全身循環性ドラッグキャリアーは可能か?

全身循環性ドラッグキャリアーは可能か?


Liposomal delivery systems: design optimization and current applications

The liposome, a closed phospholipid bilayered vesicular system, has received considerable attention as a pharmaceutical carrier of great potential over the past 30 years. The ability of liposomes to encapsulate both hydrophilic and hydrophobic drugs, coupled with their biocompatibility and biodegradability, make liposomes attractive vehicles in the field of drug delivery. In addition, great technical advances such as remote drug loading, triggered release liposomes, ligand-targeted liposomes, liposomes containing combinations of drugs, and so on, have led to the widespread use of liposomes in diverse areas as delivery vehicles for anti-cancer, bio-active molecules, diagnostics, and therapeutic agents. In this review, we summarize design optimization of liposomal systems and invaluable applications of liposomes as effective delivery systems.


Selective delivery of oxaliplatin to tumor tissue by nanocarrier system enhances overall therapeutic efficacy of the encapsulated oxaliplatin

Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatinum; l-OHP), a third-generation platinum antitumor drug, is currently approved in combination with 5-flurouracil (5-FU)/leucovorin (FOLFOX) for standard first- and second-line treatment of metastatic or advanced-stage colorectal cancer. Despite l-OHP's better tolerability in comparison with other platinum compounds such as cisplatin and carboplatin, its clinical efficiency is limited by the dose-limiting side effects including cumulative neurotoxicity and acute dysesthesias. In addition, like other platinum chemotherapeutic agents, l-OHP therapy is limited by reduced accumulation levels in tumor tissues, nonselective accumulation in healthy organs and/or tissues, inactivation by conjugation with glutathione, and the development of drug resistance. Accordingly, successful outcome of cancer treatment using l-OHP requires selective delivery of a relatively high concentration of the drug to tumor tissues. In this review we focus on utilization of different drug-delivery vehicles such as liposomes, polymeric nanocarriers, and carbon nanotubes in enhancing selective delivery of l-OHP to tumor tissues and consequently improving overall efficacy of l-OHP-containing drug-delivery systems.


The accelerated blood clearance (ABC) phenomenon: Clinical challenge and approaches to manage

Despite the clinical introduction of an increasing number of polyethylene glycol (PEG)-conjugated substances, PEG has been named as the cause of an unexpected immunogenic response known as the "accelerated blood clearance (ABC) phenomenon." This phenomenon has been extensively observed during the repeated administration of PEG-conjugated substances and PEGylated nanocarriers including PEGylated liposomes, PEGylated nanoparticles, PEGylated micelles, etc., resulting in the increased clearance and reduced efficacy of PEG-conjugated substances/PEGylated nanocarriers. In this review, therefore, we focused on the possible mechanisms underlying the induction of such a phenomenon and emphasized the factors affecting its magnitude. In addition, the clinical implications of the ABC phenomenon on the therapeutic efficacy of PEG-conjugated substances/PEGylated nanocarriers, along with the new approaches that can be applied to manage and/or abrogate the induction of the ABC phenomenon, are also discussed.


Anti-polyethyleneglycol (PEG) antibody response to PEGylated substances.

In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance.


PEG修飾製剤による抗PEG抗体分泌誘導

PEG修飾製剤による抗PEG抗体分泌誘導


Alteration of tumor microenvironment for improved delivery and intratumor distribution of nanocarriers.

Nanocarrier-based cancer chemotherapeutics are thought to increase therapeutic efficiency and reduce the side effects of associated chemotherapeutic agents by altering the agents' pharmacokinetics and tissue distribution following intravenous administration. In spite of these favorable properties, nanocarrier-based cancer chemotherapeutics are not always effective because of their heterogeneous intratumoral localization. Homogeneous distribution of nanocarriers in a tumor would improve the efficacy of nanocarrier-based cancer chemotherapeutics. In this article, we describe and discuss some trials that attempt to manipulate the barriers in the tumor microenvironment that hinder extravasation through the tumor vasculature and penetration of nanocarriers in solid tumors. Alterations of the tumor microenvironment that relate directly to the intratumoral distribution of nanocarriers may be potential strategies to improve the delivery of nanocarrier-based cancer chemotherapeutics.


