YAKUGAKU ZASSHI

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138 巻 (2018) 5 号 p. 591-598

体内動態と細胞内動態を制御する革新的リポソームDDSの創製と薬物治療・核酸医薬への展開

畠山浩人

　Nucleic acid therapy is expected to be a next generation medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel delivery system. The modification of polyethylene glycol (PEG), i.e., PEGylation, is useful for achieving the delivery of MENDs to tumors via an enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits the cellular uptake and endosomal escape of MEND, which results in significant loss of action, and therefore lost effectiveness, of the cargo therapeutic. For successful nucleic acid delivery in cancer treatment, the crucial problem associated with the use of PEG, known as the “PEG dilemma”, must be solved. In this review, we describe the development and application of MEND in overcoming the PEG dilemma based on manipulating both the pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release using a cleavable PEG lipid, a pH-sensitive fusogenic peptide, and a pH-sensitive cationic lipid. We also developed dual-ligand liposomes with a controlled diameter of around 300 nm, then modified these with a specific ligand and a cell penetrating peptide designed to target the neovasculature of tumors. Dual-ligand liposomes could induce an anti-tumor effect in drug resistant tumors by delivering drugs to tumor blood vessels, rather than to the cancer cells themselves. Here, we review our recent efforts to develop a novel liposomal drug delivery system (DDS) by manipulating pharmacokinetics and intracellular trafficking for drug therapy and nucleic acid medicine.

編集者のコメント

The modification of polyethylene glycol (PEG), i.e. PEGylation is commonly used approach for increasing stability of drug delivery systems (DDSs), but results in loss of activity simultaneously. This article describes the trade-off relationship between activity and stability as PEG dilemma and strategies to overcome PEG dilemma. The authors developed a cleavable PEG lipid in response to tumor microenvironment, a pH-sensitive fusogenic peptide, and pH-sensitive cationic lipids in response to endosome/lysosome, which balanced activity and stability of DDSs and exerted therapeutic effect of nucleic acid cargos.

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138 巻 (2018) 5 号

保険薬局薬剤師を対象とした二日間の病院実地研修の実践と評価
～地域医療連携の推進を目的とした試み～炭昌樹, 長谷川千晶, 森井博朗, 星野伸夫, 奥貫裕美, 金本賢枝, 堀江美弥, 岡本陽香, 藪田直希, 松田雅史, 神谷貴樹, 須藤正朝, 増田恭子, 岩下由梨, 松田佳織, 本岡芳子, 平大樹, 森田真也, 寺田智祐
Factors Related to the Awareness and Self-confidence of Pharmacists regarding “PRE-AVOID”: Study Using VISTA Project Data 前田直人, 庄司雅紀, 橋本萌, 荒川行生, 恩田光子
環境化学物質の内分泌撹乱活性発現における代謝活性変動の影響北村繁幸

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