In conclusion, although the mechanistic details behind the immune reaction against \"empty\" PEGylated liposomes are not yet clear, the liposomes elicit an anti-PEG IgM response in a T cell-independent manner and appear to be a TI-2 antigen, and splenic MZ B cells may be essential for the immune response against \"empty\" PEGylated liposomes."},"publication_date":"2007-05-21","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.122","number":"No.3","starting_page":"349","ending_page":"355","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2007.05.015"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:163, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507571"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/17583453","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180283","label":"url"}],"paper_title":{"en":"Tumor targeting of doxorubicin by anti MT1-MMP antibody-modified PEG liposomes.","ja":"Tumor targeting of doxorubicin by anti MT1-MMP antibody-modified PEG liposomes."},"authors":{"en":[{"name":"Hatakeyama Hiroto"},{"name":"Akita Hidetaka"},{"name":"Ishida Emi"},{"name":"Hashimoto Koichi"},{"name":"Kobayashi Hideo"},{"name":"Aoki Takanori"},{"name":"Yasuda Junko"},{"name":"Obata Kenichi"},{"name":"Kikuchi Hiroshi"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"},{"name":"Harashima Hideyoshi"}],"ja":[{"name":"畠山 浩人"},{"name":"秋田 英万"},{"name":"石田 絵美"},{"name":"橋本 浩一"},{"name":"小林 英夫"},{"name":"青木 孝則"},{"name":"安田 順子"},{"name":"小幡 健一"},{"name":"菊池 寛"},{"name":"石田 竜弘"},{"name":"際田 弘志"},{"name":"原島 秀吉"}]},"description":{"en":"Immunoliposomes are potent carriers for targeting of therapeutic drugs to specific cells. Membrane type-1 matrix metalloproteinase (MT1-MMP), which plays an important role in angiogenesis, is expressed on angiogenic endothelium cells as well as tumor cells. Then, the MT1-MMP might be useful as a target molecule for tumor and neovascularity. In the present study, we addressed a utility of antibodies against the MT1-MMP as a targeting ligand of liposomal anticancer drug. Fab' fragments of antibody against the MT1-MMP were modified at distal end of polyethylene glycol (PEG) of doxorubicin (DXR)-encapsulating liposomes, DXR-sterically stabilized immunoliposomes (DXR-SIL[anti-MT1-MMP(Fab')]). Modification with the antibody significantly enhanced cellular uptake of DXR-SIL[anti-MT1-MMP(Fab')] into the HT1080 cells, which highly express MT1-MMP, compared with the non-targeted liposomes (DXR-stealthliposomes (DXR-SL)), suggesting that MT1-MMP antibody (Fab') is a potent targeting ligand for the MT1-MMP expressed cells. In vivo systemic administration of DXR-SIL[anti-MT1-MMP(Fab')] into the tumor-bearing mice showed significant suppression of tumor growth compared to DXR-SL. This is presumably due to the active targeting of immunoliposomes for tumor and neovascularity. However, tumor accumulation of DXR-SIL[anti-MT1-MMP(Fab')] and DXR-SL were comparable, suggesting that both liposomal formulations accumulated in tumor via enhanced permeation and retention (EPR) effect, but not via targeting to the MT1-MMP expressed on both the endothelial and tumor cells. It appears that the enhanced antitumor activity of DXR-SIL[anti-MT1-MMP(Fab')] resulted from acceleration of cellular uptake of lioposomes owing to the incorporated antibody after extravasation from capillaries in tumor.","ja":"Immunoliposomes are potent carriers for targeting of therapeutic drugs to specific cells. Membrane type-1 matrix metalloproteinase (MT1-MMP), which plays an important role in angiogenesis, is expressed on angiogenic endothelium cells as well as tumor cells. Then, the MT1-MMP might be useful as a target molecule for tumor and neovascularity. In the present study, we addressed a utility of antibodies against the MT1-MMP as a targeting ligand of liposomal anticancer drug. Fab' fragments of antibody against the MT1-MMP were modified at distal end of polyethylene glycol (PEG) of doxorubicin (DXR)-encapsulating liposomes, DXR-sterically stabilized immunoliposomes (DXR-SIL[anti-MT1-MMP(Fab')]). Modification with the antibody significantly enhanced cellular uptake of DXR-SIL[anti-MT1-MMP(Fab')] into the HT1080 cells, which highly express MT1-MMP, compared with the non-targeted liposomes (DXR-stealthliposomes (DXR-SL)), suggesting that MT1-MMP antibody (Fab') is a potent targeting ligand for the MT1-MMP expressed cells. In vivo systemic administration of DXR-SIL[anti-MT1-MMP(Fab')] into the tumor-bearing mice showed significant suppression of tumor growth compared to DXR-SL. This is presumably due to the active targeting of immunoliposomes for tumor and neovascularity. However, tumor accumulation of DXR-SIL[anti-MT1-MMP(Fab')] and DXR-SL were comparable, suggesting that both liposomal formulations accumulated in tumor via enhanced permeation and retention (EPR) effect, but not via targeting to the MT1-MMP expressed on both the endothelial and tumor cells. It appears that the enhanced antitumor activity of DXR-SIL[anti-MT1-MMP(Fab')] resulted from acceleration of cellular uptake of lioposomes owing to the incorporated antibody after extravasation from capillaries in tumor."},"publication_date":"2007-05-10","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.342","number":"No.1-2","starting_page":"194","ending_page":"200","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2007.04.037"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:164, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507572"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/17473445","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164186","label":"url"}],"paper_title":{"en":"In vitro efficacy of a sterically stabilized immunoliposomes targeted to membrane type 1 matrix metalloproteinase (MT1-MMP).","ja":"In vitro efficacy of a sterically stabilized immunoliposomes targeted to membrane type 1 matrix metalloproteinase (MT1-MMP)."},"authors":{"en":[{"name":"Atobe Kazutaka"},{"name":"Ishida Tatsuhiro"},{"name":"Ishida Emi"},{"name":"Hashimoto Kouichi"},{"name":"Kobayashi Hideo"},{"name":"Yasuda Jyunko"},{"name":"Aoki Takanori"},{"name":"Obata Ken-ichi"},{"name":"Kikuchi Hiroshi"},{"name":"Akita Hidetaka"},{"name":"Asai Tomohiro"},{"name":"Harashima Hideyoshi"},{"name":"Oku Naoto"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"跡部 一孝"},{"name":"石田 竜弘"},{"name":"石田 絵美"},{"name":"橋本 浩一"},{"name":"小林 英夫"},{"name":"安田 順子"},{"name":"青木 孝則"},{"name":"小幡 健一"},{"name":"菊池 寛"},{"name":"秋田 英万"},{"name":"浅井 知浩"},{"name":"原島 秀吉"},{"name":"奥 直人"},{"name":"際田 弘志"}]},"description":{"en":"The poor selective cytotoxicity of anticancer drugs lead to dose-limiting adverse effects which compromise the clinical outcome. Solid tumors recruit new blood vessels to support their growth, and epitopes that are uniquely expressed on tumor cells and tumor endothelial cells (ECs) can function as targets for immunoliposomal anticancer drugs. Membrane type 1 matrix metalloproteinase (MT1-MMP), an important protein related to tumor growth and angiogenesis, is expressed on malignant tumor cells and is activated ECs. Selective delivery could be achieved by targeting MT1-MMP, as well as other angiogenic ECs. In this regard, an anti-MT1-MMP Fab' antibody was used to prepare a MT1-MMP targeted sterically stabilized immunoliposomes (SIL[anti-MT1-MMP(Fab')]). The binding and intracellular distribution of SIL[anti-MT1-MMP(Fab')] and a non-targeted sterically stabilized liposomes (SL) were examined using human fibrosarcoma HT-1080 cells. SIL[anti-MT1-MMP(Fab')] was taken up by the cells in a lipid concentration, temperature, and time dependent manner, ultimately accumulating in the lysosomes. The cytotoxicity of doxorubicin (DXR)-containing SIL[anti-MT1-MMP(Fab')] (DXR-SIL[anti-MT1-MMP(Fab')]) was significantly higher than that of DXR-containing SL. The cellular internalization of SIL[anti-MT1-MMP(Fab')] was inhibited by endocytosis inhibitors, suggesting that their internalization was mediated via clathrin- or caveolae-dependent endocytosis. Furthermore, the efficient binding of SIL[anti-MT1-MMP(Fab')] was observed on human umbilical vein endothelial cells (HUVEC). Based on these results, it would be expected that DXR-SIL[anti-MT1-MMP(Fab')] may achieve direct tumor cell kill and indirect tumor cell kill via the destruction of the tumor endothelium in vivo. This strategy may have the potential for overcoming some major limitations in conventional chemotherapy in vivo.","ja":"The poor selective cytotoxicity of anticancer drugs lead to dose-limiting adverse effects which compromise the clinical outcome. Solid tumors recruit new blood vessels to support their growth, and epitopes that are uniquely expressed on tumor cells and tumor endothelial cells (ECs) can function as targets for immunoliposomal anticancer drugs. Membrane type 1 matrix metalloproteinase (MT1-MMP), an important protein related to tumor growth and angiogenesis, is expressed on malignant tumor cells and is activated ECs. Selective delivery could be achieved by targeting MT1-MMP, as well as other angiogenic ECs. In this regard, an anti-MT1-MMP Fab' antibody was used to prepare a MT1-MMP targeted sterically stabilized immunoliposomes (SIL[anti-MT1-MMP(Fab')]). The binding and intracellular distribution of SIL[anti-MT1-MMP(Fab')] and a non-targeted sterically stabilized liposomes (SL) were examined using human fibrosarcoma HT-1080 cells. SIL[anti-MT1-MMP(Fab')] was taken up by the cells in a lipid concentration, temperature, and time dependent manner, ultimately accumulating in the lysosomes. The cytotoxicity of doxorubicin (DXR)-containing SIL[anti-MT1-MMP(Fab')] (DXR-SIL[anti-MT1-MMP(Fab')]) was significantly higher than that of DXR-containing SL. The cellular internalization of SIL[anti-MT1-MMP(Fab')] was inhibited by endocytosis inhibitors, suggesting that their internalization was mediated via clathrin- or caveolae-dependent endocytosis. Furthermore, the efficient binding of SIL[anti-MT1-MMP(Fab')] was observed on human umbilical vein endothelial cells (HUVEC). Based on these results, it would be expected that DXR-SIL[anti-MT1-MMP(Fab')] may achieve direct tumor cell kill and indirect tumor cell kill via the destruction of the tumor endothelium in vivo. This strategy may have the potential for overcoming some major limitations in conventional chemotherapy in vivo."},"publication_date":"2007-05","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.30","number":"No.5","starting_page":"972","ending_page":"978","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.30.972"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:165, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507573"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/17409515","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164185","label":"url"}],"paper_title":{"en":"Complex formation with plasmid DNA increases the cytotoxicity of cationic liposomes.","ja":"Complex formation with plasmid DNA increases the cytotoxicity of cationic liposomes."},"authors":{"en":[{"name":"Nguen Thi Lap"},{"name":"Atobe Kazutaka"},{"name":"Barichello Jose Mari"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Nguen Thi Lap"},{"name":"跡部 一孝"},{"name":"Barichello Jose Mari"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Cationic liposomes (CL) are one of the most widely studied non-viral vectors for gene delivery. It is well-known that CL induces cytotoxicity following lipofection. However, little is known regarding the mechanism involved in the cytotoxicity. In this study, the in vitro cytotoxicity of CL and its complex with pDNA (lipoplex) was investigated, and a part of the mechanism of induction as well. While free pDNA did not show any cytotoxicity, pDNA increased the cytotoxicity of CL via the formation of lipoplex. In addition, the lipoplex-induced cytotoxicity increased in a lipoplex dose-dependent manner, irrespective of the type of pDNA, cell line and the absence or presence of serum. An assay showed that apoptosis was largely induced by treatment with the lipoplex (lipofection), but not with CL alone, in the tested range of concentration of CL and pDNA. Furthermore, following treatment with lipoplexes, the cells exhibited the morphological features of apoptosis and DNA fragmentation. A cDNA microarray study showed that the lipofection up-regulated 45 genes related to apoptosis, transcription regulation and immune response. These results clearly indicate that pDNA in the lipoplex increases the cytotoxicity of CL as a result of inducing apoptosis. The fundamental principle for gene therapy is to deliver gene-based therapeutics to target cells for specific gene targeting with minimal cytotoxicity. Our results suggest the possibility that cytotoxicity induced by lipofection, accompanied by gene changes, could intrinsically exacerbate, attenuate or even mask the desired effects of gene-based therapy.","ja":"Cationic liposomes (CL) are one of the most widely studied non-viral vectors for gene delivery. It is well-known that CL induces cytotoxicity following lipofection. However, little is known regarding the mechanism involved in the cytotoxicity. In this study, the in vitro cytotoxicity of CL and its complex with pDNA (lipoplex) was investigated, and a part of the mechanism of induction as well. While free pDNA did not show any cytotoxicity, pDNA increased the cytotoxicity of CL via the formation of lipoplex. In addition, the lipoplex-induced cytotoxicity increased in a lipoplex dose-dependent manner, irrespective of the type of pDNA, cell line and the absence or presence of serum. An assay showed that apoptosis was largely induced by treatment with the lipoplex (lipofection), but not with CL alone, in the tested range of concentration of CL and pDNA. Furthermore, following treatment with lipoplexes, the cells exhibited the morphological features of apoptosis and DNA fragmentation. A cDNA microarray study showed that the lipofection up-regulated 45 genes related to apoptosis, transcription regulation and immune response. These results clearly indicate that pDNA in the lipoplex increases the cytotoxicity of CL as a result of inducing apoptosis. The fundamental principle for gene therapy is to deliver gene-based therapeutics to target cells for specific gene targeting with minimal cytotoxicity. Our results suggest the possibility that cytotoxicity induced by lipofection, accompanied by gene changes, could intrinsically exacerbate, attenuate or even mask the desired effects of gene-based therapy."},"publication_date":"2007-04","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.30","number":"No.4","starting_page":"751","ending_page":"757","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.30.751"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:166, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507574"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/17097247","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164183","label":"url"}],"paper_title":{"en":"The gene-silencing effect of siRNA in cationic lipoplexes is enhanced by incorporating pDNA in the complex.","ja":"The gene-silencing effect of siRNA in cationic lipoplexes is enhanced by incorporating pDNA in the complex."},"authors":{"en":[{"name":"Tagami Tatsuaki"},{"name":"Barichello Jose Mari"},{"name":"Kikuchi Hiroshi"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"田上 辰秋"},{"name":"Barichello Jose Mari"},{"name":"菊池 寛"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Efficient delivery is a key issue in translating interference RNA technology into a feasible therapy. The efficiency of carrier systems used for this technology is commonly tested by co-transfection, i.e. simultaneous transfection with an exogenous gene and with the siRNA. Two approaches can be distinguished: (1) with the two transfectants in the same carrier complex (siRNA/pDNA/carrier) and (2) with the two transfectants in different carrier complexes (pDNA/carrier and siRNA/carrier). The process to prepare the nucleic acid(s)-carrier complexes and the transfection procedure may affect the effectiveness of the gene-silencing process. In this study, two preparation methods were compared, namely the co-preparation of an siRNA/pDNA/liposome lipoplex (Method I) and the separate preparation of an siRNA/liposome lipoplex and a pDNA/liposome lipoplex (Method II). siRNA in the lipoplex produced by Method I showed a stronger gene-silencing effect than that in the lipoplexes prepared by Method II. There was no significant difference between the two methods in the amount of siRNA delivered to cells. Cellular entry and intracellular trafficking of siRNA/pDNA/liposome lipoplex is likely to differ from those of the separate lipoplexes. When in Method II non-transcriptional pDNA was included in the complex with siRNA, the gene-silencing effect was significantly enhanced. If and to what extent the experimental design is suitable to quantify RNA interference remains to be demonstrated.","ja":"Efficient delivery is a key issue in translating interference RNA technology into a feasible therapy. The efficiency of carrier systems used for this technology is commonly tested by co-transfection, i.e. simultaneous transfection with an exogenous gene and with the siRNA. Two approaches can be distinguished: (1) with the two transfectants in the same carrier complex (siRNA/pDNA/carrier) and (2) with the two transfectants in different carrier complexes (pDNA/carrier and siRNA/carrier). The process to prepare the nucleic acid(s)-carrier complexes and the transfection procedure may affect the effectiveness of the gene-silencing process. In this study, two preparation methods were compared, namely the co-preparation of an siRNA/pDNA/liposome lipoplex (Method I) and the separate preparation of an siRNA/liposome lipoplex and a pDNA/liposome lipoplex (Method II). siRNA in the lipoplex produced by Method I showed a stronger gene-silencing effect than that in the lipoplexes prepared by Method II. There was no significant difference between the two methods in the amount of siRNA delivered to cells. Cellular entry and intracellular trafficking of siRNA/pDNA/liposome lipoplex is likely to differ from those of the separate lipoplexes. When in Method II non-transcriptional pDNA was included in the complex with siRNA, the gene-silencing effect was significantly enhanced. If and to what extent the experimental design is suitable to quantify RNA interference remains to be demonstrated."},"publication_date":"2007-03-21","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.333","number":"No.1-2","starting_page":"62","ending_page":"69","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2006.09.057"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:167, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507575"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/17399838","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164189","label":"url"}],"paper_title":{"en":"Anti-PEG IgM elicited by injection of liposomes is involved in the enhanced blood clearance of a subsequent dose of PEGylated liposomes.","ja":"Anti-PEG IgM elicited by injection of liposomes is involved in the enhanced blood clearance of a subsequent dose of PEGylated liposomes."},"authors":{"en":[{"name":"Wang Xinyu"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"王 新宇"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Earlier we reported that PEGylated liposomes lose their long-circulating characteristic when they are administrated twice in the same animal with certain intervals (referred to as the accelerated blood clearance (ABC) phenomenon). We proposed that anti-PEG IgM, induced by the PEGylated liposomes, is responsible for the phenomenon, based on the observation that IgM thus produced selectively binds to the surface of PEGylated liposomes, subsequently leading to substantial complement activation. Interestingly, we found that under certain circumstances administration of conventional liposomes without PEG-coating also caused a strong ABC response upon injection of a second dose of PEGylated liposomes, but not of conventional liposomes. This suggests that also conventional liposomes not modified with PEG can promote an IgM response against PEG. We report here that, irrespective of the presence or absence PEG-coating, a single first dose of liposomes is capable of inducing a strong anti-PEG IgM response and, under certain circumstances, also weak responses against other lipid components. A good correspondence was observed between the amount of IgM associating with both PEGylated and conventional liposomes, concomitant complement activation triggered by those liposomes and the magnitude of the ABC phenomenon against those liposomes. Taken together, our results demonstrate that the ABC phenomenon is fully attributable to production of anti-PEG IgM by the first dose of liposomes and the subsequent complement activation upon a second dose of PEGylated but not conventional liposomes. Although the responsible immunogenic epitopes of the liposomes remain to be determined, the immunogenicity of 'empty' liposomes presents a serious concern in the development of liposomal formulations and their use in the clinic. Furthermore, our findings as described here raise important concerns with regard to the safety and efficiency of liposomes currently under development for clinical use.","ja":"Earlier we reported that PEGylated liposomes lose their long-circulating characteristic when they are administrated twice in the same animal with certain intervals (referred to as the accelerated blood clearance (ABC) phenomenon). We proposed that anti-PEG IgM, induced by the PEGylated liposomes, is responsible for the phenomenon, based on the observation that IgM thus produced selectively binds to the surface of PEGylated liposomes, subsequently leading to substantial complement activation. Interestingly, we found that under certain circumstances administration of conventional liposomes without PEG-coating also caused a strong ABC response upon injection of a second dose of PEGylated liposomes, but not of conventional liposomes. This suggests that also conventional liposomes not modified with PEG can promote an IgM response against PEG. We report here that, irrespective of the presence or absence PEG-coating, a single first dose of liposomes is capable of inducing a strong anti-PEG IgM response and, under certain circumstances, also weak responses against other lipid components. A good correspondence was observed between the amount of IgM associating with both PEGylated and conventional liposomes, concomitant complement activation triggered by those liposomes and the magnitude of the ABC phenomenon against those liposomes. Taken together, our results demonstrate that the ABC phenomenon is fully attributable to production of anti-PEG IgM by the first dose of liposomes and the subsequent complement activation upon a second dose of PEGylated but not conventional liposomes. Although the responsible immunogenic epitopes of the liposomes remain to be determined, the immunogenicity of 'empty' liposomes presents a serious concern in the development of liposomal formulations and their use in the clinic. Furthermore, our findings as described here raise important concerns with regard to the safety and efficiency of liposomes currently under development for clinical use."},"publication_date":"2007-02-24","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.119","number":"No.2","starting_page":"236","ending_page":"244","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2007.02.010"],"issn":["1873-4995"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:168, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507576"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/17331684","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164188","label":"url"}],"paper_title":{"en":"Efficient gene expression in Megakaryocytic cell line using Nucleofection.","ja":"Efficient gene expression in Megakaryocytic cell line using Nucleofection."},"authors":{"en":[{"name":"Isakari Yoshimasa"},{"name":"Harada Yasuo"},{"name":"Ishikawa Dai"},{"name":"Matsumura-Takeda Kuniko"},{"name":"Sogo Shinji"},{"name":"Ishida Tatsuhiro"},{"name":"Taki Takao"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"飯盛 良正"},{"name":"Harada Yasuo"},{"name":"Ishikawa Dai"},{"name":"Matsumura-Takeda Kuniko"},{"name":"Sogo Shinji"},{"name":"石田 竜弘"},{"name":"Taki Takao"},{"name":"際田 弘志"}]},"description":{"en":"To clarify the mechanism of platelet production from megakaryocytes, expression of target proteins by gene transfection was examined using various gene delivery techniques. Transfection into hematopoietic cells, including megakaryocytes, by conventional gene delivery techniques such as electroporation and lipofection are known to be difficult. In this study, in addition to electroporation and lipofection, we tested other gene-transfer methods (nucleofection, transfection using inactivated virus envelope, and transferrin-linked cationic polymer) with the green fluorescent protein (GFP) gene into the human megakaryocytic cell line MEG-01. We found that nucleofection, which uses a combination of special electrical parameters and specific solutions, was the best, judging from the expression ratio of GFP-positive cells (approximately 70% of cells) and low toxicity. The efficiency of GFP expression was not related to the amount of pDNA delivered into the MEG-01 cells. To verify the utility of nucleofection, the thrombopoietin (TPO) receptor c-mpl was transfected into MEG-01 cells. Transfected cells showed a higher responsiveness to TPO than mock-transfected MEG-01 cells. We propose that nucleofection is a useful method for transfecting target genes to megakaryocytic cells when addressing the mechanism of platelet production.","ja":"To clarify the mechanism of platelet production from megakaryocytes, expression of target proteins by gene transfection was examined using various gene delivery techniques. Transfection into hematopoietic cells, including megakaryocytes, by conventional gene delivery techniques such as electroporation and lipofection are known to be difficult. In this study, in addition to electroporation and lipofection, we tested other gene-transfer methods (nucleofection, transfection using inactivated virus envelope, and transferrin-linked cationic polymer) with the green fluorescent protein (GFP) gene into the human megakaryocytic cell line MEG-01. We found that nucleofection, which uses a combination of special electrical parameters and specific solutions, was the best, judging from the expression ratio of GFP-positive cells (approximately 70% of cells) and low toxicity. The efficiency of GFP expression was not related to the amount of pDNA delivered into the MEG-01 cells. To verify the utility of nucleofection, the thrombopoietin (TPO) receptor c-mpl was transfected into MEG-01 cells. Transfected cells showed a higher responsiveness to TPO than mock-transfected MEG-01 cells. We propose that nucleofection is a useful method for transfecting target genes to megakaryocytic cells when addressing the mechanism of platelet production."},"publication_date":"2007-02-02","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.338","number":"No.1-2","starting_page":"157","ending_page":"164","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2007.01.042"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:169, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507577"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/16997518","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164181","label":"url"}],"paper_title":{"en":"Effect of Transferrin receptor-targeted liposomal doxorubicin in P-glycoprotein-mediated drug resistant tumor cells.","ja":"Effect of Transferrin receptor-targeted liposomal doxorubicin in P-glycoprotein-mediated drug resistant tumor cells."