=== Generating (published_papers) ===
=== Generating (teaching_experience) ===
=== Generating (misc) ===
=== Generating (research_projects) ===
=== Generating (books_etc) ===
=== Generating (awards) ===
=== Generating (presentations) ===
==== begin registerFile(/WWW/pub2/data/ERD/person/277628/researchmap/published_papers.jsonl) ====
line:1, {"insert":{"user_id":"7000022165","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":"7000022165","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:3, {"insert":{"user_id":"7000022165","type":"published_papers","id":"45763798"},"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:4, {"insert":{"user_id":"7000022165","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:5, {"insert":{"user_id":"7000022165","type":"published_papers","id":"43838483"},"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:6, {"insert":{"user_id":"7000022165","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:7, {"insert":{"user_id":"7000022165","type":"published_papers","id":"42412564"},"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:8, {"insert":{"user_id":"7000022165","type":"published_papers","id":"41379362"},"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:9, {"insert":{"user_id":"7000022165","type":"published_papers","id":"41053444"},"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:10, {"insert":{"user_id":"7000022165","type":"published_papers","id":"41042825"},"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:11, {"insert":{"user_id":"7000022165","type":"published_papers","id":"40510321"},"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:12, {"insert":{"user_id":"7000022165","type":"published_papers","id":"39507269"},"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:13, {"insert":{"user_id":"7000022165","type":"published_papers","id":"39656537"},"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:14, {"insert":{"user_id":"7000022165","type":"published_papers","id":"36905613"},"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:15, {"insert":{"user_id":"7000022165","type":"published_papers","id":"36366792"},"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:16, {"insert":{"user_id":"7000022165","type":"published_papers","id":"39728141"},"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:17, {"insert":{"user_id":"7000022165","type":"published_papers","id":"36292755"},"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:18, {"insert":{"user_id":"7000022165","type":"published_papers","id":"35684138"},"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:19, {"insert":{"user_id":"7000022165","type":"published_papers","id":"35997013"},"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:20, {"insert":{"user_id":"7000022165","type":"published_papers","id":"33006580"},"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:21, {"insert":{"user_id":"7000022165","type":"published_papers","id":"33577516"},"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:22, {"insert":{"user_id":"7000022165","type":"published_papers","id":"33247651"},"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:23, {"insert":{"user_id":"7000022165","type":"published_papers","id":"32904110"},"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:24, {"insert":{"user_id":"7000022165","type":"published_papers","id":"32439490"},"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:25, {"insert":{"user_id":"7000022165","type":"published_papers","id":"32234601"},"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:26, {"insert":{"user_id":"7000022165","type":"published_papers","id":"32680490"},"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:27, {"insert":{"user_id":"7000022165","type":"published_papers","id":"32065128"},"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:28, {"insert":{"user_id":"7000022165","type":"published_papers","id":"31973246"},"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:29, {"insert":{"user_id":"7000022165","type":"published_papers","id":"31973247"},"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:30, {"insert":{"user_id":"7000022165","type":"published_papers","id":"32225137"},"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:31, {"insert":{"user_id":"7000022165","type":"published_papers","id":"31562210"},"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:32, {"insert":{"user_id":"7000022165","type":"published_papers","id":"31396055"},"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:33, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30915210"},"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:34, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512784"},"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:35, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512783"},"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:36, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512776"},"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:37, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512777"},"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:38, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512778"},"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:39, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512779"},"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:40, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512780"},"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:41, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512781"},"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:42, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512782"},"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:43, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512785"},"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:44, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512786"},"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:45, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512787"},"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:46, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512788"},"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:47, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512789"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31518109","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85073096311&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=363474","label":"url"}],"paper_title":{"en":"Engineering