PEG修飾リポソーム製剤繰り返し投与による血中滞留性低下

PEG修飾リポソーム製剤繰り返し投与による血中滞留性低下


Targeting anticancer drugs to tumor vasculature using cationic liposomes.

Liposomal drug delivery systems improve the therapeutic index of chemotherapeutic agents, and the use of cationic liposomes to deliver anticancer drugs to solid tumors has recently been recognized as a promising therapeutic strategy to improve the effectiveness of conventional chemotherapeutics. This review summarizes the selective targeting of cationic liposomes to tumor vasculature, the merits of incorporating the polymer polyethylene-glycol (PEG), and the impact of the molar percent of the cationic lipid included in cationic liposomes on liposomal targeting efficacy. In addition, the discussion herein includes the therapeutic benefit of a dual targeting approach, using PEG-coated cationic liposomes in vascular targeting (of tumor endothelial cells), and tumor targeting (of tumor cells) of anticancer drugs. Cationic liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development.


Elucidation of Accelerated Blood Clearance Phenomenon Caused by Repeat Injection of PEGylated Nanocarriers

Liposomes modified with polyethylene glycol (PEG) can stably exist in the bloodstream because the PEG on the liposomes attracts a water shell to the liposomal surface. Since these liposomes are long circulating nanocarriers, they are used as drug and gene delivery tools. Repeat injection of PEGylated liposomes, however, is known to induce the accelerated blood clearance (ABC) phenomenon. In the ABC phenomenon, PEGylated liposomes that are injected subsequent to the first injection are cleared rapidly from the bloodstream and accumulate in the liver, resulting in loss of their long-circulating characteristics. The induction of ABC phenomenon is related to the production of anti-PEG IgM from splenic B cells. To elucidate the mechanism of the phenomenon, we firstly examined the relationship between the induction of ABC phenomenon and the concentration of PEGylated liposomes, and observed that the high dose of those did not induce the phenomenon. Next, we investigated whether polymeric micelles trigger ABC phenomenon or not. Finally, the size-dependency of ABC phenomenon was investigated by use of variously sized PEGylated liposomes and polymeric micelles having PEG chains. Our data suggest that the initiation of ABC phenomenon would be size-dependent, and particles smaller than 30 nm did not induce ABC phenomenon. We anticipate that the elucidation of the ABC phenomenon will be helpful for the development of DDS formulations.

Journal of the Pharmaceutical Society of Japan


Recent advances in tumor vasculature targeting using liposomal drug delivery systems.

Tumor vessels possess unique physiological features that might be exploited for improved drug delivery. The targeting of liposomal anticancer drugs to tumor vasculature is increasingly recognized as an effective strategy to obtain superior therapeutic efficacy with limited host toxicity compared with conventional treatments. This review introduces recent advances in the field of liposomal targeting of tumor vasculature, along with new approaches that can be used in the design and optimization of liposomal delivery systems. In addition, cationic liposome is focused on as a promising carrier for achieving efficient vascular targeting. The clinical implications are discussed of several approaches using a single liposomal anticancer drug formulation: dual targeting, vascular targeting (targeting tumor endothelial cells) and tumor targeting (targeting tumor cells).


siRNA を利用したArgonaute2 遺伝子knockdown によるがん治療法の開発


Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes.

We and a Dutch group reported that "empty" PEGylated liposomes (approximately 100 nm) lose their long-circulating characteristic when they are administrated twice in the same animal with certain intervals (referred to as the accelerated blood clearance (ABC) phenomenon). Very recently, we showed that anti-PEG IgM, induced by the first dose of "empty" PEGylated liposomes, is responsible for inducing the phenomenon, based on the observation that IgM thus produced selectively binds to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no or lower immunogenicity. However, the results indicated evidence that unexpected immune responses occur even to such polymer-coated liposomes. Such immunogenicity of "empty" liposomes presents a serious concern in the development of liposomal formulations and their use in the clinic. In addition, through series of our studies, it was demonstrated that the magnitude of the ABC phenomenon depends on the physicochemical property of injected liposomes as a first dose, time interval between injection, lipid dose and drug-encapsulation.