},"authors":{"en":[{"name":"Kobayashi Tomotaka"},{"name":"Ishida Tatsuhiro"},{"name":"Okada Yurie"},{"name":"Ise Saori"},{"name":"Harashima Hideyoshi"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"小林 友貴"},{"name":"石田 竜弘"},{"name":"岡田 百合絵"},{"name":"Ise Saori"},{"name":"原島 秀吉"},{"name":"際田 弘志"}]},"description":{"en":"The over-expression of P-glycoprotein (P-gp) has been associated with the development of multidrug resistance (MDR) in cancer cells. In this study, we examined whether transferrin receptor (Tf-R) targeted liposomes can efficiently deliver encapsulated doxorubicin (DXR) into MDR cells (SBC-3/ADM) via Tf-R-mediated endocytosis thus overcoming MDR by by-passing P-gp-mediated drug efflux. We prepared four types of liposome, i.e. untargeted and Tf-R-targeted, made of either egg-PC/cholesterol or hydrogenated egg PC/cholesterol. Only with the targeted EPC-liposome we achieved significant delivery of encapsulated DXR and increased cytotoxicity of encapsulated DXR on the MDR cells (3.5-fold higher than free DXR). Confocal microscopy and an intracellular drug-accumulation assay indicated that the targeted liposomes efficiently delivered DXR into cells where it readily accumulated in the nucleus, in both drug-sensitive and MDR cells. These findings suggest that the targeted liposomes are rapidly internalized via Tf-R-mediated endocytosis followed by release of their contents into the cytoplasm. The rapid internalization and content release, most likely facilitated by the higher fluidity of the EPC-based liposomes, may explain why only targeted EPC-liposomes were able to prevent drug efflux by P-gp and to consequently circumvent MDR. Our results indicate that in order to achieve MDR circumvention by means of liposomal encapsulation of DXR the liposomes not only need to be targeted, but also to have the proper physicochemical properties for adequate release of the drug. Furthermore, these in vitro results suggest that Tf-R targeted EPC-liposomes are a potentially useful drug delivery system to circumvent P-gp-mediated MDR of tumors.","ja":"The over-expression of P-glycoprotein (P-gp) has been associated with the development of multidrug resistance (MDR) in cancer cells. In this study, we examined whether transferrin receptor (Tf-R) targeted liposomes can efficiently deliver encapsulated doxorubicin (DXR) into MDR cells (SBC-3/ADM) via Tf-R-mediated endocytosis thus overcoming MDR by by-passing P-gp-mediated drug efflux. We prepared four types of liposome, i.e. untargeted and Tf-R-targeted, made of either egg-PC/cholesterol or hydrogenated egg PC/cholesterol. Only with the targeted EPC-liposome we achieved significant delivery of encapsulated DXR and increased cytotoxicity of encapsulated DXR on the MDR cells (3.5-fold higher than free DXR). Confocal microscopy and an intracellular drug-accumulation assay indicated that the targeted liposomes efficiently delivered DXR into cells where it readily accumulated in the nucleus, in both drug-sensitive and MDR cells. These findings suggest that the targeted liposomes are rapidly internalized via Tf-R-mediated endocytosis followed by release of their contents into the cytoplasm. The rapid internalization and content release, most likely facilitated by the higher fluidity of the EPC-based liposomes, may explain why only targeted EPC-liposomes were able to prevent drug efflux by P-gp and to consequently circumvent MDR. Our results indicate that in order to achieve MDR circumvention by means of liposomal encapsulation of DXR the liposomes not only need to be targeted, but also to have the proper physicochemical properties for adequate release of the drug. Furthermore, these in vitro results suggest that Tf-R targeted EPC-liposomes are a potentially useful drug delivery system to circumvent P-gp-mediated MDR of tumors."},"publication_date":"2007-02-01","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.329","number":"No.1-2","starting_page":"94","ending_page":"102","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2006.08.039"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:170, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507578"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/17045355","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164180","label":"url"}],"paper_title":{"en":"Accelerated blood clearance of PEGylated liposomes upon repeated injections: Effect of doxorubicin-encapsulation and high-dose first injection.","ja":"Accelerated blood clearance of PEGylated liposomes upon repeated injections: Effect of doxorubicin-encapsulation and high-dose first injection."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Atobe Kazutaka"},{"name":"Wang Xinyu"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"跡部 一孝"},{"name":"王 新宇"},{"name":"際田 弘志"}]},"description":{"en":"The \"accelerated blood clearance (ABC) phenomenon\", causing PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection, has been reported to occur in rodents and rhesus monkeys. This rapid clearance was reported to be caused by the binding of PEG-specific IgM, which was generated by the first dose of injected liposomes, to the second dose of liposomes and the subsequent activation of complement, serving in turn as an opsonin. Although there are several PEGylated liposomal formulations, such as Doxil/Caelyx loaded with doxorubicin (DXR), in clinical use, the rapid clearance phenomenon has never been reported for such formulations. In the present article, we report that a first injection of PEGylated liposomes containing encapsulated DXR failed to induce the ABC phenomenon. Likewise, no rapid clearance of the test dose was observed when the first dose of \"empty\" PEGylated liposomes (without DXR) exceeded 5 micromol phospholipids/kg. By contrast, \"empty\" PEGylated liposomes at a low dose (1 micromol phospholipids/kg) induced the phenomenon as before. Western blot analysis revealed abundant binding of IgM to PEGylated liposomes when these were incubated in serum from rats that had received \"empty\" PEGylated liposomes. Substantially less binding of IgM was found when the liposomes were incubated in serum from rats treated with DXR-loaded PEGylated liposomes. For both the empty and the DXR-containing liposomes the amounts of IgM binding to the liposomes decreased with an increasing dose of injected liposomes. Serum obtained from rats following injection of empty PEGylated liposomes caused complement activation by addition of PEGylated liposomes in an inversely dose-dependent manner: the lower the dose, the higher the complement activation. By contrast, no complement activation was detected with serum from rats that had been treated with DXR-loaded PEGylated liposomes. These findings suggest that encapsulation of DXR as well as a relatively high lipid dose abrogate the immune response against PEGylated liposomes which is observed with the same liposomes but without DXR and at low doses. Our observations may thus have important implications for the development, evaluation and therapeutic use of liposomal cytotoxic drug formulations requiring multiple injection schemes.","ja":"The \"accelerated blood clearance (ABC) phenomenon\", causing PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection, has been reported to occur in rodents and rhesus monkeys. This rapid clearance was reported to be caused by the binding of PEG-specific IgM, which was generated by the first dose of injected liposomes, to the second dose of liposomes and the subsequent activation of complement, serving in turn as an opsonin. Although there are several PEGylated liposomal formulations, such as Doxil/Caelyx loaded with doxorubicin (DXR), in clinical use, the rapid clearance phenomenon has never been reported for such formulations. In the present article, we report that a first injection of PEGylated liposomes containing encapsulated DXR failed to induce the ABC phenomenon. Likewise, no rapid clearance of the test dose was observed when the first dose of \"empty\" PEGylated liposomes (without DXR) exceeded 5 micromol phospholipids/kg. By contrast, \"empty\" PEGylated liposomes at a low dose (1 micromol phospholipids/kg) induced the phenomenon as before. Western blot analysis revealed abundant binding of IgM to PEGylated liposomes when these were incubated in serum from rats that had received \"empty\" PEGylated liposomes. Substantially less binding of IgM was found when the liposomes were incubated in serum from rats treated with DXR-loaded PEGylated liposomes. For both the empty and the DXR-containing liposomes the amounts of IgM binding to the liposomes decreased with an increasing dose of injected liposomes. Serum obtained from rats following injection of empty PEGylated liposomes caused complement activation by addition of PEGylated liposomes in an inversely dose-dependent manner: the lower the dose, the higher the complement activation. By contrast, no complement activation was detected with serum from rats that had been treated with DXR-loaded PEGylated liposomes. These findings suggest that encapsulation of DXR as well as a relatively high lipid dose abrogate the immune response against PEGylated liposomes which is observed with the same liposomes but without DXR and at low doses. Our observations may thus have important implications for the development, evaluation and therapeutic use of liposomal cytotoxic drug formulations requiring multiple injection schemes."},"publication_date":"2006-09-03","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.115","number":"No.3","starting_page":"251","ending_page":"258","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2006.08.017"],"issn":["0168-3659"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:171, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507579"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/17011060","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164179","label":"url"}],"paper_title":{"en":"Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes.","ja":"Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Ichihara Masako"},{"name":"Wang Xinyu"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"市原 理子"},{"name":"王 新宇"},{"name":"際田 弘志"}]},"description":{"en":"It is well known that steric stabilization of the surface of liposomes by a polyethyleneglycol (PEG) conjugated lipid results in reduced recognition of the liposomes by the cells of the mononuclear phagocyte system and consequently extended circulation times of the liposomes (t1/2 approximately 20 h in rat). Recently, we reported on the \"accelerated blood clearance (ABC) phenomenon\", causing PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection. We also reported that abundant binding of IgM, secreted into the blood stream after the first dose and, to PEGylated liposomes, plays an essential role in the induction of the ABC phenomenon. Spleen is well known to play a central role in the immune reaction and to produce IgM following a bacterial infection. The aim of the present study was to determine whether spleen contributes to the induction of the ABC phenomenon and to unravel its role in the phenomenon. In rats that were splenectomized (surgical removal of spleen) prior to the first injection of liposomes (0.001 micromol phospholipids/kg), the ABC phenomenon was totally abolished. In these rats serum IgM concentrations as well as the amounts of IgM bound to PEGylated liposomes were substantially reduced. Splenectomy attenuated the ABC phenomenon when performed until 3 days post-first injection. Removal of the spleen 4 days post-first injection left the ABC phenomenon unchanged. This finding indicates that the immune reaction in the spleen against the PEGylated liposomes occurs during at least 2-3 days following the first administration and then IgM reactive to PEGylated liposomes is produced. The present study proves that the spleen plays a critical role in the induction phase of the ABC phenomenon. For effective clinical application, many liposomal drug formulations will require multiple injections. The ABC phenomenon described in this and several preceding papers therefore has important implications for the development and evaluation of therapeutically useful liposomal formulations requiring multiple-dose administration.","ja":"It is well known that steric stabilization of the surface of liposomes by a polyethyleneglycol (PEG) conjugated lipid results in reduced recognition of the liposomes by the cells of the mononuclear phagocyte system and consequently extended circulation times of the liposomes (t1/2 approximately 20 h in rat). Recently, we reported on the \"accelerated blood clearance (ABC) phenomenon\", causing PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection. We also reported that abundant binding of IgM, secreted into the blood stream after the first dose and, to PEGylated liposomes, plays an essential role in the induction of the ABC phenomenon. Spleen is well known to play a central role in the immune reaction and to produce IgM following a bacterial infection. The aim of the present study was to determine whether spleen contributes to the induction of the ABC phenomenon and to unravel its role in the phenomenon. In rats that were splenectomized (surgical removal of spleen) prior to the first injection of liposomes (0.001 micromol phospholipids/kg), the ABC phenomenon was totally abolished. In these rats serum IgM concentrations as well as the amounts of IgM bound to PEGylated liposomes were substantially reduced. Splenectomy attenuated the ABC phenomenon when performed until 3 days post-first injection. Removal of the spleen 4 days post-first injection left the ABC phenomenon unchanged. This finding indicates that the immune reaction in the spleen against the PEGylated liposomes occurs during at least 2-3 days following the first administration and then IgM reactive to PEGylated liposomes is produced. The present study proves that the spleen plays a critical role in the induction phase of the ABC phenomenon. For effective clinical application, many liposomal drug formulations will require multiple injections. The ABC phenomenon described in this and several preceding papers therefore has important implications for the development and evaluation of therapeutically useful liposomal formulations requiring multiple-dose administration."},"publication_date":"2006-08-07","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.115","number":"No.3","starting_page":"243","ending_page":"250","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2006.08.001"],"issn":["0168-3659"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:172, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507580"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/16919352","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164176","label":"url"}],"paper_title":{"en":"Inducing effect of liposomalization on the transdermal delivery of hydrocortisone: creation of a drug supersaturated state.","ja":"Inducing effect of liposomalization on the transdermal delivery of hydrocortisone: creation of a drug supersaturated state."},"authors":{"en":[{"name":"Barichello Jose Mario"},{"name":"Handa M."},{"name":"Kisyuku, M."},{"name":"Shibata Taiki"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Barichello Jose Mario"},{"name":"Handa M."},{"name":"Kisyuku, M."},{"name":"Shibata Taiki"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"In order to investigate the effect of liposomal drugs on skin delivery, it was postulated that the process of liposomalization might lead the drug to an overpredicted solubility state which has far-reaching implications for drug skin permeation and accumulation. In this regard, conventional (CL) and flexible liposomes (FL) were prepared by the lipid film hydration method and the particles were downsized by sonication using hydrocortisone (HC) as a poorly water soluble model drug. The solutions derived from the whole CL and FL suspensions eluted on a Sephadex G-50 column (SG-50) demonstrated that most part of HC not only resides solely in the water phase but also it might exist in an improved solubility state. The results of the in vitro study using rat abdominal skin and occlusive application indicated that HC penetrated and accumulated much better solely than when associated with CL or FL. In regard to the penetration of the non-entrapped HC associated to liposomes bilayer fragments, a very small amount of phospholipids in the non-liposomal part eluted on SG-50 was found that could not justify by itself the penetration of HC associated to liposome bilayer fragments. It was proposed that all the steps of the liposomes preparation process might contribute for the increased HC solubility state, but definitively the presence of phospholipids played a crucial role on improving the HC solubility in the absence of sodium cholate. In comparison with commercially available ointments, the non-entrapped HC solution derived from the whole CL suspension eluted on SG-50 showed a higher concentration of HC accumulated and more uniformly distributed as well in the epidermis and dermis compartments. In addition, the thermodynamic activity of the non-entrapped HC solutions maintaining a driving force of the drug across the skin barrier pointed out that the level of HC solubility achieved during liposome preparation has far-reaching implication for drug skin permeation and accumulation in the experimental conditions used. The findings also indicated that the non-entrapped drug solutions obtained on the process of liposomalization could be useful on transdermal drug delivery systems, particularly for improving the permeation and accumulation capacity of poorly soluble drugs.","ja":"In order to investigate the effect of liposomal drugs on skin delivery, it was postulated that the process of liposomalization might lead the drug to an overpredicted solubility state which has far-reaching implications for drug skin permeation and accumulation. In this regard, conventional (CL) and flexible liposomes (FL) were prepared by the lipid film hydration method and the particles were downsized by sonication using hydrocortisone (HC) as a poorly water soluble model drug. The solutions derived from the whole CL and FL suspensions eluted on a Sephadex G-50 column (SG-50) demonstrated that most part of HC not only resides solely in the water phase but also it might exist in an improved solubility state. The results of the in vitro study using rat abdominal skin and occlusive application indicated that HC penetrated and accumulated much better solely than when associated with CL or FL. In regard to the penetration of the non-entrapped HC associated to liposomes bilayer fragments, a very small amount of phospholipids in the non-liposomal part eluted on SG-50 was found that could not justify by itself the penetration of HC associated to liposome bilayer fragments. It was proposed that all the steps of the liposomes preparation process might contribute for the increased HC solubility state, but definitively the presence of phospholipids played a crucial role on improving the HC solubility in the absence of sodium cholate. In comparison with commercially available ointments, the non-entrapped HC solution derived from the whole CL suspension eluted on SG-50 showed a higher concentration of HC accumulated and more uniformly distributed as well in the epidermis and dermis compartments. In addition, the thermodynamic activity of the non-entrapped HC solutions maintaining a driving force of the drug across the skin barrier pointed out that the level of HC solubility achieved during liposome preparation has far-reaching implication for drug skin permeation and accumulation in the experimental conditions used. The findings also indicated that the non-entrapped drug solutions obtained on the process of liposomalization could be useful on transdermal drug delivery systems, particularly for improving the permeation and accumulation capacity of poorly soluble drugs."},"publication_date":"2006-07-13","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.115","number":"No.1","starting_page":"94","ending_page":"102","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2006.07.008"],"issn":["0168-3659"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:173, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507581"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/16643931","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164172","label":"url"}],"paper_title":{"en":"Electrophoretic behavior of plasmid DNA in the presence of various intercalating dyes.","ja":"Electrophoretic behavior of plasmid DNA in the presence of various intercalating dyes."},"authors":{"en":[{"name":"Dang Foi"},{"name":"Li Wenhao"},{"name":"Zhang LiGo"},{"name":"Japasini M"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"},{"name":"Kaji, N."},{"name":"Tokeshi, M."},{"name":"Baba Yoshinobu"}],"ja":[{"name":"Dang Foi"},{"name":"李 文浩"},{"name":"Zhang LiGo"},{"name":"Japasini M"},{"name":"石田 竜弘"},{"name":"際田 弘志"},{"name":"Kaji, N."},{"name":"Tokeshi, M."},{"name":"馬場 嘉信"}]},"description":{"en":"In the present study, the electrophoretic behavior of linear, supercoiled and nicked circular plasmid DNA in the presence of various intercalating dyes was characterized using pGL3 plasmid DNA as a model. The enzymatic digestion of pGL3 plasmid DNA with HindIIIwas monitored by capillary electrophoresis coupled with laser-induced fluorescence detection (CE-LIF). Nicked circular plasmid DNA was found to be relatively sensitive to enzymes, and was almost digested into the linear conformer after 10-min incubation, indicating that nicked circular plasmid DNA has little chance of targeting and entering the cell nucleus. Partly digested plasmid DNA containing only linear and supercoiled conformers can be used as a standard to confirm the migration order of plasmid DNA. In methylcellulose (MC) solution with YO-PRO-1 or YOYO-1, linear plasmid DNA eluted first, followed by supercoiled and nicked plasmid DNA, and nicked plasmid DNA eluted as a broad peak. With SYBR Green 1, nicked plasmid DNA eluted first as three sharp peaks, followed by linear and supercoiled plasmid DNA. The nuclear plasmid DNA from two transfected cell lines was successfully analyzed using the present procedure. Similar results were obtained with an analysis time of seconds using microchip electrophoresis with laser-induced fluorescence detection (mu-CE-LIF). To our knowledge, these results represent the first reported analysis of nuclear plasmid DNA from transfection cells by CE-LIF or mu-CE-LIF without pre-preparation, suggesting that the present procedure is a promising alternative method for evaluating transfection efficiency of DNA delivery systems.","ja":"In the present study, the electrophoretic behavior of linear, supercoiled and nicked circular plasmid DNA in the presence of various intercalating dyes was characterized using pGL3 plasmid DNA as a model. The enzymatic digestion of pGL3 plasmid DNA with HindIIIwas monitored by capillary electrophoresis coupled with laser-induced fluorescence detection (CE-LIF). Nicked circular plasmid DNA was found to be relatively sensitive to enzymes, and was almost digested into the linear conformer after 10-min incubation, indicating that nicked circular plasmid DNA has little chance of targeting and entering the cell nucleus. Partly digested plasmid DNA containing only linear and supercoiled conformers can be used as a standard to confirm the migration order of plasmid DNA. In methylcellulose (MC) solution with YO-PRO-1 or YOYO-1, linear plasmid DNA eluted first, followed by supercoiled and nicked plasmid DNA, and nicked plasmid DNA eluted as a broad peak. With SYBR Green 1, nicked plasmid DNA eluted first as three sharp peaks, followed by linear and supercoiled plasmid DNA. The nuclear plasmid DNA from two transfected cell lines was successfully analyzed using the present procedure. Similar results were obtained with an analysis time of seconds using microchip electrophoresis with laser-induced fluorescence detection (mu-CE-LIF). To our knowledge, these results represent the first reported analysis of nuclear plasmid DNA from transfection cells by CE-LIF or mu-CE-LIF without pre-preparation, suggesting that the present procedure is a promising alternative method for evaluating transfection efficiency of DNA delivery systems."},"publication_date":"2006-04-27","publication_name":{"en":"Journal of Chromatography. A","ja":"Journal of Chromatography. A"},"volume":"Vol.1118","number":"No.2","starting_page":"218","ending_page":"225","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.chroma.2006.03.120"],"issn":["0021-9673"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:174, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507582"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/16515818","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164175","label":"url"}],"paper_title":{"en":"Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes.","ja":"Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Ichihara Masako"},{"name":"Wang Xinyu"},{"name":"Yamamoto Kenji"},{"name":"Kimura Jyunji"},{"name":"Majima Eiji"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"市原 理子"},{"name":"王 新宇"},{"name":"Yamamoto Kenji"},{"name":"Kimura Jyunji"},{"name":"真島 英司"},{"name":"際田 弘志"}]},"description":{"en":"Steric stabilization of the surface of liposomes by a PEG conjugated lipid results in reduced recognition of the liposomes by the cells of the mononuclear phagocyte system and consequently extended their circulation times (t(1/2) approximately 20h in rat). Recently, we reported on the \"accelerated blood clearance phenomenon\", causing \"invisible\" PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection. In addition, we reported that certain serum factor(s) secreted into the blood after the first dose of PEGylated liposomes play an essential role in the phenomenon. The aim of the present study was to identify the major serum protein(s) responsible for the phenomenon and to unravel their mode of action. The amount of protein binding to PEGylated liposomes during incubation with serum hardly correlated with the extent of the phenomenon. PEGylated liposomes incubated with serum obtained from rats pre-injected 5 days before with the same liposomes showed a much more complex pattern of bound proteins than when incubated with naïve serum, as revealed by 2D-PAGE and SDS-PAGE. Subsequent analysis with LC-MS/MS and Western blot showed that the major pre-treated serum protein binding to PEGylated liposomes was IgM. Semi-quantitative analysis showed that larger amount of IgM bound to PEGylated liposomes compared to conventional liposomes. It was further demonstrated that PEGylated liposomes could activate the complement system due to IgM binding when incubated in serum from rats pre-injected with PEGylated liposomes, while conventional liposomes were not. These findings suggest that the selective binding of IgM to the second injected PEGylated liposomes and the subsequent complement activation by IgM resulted in the accelerated clearance and enhanced hepatic uptake of the second injected PEGylated liposomes. Based on the results described here, we are drawing attention to the potential occurrence of unexpected immune reactions upon intravenous administration of PEGylated liposomes or other particles and, by extension, PEGylated proteins and DNAs.","ja":"Steric stabilization of the surface of liposomes by a PEG conjugated lipid results in reduced recognition of the liposomes by the cells of the mononuclear phagocyte system and consequently extended their circulation times (t(1/2) approximately 20h in rat). Recently, we reported on the \"accelerated blood clearance phenomenon\", causing \"invisible\" PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection. In addition, we reported that certain serum factor(s) secreted into the blood after the first dose of PEGylated liposomes play an essential role in the phenomenon. The aim of the present study was to identify the major serum protein(s) responsible for the phenomenon and to unravel their mode of action. The amount of protein binding to PEGylated liposomes during incubation with serum hardly correlated with the extent of the phenomenon. PEGylated liposomes incubated with serum obtained from rats pre-injected 5 days before with the same liposomes showed a much more complex pattern of bound proteins than when incubated with naïve serum, as revealed by 2D-PAGE and SDS-PAGE. Subsequent analysis with LC-MS/MS and Western blot showed that the major pre-treated serum protein binding to PEGylated liposomes was IgM. Semi-quantitative analysis showed that larger amount of IgM bound to PEGylated liposomes compared to conventional liposomes. It was further demonstrated that PEGylated liposomes could activate the complement system due to IgM binding when incubated in serum from rats pre-injected with PEGylated liposomes, while conventional liposomes were not. These findings suggest that the selective binding of IgM to the second injected PEGylated liposomes and the subsequent complement activation by IgM resulted in the accelerated clearance and enhanced hepatic uptake of the second injected PEGylated liposomes. Based on the results described here, we are drawing attention to the potential occurrence of unexpected immune reactions upon intravenous administration of PEGylated liposomes or other particles and, by extension, PEGylated proteins and DNAs."