the binding kinetics of synthetic polymer nanoparticles for siRNA delivery","ja":"Engineering the binding kinetics of synthetic polymer nanoparticles for siRNA delivery"},"authors":{"en":[{"name":"Koide Hiroyuki"},{"name":"Fukuta Tatsuya"},{"name":"Okishim Anna"},{"name":"Ariizumi Saki"},{"name":"Kiyokawa Chiaki"},{"name":"Tsuchida Hiroki"},{"name":"Nakamoto Masahiko"},{"name":"Yoshimatsu Keiichi"},{"name":"ANDO Hidenori"},{"name":"Dewa Takehisa"},{"name":"Asai Tomohiro"},{"name":"Oku Naoto"},{"name":"Hoshino Yu"},{"name":"Shea J. Kenneth"}],"ja":[{"name":"Koide Hiroyuki"},{"name":"福田 達也"},{"name":"Okishim Anna"},{"name":"Ariizumi Saki"},{"name":"Kiyokawa Chiaki"},{"name":"Tsuchida Hiroki"},{"name":"Nakamoto Masahiko"},{"name":"Yoshimatsu Keiichi"},{"name":"安藤 英紀"},{"name":"Dewa Takehisa"},{"name":"Asai Tomohiro"},{"name":"Oku Naoto"},{"name":"Hoshino Yu"},{"name":"Shea J. Kenneth"}]},"description":{"en":"The affinity of a synthetic polymer nanoparticle (NP) to a target biomacromolecule is determined by the association and dissociation rate constants (, ) of the interaction. The individual rates and their sensitivity to local environmental influences are important factors for the on-demand capture and release a target biomacromolecule. Positively charged NPs for small interfering RNA (siRNA) delivery is a case in point. The knockdown efficacy of siRNA can be strongly influenced by the binding kinetics to the NP. Here, we show that and of siRNA to NPs can be individually engineered by tuning the chemical structure and composition of the NP. -Isopropylacrylamide-based NPs functionalized with hydrophobic and amine monomers were used. decreased by increasing the amount of amine groups in the NP, whereas did not change. Importantly, NPs showing a low at pH 5.5 together with a high at pH 7.4 showed high knockdown efficiency when NP/siRNA complexes were packaged in lipid nanoparticles. These results provide direct evidence for the premise that the efficacy of an siRNA delivery vector is linked with the strong affinity to the siRNA in the endosome and low affinity in the cytoplasm.","ja":"The affinity of a synthetic polymer nanoparticle (NP) to a target biomacromolecule is determined by the association and dissociation rate constants (, ) of the interaction. The individual rates and their sensitivity to local environmental influences are important factors for the on-demand capture and release a target biomacromolecule. Positively charged NPs for small interfering RNA (siRNA) delivery is a case in point. The knockdown efficacy of siRNA can be strongly influenced by the binding kinetics to the NP. Here, we show that and of siRNA to NPs can be individually engineered by tuning the chemical structure and composition of the NP. -Isopropylacrylamide-based NPs functionalized with hydrophobic and amine monomers were used. decreased by increasing the amount of amine groups in the NP, whereas did not change. Importantly, NPs showing a low at pH 5.5 together with a high at pH 7.4 showed high knockdown efficiency when NP/siRNA complexes were packaged in lipid nanoparticles. These results provide direct evidence for the premise that the efficacy of an siRNA delivery vector is linked with the strong affinity to the siRNA in the endosome and low affinity in the cytoplasm."},"publication_date":"2019-10-14","publication_name":{"en":"Biomacromolecules","ja":"Biomacromolecules"},"volume":"Vol.20","number":"No.10","starting_page":"3648","ending_page":"3657","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acs.biomac.9b00611"],"issn":["1526-4602"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:48, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512790"},"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:49, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512791"},"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:50, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512792"},"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:51, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512793"},"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:52, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512794"},"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:53, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512795"},"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:54, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512796"},"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:55, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512797"},"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:56, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512798"},"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:57, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512799"},"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:58, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512800"},"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:59, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512801"},"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:60, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512802"},"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:61, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512803"},"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:62, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512804"},"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:63, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512805"},"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:64, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512806"},"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:65, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512807"},"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:66, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512808"},"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:67, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512809"},"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:68, {"insert":{"user_id":"7000022165","type":"published_papers","id":"30512810"},"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"}
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====== BulkResult(7000022165, SyfMNpMBYVtrs4O8zr8K) : End ======
====== BulkResult(7000022165, WSfMNpMBYVtrs4O80L8f) : Begin ======
--- error
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