Accelerated Blood Clearance (ABC) Phenomenon Induced by Administration of PEGylated Liposome(Symposium Reviews)

ポリエチレングリコール修飾リポソーム投与時に生ずるaccelerated blood clearance (ABC)現象

PEGylated liposomes (approximately 100nm in diameter) lose their long-circulating characteristic upon repeated injection at certain intervals in the same animal (referred to as the "accelerated blood clearance (ABC) phenomenon"), as described by our group and by researchers in the Netherlands. Recently, it was demonstrated by our group that anti-PEG IgM, induced by the first dose of PEGylated liposomes, is responsible for the ABC phenomenon. The IgM produced in this manner then selectively bound to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no immunogenicity. However, unexpected immune responses occurred even in response to polymer-coated liposomes. This immunogenicity to PEGylated liposomes presents a serious concern in the development and clinical use of liposomal formulations. In this review, we demonstrate our recent observations regarding with the ABC phenomenon against liposomes.


ポリマー修飾ナノ微粒子投与による免疫活性化に関する研究

ポリマー修飾ナノ微粒子投与による免疫活性化に関する研究


リポソームと細胞の相互作用(DDSへの応用)

リポソームと細胞の相互作用(DDSへの応用)


Safe and efficient drug delivery system with liposomes for intrathecal application of an antivasospastic drug, fasudil.

Pharmacological treatment for cerebral ischemia and cerebral vasospasm following subarachnoid hemorrhage (SAH) cannot attain sufficiently high concentrations of the drugs in the cerebrospinal fluid (CSF) without precipitating systemic side effects. We recently developed a liposomal drug delivery system for intrathecal application that can maintain effective concentrations of cerebral vasodilator, fasudil, in the CSF. A single intrathecal injection of liposomal fasudil could maintain a therapeutic drug concentration in the CSF over a period time due to their sustained-release property, significantly decreasing infarct size in a rat model of acute ischemia and reducing vasoconstriction of the rat and dog basilar artery in a model of SAH. In this review, we are introducing our new less-invasive intrathecal drug delivery system that provides an alternative and safe method to deliver therapeutic agents.


がん治療を目指した機能性リポソームの開発研究

がん治療を目指した機能性リポソームの開発研究


Accelerated blood clearance of PEGylated liposomes after repeated injection

ポリエチレングリコール表面修飾リポソームの繰り返し投与時に発現するaccelerated blood clearance(ABC)現象

We and a Dutch group have recently reported the accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes, that is the enhanced accumulation of PEGylated liposomes in liver and consequently rapidly cleared the liposomes from blood circulation. The phenomenon is a general characteristic of liposomes and the induction of the phenomenon depends on the physicochemical property and dose of liposomes and animal species. In addition, our study indicated that the IgM secreted in response to first dose is involved in the occurrence of the phenomenon. In this article, our and a Dutch group's recent results related to the ABC phenomenon were described.


脳脊髄腔内直接投与可能なDDSの開発とその脳保護効果

脳脊髄腔内直接投与可能なDDSの開発とその脳保護効果


pH-Sensitive Liposomes in Nuclear Targeting of macromolecules


Pharmacokinetics of Targeting with Liposomes

Critcal Reviews in Therapeutic Drug Carrier Systems


Interactions of Liposomes with Cells In Vitro and In Vivo:Opsonins and Receptors


Quantitative studies on the nuclear transport of plasmid DNA and gene expression employing nonviarl vectors


Intracellular control of gene trafficking using liposomes as drug carriers

The objective of this review is to summarize some of the critical barriers in gene delivery and recent progress in overcoming such barriers using non-viral carrier systems. Receptor-mediated endocytosis is generally considered to be a principal entering pathway. Therefore, endosomal escape is an essential step for achieving efficient transfection. The nuclear membrane is also a critical barrier in gene delivery and the application of the nuclear localization signal is discussed, based on recent strategies. It is essential to optimize the carrier system, in order to enhance the transfection ability equivalent to a viral system. The importance of developing an intracellular pharmacokinetic model of genes is emphasized in the optimization of non-viral carrier systems.