},"publication_date":"2006-03-03","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.112","number":"No.1","starting_page":"15","ending_page":"25","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2006.01.005"],"issn":["0168-3659"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:175, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507583"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/16288498","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164168","label":"url"}],"paper_title":{"en":"Stimulatory effect of polyethylene glycol (PEG) on gene expression in mouse liver following hydrodynamics-based transfection.","ja":"Stimulatory effect of polyethylene glycol (PEG) on gene expression in mouse liver following hydrodynamics-based transfection."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Liu Wenhao"},{"name":"Li Zhung"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"Liu Wenhao"},{"name":"Li Zhung"},{"name":"際田 弘志"}]},"description":{"en":"Rapid intravenous injection of a large volume of plasmid DNA (pDNA), i.e. a transfection procedure based on hydrodynamics, is known to be an efficient and liver-specific method of in vivo gene delivery. However, the gene expression is transient. We investigated the effect of addition of polyethylene glycol (PEG) to a solution of naked pDNA (luciferase) on the expression of the gene in mouse liver following transfection by the hydrodynamics-based technique. In addition, the mechanism leading to the enhancement of the gene expression was studied. The addition of 1% (w/v) PEG2000 to the pDNA solution enhanced the resulting gene expression in the liver. Increasing the PEG2000 concentration to more than 1 and up to 10% (w/v) rather diminished the gene expression level. By contrast, increasing the molecular weight of PEG to over 2000 up to 10 000 did not affect the level of gene expression. Histopathological and serum-chemistry examinations indicated that hydrostatic or osmotic pressure increased tissue and hepatocellular damage in a PEG-concentration-dependent manner, and resulted in a decrease in gene expression. Quantitative evaluation showed that the enhanced gene expression resulted from stabilization of the pDNA introduced into the hepatocytes and an enhancement of the transport of intact pDNA to the nucleus. For most gene therapy applications and gene function studies, sustained expression of the introduced gene(s) is necessary. This simple method to achieve enhanced gene expression in liver may have a great potential for a wide variety of laboratory studies in molecular and cellular biology as well as possibly for future clinical applications in humans.","ja":"Rapid intravenous injection of a large volume of plasmid DNA (pDNA), i.e. a transfection procedure based on hydrodynamics, is known to be an efficient and liver-specific method of in vivo gene delivery. However, the gene expression is transient. We investigated the effect of addition of polyethylene glycol (PEG) to a solution of naked pDNA (luciferase) on the expression of the gene in mouse liver following transfection by the hydrodynamics-based technique. In addition, the mechanism leading to the enhancement of the gene expression was studied. The addition of 1% (w/v) PEG2000 to the pDNA solution enhanced the resulting gene expression in the liver. Increasing the PEG2000 concentration to more than 1 and up to 10% (w/v) rather diminished the gene expression level. By contrast, increasing the molecular weight of PEG to over 2000 up to 10 000 did not affect the level of gene expression. Histopathological and serum-chemistry examinations indicated that hydrostatic or osmotic pressure increased tissue and hepatocellular damage in a PEG-concentration-dependent manner, and resulted in a decrease in gene expression. Quantitative evaluation showed that the enhanced gene expression resulted from stabilization of the pDNA introduced into the hepatocytes and an enhancement of the transport of intact pDNA to the nucleus. For most gene therapy applications and gene function studies, sustained expression of the introduced gene(s) is necessary. This simple method to achieve enhanced gene expression in liver may have a great potential for a wide variety of laboratory studies in molecular and cellular biology as well as possibly for future clinical applications in humans."},"publication_date":"2006-03","publication_name":{"en":"The Journal of Gene Medicine","ja":"The Journal of Gene Medicine"},"volume":"Vol.8","number":"No.3","starting_page":"324","ending_page":"334","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/jgm.850"],"issn":["1099-498X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:176, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507584"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/16364578","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-31144443980&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164166","label":"url"}],"paper_title":{"en":"Development of pH-sensitive liposomes that efficiently retain encapsulated doxorubicin (DXR) in blood.","ja":"Development of pH-sensitive liposomes that efficiently retain encapsulated doxorubicin (DXR) in blood."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Okada Yurie"},{"name":"Kobayashi Tomotaka"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"岡田 百合絵"},{"name":"Kobayashi Tomotaka"},{"name":"際田 弘志"}]},"description":{"en":"We have reported that targeted, pH-sensitive sterically stabilized liposomes are able to increase the cytotoxicity of DXR in vitro against B lymphoma cells, but the rate of release of DXR in plasma was too rapid to permit the results to be extended to in vivo applications. The purpose of the study reported here is two-fold. First, to understand the mechanism of the rapid release of DXR from pH-sensitive sterically stabilized liposomes (PSL) in human plasma. Second, to reformulate the above liposomes to improve their drug retention, while retaining their pH sensitivity. The stability of the PSL formulations in human plasma was evaluated by comparing the rate of release of encapsulated DXR with that of HPTS, a water-soluble fluorescent marker. Since DXR, but not HPTS, a water soluble-less membrane permeable fluorescence marker, was rapidly released from liposomes in the presence of plasma, the rapid release of DXR is likely caused by the diffusion of DXR molecules through the lipid bilayer, not by the disruption of the membrane. In order to develop more stable PSL formulations, various molar ratios of the membrane rigidifying lipid, hydrogenated soy HSPC and/or CHOL, were added to the lipid composition and the rate of release of encapsulated solutes and pH-sensitivity were evaluated. The compositions that showed the best drug retention and pH-sensitivity were a mixture of DOPE/HSPC/CHEMS/CHOL/mPEG(2000)-DSPE at a molar ratio of 4:2:2:2:0.3 and DOPE/HSPC/CHEMS/CHOL at a molar ratio of 4:2:2:2. Our formulations, if targeted to internalizing antigens on cancer cells, may increase intracellular drug release rates within acidic compartment, resulting in a further increase in the therapeutic efficacy of targeted anticancer drug-containing liposomes.","ja":"We have reported that targeted, pH-sensitive sterically stabilized liposomes are able to increase the cytotoxicity of DXR in vitro against B lymphoma cells, but the rate of release of DXR in plasma was too rapid to permit the results to be extended to in vivo applications. The purpose of the study reported here is two-fold. First, to understand the mechanism of the rapid release of DXR from pH-sensitive sterically stabilized liposomes (PSL) in human plasma. Second, to reformulate the above liposomes to improve their drug retention, while retaining their pH sensitivity. The stability of the PSL formulations in human plasma was evaluated by comparing the rate of release of encapsulated DXR with that of HPTS, a water-soluble fluorescent marker. Since DXR, but not HPTS, a water soluble-less membrane permeable fluorescence marker, was rapidly released from liposomes in the presence of plasma, the rapid release of DXR is likely caused by the diffusion of DXR molecules through the lipid bilayer, not by the disruption of the membrane. In order to develop more stable PSL formulations, various molar ratios of the membrane rigidifying lipid, hydrogenated soy HSPC and/or CHOL, were added to the lipid composition and the rate of release of encapsulated solutes and pH-sensitivity were evaluated. The compositions that showed the best drug retention and pH-sensitivity were a mixture of DOPE/HSPC/CHEMS/CHOL/mPEG(2000)-DSPE at a molar ratio of 4:2:2:2:0.3 and DOPE/HSPC/CHEMS/CHOL at a molar ratio of 4:2:2:2. Our formulations, if targeted to internalizing antigens on cancer cells, may increase intracellular drug release rates within acidic compartment, resulting in a further increase in the therapeutic efficacy of targeted anticancer drug-containing liposomes."},"publication_date":"2006-02","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.309","number":"No.1-2","starting_page":"94","ending_page":"100","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2005.11.010"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:177, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507585"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/16079495","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130589","label":"url"}],"paper_title":{"en":"Gene Expression in Primary Cultured Mouse Hepatocytes with a Cationic Liposomal Vector, TFL-3: Comparison with Rat Hepatocytes","ja":"Gene Expression in Primary Cultured Mouse Hepatocytes with a Cationic Liposomal Vector, TFL-3: Comparison with Rat Hepatocytes"},"authors":{"en":[{"name":"Nguyen Thi Lap"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Nguyen Lap Thi"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"We recently reported that a cationic liposomal vector, TFL-3, could be used to achieve significant gene expression in primary cultured rat hepatocytes (Nguyen et al., Biol. Pharm. Bull., 26, 880-885 (2003)). A combination of hepatocyte transplantation and hepatocyte-targeted gene transfer represents a potentially important strategy for expanding treatment options for liver disease. A widely applied approach to support cross-species is necessary before human applications can be realized. Therefore, in this study, we examined the utility of TFL-3 in another species of rodent hepatocytes, namely mouse hepatocytes. Gene expression in mouse hepatocytes by TFL-3 was successful and the level was higher than those in rat hepatocytes that we recently reported on. Interestingly, it appears that both the degree and rate of gene expression were dependent on the incubation time prior to lipofection as well as on the density of cells per dish, but these parameters were independent of the amount of pDNA associated with the cells. These significantly suggest that the culture time prior to and following lipofection, which are related to the biological condition of the cells, may be one of major factors that affect gene expression in hepatocytes and non- or less dividing cells.","ja":"We recently reported that a cationic liposomal vector, TFL-3, could be used to achieve significant gene expression in primary cultured rat hepatocytes (Nguyen et al., Biol. Pharm. Bull., 26, 880-885 (2003)). A combination of hepatocyte transplantation and hepatocyte-targeted gene transfer represents a potentially important strategy for expanding treatment options for liver disease. A widely applied approach to support cross-species is necessary before human applications can be realized. Therefore, in this study, we examined the utility of TFL-3 in another species of rodent hepatocytes, namely mouse hepatocytes. Gene expression in mouse hepatocytes by TFL-3 was successful and the level was higher than those in rat hepatocytes that we recently reported on. Interestingly, it appears that both the degree and rate of gene expression were dependent on the incubation time prior to lipofection as well as on the density of cells per dish, but these parameters were independent of the amount of pDNA associated with the cells. These significantly suggest that the culture time prior to and following lipofection, which are related to the biological condition of the cells, may be one of major factors that affect gene expression in hepatocytes and non- or less dividing cells."},"publication_date":"2005-08","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.28","number":"No.8","starting_page":"1472","ending_page":"1475","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.28.1472"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:178, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507586"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/15908032","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130620","label":"url"}],"paper_title":{"en":"Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: Effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes","ja":"Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: Effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Harada Masae"},{"name":"Xinyu Wang"},{"name":"Ichihara Masako"},{"name":"Irimura Kenji"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"原田 真恵"},{"name":"王 新宇"},{"name":"市原 理子"},{"name":"入村 兼司"},{"name":"際田 弘志"}]},"description":{"en":"We recently reported that a second dose of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG2000-liposomes) is rapidly cleared from the blood and accumulates in the liver when injected twice in the same rat or mouse at several-day intervals (referred to as the \"accelerated blood clearance (ABC) phenomenon\"). In the present study we observed that a high dose (5 micromol/kg) of conventional liposomes (CL: without a PEG-coating) can induce the same phenomenon, while a low lipid dose (0.001 micromol/kg) did not. The induction of the phenomenon by mPEG2000-liposomes decreased with increasing first dose (0.001-5 micromol/kg). We observed a strong inverse relationship between the dose of initially injected PEG2000-liposomes and the extent to which the ABC phenomenon was induced: the higher the dose the smaller the phenomenon. Increasing the PEG density at the liposome surface beyond 5 mol% attenuated rather than induced the induction of the phenomenon, but elongation of the PEG chain length up to M.W. 5000, had no effect. In a series of hematological, serum-biochemical and histopathological safety evaluations we observed neither acute toxicity nor any signs of hepatic damage during the induction of the ABC phenomenon. Morphological examination of the liver by transmission electron microscopy (TEM) showed extensive accumulation of the second dose of mPEG2000-liposomes in the Kupffer cells, even already after 15 min, suggesting that the PEG liposomes had somehow lost the protective effect of the surface-grafted PEG against rapid clearance. The observations reported in this paper may have a considerable impact on the design and engineering of PEGylated liposomal formulations for use in multiple drug therapy.","ja":"We recently reported that a second dose of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG2000-liposomes) is rapidly cleared from the blood and accumulates in the liver when injected twice in the same rat or mouse at several-day intervals (referred to as the \"accelerated blood clearance (ABC) phenomenon\"). In the present study we observed that a high dose (5 micromol/kg) of conventional liposomes (CL: without a PEG-coating) can induce the same phenomenon, while a low lipid dose (0.001 micromol/kg) did not. The induction of the phenomenon by mPEG2000-liposomes decreased with increasing first dose (0.001-5 micromol/kg). We observed a strong inverse relationship between the dose of initially injected PEG2000-liposomes and the extent to which the ABC phenomenon was induced: the higher the dose the smaller the phenomenon. Increasing the PEG density at the liposome surface beyond 5 mol% attenuated rather than induced the induction of the phenomenon, but elongation of the PEG chain length up to M.W. 5000, had no effect. In a series of hematological, serum-biochemical and histopathological safety evaluations we observed neither acute toxicity nor any signs of hepatic damage during the induction of the ABC phenomenon. Morphological examination of the liver by transmission electron microscopy (TEM) showed extensive accumulation of the second dose of mPEG2000-liposomes in the Kupffer cells, even already after 15 min, suggesting that the PEG liposomes had somehow lost the protective effect of the surface-grafted PEG against rapid clearance. The observations reported in this paper may have a considerable impact on the design and engineering of PEGylated liposomal formulations for use in multiple drug therapy."},"publication_date":"2005-07-20","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.105","number":"No.3","starting_page":"305","ending_page":"317","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2005.04.003"],"issn":["0168-3659"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:179, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507587"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/15866337","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130601","label":"url"}],"paper_title":{"en":"Influence of the physicochemical properties of liposomes on the accelerated blood clearance phenomenon in rat","ja":"Influence of the physicochemical properties of liposomes on the accelerated blood clearance phenomenon in rat"},"authors":{"en":[{"name":"Xinyu Wang"},{"name":"Ishida Tatsuhiro"},{"name":"Ichihara Masako"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"王 新宇"},{"name":"石田 竜弘"},{"name":"市原 理子"},{"name":"際田 弘志"}]},"description":{"en":"We have recently reported that PEGylated liposomes (PL) are cleared rapidly from the blood circulation when they are administered twice in the same rat at certain intervals, even if the liposomes are sterically stabilized by a surface modification with PEG (referred to as the accelerated blood clearance (ABC) phenomenon, J. Control. Release, 88, 35-42 (2003)). Now we report on the influence of physicochemical properties (PEG-modification, size and surface charge) of either the first or the second dose of liposomes on the ABC phenomenon. When, for the first dose, conventional liposomes (CL; without a PEG coating) of 110-nm diameter were injected, only a very slight ABC phenomenon was observed, irrespective of the liposomal surface charge: both clearance rate and hepatic accumulation of the second injected PL were only slightly enhanced compared to those of a single dose of PL. Interestingly, when for the first injection small-size liposomes (60 nm) were used, either charged or PEG-modified, but not neutral, the ABC phenomenon was clearly manifest. Apparently, the induction of the ABC phenomenon is not only determined by the PEG coating but also by the size and surface charge of the first dose of liposomes. Also when for the second dose small-size PEGylated liposomes were used, the ABC phenomenon was observed after induction by a first injection of PL, whereas plasma kinetics and organ uptake of a second dose of negatively charged CL (NCL, 110 nm) or small-sized NCL (SNCL, 60 nm) were not altered. Apparently, the PEG coating on the second dose is essential for the liposomes to be susceptible to the ABC phenomenon. The results reported here suggest that the physicochemical properties of both the first and second dose of liposomes are important either for the induction of the phenomenon or for its expression. Our observations may have a considerable impact on the clinical application and engineering of liposomal formulations for use in multiple drug therapy.","ja":"We have recently reported that PEGylated liposomes (PL) are cleared rapidly from the blood circulation when they are administered twice in the same rat at certain intervals, even if the liposomes are sterically stabilized by a surface modification with PEG (referred to as the accelerated blood clearance (ABC) phenomenon, J. Control. Release, 88, 35-42 (2003)). Now we report on the influence of physicochemical properties (PEG-modification, size and surface charge) of either the first or the second dose of liposomes on the ABC phenomenon. When, for the first dose, conventional liposomes (CL; without a PEG coating) of 110-nm diameter were injected, only a very slight ABC phenomenon was observed, irrespective of the liposomal surface charge: both clearance rate and hepatic accumulation of the second injected PL were only slightly enhanced compared to those of a single dose of PL. Interestingly, when for the first injection small-size liposomes (60 nm) were used, either charged or PEG-modified, but not neutral, the ABC phenomenon was clearly manifest. Apparently, the induction of the ABC phenomenon is not only determined by the PEG coating but also by the size and surface charge of the first dose of liposomes. Also when for the second dose small-size PEGylated liposomes were used, the ABC phenomenon was observed after induction by a first injection of PL, whereas plasma kinetics and organ uptake of a second dose of negatively charged CL (NCL, 110 nm) or small-sized NCL (SNCL, 60 nm) were not altered. Apparently, the PEG coating on the second dose is essential for the liposomes to be susceptible to the ABC phenomenon. The results reported here suggest that the physicochemical properties of both the first and second dose of liposomes are important either for the induction of the phenomenon or for its expression. Our observations may have a considerable impact on the clinical application and engineering of liposomal formulations for use in multiple drug therapy."},"publication_date":"2005-05-05","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.104","number":"No.1","starting_page":"91","ending_page":"102","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2005.01.008"],"issn":["0168-3659"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:180, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507588"},"force":{"see_also":[{"@id":"http://ajpheart.physiology.org/cgi/content/abstract/288/5/H2163","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/15626692","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=131097","label":"url"}],"paper_title":{"en":"Nitrite is an alternative source of NO in vivo","ja":"Nitrite is an alternative source of NO in vivo"},"authors":{"en":[{"name":"Tsuchiya Koichiro"},{"name":"Kanematsu Yasuhisa"},{"name":"Yoshizumi Masanori"},{"name":"Ohnishi Hideki"},{"name":"Kirima Kazuyoshi"},{"name":"Izawa Yuki"},{"name":"Shikishima Michiyo"},{"name":"Ishida Tatsuhiro"},{"name":"Kondo Shuji"},{"name":"Kagami Shoji"},{"name":"Takiguchi Yoshiharu"},{"name":"Tamaki Toshiaki"}],"ja":[{"name":"土屋 浩一郎"},{"name":"兼松 康久"},{"name":"Yoshizumi Masanori"},{"name":"Ohnishi Hideki"},{"name":"Kirima Kazuyoshi"},{"name":"井澤 有紀"},{"name":"Shikishima Michiyo"},{"name":"石田 竜弘"},{"name":"Kondo Shuji"},{"name":"香美 祥二"},{"name":"滝口 祥令"},{"name":"玉置 俊晃"}]},"description":{"en":"In this study, we investigated whether orally administered nitrite is changed to NO and whether nitrite attenuates hypertension in a dose-dependent manner. We utilized a stable isotope of [15N]nitrite (15NO2-) as a source of nitrite to distinguish between endogenous nitrite and that exogenously administered and measured hemoglobin (Hb)-NO as an index of circulating NO in whole blood using electron paramagnetic resonance (EPR) spectroscopy. When 1 mg/kg Na15NO2 was orally administered to rats, an apparent EPR signal derived from Hb15NO (A(Z) = 23.4 gauss) appeared in the blood. The peak blood HbNO concentration occurred at the first measurement after intake (5 min) for treatment with 1 and 3 mg/kg (HbNO: 4.93 +/- 0.52 and 10.58 +/- 0.40 microM, respectively) and at 15 min with 10 mg/kg (HbNO: 38.27 +/- 9.23 microM). In addition, coadministration of nitrite (100 mg/l drinking water) with N(omega)-nitro-L-arginine methyl ester (L-NAME; 1 g/l) for 3 wk significantly attenuated the L-NAME-induced hypertension (149 +/- 10 mmHg) compared with L-NAME alone (170 +/- 13 mmHg). Furthermore, this phenomenon was associated with an increase in circulating HbNO. Our findings clearly indicate that orally ingested nitrite can be an alternative to L-arginine as a source of NO in vivo and may explain, at least in part, the mechanism of the nitrite/nitrate-rich Dietary Approaches to Stop Hypertension diet-induced hypotensive effects.","ja":"In this study, we investigated whether orally administered nitrite is changed to NO and whether nitrite attenuates hypertension in a dose-dependent manner. We utilized a stable isotope of [15N]nitrite (15NO2-) as a source of nitrite to distinguish between endogenous nitrite and that exogenously administered and measured hemoglobin (Hb)-NO as an index of circulating NO in whole blood using electron paramagnetic resonance (EPR) spectroscopy. When 1 mg/kg Na15NO2 was orally administered to rats, an apparent EPR signal derived from Hb15NO (A(Z) = 23.4 gauss) appeared in the blood. The peak blood HbNO concentration occurred at the first measurement after intake (5 min) for treatment with 1 and 3 mg/kg (HbNO: 4.93 +/- 0.52 and 10.58 +/- 0.40 microM, respectively) and at 15 min with 10 mg/kg (HbNO: 38.27 +/- 9.23 microM). In addition, coadministration of nitrite (100 mg/l drinking water) with N(omega)-nitro-L-arginine methyl ester (L-NAME; 1 g/l) for 3 wk significantly attenuated the L-NAME-induced hypertension (149 +/- 10 mmHg) compared with L-NAME alone (170 +/- 13 mmHg). Furthermore, this phenomenon was associated with an increase in circulating HbNO. Our findings clearly indicate that orally ingested nitrite can be an alternative to L-arginine as a source of NO in vivo and may explain, at least in part, the mechanism of the nitrite/nitrate-rich Dietary Approaches to Stop Hypertension diet-induced hypotensive effects."