European Journal of Pharmaceutical Sciences


Intracellular control of macromolecules by use of liposomes as drug carriers


血中滞留性リポソームによる抗癌剤の処方設計における最適化

血中滞留性リポソームによる抗癌剤の処方設計における最適化


The size of liposomes:Factor which affects their targeting efficiency to tumors and therapeutic activity of liposomal antitumor drugs

The size of liposomes has been shown to be an important factor in the efficient delivery of an antitumor agent to a tumor. In this paper, the effects of the size of liposomes on the pharmacokinetics of liposomes and liposome-encapsulated drugs are discussed with reference to: (1) the circulation amount and residence time of liposomes in the blood, (2) the accumulation of liposomes in the tumor, and (3) in vivo drug release from liposomes. In addition, the effect of size on therapeutic activity (antitumor efficacy and toxicity) of a liposomal anticancer preparation is discussed. Finally we discuss the importance of liposome size in the design of a more effective liposomal antitumor preparation.


Pharmacokinetic/Pharmacodynamic modeling of antitumor agents encapsulated into Liposomes

Pharmacokinetic/pharmacodynamic (PK/PD) modeling of antitumor agents has been developed for doxorubicin (DOX) in order to predict the optimum conditions for a drug carrier to maximize the antitumor effect. A PK model was constructed for free and liposomal doxorubicin using a hybrid model wherein the disposition in the whole body is described by compartment models, which were linked to the tumor compartment via the blood flow rate. The PD model for doxorubicin was described by a cell-kill kinetic model, which represents the number of tumor cells quantitatively, as a function of the free concentration of doxorubicin in the tumor compartment. The influence of each parameter on the antitumor effects was examined by sensitivity analysis based on the PK/PD model, which clearly showed the importance of optimizing the release rate of DOX from liposomes. The validity of the model has been tested using animal experiments. Preliminary simulations were also performed for humans after scaling up the PK/PD model from rodents to humans. The optimum conditions in the rate of drug release from liposomes were different for rodents vis-a-vis humans, which indicates the limitations involved in extrapolating optimum conditions for experimental animals to those for humans.


The pharmacokinetics of liposomes in tumor targeting


キャリアによる細胞内デリバリー戦略と今後の課題

キャリアによる細胞内デリバリー戦略と今後の課題


Identification of proteins mediating clearance of liposomes using a liver perfusion system

The objective of this paper is to identify the principal blood components governing the fate of liposomes in blood circulation. Information based on an isolated perfused liver system in rats has revealed the central role of the complement system in enhancing the uptake of liposomes by the liver. A species difference was an important factor in determining the uptake mechanisms of liposomes by the liver. Limited evidence revealed the tendency that opsonin-dependent hepatic uptake is principal in rats, while opsonin-independent or dysopsonin-dependent uptake governs in mice, although there are some exceptions. These studies provide us with important information for understanding the uptake mechanisms of liposomes by the liver, and useful insights in predicting the in vivo disposition of liposomes in humans.


Plasma factors affecting disposition of liposomes


リポソームの体内動態における粒子径認識機構

リポソームの体内動態における粒子径認識機構


ステルスイムノリポソーム

ステルスイムノリポソーム


Liposomal Targeting and Drug Delivery:Kinetic Consideration


Studies on the Mechanism of Uptake of Liposomes Using an Isolated Perfused Liver System


リポソームによるDDSの設計

リポソームによるDDSの設計


リポソーム製剤の臨床応用は世界的にどこまで進んでいるか

リポソーム製剤の臨床応用は世界的にどこまで進んでいるか

Journal of Clinical and Experimental Medicine


消化管吸収におけるドラッグデリバリーシステム

消化管吸収におけるドラッグデリバリーシステム


リポソームを利用した薬物投与ーより有効なキャリアーシステムへの可能性

リポソームを利用した薬物投与ーより有効なキャリアーシステムへの可能性


Liposomes-Are they effective drug carriers?


リポソーム2ードラッグキャリアーとしてのリポソーム

リポソーム2ードラッグキャリアーとしてのリポソーム