},"publication_date":"2005-05","publication_name":{"en":"American Journal of Physiology, Heart and Circulatory Physiology","ja":"American Journal of Physiology, Heart and Circulatory Physiology"},"volume":"Vol.288","number":"No.5","starting_page":"H2163","ending_page":"H2170","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1152/ajpheart.00525.2004"],"issn":["0363-6135"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:181, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507589"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/15802813","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130612","label":"url"}],"paper_title":{"en":"Increased Gene Expression by Cationic Liposomes (TFL-3) in Lung Metastases Following Intravenous Injection","ja":"Increased Gene Expression by Cationic Liposomes (TFL-3) in Lung Metastases Following Intravenous Injection"},"authors":{"en":[{"name":"Li Wenhao"},{"name":"Ishida Tatsuhiro"},{"name":"Okada Yurie"},{"name":"Oku Naoto"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"李 文浩"},{"name":"石田 竜弘"},{"name":"岡田 百合絵"},{"name":"Oku Naoto"},{"name":"際田 弘志"}]},"description":{"en":"We recently showed that size, not surface charge, is a major determinant of the in vitro lipofection efficiency of pDNA/TFL-3 complex (lipoplex), even in the presence of serum. In this study, the effect of lipoplex size as a result of interaction with serum proteins on in vitro lipofection and the relationship of this with in vivo lipofection was examined in a murine lung metastasis model. As previously described, the pDNA to lipid ratio (P/L ratio) affected both the size and zeta potential of the lipoplex. In vitro studies also indicated that transgene expression in B16BL6 cells was largely dependent on the size of the lipoplex, both in the absence or presence (50% (v/v)) of serum. An in vivo lipofection experiment showed that predominant gene expression in lungs occurred only in tumor-bearing mice, not in normal mice. Based on the in vitro study, this tumor-related gene expression was not related to lipoplex size in the presence of serum (50% (v/v)), suggesting that the size alteration, as the result of interactions with serum proteins in the blood stream may not play an important role in the case of systemic injections. In addition, the efficient gene expression in tumor-bearing lung was not related to the progression of lung metastases. The area-specific gene expression in tumor-bearing lungs, which was largely dependent on the P/L ratio of the lipoplexes, was observed by fluorescent microscopy. Although the underlying mechanism for the area-specific transgene expression is not clear, it may be related to the interaction of lipoplexes with tumor cells, vascular endothelial cells under angiogenesis and normal cells in the lungs. The possibility that TFL-3 is a useful utility to the targeted delivery of pDNA to lungs and tumor-related lipofection is demonstrated. This result suggests that area-specific gene expression in lung metastases may be achieved by controlling the physicochemical properties of the lipoplex, i.e. the P/L ratio.","ja":"We recently showed that size, not surface charge, is a major determinant of the in vitro lipofection efficiency of pDNA/TFL-3 complex (lipoplex), even in the presence of serum. In this study, the effect of lipoplex size as a result of interaction with serum proteins on in vitro lipofection and the relationship of this with in vivo lipofection was examined in a murine lung metastasis model. As previously described, the pDNA to lipid ratio (P/L ratio) affected both the size and zeta potential of the lipoplex. In vitro studies also indicated that transgene expression in B16BL6 cells was largely dependent on the size of the lipoplex, both in the absence or presence (50% (v/v)) of serum. An in vivo lipofection experiment showed that predominant gene expression in lungs occurred only in tumor-bearing mice, not in normal mice. Based on the in vitro study, this tumor-related gene expression was not related to lipoplex size in the presence of serum (50% (v/v)), suggesting that the size alteration, as the result of interactions with serum proteins in the blood stream may not play an important role in the case of systemic injections. In addition, the efficient gene expression in tumor-bearing lung was not related to the progression of lung metastases. The area-specific gene expression in tumor-bearing lungs, which was largely dependent on the P/L ratio of the lipoplexes, was observed by fluorescent microscopy. Although the underlying mechanism for the area-specific transgene expression is not clear, it may be related to the interaction of lipoplexes with tumor cells, vascular endothelial cells under angiogenesis and normal cells in the lungs. The possibility that TFL-3 is a useful utility to the targeted delivery of pDNA to lungs and tumor-related lipofection is demonstrated. This result suggests that area-specific gene expression in lung metastases may be achieved by controlling the physicochemical properties of the lipoplex, i.e. the P/L ratio."},"publication_date":"2005-04","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.28","number":"No.4","starting_page":"701","ending_page":"706","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.28.701"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:182, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507590"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/15113615","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130636","label":"url"}],"paper_title":{"en":"Cell type-specific gene expression, mediated by TFL-3, a cationic liposomal vector, is controlled by a post-transcription process of delivered plasmid DNA","ja":"Cell type-specific gene expression, mediated by TFL-3, a cationic liposomal vector, is controlled by a post-transcription process of delivered plasmid DNA"},"authors":{"en":[{"name":"Li Wenhao"},{"name":"Ishida Tatsuhiro"},{"name":"Tachibana Rieko"},{"name":"Almofti Radwan Mohamad"},{"name":"Wang Xinyu"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"李 文浩"},{"name":"石田 竜弘"},{"name":"橘 理恵子"},{"name":"MOHAMAD RADWAN ALMOFTI"},{"name":"王 新宇"},{"name":"際田 弘志"}]},"description":{"en":"The issue of whether the TFL-3, a recently developed cationic liposome, achieves efficient gene expression in different mammalian cell lines (NIH/3T3, LLC, A431 and HeLa cells) was examined. The issue of whether gene expression is related to the amount of plasmid DNA (pDNA) delivered in cells or nuclei following transfection was also examined. The cells were transfected for 1h with pDNA/TFL-3 lipoplexes, and the transfection efficiency was determined by means of a luciferase activity assay. The amount of intracellular and intranuclear pDNA following the transfection was also quantitatively determined. Successful transgene expressions in all cell lines we tested were observed under our experimental conditions, suggesting that the TFL-3 represents a suitable nonviral vector system for the successful gene expression in mammalian cells in vitro. The degree and rate of gene expression were dependent on the type of cells used as well as the incubation time after transfection, but these parameters were independent of the amount of gene delivered to cells and nuclei. These results suggest that TFL-3 mediated gene expression is largely controlled by the process of post-transcription of the delivered pDNA, and not by the process of cellular entry of pDNA and cytoplasmic trafficking of pDNA into nuclei, which is dependent on the cell type. Therefore, the results obtained here clearly suggest that the cell type-specific improvement in transcription efficiency of pDNA and translation of the derived mRNA, together with an improved delivery system to enhance the nuclear delivery of pDNA, is necessary to achieve efficient transgene expression in mammalian cells.","ja":"The issue of whether the TFL-3, a recently developed cationic liposome, achieves efficient gene expression in different mammalian cell lines (NIH/3T3, LLC, A431 and HeLa cells) was examined. The issue of whether gene expression is related to the amount of plasmid DNA (pDNA) delivered in cells or nuclei following transfection was also examined. The cells were transfected for 1h with pDNA/TFL-3 lipoplexes, and the transfection efficiency was determined by means of a luciferase activity assay. The amount of intracellular and intranuclear pDNA following the transfection was also quantitatively determined. Successful transgene expressions in all cell lines we tested were observed under our experimental conditions, suggesting that the TFL-3 represents a suitable nonviral vector system for the successful gene expression in mammalian cells in vitro. The degree and rate of gene expression were dependent on the type of cells used as well as the incubation time after transfection, but these parameters were independent of the amount of gene delivered to cells and nuclei. These results suggest that TFL-3 mediated gene expression is largely controlled by the process of post-transcription of the delivered pDNA, and not by the process of cellular entry of pDNA and cytoplasmic trafficking of pDNA into nuclei, which is dependent on the cell type. Therefore, the results obtained here clearly suggest that the cell type-specific improvement in transcription efficiency of pDNA and translation of the derived mRNA, together with an improved delivery system to enhance the nuclear delivery of pDNA, is necessary to achieve efficient transgene expression in mammalian cells."},"publication_date":"2004-05-19","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.276","number":"No.1-2","starting_page":"67","ending_page":"74","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.ijpharm.2004.02.011"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:183, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507591"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/15023452","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=91837","label":"url"}],"paper_title":{"en":"Effect of the physicochemical properties of initially injected liposomes on the clearance of subsequently injected PEGylated liposomes in mice.","ja":"Effect of the physicochemical properties of initially injected liposomes on the clearance of subsequently injected PEGylated liposomes in mice."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Ichikawa Takako"},{"name":"Ichihara Masako"},{"name":"Sadzuka Yasuyuki"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"市川 高子"},{"name":"市原 理子"},{"name":"佐塚 泰之"},{"name":"際田 弘志"}]},"description":{"en":"Using mice as a model, we recently reported that the long-circulating properties of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG(2000)-liposomes) disappeared when they were intravenously injected at certain intervals [referred to as the \"accelerated blood clearance (ABC) phenomenon\"]. Herein, we report on a study of issue of whether physicochemical properties of a prior dose of liposomes such as degree of PEGylation, PEG chain length, lipid dose, surface charge, size, play a role in inducing this phenomenon. The injection of conventional liposomes (without a PEG-coating) significantly induced the phenomenon. The PEGylation of conventional liposomes attenuated the induction of the phenomenon somewhat with increasing molar content of PEG derivative and PEG chain length. These findings clearly suggest that the PEGylation of liposomes are not the major cause of the ABC phenomenon but, rather, played a role in preventing it. In addition, increasing the lipid dose in a prior dose of mPEG(2000)-liposomes (0-25 micromol/kg) increased the induction of the phenomenon in a sigmoid manner. The surface charge and size of the liposomes were not critical for the induction of the phenomenon, although generally these serve as determinants in the biodistribution of liposomes. The results reported here clearly indicate that the physicochemical properties of a prior dose of liposomes strongly affect the pharmacokinetic behavior of a subsequent injection of mPEG(2000)-liposomes: The extent of PEGylation and the lipid dose had an effect, but the surface charge and size did not. The results reported herein have a considerable impact on the design and engineering of liposomal formulations for use in multiple drug therapy as well as in therapy that involves the use of liposomal drugs.","ja":"Using mice as a model, we recently reported that the long-circulating properties of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG(2000)-liposomes) disappeared when they were intravenously injected at certain intervals [referred to as the \"accelerated blood clearance (ABC) phenomenon\"]. Herein, we report on a study of issue of whether physicochemical properties of a prior dose of liposomes such as degree of PEGylation, PEG chain length, lipid dose, surface charge, size, play a role in inducing this phenomenon. The injection of conventional liposomes (without a PEG-coating) significantly induced the phenomenon. The PEGylation of conventional liposomes attenuated the induction of the phenomenon somewhat with increasing molar content of PEG derivative and PEG chain length. These findings clearly suggest that the PEGylation of liposomes are not the major cause of the ABC phenomenon but, rather, played a role in preventing it. In addition, increasing the lipid dose in a prior dose of mPEG(2000)-liposomes (0-25 micromol/kg) increased the induction of the phenomenon in a sigmoid manner. The surface charge and size of the liposomes were not critical for the induction of the phenomenon, although generally these serve as determinants in the biodistribution of liposomes. The results reported here clearly indicate that the physicochemical properties of a prior dose of liposomes strongly affect the pharmacokinetic behavior of a subsequent injection of mPEG(2000)-liposomes: The extent of PEGylation and the lipid dose had an effect, but the surface charge and size did not. The results reported herein have a considerable impact on the design and engineering of liposomal formulations for use in multiple drug therapy as well as in therapy that involves the use of liposomal drugs."},"publication_date":"2004-03-24","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.95","number":"No.3","starting_page":"403","ending_page":"412","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jconrel.2003.12.011"],"issn":["0168-3659"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:184, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507592"},"force":{"see_also":[{"@id":"http://ci.nii.ac.jp/naid/110003608537/","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/12808305","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390282679603298048/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130656","label":"url"}],"paper_title":{"en":"Culture Time-Dependent Gene Expression in Isolated Primary Cultured Rat Hepatocytes by Transfection with the Cationic Liposomal Vector TFL-3","ja":"Culture Time-Dependent Gene Expression in Isolated Primary Cultured Rat Hepatocytes by Transfection with the Cationic Liposomal Vector TFL-3"},"authors":{"en":[{"name":"Nguyen Thi Lap"},{"name":"Ishida Tatsuhiro"},{"name":"Ukitsu Sachiko"},{"name":"Li Hao Wen"},{"name":"Tachibana Rieko"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Nguyen Lap Thi"},{"name":"石田 竜弘"},{"name":"浮津 佐知子"},{"name":"李 文浩"},{"name":"橘 理恵子"},{"name":"際田 弘志"}]},"description":{"en":"The development of a carrier system that enables the transfer of a functional exogenous gene to non- or less frequently dividing mammalian cells is essential for increasing the available options for the treatment of various diseases. The issue of whether TFL-3, a recently developed cationic liposome, can be successfully used to achieve gene expression in primary cultured rat hepatocytes was examined. The hepatocytes were transfected for 4 h with plasmid DNA (pDNA) in TFL-3 at various time points after 4-h preculture. The transfection efficiency was determined at various times posttransfection with pDNA coding for chloramphenicol acetyltransferase (CAT), luciferase, or beta-galactosidase. The amount of intranuclear pDNA present, as a consequence of the lipofection, was also quantitatively determined. Successful lipofections were observed for all pDNA tested, and the efficiencies were superior to that of commercially available LIPOFECTAMINE under our experimental conditions. The degree and rate of gene expression were dependent on incubation time prior to lipofection as well as on the density of the cells per dish, but this relationship did not hold for the amount of gene delivered to the nuclei. These results indicate that TFL-3 could be a useful vector for achieving sufficient gene expression in rat hepatocytes and suggest that the culture time prior to and following lipofection, which is related to the biological condition of the cells, may be one major factor affecting efficient gene expression in nondividing cells.","ja":"The development of a carrier system that enables the transfer of a functional exogenous gene to non- or less frequently dividing mammalian cells is essential for increasing the available options for the treatment of various diseases. The issue of whether TFL-3, a recently developed cationic liposome, can be successfully used to achieve gene expression in primary cultured rat hepatocytes was examined. The hepatocytes were transfected for 4 h with plasmid DNA (pDNA) in TFL-3 at various time points after 4-h preculture. The transfection efficiency was determined at various times posttransfection with pDNA coding for chloramphenicol acetyltransferase (CAT), luciferase, or beta-galactosidase. The amount of intranuclear pDNA present, as a consequence of the lipofection, was also quantitatively determined. Successful lipofections were observed for all pDNA tested, and the efficiencies were superior to that of commercially available LIPOFECTAMINE under our experimental conditions. The degree and rate of gene expression were dependent on incubation time prior to lipofection as well as on the density of the cells per dish, but this relationship did not hold for the amount of gene delivered to the nuclei. These results indicate that TFL-3 could be a useful vector for achieving sufficient gene expression in rat hepatocytes and suggest that the culture time prior to and following lipofection, which is related to the biological condition of the cells, may be one major factor affecting efficient gene expression in nondividing cells."},"publication_date":"2003-06-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.26","number":"No.6","starting_page":"880","ending_page":"885","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.26.880"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:185, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507593"},"force":{"see_also":[{"@id":"http://dx.doi.org/10.1016/S0378-5173(03)00085-1","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/12672612","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=91964","label":"url"}],"paper_title":{"en":"Accelerated clearance of a second injection of PEGylated liposomes in mice.","ja":"Accelerated clearance of a second injection of PEGylated liposomes in mice."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Masuda Kaori"},{"name":"Ichikawa Takako"},{"name":"Ichihara Masako"},{"name":"Irimura Kenji"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"増田 佳織"},{"name":"市川 高子"},{"name":"市原 理子"},{"name":"入村 兼司"},{"name":"際田 弘志"}]},"publication_date":"2003-04-14","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.255","number":"No.1-2","starting_page":"167","ending_page":"174","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/S0378-5173(03)00085-1"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:186, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507594"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/12586501","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=91878","label":"url"}],"paper_title":{"en":"Accelerated clearance of PEGylated liposomes in rats after repeated injections.","ja":"Accelerated clearance of PEGylated liposomes in rats after repeated injections."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Maeda Ryuhei"},{"name":"Ichihara Masako"},{"name":"Irimura Kenji"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"前田 龍平"},{"name":"市原 理子"},{"name":"入村 兼司"},{"name":"際田 弘志"}]},"description":{"en":"Polyethylene glycol-modified liposomes (PEGylated liposomes) represent promising carrier systems for therapeutic agents. Herein, we report on a study of the effect of repeated injection of PEGylated liposomes on their pharmacokinetics in rats. The first dose resulted in a reduction in the circulation time and an increase in hepatic accumulation of the second dose in a time-interval of injection-dependent manner. No significant increases in the number of Kupffer cells were detectable, although the liver most likely played an important role in the accelerated clearance. Interestingly, the acceleration in clearance became less pronounced, when the third dose was injected at 4, 7 or 14 days after the second injection (the second dose was given 5 weeks after the first injection). An accelerated clearance was evoked in normal rats by the transfusion of serum from rats that had received PEGylated liposomes 5 days earlier, indicating that humoral serum factor(s) are also involved in causing the accelerated clearance. A complement consumption assay indicated that the complement system is not the factor. In summary, multiple injections of PEGylated liposomes clearly altered their pharmacokinetic behavior in rats. It is likely that cellular immunity (Kupffer cells) and humoral immunity are required to cause the phenomenon. The results reported here have a considerable impact in and important implications on the clinical application, design and engineering of PEGylated liposomes for use in repeated intravenous administration.","ja":"Polyethylene glycol-modified liposomes (PEGylated liposomes) represent promising carrier systems for therapeutic agents. Herein, we report on a study of the effect of repeated injection of PEGylated liposomes on their pharmacokinetics in rats. The first dose resulted in a reduction in the circulation time and an increase in hepatic accumulation of the second dose in a time-interval of injection-dependent manner. No significant increases in the number of Kupffer cells were detectable, although the liver most likely played an important role in the accelerated clearance. Interestingly, the acceleration in clearance became less pronounced, when the third dose was injected at 4, 7 or 14 days after the second injection (the second dose was given 5 weeks after the first injection). An accelerated clearance was evoked in normal rats by the transfusion of serum from rats that had received PEGylated liposomes 5 days earlier, indicating that humoral serum factor(s) are also involved in causing the accelerated clearance. A complement consumption assay indicated that the complement system is not the factor. In summary, multiple injections of PEGylated liposomes clearly altered their pharmacokinetic behavior in rats. It is likely that cellular immunity (Kupffer cells) and humoral immunity are required to cause the phenomenon. The results reported here have a considerable impact in and important implications on the clinical application, design and engineering of PEGylated liposomes for use in repeated intravenous administration."},"publication_date":"2003-02-14","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.88","number":"No.1","starting_page":"35","ending_page":"42","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/S0168-3659(02)00462-5"],"issn":["0168-3659"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:187, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507595"},"force":{"see_also":[{"@id":"http://dx.doi.org/10.1016/S0378-5173(02)00026-1","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11891076","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130819","label":"url"}],"paper_title":{"en":"HEPC-based liposomes trigger cytokine release from peripheral blood cells: effects of liposomal size, dose and lipid composition","ja":"HEPC-based liposomes trigger cytokine release from peripheral blood cells: effects of liposomal size, dose and lipid composition"},"authors":{"en":[{"name":"Yamamoto Sayaka"},{"name":"Ishida Tatsuhiro"},{"name":"Inoue Akiko"},{"name":"Mikami Junko"},{"name":"Muraguchi Masahiro"},{"name":"Ohmoto Yasukazu"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"山本 早弥香"},{"name":"石田 竜弘"},{"name":"Inoue Akiko"},{"name":"三上 純子"},{"name":"村口 正宏"},{"name":"大本 安一"},{"name":"際田 弘志"}]},"publication_date":"2002-04-02","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.236","number":"No.1-2","starting_page":"125","ending_page":"133","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/S0378-5173(02)00026-1"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:188, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507596"},"force":{"see_also":[{"@id":"http://bpb.pharm.or.jp/abst/200204/ab25040529.html","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11995939","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130822","label":"url"}],"paper_title":{"en":"Effect of Cationic Liposomes in an in Vitro Transcription and Translation System","ja":"Effect of Cationic Liposomes in an in Vitro Transcription and Translation System"},"authors":{"en":[{"name":"Tachibana Rieko"},{"name":"Harashima Hideyoshi"},{"name":"Ishida Tatsuhiro"},{"name":"Shinohara Yasuo"},{"name":"Hino Mari"},{"name":"Terada Hiroshi"},{"name":"Baba Yoshinobu"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"橘 理恵子"},{"name":"原島 秀吉"},{"name":"石田 竜弘"},{"name":"篠原 康雄"},{"name":"Hino Mari"},{"name":"Terada Hiroshi"},{"name":"Baba Yoshinobu"},{"name":"際田 弘志"}]},"description":{"en":"The effects of cationic liposomes complexed with plasmid DNA on the process of transcription was examined using a recently developed rapid cell free translation system. The findings indicate that the liposome itself inhibited the process when the ratio of DNA/liposome typically used in transfection studies was used.","ja":"The effects of cationic liposomes complexed with plasmid DNA on the process of transcription was examined using a recently developed rapid cell free translation system. The findings indicate that the liposome itself inhibited the process when the ratio of DNA/liposome typically used in transfection studies was used."},"publication_date":"2002-04","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.25","number":"No.4","starting_page":"529","ending_page":"531","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.25.529"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:189, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507597"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11934232","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=132273","label":"url"}],"paper_title":{"en":"Use of the post-insertion technique to insert peptide ligands into pre-formed Stealth liposomes with retention of binding activity and cytotoxicity","ja":"Use of the post-insertion technique to insert peptide ligands into pre-formed Stealth liposomes with retention of binding activity and cytotoxicity"},"authors":{"en":[{"name":"Moreira N. João"},{"name":"Ishida Tatsuhiro"},{"name":"Gaspar Rogério"},{"name":"Allen M. Theresa"}],"ja":[{"name":"Moreira N. João"},{"name":"石田 竜弘"},{"name":"Gaspar Rogério"},{"name":"Allen M. Theresa"}]},"description":{"en":"Simple methods for the large-scale manufacture of ligand-targeted liposomes will be needed if clinical trials are to proceed. We tested a recently developed technology for inserting peptide ligands into preformed Stealth liposomes. Antagonist G-targeted liposomes (PLG) were prepared and loaded with doxorubicin and their cellular association and cytotoxicity were evaluated using the human small cell lung cancer H69 cell line. The hexapeptide antagonist G was covalently coupled via a thioether bond to the terminus of polyethylene glycol (PEG) in micelles formed from maleimide-derivatized poly(ethylene glycol) (Mr 2000) distearoylphosphatidylethanolamine followed by transfer into preformed liposomes during a one-step incubation. For cellular association, we used radiolabeled liposomes. Cytotoxicity was evaluated using the MTT in vitro proliferation assay. The postinsertion approach to the formation of peptide-targeted liposomes led to the production of PLG bearing a maximum of approximately 0.3 microg antagonist G/micromol phospholipid. These liposomes had increased cellular association to H69 cells relative to nontargeted liposomes and, when loaded with doxorubicin, they resulted in similar levels of cytotoxicity to those obtained by conventional coupling techniques. The postinsertion technique is a simple, effective means for the production of biologically active peptide-targeted liposomes.","ja":"Simple methods for the large-scale manufacture of ligand-targeted liposomes will be needed if clinical trials are to proceed. We tested a recently developed technology for inserting peptide ligands into preformed Stealth liposomes. Antagonist G-targeted liposomes (PLG) were prepared and loaded with doxorubicin and their cellular association and cytotoxicity were evaluated using the human small cell lung cancer H69 cell line. The hexapeptide antagonist G was covalently coupled via a thioether bond to the terminus of polyethylene glycol (PEG) in micelles formed from maleimide-derivatized poly(ethylene glycol) (Mr 2000) distearoylphosphatidylethanolamine followed by transfer into preformed liposomes during a one-step incubation. For cellular association, we used radiolabeled liposomes. Cytotoxicity was evaluated using the MTT in vitro proliferation assay. The postinsertion approach to the formation of peptide-targeted liposomes led to the production of PLG bearing a maximum of approximately 0.3 microg antagonist G/micromol phospholipid. These liposomes had increased cellular association to H69 cells relative to nontargeted liposomes and, when loaded with doxorubicin, they resulted in similar levels of cytotoxicity to those obtained by conventional coupling techniques. The postinsertion technique is a simple, effective means for the production of biologically active peptide-targeted liposomes."},"publication_date":"2002-03","publication_name":{"en":"Pharmaceutical Research","ja":"Pharmaceutical Research"},"volume":"Vol.19","number":"No.3","starting_page":"265","ending_page":"269","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1023/A:1014434732752"],"issn":["0724-8741"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:190, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507598"},"force":{"see_also":[{"@id":"http://dx.doi.org/10.1016/S0378-5173(01)00896-1","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11790490","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1570291226801262464/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=91985","label":"url"}],"paper_title":{"en":"Encapsulation of an antivasospastic drug, fasudil, into liposomes, and in vitro stabiliy of the fasudil-loaded liposomes gradient.","ja":"Encapsulation of an antivasospastic drug, fasudil, into liposomes, and in vitro stabiliy of the fasudil-loaded liposomes gradient."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Takanashi Yoshihiro"},{"name":"Doi Hisako"},{"name":"Yamamoto Isao"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"高梨 吉裕"},{"name":"土井 久子"},{"name":"山本 勇夫"},{"name":"際田 弘志"}]},"description":{"en":"The objectives of this work were to develop a liposomal fasudil, an antivasospastic drug, as a possible means to deliver the encapsulated drug to the brain, and to characterize the stability of the liposomal formulation in vitro. Transmembrane electrochemical gradients of H+ or ammonium sulfate were created, and their effect on the uptake of fasudil into preformed hydrogenated soy phosphatidylcholine/cholesterol (HSPC/CHOL) liposomes were examined. Fasudil was successfully loaded into preformed liposomes in response to sulfate ion (SO4(2-)) and, in part, by H+. Encapsulation levels approaching 100% could be achieved up to a drug to lipid ratio of 0.364 (mol/mol). A stability study of the fasudil-loaded liposomes was performed by storage at 4 degrees C in 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid (HEPES)-buffer (pH 7.4) and by incubation in human cerebrospinal fluid (CSF) at 37 degrees C. The formulations were stable with respect to drug retention as well as size alteration, for the period studied. A leakage study clearly showed the sustained release properties of the fasudil-loaded liposomes in human CSF. We recently reported that the intrathecal administration of liposomal fasudil significantly decreased ischemia, with no obvious adverse effect in a rat model [Neurol. Med. Chir. 41 (2001) 109]. Taken together, efficient encapsulation of fasudil into preformed liposomes, their long-term stability at 4 degrees C and the sustained release characteristics in CSF indicate that fasudil-loaded liposomes could be potential candidates for further clinical evaluation.","ja":"The objectives of this work were to develop a liposomal fasudil, an antivasospastic drug, as a possible means to deliver the encapsulated drug to the brain, and to characterize the stability of the liposomal formulation in vitro. Transmembrane electrochemical gradients of H+ or ammonium sulfate were created, and their effect on the uptake of fasudil into preformed hydrogenated soy phosphatidylcholine/cholesterol (HSPC/CHOL) liposomes were examined. Fasudil was successfully loaded into preformed liposomes in response to sulfate ion (SO4(2-)) and, in part, by H+. Encapsulation levels approaching 100% could be achieved up to a drug to lipid ratio of 0.364 (mol/mol). A stability study of the fasudil-loaded liposomes was performed by storage at 4 degrees C in 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid (HEPES)-buffer (pH 7.4) and by incubation in human cerebrospinal fluid (CSF) at 37 degrees C. The formulations were stable with respect to drug retention as well as size alteration, for the period studied. A leakage study clearly showed the sustained release properties of the fasudil-loaded liposomes in human CSF. We recently reported that the intrathecal administration of liposomal fasudil significantly decreased ischemia, with no obvious adverse effect in a rat model [Neurol. Med. Chir. 41 (2001) 109]. Taken together, efficient encapsulation of fasudil into preformed liposomes, their long-term stability at 4 degrees C and the sustained release characteristics in CSF indicate that fasudil-loaded liposomes could be potential candidates for further clinical evaluation."},"publication_date":"2002-01","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.232","number":"No.1-2","starting_page":"59","ending_page":"67","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/S0378-5173(01)00896-1"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:191, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507599"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180291","label":"url"}],"paper_title":{"en":"くも膜下出血後の脳血管簾縮に対する髄液内投与可能な徐放性塩酸ファスジル(エリル)の開発","ja":"くも膜下出血後の脳血管簾縮に対する髄液内投与可能な徐放性塩酸ファスジル(エリル)の開発"},"authors":{"en":[{"name":"高梨 吉裕"},{"name":"Ishida Tatsuhiro"},{"name":"目黒 俊成"},{"name":"Zhang J"},{"name":"山本 勇夫"}],"ja":[{"name":"高梨 吉裕"},{"name":"石田 竜弘"},{"name":"目黒 俊成"},{"name":"Zhang J"},{"name":"山本 勇夫"}]},"publication_date":"2002","publication_name":{"en":"Surgery for Cerebral Stroke","ja":"脳卒中の外科"},"volume":"Vol.30","starting_page":"133","ending_page":"136","languages":["jpn"],"referee":true,"identifiers":{"issn":["0914-5508"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:192, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507600"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11718670","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=92015","label":"url"}],"paper_title":{"en":"Targeted delivery and triggered release of liposomal doxorubicin (DXR) enhances cytotoxicity against human B-cell lymphoma cells.","ja":"Targeted delivery and triggered release of liposomal doxorubicin (DXR) enhances cytotoxicity against human B-cell lymphoma cells."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kirchmeier, M.J."},{"name":"Moase, E.H."},{"name":"Zalipsky, S."},{"name":"Allen, T.M."}],"ja":[{"name":"石田 竜弘"},{"name":"Kirchmeier, M.J."},{"name":"Moase, E.H."},{"name":"Zalipsky, S."},{"name":"Allen, T.M."}]},"description":{"en":"Dioleoylphosphatidylethanolamine (DOPE)-containing liposomes that demonstrated pH-dependent release of their contents were stabilized in the bilayer form through the addition of a cleavable lipid derivative of polyethylene glycol (PEG) in which the PEG was attached to a lipid anchor via a disulfide linkage (mPEG-S-S-DSPE). Liposomes stabilized with either a non-cleavable PEG (mPEG-DSPE) or mPEG-S-S-DSPE retained an encapsulated dye at pH 5.5, but treatment at pH 5.5 of liposomes stabilized with mPEG-S-S-DSPE with either dithiothreitol or cell-free extracts caused contents release due to cleavage of the PEG chains and concomitant destabilization of the DOPE liposomes. While formulations loaded with doxorubicin (DXR) were stable in culture media, DXR was rapidly released in human plasma. pH-Sensitive liposomes, targeted to the CD19 epitope on B-lymphoma cells, showed enhanced DXR delivery into the nuclei of the target cells and increased cytotoxicity compared to non-pH-sensitive liposomes. Pharmacokinetic studies suggested that mPEG-S-S-DSPE was rapidly cleaved in circulation. In a murine model of B-cell lymphoma, the therapeutic efficacy of an anti-CD19-targeted pH-sensitive formulation was superior to that of a stable long-circulating formulation of targeted liposomes despite the more rapid drug release and clearance of the pH-sensitive formulation. These results suggest that targeted pH-sensitive formulations of drugs may be able to increase the therapeutic efficacy of entrapped drugs.","ja":"Dioleoylphosphatidylethanolamine (DOPE)-containing liposomes that demonstrated pH-dependent release of their contents were stabilized in the bilayer form through the addition of a cleavable lipid derivative of polyethylene glycol (PEG) in which the PEG was attached to a lipid anchor via a disulfide linkage (mPEG-S-S-DSPE). Liposomes stabilized with either a non-cleavable PEG (mPEG-DSPE) or mPEG-S-S-DSPE retained an encapsulated dye at pH 5.5, but treatment at pH 5.5 of liposomes stabilized with mPEG-S-S-DSPE with either dithiothreitol or cell-free extracts caused contents release due to cleavage of the PEG chains and concomitant destabilization of the DOPE liposomes. While formulations loaded with doxorubicin (DXR) were stable in culture media, DXR was rapidly released in human plasma. pH-Sensitive liposomes, targeted to the CD19 epitope on B-lymphoma cells, showed enhanced DXR delivery into the nuclei of the target cells and increased cytotoxicity compared to non-pH-sensitive liposomes. Pharmacokinetic studies suggested that mPEG-S-S-DSPE was rapidly cleaved in circulation. In a murine model of B-cell lymphoma, the therapeutic efficacy of an anti-CD19-targeted pH-sensitive formulation was superior to that of a stable long-circulating formulation of targeted liposomes despite the more rapid drug release and clearance of the pH-sensitive formulation. These results suggest that targeted pH-sensitive formulations of drugs may be able to increase the therapeutic efficacy of entrapped drugs."},"publication_date":"2001-12-01","publication_name":{"en":"Biochimica et Biophysica Acta (BBA) - Biomembranes","ja":"Biochimica et Biophysica Acta (BBA) - Biomembranes"},"volume":"Vol.1515","number":"No.2","starting_page":"144","ending_page":"158","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/S0005-2736(01)00409-6"],"issn":["0005-2736"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:193, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507601"},"force":{"see_also":[{"@id":"http://dx.doi.org/10.1054/jocn.2001.0998","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=132281","label":"url"}],"paper_title":{"en":"Intrathecal application with liposome-entrapped Fasudil for cerebral vasospasm following subarachnoid hemorrhage in rats","ja":"Intrathecal application with liposome-entrapped Fasudil for cerebral vasospasm following subarachnoid hemorrhage in rats"},"authors":{"en":[{"name":"Takanashi Yoshihiro"},{"name":"Ishida Tatsuhiro"},{"name":"Meguro Toshinari"},{"name":"Kirchmeier J. Marc"},{"name":"Allen M. Theresa"},{"name":"Zhang H. John"}],"ja":[{"name":"Takanashi Yoshihiro"},{"name":"石田 竜弘"},{"name":"Meguro Toshinari"},{"name":"Kirchmeier J. Marc"},{"name":"Allen M. Theresa"},{"name":"Zhang H. John"}]},"publication_date":"2001-11","publication_name":{"en":"Journal of Clinical Neuroscience","ja":"Journal of Clinical Neuroscience"},"volume":"Vol.8","number":"No.6","starting_page":"557","ending_page":"561","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1054/jocn.2001.0998"],"issn":["0967-5868"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:194, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507602"},"force":{"see_also":[{"@id":"http://dx.doi.org/10.1016/S0378-5173(01)00737-2","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11472816","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130849","label":"url"}],"paper_title":{"en":"Effect of cholesterol content in activation of the classical versus the alternative pathway of rat complement system induced by hydrogenated egg phosphatidylcholine-based liposomes","ja":"Effect of cholesterol content in activation of the classical versus the alternative pathway of rat complement system induced by hydrogenated egg phosphatidylcholine-based liposomes"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Yasukawa Kazumi"},{"name":"Kojima Hiroko"},{"name":"Harashima Hideyoshi"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"Yasukawa Kazumi"},{"name":"Kojima Hiroko"},{"name":"Harashima Hideyoshi"},{"name":"際田 弘志"}]},"description":{"en":"Liposomes composed of hydrogenated egg phosphatidylcholine (HEPC) and cholesterol (CHOL) were found to activate the rat complement (C) system in a CHOL content-dependent manner. Liposomes containing 22 or 33 mol% CHOL activated the C system in a Ca(2+)-dependent manner, suggesting that C activation occurred via the classical pathway. Liposomes containing 44 mol% CHOL activated the C system in a Ca(2+) independent manner, suggesting that C activation occurred via the alternative pathway. The CHOL content appeared to dictate the pathway by which the C system was activated. This C activation was inhibited by removal of serum component(s), which adsorb to the liposomes. Activation of the alternative pathway, induced by the liposomes, was reduced by the depletion of IgG and IgM, whereas the classical pathway activation was reduced by the depletion of IgG, but not IgM. In addition, the removal of adsorbed serum component(s) by treatment with 44 mol% CHOL-containing liposomes decreased serum IgG and IgM levels that adsorb to the same liposomes, whereas the removal of adsorbed serum component(s) by treatment with 22 mol% CHOL-containing liposomes only slightly decreased serum IgG levels, which adsorbs to the same liposomes. Collectively, both IgG and IgM, which are specifically adsorbed to the liposomes in a CHOL-content dependent manner, were responsible for C activation via the alternative pathway induced by the 44 mol% CHOL containing liposomes. IgG alone would be partially responsible for C activation via the classical pathway induced by 22 or 33 mol% CHOL-containing liposomes. The discovery of this unique C-activating property of liposomes will be of value in attempts to decipher the underlying mechanism of C activation by providing a useful model membrane system.","ja":"Liposomes composed of hydrogenated egg phosphatidylcholine (HEPC) and cholesterol (CHOL) were found to activate the rat complement (C) system in a CHOL content-dependent manner. Liposomes containing 22 or 33 mol% CHOL activated the C system in a Ca(2+)-dependent manner, suggesting that C activation occurred via the classical pathway. Liposomes containing 44 mol% CHOL activated the C system in a Ca(2+) independent manner, suggesting that C activation occurred via the alternative pathway. The CHOL content appeared to dictate the pathway by which the C system was activated. This C activation was inhibited by removal of serum component(s), which adsorb to the liposomes. Activation of the alternative pathway, induced by the liposomes, was reduced by the depletion of IgG and IgM, whereas the classical pathway activation was reduced by the depletion of IgG, but not IgM. In addition, the removal of adsorbed serum component(s) by treatment with 44 mol% CHOL-containing liposomes decreased serum IgG and IgM levels that adsorb to the same liposomes, whereas the removal of adsorbed serum component(s) by treatment with 22 mol% CHOL-containing liposomes only slightly decreased serum IgG levels, which adsorbs to the same liposomes. Collectively, both IgG and IgM, which are specifically adsorbed to the liposomes in a CHOL-content dependent manner, were responsible for C activation via the alternative pathway induced by the 44 mol% CHOL containing liposomes. IgG alone would be partially responsible for C activation via the classical pathway induced by 22 or 33 mol% CHOL-containing liposomes. The discovery of this unique C-activating property of liposomes will be of value in attempts to decipher the underlying mechanism of C activation by providing a useful model membrane system."},"publication_date":"2001-08-14","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.224","number":"No.1-2","starting_page":"69","ending_page":"79","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/S0378-5173(01)00737-2"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:195, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507603"},"force":{"see_also":[{"@id":"http://bpb.pharm.or.jp/abst/200104/ab24040439.html","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11305612","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130847","label":"url"}],"paper_title":{"en":"Species Difference in Correlation between in Vivo/ in Vitro LiposomeComplement Interactions","ja":"Species Difference in Correlation between in Vivo/ in Vitro LiposomeComplement Interactions"},"authors":{"en":[{"name":"Huong Minh Tran"},{"name":"Ishida Tatsuhiro"},{"name":"Harashima Hideyoshi"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Huong Minh Tran"},{"name":"石田 竜弘"},{"name":"Harashima Hideyoshi"},{"name":"際田 弘志"}]},"description":{"en":"The objective of this study was to investigate the correlation between in vitro and in vivo liposome-complement interactions. Third component of the complement (C3) fragments associated with hydrogenated egg phosphatidylcholine (HEPC)-based liposomes in vivo and complement-dependent destabilization in vitro were determined as an indication of liposome-complement interaction in vivo and in vitro, respectively. C3 fragments on the liposomes were detected in both rats and guinea pigs. Pretreatment with K76COOH (K76), a complement inactivating agent, reduced the binding of C3 fragments. These findings indicated that the liposomes remarkably activated the complement system in both animals in vivo. Interestingly, significant complement-dependent liposome destabilization was observed in rat serum, but not in guinea pig serum, indicating that the liposomes activated the complement system in rats, but not in guinea pigs in vitro. Taken together, it is apparent that in vitro complement activation by the liposomes is not in agreement with in vivo complement activation in ginea pigs. This discrepancy in the liposome-complement interaction would suggest the need for further investigation to utilize the information obtained from the liposome-complement interaction to predict in vivo behavior of the liposomes.","ja":"The objective of this study was to investigate the correlation between in vitro and in vivo liposome-complement interactions. Third component of the complement (C3) fragments associated with hydrogenated egg phosphatidylcholine (HEPC)-based liposomes in vivo and complement-dependent destabilization in vitro were determined as an indication of liposome-complement interaction in vivo and in vitro, respectively. C3 fragments on the liposomes were detected in both rats and guinea pigs. Pretreatment with K76COOH (K76), a complement inactivating agent, reduced the binding of C3 fragments. These findings indicated that the liposomes remarkably activated the complement system in both animals in vivo. Interestingly, significant complement-dependent liposome destabilization was observed in rat serum, but not in guinea pig serum, indicating that the liposomes activated the complement system in rats, but not in guinea pigs in vitro. Taken together, it is apparent that in vitro complement activation by the liposomes is not in agreement with in vivo complement activation in ginea pigs. This discrepancy in the liposome-complement interaction would suggest the need for further investigation to utilize the information obtained from the liposome-complement interaction to predict in vivo behavior of the liposomes."},"publication_date":"2001-04","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.24","number":"No.4","starting_page":"439","ending_page":"441","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.24.439"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:196, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507604"},"force":{"see_also":[{"@id":"http://www.neurosurgery-online.com/pt/re/neurosurg/abstract.00006123-200104000-00041.htm","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11322450","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130839","label":"url"}],"paper_title":{"en":"Efficacy of Intrathecal Liposomal Fasudil for Experimental Cerebral Vasospasm after Subarachnoid Hemorrhage","ja":"Efficacy of Intrathecal Liposomal Fasudil for Experimental Cerebral Vasospasm after Subarachnoid Hemorrhage"},"authors":{"en":[{"name":"Takanashi Yoshihiro"},{"name":"Ishida Tatsuhiro"},{"name":"Meguro Toshinari"},{"name":"Kiwada Hiroshi"},{"name":"Zhang H John"},{"name":"Yamamoto Isao"}],"ja":[{"name":"Takanashi Yoshihiro"},{"name":"石田 竜弘"},{"name":"Meguro Toshinari"},{"name":"際田 弘志"},{"name":"Zhang H John"},{"name":"Yamamoto Isao"}]},"description":{"en":"To investigate the safety and efficacy of liposomal fasudil in a sustained-release form for the prevention of cerebral vasospasm after subarachnoid hemorrhage (SAH). Eighteen rats were divided into three groups, each of which received 2.5 mg/kg of liposomal fasudil, 5 mg/kg of liposomal fasudil, or drug-free liposomes after SAH. Next, experimental SAH was induced in 15 dogs by injection of autologous arterial blood into the cisterna magna twice after baseline vertebral angiography. In six dogs, 0.94 mg/kg of liposomal fasudil was injected into the cisterna magna (treatment group). In four dogs, drug-free liposomes were similarly injected (placebo group), and the remaining five dogs were not treated with liposomal injection after SAH (control group). Angiography was repeated on Day 7, and cerebrospinal fluid was collected before the dogs were killed. A high dose of liposomal fasudil caused no significant changes in mean arterial blood pressure and did not induce seizures during the observation period. Gross and microscopic examination of the brains revealed no abnormalities, but severe vasospasm was noted in the rat basilar artery, mainly in the group treated with drug-free liposomes. Likewise, in the canine placebo and control groups, significant vasospasm occurred in the basilar artery on Day 7. In the treatment group, vasospasm in the basilar artery was significantly ameliorated (P < 0.01). In vivo, 90% of fasudil was released from liposomes in the cerebrospinal fluid. A single injection of intrathecal liposomal fasudil is safe and effective for the prevention of vasospasm in experimental SAH.","ja":"To investigate the safety and efficacy of liposomal fasudil in a sustained-release form for the prevention of cerebral vasospasm after subarachnoid hemorrhage (SAH). Eighteen rats were divided into three groups, each of which received 2.5 mg/kg of liposomal fasudil, 5 mg/kg of liposomal fasudil, or drug-free liposomes after SAH. Next, experimental SAH was induced in 15 dogs by injection of autologous arterial blood into the cisterna magna twice after baseline vertebral angiography. In six dogs, 0.94 mg/kg of liposomal fasudil was injected into the cisterna magna (treatment group). In four dogs, drug-free liposomes were similarly injected (placebo group), and the remaining five dogs were not treated with liposomal injection after SAH (control group). Angiography was repeated on Day 7, and cerebrospinal fluid was collected before the dogs were killed. A high dose of liposomal fasudil caused no significant changes in mean arterial blood pressure and did not induce seizures during the observation period. Gross and microscopic examination of the brains revealed no abnormalities, but severe vasospasm was noted in the rat basilar artery, mainly in the group treated with drug-free liposomes. Likewise, in the canine placebo and control groups, significant vasospasm occurred in the basilar artery on Day 7. In the treatment group, vasospasm in the basilar artery was significantly ameliorated (P < 0.01). In vivo, 90% of fasudil was released from liposomes in the cerebrospinal fluid. A single injection of intrathecal liposomal fasudil is safe and effective for the prevention of vasospasm in experimental SAH."},"publication_date":"2001-04","publication_name":{"en":"Neurosurgery","ja":"Neurosurgery"},"volume":"Vol.48","number":"No.4","starting_page":"894","ending_page":"901","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1097/00006123-200104000-00041"],"issn":["0148-396X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:197, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507605"},"force":{"see_also":[{"@id":"http://dx.doi.org/10.1016/S0378-5173(00)00691-8","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11250105","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-0035857696&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130845","label":"url"}],"paper_title":{"en":"The complement system enhances the clearance of phosphatidylserine (PS)-liposomes in rat and guinea pig","ja":"The complement system enhances the clearance of phosphatidylserine (PS)-liposomes in rat and guinea pig"},"authors":{"en":[{"name":"Huong Minh Tran"},{"name":"Ishida Tatsuhiro"},{"name":"Harashima Hideyoshi"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Huong Minh Tran"},{"name":"石田 竜弘"},{"name":"Harashima Hideyoshi"},{"name":"際田 弘志"}]},"description":{"en":"In this study, we investigated the contribution of the complement system to the biodistribution of phosphatidylserine (PS)-containing liposomes in rat and guinea pig. It appeared that the inclusion of PS in the liposome formulation accelerates the rate of liposome uptake by liver, resulting in rapid elimination of the liposomes from blood circulation. Pretreatment with K76COOH (K76), an anti-complement agent, decreased the rapid uptake of PS-containing liposomes by guinea pig liver, resulting in increasing blood concentration of the liposomes. Significant complement-dependent liposome destabilization was observed in vitro in both animals, whereas the complement-dependent destabilization in vivo was likely only a part of the process of the clearance of the PS-containing liposomes. This discrepancy suggests that the rate of complement-dependent liposome uptake by liver is much faster than the rate of complement-dependent liposome destabilization in vivo. Pretreatment of K76 dramatically inhibited the binding of C3 fragments, one of dominant opsonins, to PS-containing liposomes in guinea pig under both in vivo and in vitro conditions. This finding suggests that the C3 fragments in the system are responsible for the clearance of the PS-containing liposomes in guinea pig. In rat, in contrast to guinea pig, in vivo binding of C3 fragments was not inhibited by K76-pretreatment, while in vitro binding was inhibited. This discrepancy may be due to different experimental conditions between in vitro and in vivo assay. Nevertheless, based on the observations in this study, the complement components are most likely involved in the clearance of the PS-containing liposomes in rat. Taken together, the activity of PS in enhancing the liposome clearance appears to be mediated by the complement components, presumably C3 fragments, in both guinea pig and rat. This is a first report showing the mechanism on the hepatic uptake of the PS-containing liposomes in guinea pig.","ja":"In this study, we investigated the contribution of the complement system to the biodistribution of phosphatidylserine (PS)-containing liposomes in rat and guinea pig. It appeared that the inclusion of PS in the liposome formulation accelerates the rate of liposome uptake by liver, resulting in rapid elimination of the liposomes from blood circulation. Pretreatment with K76COOH (K76), an anti-complement agent, decreased the rapid uptake of PS-containing liposomes by guinea pig liver, resulting in increasing blood concentration of the liposomes. Significant complement-dependent liposome destabilization was observed in vitro in both animals, whereas the complement-dependent destabilization in vivo was likely only a part of the process of the clearance of the PS-containing liposomes. This discrepancy suggests that the rate of complement-dependent liposome uptake by liver is much faster than the rate of complement-dependent liposome destabilization in vivo. Pretreatment of K76 dramatically inhibited the binding of C3 fragments, one of dominant opsonins, to PS-containing liposomes in guinea pig under both in vivo and in vitro conditions. This finding suggests that the C3 fragments in the system are responsible for the clearance of the PS-containing liposomes in guinea pig. In rat, in contrast to guinea pig, in vivo binding of C3 fragments was not inhibited by K76-pretreatment, while in vitro binding was inhibited. This discrepancy may be due to different experimental conditions between in vitro and in vivo assay. Nevertheless, based on the observations in this study, the complement components are most likely involved in the clearance of the PS-containing liposomes in rat. Taken together, the activity of PS in enhancing the liposome clearance appears to be mediated by the complement components, presumably C3 fragments, in both guinea pig and rat. This is a first report showing the mechanism on the hepatic uptake of the PS-containing liposomes in guinea pig."},"publication_date":"2001-03-14","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.215","number":"No.1-2","starting_page":"197","ending_page":"205","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/S0378-5173(00)00691-8"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:198, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507606"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11372552","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=132277","label":"url"}],"paper_title":{"en":"Neuroprotection by intrathecal application of liposome-entrapped Fasudil in a rat model of ischemia","ja":"Neuroprotection by intrathecal application of liposome-entrapped Fasudil in a rat model of ischemia"},"authors":{"en":[{"name":"Takanashi Yoshihiro"},{"name":"Ishida Tatsuhiro"},{"name":"Kirchmeier J. Marc"},{"name":"Shuaib Ashfaq"},{"name":"Alien M. Theresa"}],"ja":[{"name":"Takanashi Yoshihiro"},{"name":"石田 竜弘"},{"name":"Kirchmeier J. Marc"},{"name":"Shuaib Ashfaq"},{"name":"Alien M. Theresa"}]},"description":{"en":"Pharmacological treatment for cerebral ischemia cannot attain sufficiently high concentrations of the drugs in the cerebrospinal fluid (CSF) without precipitating systemic side effects. The objective of this study is the development of a liposomal drug delivery system that maintains effective concentrations of protein kinase inhibitors fasudil in the CSF, resulting in neuroprotection against cerebral ischemia. Focal cerebral ischemia in rats was induced by middle cerebral artery occlusion using an intraluminal suture technique. Treated rats received 0.25 mg liposome-entrapped fasudil via the cisterna magna 2 hours after ischemic insult. Control rats received drug-free liposomes. Neurological condition and the infarct size were assessed at 24 and 72 hours after ischemia. The concentration of liposome-entrapped fasudil in the CSF was measured before sacrifice. Treated animals showed significantly improved neurological outcomes after the 24-hour observation period compared to the control group (p < 0.001). Treatment with 0.25 mg liposomal fasudil resulted in a reduction in the infarct area (24 hours: 29.0 +/- 4.4%, 72 hours: 28.1 +/- 3.9% of total brain slices) compared to controls (49.6 +/- 4.6%, p < 0.001), but there was no statistical difference between 24 and 72 hours. At 24 hours post-administration, CSF concentrations of liposome-entrapped fasudil were 45.4 +/- 31.5 micrograms/ml (20% of the injected dose). A single intrathecal injection of liposomal fasudil can maintain a therapeutic drug concentration in the CSF over a period of time, significantly decreasing infarct size in a rat model of acute ischemia.","ja":"Pharmacological treatment for cerebral ischemia cannot attain sufficiently high concentrations of the drugs in the cerebrospinal fluid (CSF) without precipitating systemic side effects. The objective of this study is the development of a liposomal drug delivery system that maintains effective concentrations of protein kinase inhibitors fasudil in the CSF, resulting in neuroprotection against cerebral ischemia. Focal cerebral ischemia in rats was induced by middle cerebral artery occlusion using an intraluminal suture technique. Treated rats received 0.25 mg liposome-entrapped fasudil via the cisterna magna 2 hours after ischemic insult. Control rats received drug-free liposomes. Neurological condition and the infarct size were assessed at 24 and 72 hours after ischemia. The concentration of liposome-entrapped fasudil in the CSF was measured before sacrifice. Treated animals showed significantly improved neurological outcomes after the 24-hour observation period compared to the control group (p < 0.001). Treatment with 0.25 mg liposomal fasudil resulted in a reduction in the infarct area (24 hours: 29.0 +/- 4.4%, 72 hours: 28.1 +/- 3.9% of total brain slices) compared to controls (49.6 +/- 4.6%, p < 0.001), but there was no statistical difference between 24 and 72 hours. At 24 hours post-administration, CSF concentrations of liposome-entrapped fasudil were 45.4 +/- 31.5 micrograms/ml (20% of the injected dose). A single intrathecal injection of liposomal fasudil can maintain a therapeutic drug concentration in the CSF over a period of time, significantly decreasing infarct size in a rat model of acute ischemia."},"publication_date":"2001-03","publication_name":{"en":"Neurologia Medico-Chirurgica","ja":"Neurologia Medico-Chirurgica"},"volume":"Vol.41","number":"No.3","starting_page":"107","ending_page":"114","languages":["eng"],"referee":true,"identifiers":{"doi":["10.2176/nmc.41.107"],"issn":["0470-8105"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:199, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507607"},"force":{"see_also":[{"@id":"http://www.metapress.com/(dazrqxqwncsow455xa4xforn)/app/home/contribution.asp?referrer=parent&backto=issue,2,9;journal,13,13;linkingpublicationresults,1:107847,1","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19530916","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-0035031851&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=132276","label":"url"}],"paper_title":{"en":"Correlations between the rate of intracellular release of endocytosed liposomal doxorubicin and cytotoxicity as determined by a new assay","ja":"Correlations between the rate of intracellular release of endocytosed liposomal doxorubicin and cytotoxicity as determined by a new assay"},"authors":{"en":[{"name":"Kirchmeier J. Marc"},{"name":"Ishida Tatsuhiro"},{"name":"Chevrette Julie"},{"name":"Allen M. Theresa"}],"ja":[{"name":"Kirchmeier J. Marc"},{"name":"石田 竜弘"},{"name":"Chevrette Julie"},{"name":"Allen M. Theresa"}]},"description":{"en":"Previously, we showed that liposomes with surface-attached anti-CD19 were internalized into human B lymphoma cells through receptor-mediated endocytosis, resulting in improved anti-tumor efficacy 1-2 . In order to further increase the efficacy of antineoplastic drug-containing liposomes, we have taken advantage of this internalization process by producing triggered release liposomes that rapidly release drug from the enzyme-rich, acidic environment of lysosomes. To analyze the effectiveness of these triggered-release formulations, we developed a nuclear accumulation assay for doxorubicin (DXR) that allows us to determine the rate of cytoplasmic drug delivery subsequent to drug release from the endosomal/lysosomal compartments by examining the rate of accumulation of drug in cellular nuclei. We demonstrate the usefulness of this assay by comparing the kinetics of cytoplasmic drug delivery for DXR-containing, pH-sensitive, triggered release liposomes versus DXR-containing, non-sensitive, liposomal formulations. We see a significant correlation between the rate of nuclear accumulation of DXR and its in vitrocytotoxicity. This indicates that pH-sensitive formulations traffic drug to the cytoplasm and the nucleus significantly more rapidly than do non-sensitive formulations. We conclude that the development of triggered release liposomes is a promising strategy for further improving the therapeutic efficacy of liposomal antineoplastic drugs targeted selectively to cancer cells by surface-attached ligands that bind to internalizing epitopes.","ja":"Previously, we showed that liposomes with surface-attached anti-CD19 were internalized into human B lymphoma cells through receptor-mediated endocytosis, resulting in improved anti-tumor efficacy 1-2 . In order to further increase the efficacy of antineoplastic drug-containing liposomes, we have taken advantage of this internalization process by producing triggered release liposomes that rapidly release drug from the enzyme-rich, acidic environment of lysosomes. To analyze the effectiveness of these triggered-release formulations, we developed a nuclear accumulation assay for doxorubicin (DXR) that allows us to determine the rate of cytoplasmic drug delivery subsequent to drug release from the endosomal/lysosomal compartments by examining the rate of accumulation of drug in cellular nuclei. We demonstrate the usefulness of this assay by comparing the kinetics of cytoplasmic drug delivery for DXR-containing, pH-sensitive, triggered release liposomes versus DXR-containing, non-sensitive, liposomal formulations. We see a significant correlation between the rate of nuclear accumulation of DXR and its in vitrocytotoxicity. This indicates that pH-sensitive formulations traffic drug to the cytoplasm and the nucleus significantly more rapidly than do non-sensitive formulations. We conclude that the development of triggered release liposomes is a promising strategy for further improving the therapeutic efficacy of liposomal antineoplastic drugs targeted selectively to cancer cells by surface-attached ligands that bind to internalizing epitopes."},"publication_date":"2001-03","publication_name":{"en":"Journal of Liposome Research","ja":"Journal of Liposome Research"},"volume":"Vol.11","number":"No.1","starting_page":"15","ending_page":"29","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1081/LPR-100103167"],"issn":["1532-2394"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:200, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507608"},"force":{"see_also":[{"@id":"http://dx.doi.org/10.1016/S0005-2736(00)00334-5","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11342146","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=132292","label":"url"}],"paper_title":{"en":"Anti-MUC-1 immunoliposomal doxorubicin in the treatment of murine models of metastatic breast cancer","ja":"Anti-MUC-1 immunoliposomal doxorubicin in the treatment of murine models of metastatic breast cancer"},"authors":{"en":[{"name":"Moase E H"},{"name":"Qi W"},{"name":"Ishida Tatsuhiro"},{"name":"Gabos Z"},{"name":"Longenecker B M"},{"name":"Zimmermann G L"},{"name":"Ding L"},{"name":"Krantz M"},{"name":"Allen T M"}],"ja":[{"name":"Moase E H"},{"name":"Qi W"},{"name":"石田 竜弘"},{"name":"Gabos Z"},{"name":"Longenecker B M"},{"name":"Zimmermann G L"},{"name":"Ding L"},{"name":"Krantz M"},{"name":"Allen T M"}]},"description":{"en":"The fate of breast cancer patients is dependent upon elimination or control of metastases. We studied the effect of antibody-targeted liposomes containing entrapped doxorubicin (DXR) on development of tumours in two models of breast cancer, pseudometastatic and metastatic, in mice. The former used the mouse mammary carcinoma cell line GZHI, which expresses the human MUC-1 gene (L. Ding, E.N. Lalani, M. Reddish, R. Koganty, T. Wong, J. Samuel, M.B. Yacyshyn, A. Meikle, P.Y.S. Fung, J. Taylor-Papadimitriou, B.M. Longenecker, Cancer Immunol. Immunother. 36 (1993) 9--17). GZHI cells seed into the lungs of Balb/c mice following intravenous injection. The latter used the 4T1-MUC1 cell line, a MUC-1 transfectant of the mouse mammary carcinoma cell line 4T1, which metastasizes from a primary mammary fatpad (mfp) implant to the lungs (C.J. Aslakson, F.R. Miller, Cancer Res. 52 (1992) 1399--1405). B27.29, a monoclonal antibody against the MUC-1 antigen, was used to target sterically stabilized immunoliposomes (SIL[B27.29]) to tumour cells. In vitro, SIL[B27.29] showed high specific binding to both GZHI and 4T1-MUC1 cells. The IC(50) of DXR-loaded SIL[B27.29] was similar to that of free drug for GZHI cells. In the pseudometastatic model, mice treated with a single injection of 6 mg DXR/kg in DXR-SIL[B27.29] at 24 h after cell implantation had longer survival times than those injected with non-targeted liposomal drug. In the metastatic model, severe combined immune deficiency mice given weekly injectionsx3 of 2.5 mg DXR/kg encapsulated in either targeted or non-targeted liposomes were almost equally effective in slowing growth of the primary tumour and reducing development of lung tumours. Surgical removal of the primary tumour from mfp, followed by various chemotherapy regimens, was attempted, but removal of the primary tumour was generally incomplete; tumour regrowth occurred and metastases developed in the lungs in all treatment groups. DXR-SL reduced the occurrence of regrowth of the primary tumour, whereas neither targeted liposomal drug or free drug prevented regrowth. We conclude that monoclonal antibody-targeted liposomal DXR is effective in treating early lesions in both the pseudometastatic and metastatic models, but limitations to the access of the targeted liposomes to tumour cells in the primary tumour compromised their therapeutic efficacy in treating the more advanced lesions.","ja":"The fate of breast cancer patients is dependent upon elimination or control of metastases. We studied the effect of antibody-targeted liposomes containing entrapped doxorubicin (DXR) on development of tumours in two models of breast cancer, pseudometastatic and metastatic, in mice. The former used the mouse mammary carcinoma cell line GZHI, which expresses the human MUC-1 gene (L. Ding, E.N. Lalani, M. Reddish, R. Koganty, T. Wong, J. Samuel, M.B. Yacyshyn, A. Meikle, P.Y.S. Fung, J. Taylor-Papadimitriou, B.M. Longenecker, Cancer Immunol. Immunother. 36 (1993) 9--17). GZHI cells seed into the lungs of Balb/c mice following intravenous injection. The latter used the 4T1-MUC1 cell line, a MUC-1 transfectant of the mouse mammary carcinoma cell line 4T1, which metastasizes from a primary mammary fatpad (mfp) implant to the lungs (C.J. Aslakson, F.R. Miller, Cancer Res. 52 (1992) 1399--1405). B27.29, a monoclonal antibody against the MUC-1 antigen, was used to target sterically stabilized immunoliposomes (SIL[B27.29]) to tumour cells. In vitro, SIL[B27.29] showed high specific binding to both GZHI and 4T1-MUC1 cells. The IC(50) of DXR-loaded SIL[B27.29] was similar to that of free drug for GZHI cells. In the pseudometastatic model, mice treated with a single injection of 6 mg DXR/kg in DXR-SIL[B27.29] at 24 h after cell implantation had longer survival times than those injected with non-targeted liposomal drug. In the metastatic model, severe combined immune deficiency mice given weekly injectionsx3 of 2.5 mg DXR/kg encapsulated in either targeted or non-targeted liposomes were almost equally effective in slowing growth of the primary tumour and reducing development of lung tumours. Surgical removal of the primary tumour from mfp, followed by various chemotherapy regimens, was attempted, but removal of the primary tumour was generally incomplete; tumour regrowth occurred and metastases developed in the lungs in all treatment groups. DXR-SL reduced the occurrence of regrowth of the primary tumour, whereas neither targeted liposomal drug or free drug prevented regrowth. We conclude that monoclonal antibody-targeted liposomal DXR is effective in treating early lesions in both the pseudometastatic and metastatic models, but limitations to the access of the targeted liposomes to tumour cells in the primary tumour compromised their therapeutic efficacy in treating the more advanced lesions."},"publication_date":"2001-02-09","publication_name":{"en":"Biochimica et Biophysica Acta (BBA) - Biomembranes","ja":"Biochimica et Biophysica Acta (BBA) - Biomembranes"},"volume":"Vol.1510","number":"No.1-2","starting_page":"43","ending_page":"55","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/S0005-2736(00)00334-5"],"issn":["0005-2736"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:201, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507609"},"force":{"see_also":[{"@id":"http://dx.doi.org/10.1016/S0378-5173(00)00511-1","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/11000555","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130863","label":"url"}],"paper_title":{"en":"Biodistribution of liposomes and C3 fragments associated with liposomes:evaluation of their relationship","ja":"Biodistribution of liposomes and C3 fragments associated with liposomes:evaluation of their relationship"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kojima Hiroko"},{"name":"Harashima Hideyoshi"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"Kojima Hiroko"},{"name":"Harashima Hideyoshi"},{"name":"際田 弘志"}]},"description":{"en":"The biodistribution of liposomes with two different kind phospholipids (hydrogenated egg phosphatidylcholine and egg phosphatidylcholine) plus cholesterol (CHOL) were investigated after intravenous administration to rats. Elimination of liposomes from blood circulation was affected by the lipid composition. It appeared that the inclusion of CHOL in liposomes accelerates the rate of liposome uptake by liver, resulting in rapid elimination of liposomes. The amount of C3 fragments bound to liposomes was quantitatively determined to assess the contribution of the complement system to liposome accumulation into organs and liposome destabilization in vivo and in vitro. The amount of bound C3 fragments was directly proportional to CHOL content, and the amount was also proportional to the CLh, CLs as well as CLrel. This relationship suggests that the complement system is responsible for the elimination of liposomes from blood circulation, presumably as a consequence of opsonization by C3 fragments and assembly of membrane attack complex (MAC) onto liposomes. In addition, substitution of cholesteryl methyl ether into the liposome formulation for CHOL significantly diminished not only the binding of C3 fragments but also the CLh, CLs and CLrel, resulting in increased mean resident time (MRT) of the liposomes. This result suggests that the hydroxyl-group on CHOL is a binding site for C3 fragments on the liposomes and that CHOL in a liposome formulation promotes the accumulation of liposomes into the liver and spleen, probably due to their uptake by phagocytic cells, and impairs the stability of the liposomes in blood circulation, via a mechanism involving the complement system.","ja":"The biodistribution of liposomes with two different kind phospholipids (hydrogenated egg phosphatidylcholine and egg phosphatidylcholine) plus cholesterol (CHOL) were investigated after intravenous administration to rats. Elimination of liposomes from blood circulation was affected by the lipid composition. It appeared that the inclusion of CHOL in liposomes accelerates the rate of liposome uptake by liver, resulting in rapid elimination of liposomes. The amount of C3 fragments bound to liposomes was quantitatively determined to assess the contribution of the complement system to liposome accumulation into organs and liposome destabilization in vivo and in vitro. The amount of bound C3 fragments was directly proportional to CHOL content, and the amount was also proportional to the CLh, CLs as well as CLrel. This relationship suggests that the complement system is responsible for the elimination of liposomes from blood circulation, presumably as a consequence of opsonization by C3 fragments and assembly of membrane attack complex (MAC) onto liposomes. In addition, substitution of cholesteryl methyl ether into the liposome formulation for CHOL significantly diminished not only the binding of C3 fragments but also the CLh, CLs and CLrel, resulting in increased mean resident time (MRT) of the liposomes. This result suggests that the hydroxyl-group on CHOL is a binding site for C3 fragments on the liposomes and that CHOL in a liposome formulation promotes the accumulation of liposomes into the liver and spleen, probably due to their uptake by phagocytic cells, and impairs the stability of the liposomes in blood circulation, via a mechanism involving the complement system."},"publication_date":"2000-09-15","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.205","number":"No.1-2","starting_page":"183","ending_page":"193","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/S0378-5173(00)00511-1"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:202, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507610"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=132297","label":"url"}],"paper_title":{"en":"A combinatorial approach to producing sterically stabilized(Stealth)immunoliposomal drugs","ja":"A combinatorial approach to producing sterically stabilized(Stealth)immunoliposomal drugs"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Iden L. Dbbie"},{"name":"Allen M. Theresa"}],"ja":[{"name":"石田 竜弘"},{"name":"Iden L. Dbbie"},{"name":"Allen M. Theresa"}]},"publication_date":"1999-10-22","publication_name":{"en":"FEBS Letters","ja":"FEBS Letters"},"volume":"Vol.460","number":"No.1","starting_page":"129","ending_page":"133","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/S0014-5793(99)01320-4"],"issn":["0014-5793"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:203, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507611"},"force":{"see_also":[{"@id":"http://dx.doi.org/10.1016/S0378-5173(97)00403-1","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130895","label":"url"}],"paper_title":{"en":"A novel plasma factor initiating complement activation on cetylmannoside-modified liposomes in human plasma","ja":"A novel plasma factor initiating complement activation on cetylmannoside-modified liposomes in human plasma"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Iida Shinya"},{"name":"Funato Kouichi"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"Iida Shinya"},{"name":"Funato Kouichi"},{"name":"際田 弘志"}]},"publication_date":"1998-04-13","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.164","number":"No.1-2","starting_page":"91","ending_page":"102","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/S0378-5173(97)00403-1"],"issn":["0378-5173"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:204, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507613"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130896","label":"url"}],"paper_title":{"en":"Characterization of Bovine Serum Factor Triggering the Lysis of Liposomes via Complement Activation","ja":"Characterization of Bovine Serum Factor Triggering the Lysis of Liposomes via Complement Activation"},"authors":{"en":[{"name":"Liu Shicheng"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Liu Shicheng"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"publication_date":"1998-01-07","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.21","number":"No.4","starting_page":"390","ending_page":"397","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1248/bpb.21.390"],"issn":["0918-6158"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:205, {"insert":{"user_id":"1000300291","type":"published_papers","id":"30507612"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130899","label":"url"}],"paper_title":{"en":"リポソーム膜中のコレステロール含量が及ぼす補体第3成分(C3)の結合と体内動態への影響","ja":"リポソーム膜中のコレステロール含量が及ぼす補体第3成分(C3)の結合と体内動態への影響"},"authors":{"en":[{"name":"小島 弘子"},{"name":"Ishida Tatsuhiro"},{"name":"原島 秀吉"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"小島 弘子"},{"name":"石田 竜弘"},{"name":"原島 秀吉"},{"name":"際田 弘志"}]},"publication_date":"1998","publication_name":{"en":"Drug Delivery System","ja":"Drug Delivery System"},"volume":"Vol.13","starting_page":"55","ending_page":"61","languages":["jpn"],"referee":true,"identifiers":{"issn":["0913-5006"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
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line:14, {"insert":{"user_id":"1000300291","type":"misc","id":"30512983"},"force":{"see_also":[{"@id":"https://cir.nii.ac.jp/crid/1390283659849385728/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=362751","label":"url"}],"paper_title":{"en":"リポソームDDS 製剤開発における免疫系の制御と動態解析の重要性","ja":"リポソームDDS 製剤開発における免疫系の制御と動態解析の重要性"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"清水 太郎"},{"name":"石田 竜弘"}]},"publication_date":"2020-02","publication_name":{"en":"Oleoscience","ja":"オレオサイエンス"},"volume":"Vol.20","number":"No.2","starting_page":"71","ending_page":"76","languages":["jpn"],"identifiers":{"doi":["10.5650/oleoscience.20.71"],"issn":["2187-3461"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:15, {"insert":{"user_id":"1000300291","type":"misc","id":"30512985"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=361984","label":"url"}],"paper_title":{"en":"ナノフィブリル化バクテリアセルロース(Fibnano)を用いた腹腔内投与型がん治療製剤への応用","ja":"ナノフィブリル化バクテリアセルロース(Fibnano)を用いた腹腔内投与型がん治療製剤への応用"},"authors":{"en":[{"name":"ANDO Hidenori"},{"name":"田島 健次"},{"name":"松島 得雄"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"安藤 英紀"},{"name":"田島 健次"},{"name":"松島 得雄"},{"name":"石田 竜弘"}]},"publication_date":"2019-12","publication_name":{"en":"Cellulose Communications","ja":"Cellulose Communications"},"volume":"Vol.26","number":"No.4","starting_page":"173","ending_page":"177","languages":["jpn"],"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:16, {"insert":{"user_id":"1000300291","type":"misc","id":"30512986"},"force":{"see_also":[{"@id":"https://cir.nii.ac.jp/crid/1050287462784741632/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=359930","label":"url"}],"paper_title":{"en":"フルーツ由来新奇酢酸菌によるナノセルロースの合成とその応用","ja":"フルーツ由来新奇酢酸菌によるナノセルロースの合成とその応用"},"authors":{"en":[{"name":"田島 健次"},{"name":"小瀬 亮太"},{"name":"松島 得雄"},{"name":"Ishida Tatsuhiro"},{"name":"ANDO Hidenori"}],"ja":[{"name":"田島 健次"},{"name":"小瀬 亮太"},{"name":"松島 得雄"},{"name":"石田 竜弘"},{"name":"安藤 英紀"}]},"publication_date":"2019-09","publication_name":{"en":"Journal of The Brewing Society of Japan","ja":"日本醸造協会誌"},"volume":"Vol.114","number":"No.9","starting_page":"540","ending_page":"549","languages":["jpn"],"identifiers":{"issn":["0914-7314"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:17, {"insert":{"user_id":"1000300291","type":"misc","id":"30512987"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115719","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31275462","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85068089055&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=352146","label":"url"}],"paper_title":{"en":"PEGylated liposomes: immunological responses","ja":"PEGylated liposomes: immunological responses"},"authors":{"en":[{"name":"Mohamed M"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Shimizu Taro"},{"name":"Alaaeldin E"},{"name":"Hussein A"},{"name":"Sarhan H"},{"name":"Szebeni J"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Mohamed M"},{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"清水 太郎"},{"name":"Alaaeldin E"},{"name":"Hussein A"},{"name":"Sarhan H"},{"name":"Szebeni J"},{"name":"石田 竜弘"}]},"description":{"en":"A commonly held view is that nanocarriers conjugated to polyethylene glycol (PEG) are non-immunogenic. However, many studies have reported that unexpected immune responses have occurred against PEG-conjugated nanocarriers. One unanticipated response is the rapid clearance of PEGylated nanocarriers upon repeat administration, called the accelerated blood clearance (ABC) phenomenon. ABC involves the production of antibodies toward nanocarrier components, including PEG, which reduces the safety and effectiveness of encapsulated therapeutic agents. Another immune response is the hypersensitivity or infusion reaction referred to as complement (C) activation-related pseudoallergy (CARPA). Such immunogenicity and adverse reactivities of PEGylated nanocarriers may be of potential concern for the clinical use of PEGylated therapeutics. Accordingly, screening of the immunogenicity and CARPA reactogenicity of nanocarrier-based therapeutics should be a prerequisite before they can proceed into clinical studies. This review presents PEGylated liposomes, immunogenicity of PEG, the ABC phenomenon, C activation and lipid-induced CARPA from a toxicological point of view, and also addresses the factors that influence these adverse interactions with the immune system.","ja":"A commonly held view is that nanocarriers conjugated to polyethylene glycol (PEG) are non-immunogenic. However, many studies have reported that unexpected immune responses have occurred against PEG-conjugated nanocarriers. One unanticipated response is the rapid clearance of PEGylated nanocarriers upon repeat administration, called the accelerated blood clearance (ABC) phenomenon. ABC involves the production of antibodies toward nanocarrier components, including PEG, which reduces the safety and effectiveness of encapsulated therapeutic agents. Another immune response is the hypersensitivity or infusion reaction referred to as complement (C) activation-related pseudoallergy (CARPA). Such immunogenicity and adverse reactivities of PEGylated nanocarriers may be of potential concern for the clinical use of PEGylated therapeutics. Accordingly, screening of the immunogenicity and CARPA reactogenicity of nanocarrier-based therapeutics should be a prerequisite before they can proceed into clinical studies. This review presents PEGylated liposomes, immunogenicity of PEG, the ABC phenomenon, C activation and lipid-induced CARPA from a toxicological point of view, and also addresses the factors that influence these adverse interactions with the immune system."},"publication_date":"2019-06-26","publication_name":{"en":"Science and Technology of Advanced Materials","ja":"Science and Technology of Advanced Materials"},"volume":"Vol.20","number":"No.1","starting_page":"710","ending_page":"724","languages":["eng"],"identifiers":{"doi":["10.1080/14686996.2019.1627174"],"issn":["1468-6996"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:18, {"insert":{"user_id":"1000300291","type":"misc","id":"30512988"},"force":{"see_also":[{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85059276671&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=349465","label":"url"}],"paper_title":{"en":"生体内動態の理解を基盤としたリポソームDDSの開発∼臨床応用を目指して∼ 第11回日本DDS学会水島賞によせて","ja":"生体内動態の理解を基盤としたリポソームDDSの開発∼臨床応用を目指して∼ 第11回日本DDS学会水島賞によせて"},"authors":{"en":[{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"石田 竜弘"}]},"publication_date":"2018-09-25","publication_name":{"en":"Drug Delivery System","ja":"Drug Delivery System"},"volume":"Vol.33","number":"No.4","starting_page":"318","ending_page":"328","languages":["jpn"],"identifiers":{"doi":["10.2745/dds.33.318"],"issn":["0913-5006"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:19, {"insert":{"user_id":"1000300291","type":"misc","id":"30512989"},"force":{"see_also":[{"@id":"http://id.ndl.go.jp/bib/028929708","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390282763015033344/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=337619","label":"url"}],"paper_title":{"en":"Control of EPR effect by tumor-targeted NO donor via endogenous albumin transport system","ja":"内因性アルブミン輸送システムを利用した腫瘍選択的NO供与によるEPR効果の制御"},"authors":{"en":[{"name":"Ishima Yu"},{"name":"丸山 徹"},{"name":"Ishida Tatsuhiro"},{"name":"小田切 優樹"}],"ja":[{"name":"異島 優"},{"name":"丸山 徹"},{"name":"石田 竜弘"},{"name":"小田切 優樹"}]},"description":{"en":"A unique phenomenon in solid tumors, enhanced permeability and retention(EPR) effect, is very famous for the development of macromolecular anticancer therapy. However, cancers with low vascular permeability posed a challenge for these EPR based therapeutic systems. An intrinsic vascular modulator such as nitric oxide(NO) could augment the intrinsic EPR effect. We have demonstrated that S-nitrosated human serum albumin dimer(SNO-HSA Dimer) becomes an enhancer of the EPR effect in various tumor-bearing mice models. Here, we summarized the enhanced effect of SNO-HSA Dimer on the anticancer effect of two types of macromolecular anticancer drugs, namely PEGylated liposomal doxorubicin(Doxil<sup>®</sup>) and albumin bound paclitaxel nanoparticle(Abraxane<sup>®</sup>). In C26-bearing mice with highly permeable vasculature, SNO-HSA Dimer could increase tumor accumulation of these anticancer drugs and thereby their anticancer effects. Interestingly, the tumor accumulation of Doxil<sup>®</sup> in B16-bearing mice, which are characterized by a low permeable vasculature, increased more 6-fold in the presence of SNO-HSA Dimer, and the improved accumulation of Doxil<sup>®</sup> led to increased survival and decreased tumor volume. On the other hand, SNO-HSA Dimer also augmented the tumor growth inhibition of Abraxane<sup>®</sup> in low vascular permeability B16-bearing mice. Furthermore, Abraxane<sup>®</sup> combined with SNO-HSA Dimer showed higher antitumor activity and improved survival rate of SUIT2 human pancreatic cancer orthotopic model. We also showed that the administration of SNO-HSA Dimer had no effect on blood pressure, heart rate and biochemical parameters, suggesting that SNO-HSA Dimer alone is very safe. Accordingly, we conclude that SNO-HSA Dimer is promising for regulating the EPR effect and enhanced therapeutic effects of many macromolecular anticancer drugs.","ja":"EPR効果は，高分子抗がん療法の開発の基礎となり得るが，低い血管透過性を有するがん領域では，このEPR効果のみでは十分な送達性が得られない．したがって，一酸化窒素(NO)のような血管調節分子で内因性EPR効果を増強することは極めて有望な戦略である．筆者らは，ヒト血清アルブミン二量体の<i>S</i>―ニトロソ化体(SNO―HSA Dimer)がEPR効果の増強剤であることを検討してきた．ここでは，すでに承認されたPEG化リポソーム・ドキソルビシン(Doxil®)およびアルブミン結合型パクリタキセル・ナノ粒子(Abraxane<sup>®</sup>)の2種類の高分子抗がん剤を用い，血管透過性が高いC26や血管透過性が低いB16担がんモデル，臨床病態に近いとされているSUIT2ヒト膵臓がん同所性モデルにて得られた結果を中心に報告する．"},"publication_date":"2018-03-25","publication_name":{"en":"Drug Delivery System","ja":"Drug Delivery System"},"volume":"Vol.33","number":"No.2","starting_page":"130","ending_page":"138","languages":["jpn"],"identifiers":{"doi":["10.2745/dds.33.130"],"issn":["0913-5006"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:20, {"insert":{"user_id":"1000300291","type":"misc","id":"30512990"},"force":{"see_also":[{"@id":"https://cir.nii.ac.jp/crid/1390001204641700864/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=335199","label":"url"}],"paper_title":{"en":"Accelerated blood clearance (ABC) 現象における動物種差","ja":"Accelerated blood clearance (ABC) 現象における動物種差"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"publication_date":"2017-11","publication_name":{"en":"Drug Delivery System","ja":"Drug Delivery System"},"volume":"Vol.32","number":"No.5","starting_page":"396","ending_page":"401","languages":["jpn"],"identifiers":{"doi":["10.2745/dds.32.396"],"issn":["1881-2732"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:21, {"insert":{"user_id":"1000300291","type":"misc","id":"30512991"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27838415","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85006801883&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=321161","label":"url"}],"paper_title":{"en":"Metronomic chemotherapy and nanocarrier platforms","ja":"Metronomic chemotherapy and nanocarrier platforms"},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"石田 竜弘"}]},"description":{"en":"The therapeutic concept of administering chemotherapeutic agents continuously at lower doses, relative to the maximum tolerated dose (MTD) without drug-free breaks over extended periods -known as \"metronomic chemotherapy\"- is a promising approach for anti-angiogenic cancer therapy. In comparison with MTD chemotherapy regimens, metronomic chemotherapy has demonstrated reduced toxicity. However, as a monotherapy, metronomic chemotherapy has failed to provide convincing results in clinical trials. Therapeutic approaches including combining the anti-angiogenic \"metronomic\" therapy with conventional radio-/chemo-therapy and/or targeted delivery of chemotherapeutic agents to tumor tissues via their encapsulation with nanocarrier-based platforms have proven to potentiate the overall therapeutic outcomes. In this review, therefore, we focused on the mutual contribution made by nanoscale drug delivery platforms to the therapeutic efficacy of metronomic-based chemotherapy. In addition, the influence that the dosing schedule has on the overall therapeutic efficacy of metronomic chemotherapy is discussed.","ja":"The therapeutic concept of administering chemotherapeutic agents continuously at lower doses, relative to the maximum tolerated dose (MTD) without drug-free breaks over extended periods -known as \"metronomic chemotherapy\"- is a promising approach for anti-angiogenic cancer therapy. In comparison with MTD chemotherapy regimens, metronomic chemotherapy has demonstrated reduced toxicity. However, as a monotherapy, metronomic chemotherapy has failed to provide convincing results in clinical trials. Therapeutic approaches including combining the anti-angiogenic \"metronomic\" therapy with conventional radio-/chemo-therapy and/or targeted delivery of chemotherapeutic agents to tumor tissues via their encapsulation with nanocarrier-based platforms have proven to potentiate the overall therapeutic outcomes. In this review, therefore, we focused on the mutual contribution made by nanoscale drug delivery platforms to the therapeutic efficacy of metronomic-based chemotherapy. In addition, the influence that the dosing schedule has on the overall therapeutic efficacy of metronomic chemotherapy is discussed."},"publication_date":"2017-08-01","publication_name":{"en":"Cancer Letters","ja":"Cancer Letters"},"volume":"Vol.400","starting_page":"232","ending_page":"242","languages":["eng"],"identifiers":{"doi":["10.1016/j.canlet.2016.11.007"],"issn":["0304-3835"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:22, {"insert":{"user_id":"1000300291","type":"misc","id":"30512992"},"force":{"see_also":[{"@id":"https://cir.nii.ac.jp/crid/1390282679617948032/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=328447","label":"url"}],"paper_title":{"en":"ナノ粒子に対する補体活性化の功罪","ja":"ナノ粒子に対する補体活性化の功罪"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Ishima Yu"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"異島 優"},{"name":"石田 竜弘"}]},"publication_date":"2017-08","publication_name":{"en":"Drug Delivery System","ja":"Drug Delivery System"},"volume":"Vol.32","number":"No.3","starting_page":"199","ending_page":"207","languages":["jpn"],"identifiers":{"doi":["10.2745/dds.32.199"],"issn":["1881-2732"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:23, {"insert":{"user_id":"1000300291","type":"misc","id":"30512993"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28049940","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=320422","label":"url"}],"paper_title":{"en":"Liposomal delivery systems: design optimization and current applications","ja":"Liposomal delivery systems: design optimization and current applications"},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Kiwada Hiroshi"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"際田 弘志"},{"name":"石田 竜弘"}]},"description":{"en":"The liposome, a closed phospholipid bilayered vesicular system, has received considerable attention as a pharmaceutical carrier of great potential over the past 30 years. The ability of liposomes to encapsulate both hydrophilic and hydrophobic drugs, coupled with their biocompatibility and biodegradability, make liposomes attractive vehicles in the field of drug delivery. In addition, great technical advances such as remote drug loading, triggered release liposomes, ligand-targeted liposomes, liposomes containing combinations of drugs, and so on, have led to the widespread use of liposomes in diverse areas as delivery vehicles for anti-cancer, bio-active molecules, diagnostics, and therapeutic agents. In this review, we summarize design optimization of liposomal systems and invaluable applications of liposomes as effective delivery systems.","ja":"The liposome, a closed phospholipid bilayered vesicular system, has received considerable attention as a pharmaceutical carrier of great potential over the past 30 years. The ability of liposomes to encapsulate both hydrophilic and hydrophobic drugs, coupled with their biocompatibility and biodegradability, make liposomes attractive vehicles in the field of drug delivery. In addition, great technical advances such as remote drug loading, triggered release liposomes, ligand-targeted liposomes, liposomes containing combinations of drugs, and so on, have led to the widespread use of liposomes in diverse areas as delivery vehicles for anti-cancer, bio-active molecules, diagnostics, and therapeutic agents. In this review, we summarize design optimization of liposomal systems and invaluable applications of liposomes as effective delivery systems."},"publication_date":"2017-01-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.40","number":"No.1","starting_page":"1","ending_page":"10","languages":["eng"],"identifiers":{"doi":["10.1248/bpb.b16-00624"],"issn":["1347-5215"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:24, {"insert":{"user_id":"1000300291","type":"misc","id":"30512994"},"force":{"see_also":[{"@id":"http://ci.nii.ac.jp/naid/40020967242/","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390001204640457984/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=320649","label":"url"}],"paper_title":{"en":"Characteristics, evaluation and suppression of anti-poly(ethylene glycol) antibody","ja":"Poly(ethylene glycol)に対する抗体の特性，評価，抑制"},"authors":{"en":[{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"清水 太郎"},{"name":"石田 竜弘"}]},"description":{"en":"Modification with PEG(poly(ethylene glycol)), so-called PEGylation, is a golden standard to increase stability of biological medicine. However, PEGylated materials cause anti-PEG antibody after first injection. Then, the anti-PEG antibody induce the accelerated blood clearance(ABC) phenomenon of subsequent dose of PEGylated materials. So far, it has been reported that anti-PEG antibody production occurs not only in experimental animals, but also in human. In addition, characteristics of anti-PEG antibody induced by one PEGylated material differ from that of anti-PEG antibody induced by other PEGylated materials. In order to preserve the merit of PEGylation technology, it is important to understand the correct characteristics of anti-PEG immune response and develop strategy for escaping the immune response. In this review, we show the characteristics, evaluation and suppression of anti-PEG antibody.","ja":"PEG(poly(ethylene glycol))修飾は，バイオ医薬品の生体内安定性を向上させる最も標準的な方法である．しかし，PEG修飾体投与後にPEGに特異的な抗体(抗PEG抗体)が誘導され，繰り返し投与時のPEG修飾体の血中滞留性を著しく低下させることが明らかになっている．これまでに，実験動物だけでなく，ヒトにおいても抗PEG抗体の誘導が確認されている．また，さまざまなPEG修飾体投与によって，さまざまな特性を持った抗PEG抗体が誘導されることも明らかになっている．PEG修飾技術による治療効果の向上を損なわないためにも，抗PEG免疫応答の正しい理解と抑制法の開発は非常に重要である．本稿では，抗PEG抗体の特性・評価・抑制法について概説する．"},"publication_date":"2016-06","publication_name":{"en":"Drug Delivery System","ja":"Drug Delivery System"},"volume":"Vol.31","number":"No.4","starting_page":"300","ending_page":"307","languages":["jpn"],"identifiers":{"doi":["10.2745/dds.31.300"],"issn":["0913-5006"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:25, {"insert":{"user_id":"1000300291","type":"misc","id":"30512995"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=305445","label":"url"}],"paper_title":{"en":"PEGに対する免疫反応∼PEG修飾製剤の安全性に関する研究∼","ja":"PEGに対する免疫反応∼PEG修飾製剤の安全性に関する研究∼"},"authors":{"en":[{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"石田 竜弘"}]},"publication_date":"2015-12","publication_name":{"en":"製剤機械技術学会誌","ja":"製剤機械技術学会誌"},"volume":"Vol.24","number":"No.5","starting_page":"78","ending_page":"83","languages":["jpn"],"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:26, {"insert":{"user_id":"1000300291","type":"misc","id":"30512996"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=304399","label":"url"}],"paper_title":{"en":"Pharmaceutics of Nanoparticles","ja":"Pharmaceutics of Nanoparticles"},"authors":{"en":[{"name":"Ukawa Masami"},{"name":"ANDO Hidenori"},{"name":"Shimizu Taro"},{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"鵜川 真実"},{"name":"安藤 英紀"},{"name":"清水 太郎"},{"name":"石田 竜弘"}]},"publication_date":"2015-11-14","publication_name":{"en":"Nanomaterials in Pharmacology","ja":"Nanomaterials in Pharmacology"},"starting_page":"219","ending_page":"238","languages":["eng"],"identifiers":{"doi":["10.1007/978-1-4939-3121-7_11"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:27, {"insert":{"user_id":"1000300291","type":"misc","id":"30512997"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24492717","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390282679609960064/","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84893510536&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=272248","label":"url"}],"paper_title":{"en":"Selective delivery of oxaliplatin to tumor tissue by nanocarrier system enhances overall therapeutic efficacy of the encapsulated oxaliplatin","ja":"Selective delivery of oxaliplatin to tumor tissue by nanocarrier system enhances overall therapeutic efficacy of the encapsulated oxaliplatin"},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatinum; l-OHP), a third-generation platinum antitumor drug, is currently approved in combination with 5-flurouracil (5-FU)/leucovorin (FOLFOX) for standard first- and second-line treatment of metastatic or advanced-stage colorectal cancer. Despite l-OHP's better tolerability in comparison with other platinum compounds such as cisplatin and carboplatin, its clinical efficiency is limited by the dose-limiting side effects including cumulative neurotoxicity and acute dysesthesias. In addition, like other platinum chemotherapeutic agents, l-OHP therapy is limited by reduced accumulation levels in tumor tissues, nonselective accumulation in healthy organs and/or tissues, inactivation by conjugation with glutathione, and the development of drug resistance. Accordingly, successful outcome of cancer treatment using l-OHP requires selective delivery of a relatively high concentration of the drug to tumor tissues. In this review we focus on utilization of different drug-delivery vehicles such as liposomes, polymeric nanocarriers, and carbon nanotubes in enhancing selective delivery of l-OHP to tumor tissues and consequently improving overall efficacy of l-OHP-containing drug-delivery systems.","ja":"Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatinum; l-OHP), a third-generation platinum antitumor drug, is currently approved in combination with 5-flurouracil (5-FU)/leucovorin (FOLFOX) for standard first- and second-line treatment of metastatic or advanced-stage colorectal cancer. Despite l-OHP's better tolerability in comparison with other platinum compounds such as cisplatin and carboplatin, its clinical efficiency is limited by the dose-limiting side effects including cumulative neurotoxicity and acute dysesthesias. In addition, like other platinum chemotherapeutic agents, l-OHP therapy is limited by reduced accumulation levels in tumor tissues, nonselective accumulation in healthy organs and/or tissues, inactivation by conjugation with glutathione, and the development of drug resistance. Accordingly, successful outcome of cancer treatment using l-OHP requires selective delivery of a relatively high concentration of the drug to tumor tissues. In this review we focus on utilization of different drug-delivery vehicles such as liposomes, polymeric nanocarriers, and carbon nanotubes in enhancing selective delivery of l-OHP to tumor tissues and consequently improving overall efficacy of l-OHP-containing drug-delivery systems."},"publication_date":"2014-02-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.37","number":"No.2","starting_page":"206","ending_page":"211","languages":["eng"],"identifiers":{"doi":["10.1248/bpb.b13-00540"],"issn":["1347-5215"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:28, {"insert":{"user_id":"1000300291","type":"misc","id":"30512998"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23933235","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=265735","label":"url"}],"paper_title":{"en":"The accelerated blood clearance (ABC) phenomenon: Clinical challenge and approaches to manage","ja":"The accelerated blood clearance (ABC) phenomenon: Clinical challenge and approaches to manage"},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Despite the clinical introduction of an increasing number of polyethylene glycol (PEG)-conjugated substances, PEG has been named as the cause of an unexpected immunogenic response known as the \"accelerated blood clearance (ABC) phenomenon.\" This phenomenon has been extensively observed during the repeated administration of PEG-conjugated substances and PEGylated nanocarriers including PEGylated liposomes, PEGylated nanoparticles, PEGylated micelles, etc., resulting in the increased clearance and reduced efficacy of PEG-conjugated substances/PEGylated nanocarriers. In this review, therefore, we focused on the possible mechanisms underlying the induction of such a phenomenon and emphasized the factors affecting its magnitude. In addition, the clinical implications of the ABC phenomenon on the therapeutic efficacy of PEG-conjugated substances/PEGylated nanocarriers, along with the new approaches that can be applied to manage and/or abrogate the induction of the ABC phenomenon, are also discussed.","ja":"Despite the clinical introduction of an increasing number of polyethylene glycol (PEG)-conjugated substances, PEG has been named as the cause of an unexpected immunogenic response known as the \"accelerated blood clearance (ABC) phenomenon.\" This phenomenon has been extensively observed during the repeated administration of PEG-conjugated substances and PEGylated nanocarriers including PEGylated liposomes, PEGylated nanoparticles, PEGylated micelles, etc., resulting in the increased clearance and reduced efficacy of PEG-conjugated substances/PEGylated nanocarriers. In this review, therefore, we focused on the possible mechanisms underlying the induction of such a phenomenon and emphasized the factors affecting its magnitude. In addition, the clinical implications of the ABC phenomenon on the therapeutic efficacy of PEG-conjugated substances/PEGylated nanocarriers, along with the new approaches that can be applied to manage and/or abrogate the induction of the ABC phenomenon, are also discussed."},"publication_date":"2013-08-07","publication_name":{"en":"Journal of Controlled Release","ja":"Journal of Controlled Release"},"volume":"Vol.172","number":"No.1","starting_page":"38","ending_page":"47","languages":["eng"],"identifiers":{"doi":["10.1016/j.jconrel.2013.07.026"],"issn":["1873-4995"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:29, {"insert":{"user_id":"1000300291","type":"misc","id":"30512999"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23727911","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=259996","label":"url"}],"paper_title":{"en":"Anti-polyethyleneglycol (PEG) antibody response to PEGylated substances.","ja":"Anti-polyethyleneglycol (PEG) antibody response to PEGylated substances."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance.","ja":"In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance."},"publication_date":"2013-06-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.36","number":"No.6","starting_page":"889","ending_page":"891","languages":["eng"],"identifiers":{"doi":["10.1248/bpb.b13-00107"],"issn":["1347-5215"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:30, {"insert":{"user_id":"1000300291","type":"misc","id":"30513000"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=263270","label":"url"}],"paper_title":{"en":"PEG修飾製剤による抗PEG抗体分泌誘導","ja":"PEG修飾製剤による抗PEG抗体分泌誘導"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"publication_date":"2013-06","publication_name":{"en":"ファルマシア:最前線","ja":"ファルマシア:最前線"},"volume":"Vol.49","number":"No.6","starting_page":"503","ending_page":"507","languages":["jpn"],"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:31, {"insert":{"user_id":"1000300291","type":"misc","id":"30513001"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23649327","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=260619","label":"url"}],"paper_title":{"en":"Alteration of tumor microenvironment for improved delivery and intratumor distribution of nanocarriers.","ja":"Alteration of tumor microenvironment for improved delivery and intratumor distribution of nanocarriers."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Nanocarrier-based cancer chemotherapeutics are thought to increase therapeutic efficiency and reduce the side effects of associated chemotherapeutic agents by altering the agents' pharmacokinetics and tissue distribution following intravenous administration. In spite of these favorable properties, nanocarrier-based cancer chemotherapeutics are not always effective because of their heterogeneous intratumoral localization. Homogeneous distribution of nanocarriers in a tumor would improve the efficacy of nanocarrier-based cancer chemotherapeutics. In this article, we describe and discuss some trials that attempt to manipulate the barriers in the tumor microenvironment that hinder extravasation through the tumor vasculature and penetration of nanocarriers in solid tumors. Alterations of the tumor microenvironment that relate directly to the intratumoral distribution of nanocarriers may be potential strategies to improve the delivery of nanocarrier-based cancer chemotherapeutics.","ja":"Nanocarrier-based cancer chemotherapeutics are thought to increase therapeutic efficiency and reduce the side effects of associated chemotherapeutic agents by altering the agents' pharmacokinetics and tissue distribution following intravenous administration. In spite of these favorable properties, nanocarrier-based cancer chemotherapeutics are not always effective because of their heterogeneous intratumoral localization. Homogeneous distribution of nanocarriers in a tumor would improve the efficacy of nanocarrier-based cancer chemotherapeutics. In this article, we describe and discuss some trials that attempt to manipulate the barriers in the tumor microenvironment that hinder extravasation through the tumor vasculature and penetration of nanocarriers in solid tumors. Alterations of the tumor microenvironment that relate directly to the intratumoral distribution of nanocarriers may be potential strategies to improve the delivery of nanocarrier-based cancer chemotherapeutics."},"publication_date":"2013-05-01","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.36","number":"No.5","starting_page":"692","ending_page":"697","languages":["eng"],"identifiers":{"doi":["10.1248/bpb.b13-00121"],"issn":["1347-5215"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:32, {"insert":{"user_id":"1000300291","type":"misc","id":"30513002"},"force":{"see_also":[{"@id":"http://ci.nii.ac.jp/naid/10029888432/","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390845713054819072/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=242758","label":"url"}],"paper_title":{"en":"リポソームDDSの開発研究∼トランスレーショナルリサーチの実現を目指して∼","ja":"リポソームDDSの開発研究∼トランスレーショナルリサーチの実現を目指して∼"},"authors":{"en":[{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"石田 竜弘"}]},"publication_date":"2011-11-01","publication_name":{"en":"Journal of Pharmaceutical Science and Technology, Japan","ja":"薬剤学"},"volume":"Vol.71","starting_page":"315","ending_page":"320","languages":["jpn"],"identifiers":{"issn":["0372-7629"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:33, {"insert":{"user_id":"1000300291","type":"misc","id":"30513003"},"force":{"see_also":[{"@id":"http://ci.nii.ac.jp/naid/40020187439/","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1520290884281863808/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=223983","label":"url"}],"paper_title":{"en":"PEG修飾リポソーム製剤繰り返し投与による血中滞留性低下","ja":"PEG修飾リポソーム製剤繰り返し投与による血中滞留性低下"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"publication_date":"2011","publication_name":{"en":"C&I Commun.","ja":"C&I Commun."},"volume":"Vol.36","starting_page":"19","ending_page":"21","languages":["jpn"],"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:34, {"insert":{"user_id":"1000300291","type":"misc","id":"30513004"},"force":{"see_also":[{"@id":"http://ci.nii.ac.jp/naid/10026692951/","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1520290883385786880/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=214770","label":"url"}],"paper_title":{"en":"Development of efficient and safe drug delivery system with liposomes : the 2nd Encouragement Award in the 26th Annual Meeting of the Japan Society of Drug Delivery System","ja":"生体内動態検討を基盤としたリポソームDDSの開発∼第2回日本DDS学会奨励賞(臨床)受賞によせて∼"},"authors":{"en":[{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"石田 竜弘"}]},"publication_date":"2010-10-06","publication_name":{"en":"Drug Delivery System","ja":"Drug Delivery System"},"volume":"Vol.25","number":"No.5","starting_page":"511","ending_page":"516","languages":["jpn"],"identifiers":{"issn":["0913-5006"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:35, {"insert":{"user_id":"1000300291","type":"misc","id":"30513005"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/20333455","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=206590","label":"url"}],"paper_title":{"en":"Targeting anticancer drugs to tumor vasculature using cationic liposomes.","ja":"Targeting anticancer drugs to tumor vasculature using cationic liposomes."},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Liposomal drug delivery systems improve the therapeutic index of chemotherapeutic agents, and the use of cationic liposomes to deliver anticancer drugs to solid tumors has recently been recognized as a promising therapeutic strategy to improve the effectiveness of conventional chemotherapeutics. This review summarizes the selective targeting of cationic liposomes to tumor vasculature, the merits of incorporating the polymer polyethylene-glycol (PEG), and the impact of the molar percent of the cationic lipid included in cationic liposomes on liposomal targeting efficacy. In addition, the discussion herein includes the therapeutic benefit of a dual targeting approach, using PEG-coated cationic liposomes in vascular targeting (of tumor endothelial cells), and tumor targeting (of tumor cells) of anticancer drugs. Cationic liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development.","ja":"Liposomal drug delivery systems improve the therapeutic index of chemotherapeutic agents, and the use of cationic liposomes to deliver anticancer drugs to solid tumors has recently been recognized as a promising therapeutic strategy to improve the effectiveness of conventional chemotherapeutics. This review summarizes the selective targeting of cationic liposomes to tumor vasculature, the merits of incorporating the polymer polyethylene-glycol (PEG), and the impact of the molar percent of the cationic lipid included in cationic liposomes on liposomal targeting efficacy. In addition, the discussion herein includes the therapeutic benefit of a dual targeting approach, using PEG-coated cationic liposomes in vascular targeting (of tumor endothelial cells), and tumor targeting (of tumor cells) of anticancer drugs. Cationic liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development."},"publication_date":"2010-03-24","publication_name":{"en":"Pharmaceutical Research","ja":"Pharmaceutical Research"},"volume":"Vol.27","number":"No.7","starting_page":"1171","ending_page":"1183","languages":["eng"],"identifiers":{"doi":["10.1007/s11095-010-0110-1"],"issn":["1573-904X"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:36, {"insert":{"user_id":"1000300291","type":"misc","id":"30513006"},"force":{"see_also":[{"@id":"http://ci.nii.ac.jp/naid/130000136135/","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390001206128807680/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=204370","label":"url"}],"paper_title":{"en":"Elucidation of Accelerated Blood Clearance Phenomenon Caused by Repeat Injection of PEGylated Nanocarriers","ja":"PEG化キャリア頻回投与によるaccelerated blood clearance現象の機構解明"},"authors":{"en":[{"name":"小出 裕之"},{"name":"浅井 知浩"},{"name":"畑中 剣太朗"},{"name":"清水 広介"},{"name":"横山 昌幸"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"},{"name":"奥 直人"}],"ja":[{"name":"小出 裕之"},{"name":"浅井 知浩"},{"name":"畑中 剣太朗"},{"name":"清水 広介"},{"name":"横山 昌幸"},{"name":"石田 竜弘"},{"name":"際田 弘志"},{"name":"奥 直人"}]},"description":{"en":"Liposomes modified with polyethylene glycol (PEG) can stably exist in the bloodstream because the PEG on the liposomes attracts a water shell to the liposomal surface. Since these liposomes are long circulating nanocarriers, they are used as drug and gene delivery tools. Repeat injection of PEGylated liposomes, however, is known to induce the accelerated blood clearance (ABC) phenomenon. In the ABC phenomenon, PEGylated liposomes that are injected subsequent to the first injection are cleared rapidly from the bloodstream and accumulate in the liver, resulting in loss of their long-circulating characteristics. The induction of ABC phenomenon is related to the production of anti-PEG IgM from splenic B cells. To elucidate the mechanism of the phenomenon, we firstly examined the relationship between the induction of ABC phenomenon and the concentration of PEGylated liposomes, and observed that the high dose of those did not induce the phenomenon. Next, we investigated whether polymeric micelles trigger ABC phenomenon or not. Finally, the size-dependency of ABC phenomenon was investigated by use of variously sized PEGylated liposomes and polymeric micelles having PEG chains. Our data suggest that the initiation of ABC phenomenon would be size-dependent, and particles smaller than 30 nm did not induce ABC phenomenon. We anticipate that the elucidation of the ABC phenomenon will be helpful for the development of DDS formulations.","ja":"Liposomes modified with polyethylene glycol (PEG) can stably exist in the bloodstream because the PEG on the liposomes attracts a water shell to the liposomal surface. Since these liposomes are long circulating nanocarriers, they are used as drug and gene delivery tools. Repeat injection of PEGylated liposomes, however, is known to induce the accelerated blood clearance (ABC) phenomenon. In the ABC phenomenon, PEGylated liposomes that are injected subsequent to the first injection are cleared rapidly from the bloodstream and accumulate in the liver, resulting in loss of their long-circulating characteristics. The induction of ABC phenomenon is related to the production of anti-PEG IgM from splenic B cells. To elucidate the mechanism of the phenomenon, we firstly examined the relationship between the induction of ABC phenomenon and the concentration of PEGylated liposomes, and observed that the high dose of those did not induce the phenomenon. Next, we investigated whether polymeric micelles trigger ABC phenomenon or not. Finally, the size-dependency of ABC phenomenon was investigated by use of variously sized PEGylated liposomes and polymeric micelles having PEG chains. Our data suggest that the initiation of ABC phenomenon would be size-dependent, and particles smaller than 30 nm did not induce ABC phenomenon. We anticipate that the elucidation of the ABC phenomenon will be helpful for the development of DDS formulations."},"publication_date":"2009-12-01","publication_name":{"en":"Journal of the Pharmaceutical Society of Japan","ja":"薬学雑誌"},"volume":"Vol.129","number":"No.12","starting_page":"1445","ending_page":"1451","languages":["jpn"],"identifiers":{"doi":["10.1248/yakushi.129.1445"],"issn":["0031-6903"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:37, {"insert":{"user_id":"1000300291","type":"misc","id":"30513007"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19780711","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=204377","label":"url"}],"paper_title":{"en":"Recent advances in tumor vasculature targeting using liposomal drug delivery systems.","ja":"Recent advances in tumor vasculature targeting using liposomal drug delivery systems."},"authors":{"en":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"Amr Selim Ahmed Ali Abu Lila"},{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"Tumor vessels possess unique physiological features that might be exploited for improved drug delivery. The targeting of liposomal anticancer drugs to tumor vasculature is increasingly recognized as an effective strategy to obtain superior therapeutic efficacy with limited host toxicity compared with conventional treatments. This review introduces recent advances in the field of liposomal targeting of tumor vasculature, along with new approaches that can be used in the design and optimization of liposomal delivery systems. In addition, cationic liposome is focused on as a promising carrier for achieving efficient vascular targeting. The clinical implications are discussed of several approaches using a single liposomal anticancer drug formulation: dual targeting, vascular targeting (targeting tumor endothelial cells) and tumor targeting (targeting tumor cells).","ja":"Tumor vessels possess unique physiological features that might be exploited for improved drug delivery. The targeting of liposomal anticancer drugs to tumor vasculature is increasingly recognized as an effective strategy to obtain superior therapeutic efficacy with limited host toxicity compared with conventional treatments. This review introduces recent advances in the field of liposomal targeting of tumor vasculature, along with new approaches that can be used in the design and optimization of liposomal delivery systems. In addition, cationic liposome is focused on as a promising carrier for achieving efficient vascular targeting. The clinical implications are discussed of several approaches using a single liposomal anticancer drug formulation: dual targeting, vascular targeting (targeting tumor endothelial cells) and tumor targeting (targeting tumor cells)."},"publication_date":"2009-12","publication_name":{"en":"Expert Opinion on Drug Delivery","ja":"Expert Opinion on Drug Delivery"},"volume":"Vol.6","number":"No.12","starting_page":"1297","ending_page":"1309","languages":["eng"],"identifiers":{"doi":["10.1517/17425240903289928"],"issn":["1744-7593"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:38, {"insert":{"user_id":"1000300291","type":"misc","id":"30513008"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=190456","label":"url"}],"paper_title":{"en":"siRNA を利用したArgonaute2 遺伝子knockdown によるがん治療法の開発","ja":"siRNA を利用したArgonaute2 遺伝子knockdown によるがん治療法の開発"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Tagami Tatsuaki"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"田上 辰秋"},{"name":"際田 弘志"}]},"publication_date":"2009-04-15","publication_name":{"en":"和光純薬時報","ja":"和光純薬時報"},"volume":"Vol.77","number":"No.2","starting_page":"8","ending_page":"11","languages":["jpn"],"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:39, {"insert":{"user_id":"1000300291","type":"misc","id":"30513009"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/18083313","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180294","label":"url"}],"paper_title":{"en":"Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes.","ja":"Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"We and a Dutch group reported that \"empty\" PEGylated liposomes (approximately 100 nm) lose their long-circulating characteristic when they are administrated twice in the same animal with certain intervals (referred to as the accelerated blood clearance (ABC) phenomenon). Very recently, we showed that anti-PEG IgM, induced by the first dose of \"empty\" PEGylated liposomes, is responsible for inducing the phenomenon, based on the observation that IgM thus produced selectively binds to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no or lower immunogenicity. However, the results indicated evidence that unexpected immune responses occur even to such polymer-coated liposomes. Such immunogenicity of \"empty\" liposomes presents a serious concern in the development of liposomal formulations and their use in the clinic. In addition, through series of our studies, it was demonstrated that the magnitude of the ABC phenomenon depends on the physicochemical property of injected liposomes as a first dose, time interval between injection, lipid dose and drug-encapsulation.","ja":"We and a Dutch group reported that \"empty\" PEGylated liposomes (approximately 100 nm) lose their long-circulating characteristic when they are administrated twice in the same animal with certain intervals (referred to as the accelerated blood clearance (ABC) phenomenon). Very recently, we showed that anti-PEG IgM, induced by the first dose of \"empty\" PEGylated liposomes, is responsible for inducing the phenomenon, based on the observation that IgM thus produced selectively binds to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no or lower immunogenicity. However, the results indicated evidence that unexpected immune responses occur even to such polymer-coated liposomes. Such immunogenicity of \"empty\" liposomes presents a serious concern in the development of liposomal formulations and their use in the clinic. In addition, through series of our studies, it was demonstrated that the magnitude of the ABC phenomenon depends on the physicochemical property of injected liposomes as a first dose, time interval between injection, lipid dose and drug-encapsulation."},"publication_date":"2008-04-16","publication_name":{"en":"International Journal of Pharmaceutics","ja":"International Journal of Pharmaceutics"},"volume":"Vol.354","number":"No.1-2","starting_page":"56","ending_page":"62","languages":["eng"],"identifiers":{"doi":["10.1016/j.ijpharm.2007.11.005"],"issn":["0378-5173"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:40, {"insert":{"user_id":"1000300291","type":"misc","id":"30513010"},"force":{"see_also":[{"@id":"http://ci.nii.ac.jp/naid/110006572176/","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390001206127402624/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=180301","label":"url"}],"paper_title":{"en":"Accelerated Blood Clearance (ABC) Phenomenon Induced by Administration of PEGylated Liposome(Symposium Reviews)","ja":"ポリエチレングリコール修飾リポソーム投与時に生ずるaccelerated blood clearance (ABC)現象"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"PEGylated liposomes (approximately 100nm in diameter) lose their long-circulating characteristic upon repeated injection at certain intervals in the same animal (referred to as the \"accelerated blood clearance (ABC) phenomenon\"), as described by our group and by researchers in the Netherlands. Recently, it was demonstrated by our group that anti-PEG IgM, induced by the first dose of PEGylated liposomes, is responsible for the ABC phenomenon. The IgM produced in this manner then selectively bound to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no immunogenicity. However, unexpected immune responses occurred even in response to polymer-coated liposomes. This immunogenicity to PEGylated liposomes presents a serious concern in the development and clinical use of liposomal formulations. In this review, we demonstrate our recent observations regarding with the ABC phenomenon against liposomes.","ja":"PEGylated liposomes (approximately 100nm in diameter) lose their long-circulating characteristic upon repeated injection at certain intervals in the same animal (referred to as the \"accelerated blood clearance (ABC) phenomenon\"), as described by our group and by researchers in the Netherlands. Recently, it was demonstrated by our group that anti-PEG IgM, induced by the first dose of PEGylated liposomes, is responsible for the ABC phenomenon. The IgM produced in this manner then selectively bound to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no immunogenicity. However, unexpected immune responses occurred even in response to polymer-coated liposomes. This immunogenicity to PEGylated liposomes presents a serious concern in the development and clinical use of liposomal formulations. In this review, we demonstrate our recent observations regarding with the ABC phenomenon against liposomes."},"publication_date":"2008-02-01","publication_name":{"en":"Journal of the Pharmaceutical Society of Japan","ja":"薬学雑誌"},"volume":"Vol.128","number":"No.2","starting_page":"233","ending_page":"243","languages":["jpn"],"identifiers":{"doi":["10.1248/yakushi.128.233"],"issn":["0031-6903"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
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line:44, {"insert":{"user_id":"1000300291","type":"misc","id":"30513014"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164190","label":"url"}],"paper_title":{"en":"リポソームと細胞の相互作用(DDSへの応用)","ja":"リポソームと細胞の相互作用(DDSへの応用)"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"publication_date":"2007-01","publication_name":{"en":"MEMBRANE","ja":"膜"},"volume":"Vol.32","number":"No.1","starting_page":"18","ending_page":"24","languages":["jpn"],"identifiers":{"doi":["10.5360/membrane.32.18"],"issn":["1884-6440"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:45, {"insert":{"user_id":"1000300291","type":"misc","id":"30513015"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/16508135","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=164191","label":"url"}],"paper_title":{"en":"Safe and efficient drug delivery system with liposomes for intrathecal application of an antivasospastic drug, fasudil.","ja":"Safe and efficient drug delivery system with liposomes for intrathecal application of an antivasospastic drug, fasudil."},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Takanashi Yoshihiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"Takanashi Yoshihiro"},{"name":"際田 弘志"}]},"description":{"en":"Pharmacological treatment for cerebral ischemia and cerebral vasospasm following subarachnoid hemorrhage (SAH) cannot attain sufficiently high concentrations of the drugs in the cerebrospinal fluid (CSF) without precipitating systemic side effects. We recently developed a liposomal drug delivery system for intrathecal application that can maintain effective concentrations of cerebral vasodilator, fasudil, in the CSF. A single intrathecal injection of liposomal fasudil could maintain a therapeutic drug concentration in the CSF over a period time due to their sustained-release property, significantly decreasing infarct size in a rat model of acute ischemia and reducing vasoconstriction of the rat and dog basilar artery in a model of SAH. In this review, we are introducing our new less-invasive intrathecal drug delivery system that provides an alternative and safe method to deliver therapeutic agents.","ja":"Pharmacological treatment for cerebral ischemia and cerebral vasospasm following subarachnoid hemorrhage (SAH) cannot attain sufficiently high concentrations of the drugs in the cerebrospinal fluid (CSF) without precipitating systemic side effects. We recently developed a liposomal drug delivery system for intrathecal application that can maintain effective concentrations of cerebral vasodilator, fasudil, in the CSF. A single intrathecal injection of liposomal fasudil could maintain a therapeutic drug concentration in the CSF over a period time due to their sustained-release property, significantly decreasing infarct size in a rat model of acute ischemia and reducing vasoconstriction of the rat and dog basilar artery in a model of SAH. In this review, we are introducing our new less-invasive intrathecal drug delivery system that provides an alternative and safe method to deliver therapeutic agents."},"publication_date":"2006-03","publication_name":{"en":"Biological & Pharmaceutical Bulletin","ja":"Biological & Pharmaceutical Bulletin"},"volume":"Vol.29","number":"No.3","starting_page":"397","ending_page":"402","languages":["eng"],"identifiers":{"doi":["10.1248/bpb.29.397"],"issn":["0918-6158"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
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line:48, {"insert":{"user_id":"1000300291","type":"misc","id":"30513018"},"force":{"see_also":[{"@id":"http://ci.nii.ac.jp/naid/10014117131/","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390001204640586880/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130630","label":"url"}],"paper_title":{"en":"Accelerated blood clearance of PEGylated liposomes after repeated injection","ja":"ポリエチレングリコール表面修飾リポソームの繰り返し投与時に発現するaccelerated blood clearance(ABC)現象"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"description":{"en":"We and a Dutch group have recently reported the accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes, that is the enhanced accumulation of PEGylated liposomes in liver and consequently rapidly cleared the liposomes from blood circulation. The phenomenon is a general characteristic of liposomes and the induction of the phenomenon depends on the physicochemical property and dose of liposomes and animal species. In addition, our study indicated that the IgM secreted in response to first dose is involved in the occurrence of the phenomenon. In this article, our and a Dutch group's recent results related to the ABC phenomenon were described.","ja":"We and a Dutch group have recently reported the accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes, that is the enhanced accumulation of PEGylated liposomes in liver and consequently rapidly cleared the liposomes from blood circulation. The phenomenon is a general characteristic of liposomes and the induction of the phenomenon depends on the physicochemical property and dose of liposomes and animal species. In addition, our study indicated that the IgM secreted in response to first dose is involved in the occurrence of the phenomenon. In this article, our and a Dutch group's recent results related to the ABC phenomenon were described."},"publication_date":"2004-11-10","publication_name":{"en":"Drug Delivery System","ja":"Drug Delivery System"},"volume":"Vol.19","number":"No.6","starting_page":"495","ending_page":"510","languages":["jpn"],"identifiers":{"doi":["10.2745/dds.19.495"],"issn":["0913-5006"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:49, {"insert":{"user_id":"1000300291","type":"misc","id":"30513019"},"force":{"see_also":[{"@id":"http://ci.nii.ac.jp/naid/110003614984/","label":"url"},{"@id":"https://cir.nii.ac.jp/crid/1390282681105634816/","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=132270","label":"url"}],"paper_title":{"en":"Development of Drug Delivery System for Intrathecal Administration and Its Therapeutic Effect on Cerebral Vasospasm and Ischemia","ja":"脳脊髄腔投与可能なDDSの開発とその脳保護効果の検討"},"authors":{"en":[{"name":"Ishida Tatsuhiro"}],"ja":[{"name":"石田 竜弘"}]},"description":{"en":"To date, the pharmacologic approach to cerebral vasospasm and ischemia has been hampered in part by an inability to attain sufficiently high concentrations of drugs in the cerebrospinal fluid (CSF). To overcome this limitation of current drug therapy, we have developed a sustained-release preparation of the protein kinase inhibitor fasudil. Experimental cerebral vasospasm in rats and dogs was induced by double injection of autologous arterial blood into the cisterna magna. Focal cerebral ischemia in rats was induced by middle cerebral artery occlusion using an intraluminal suture technique. A single intrathecal injection of liposomal fasudil can maintain a therapeutic the drug concentration in the CSF due to the sustained-release property of liposomes, significantly decreasing intarct size of acute ischemia and decreasing vasoconstriction of the basilar artery in cerebral vasospasm. This novel approach for the treatment of cerebral vasospasm and ischemia may have significant potential for use in the clinical setting.","ja":"To date, the pharmacologic approach to cerebral vasospasm and ischemia has been hampered in part by an inability to attain sufficiently high concentrations of drugs in the cerebrospinal fluid (CSF). To overcome this limitation of current drug therapy, we have developed a sustained-release preparation of the protein kinase inhibitor fasudil. Experimental cerebral vasospasm in rats and dogs was induced by double injection of autologous arterial blood into the cisterna magna. Focal cerebral ischemia in rats was induced by middle cerebral artery occlusion using an intraluminal suture technique. A single intrathecal injection of liposomal fasudil can maintain a therapeutic the drug concentration in the CSF due to the sustained-release property of liposomes, significantly decreasing intarct size of acute ischemia and decreasing vasoconstriction of the basilar artery in cerebral vasospasm. This novel approach for the treatment of cerebral vasospasm and ischemia may have significant potential for use in the clinical setting."},"publication_date":"2004-08-01","publication_name":{"en":"Journal of the Pharmaceutical Society of Japan","ja":"薬学雑誌"},"volume":"Vol.124","number":"No.8","starting_page":"541","ending_page":"547","languages":["jpn"],"identifiers":{"doi":["10.1248/yakushi.124.541"],"issn":["0031-6903"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:50, {"insert":{"user_id":"1000300291","type":"misc","id":"30513020"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=130638","label":"url"}],"paper_title":{"en":"脳脊髄腔内直接投与可能なDDSの開発とその脳保護効果","ja":"脳脊髄腔内直接投与可能なDDSの開発とその脳保護効果"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"高梨 吉裕"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"高梨 吉裕"},{"name":"際田 弘志"}]},"publication_date":"2004-06","publication_name":{"en":"月刊 薬事","ja":"月刊 薬事"},"volume":"Vol.46","number":"No.7","starting_page":"1333","ending_page":"1338","languages":["jpn"],"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:51, {"insert":{"user_id":"1000300291","type":"misc","id":"30513021"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=193520","label":"url"}],"paper_title":{"en":"DDS研究の現状","ja":"DDS研究の現状"},"authors":{"en":[{"name":"Ishida Tatsuhiro"},{"name":"Kiwada Hiroshi"}],"ja":[{"name":"石田 竜弘"},{"name":"際田 弘志"}]},"publication_date":"2003-12","publication_name":{"en":"科学フォーラム","ja":"科学フォーラム"},"starting_page":"22","ending_page":"28","languages":["jpn"],"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
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====== BulkResult(1000300291, 4SfNNpMBYVtrs4O8AsAs) : Begin ======
--- error
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====== BulkResult(1000300291, 4SfNNpMBYVtrs4O8AsAs) : End ======
====== BulkResult(1000300291, 5ifNNpMBYVtrs4O8AsC8) : Begin ======
--- error
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====== BulkResult(1000300291, 5ifNNpMBYVtrs4O8AsC8) : End ======
====== BulkResult(1000300291, 6ifNNpMBYVtrs4O8A8Ap) : Begin ======
--- error
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--- success
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====== BulkResult(1000300291, 6ifNNpMBYVtrs4O8A8Ap) : End ======
====== BulkResult(1000300291, 9SfNNpMBYVtrs4O8BsC9) : Begin ======
--- error
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--- success
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