1 0 0 0 OA PEGジレンマ-生体内安定性と細胞内動態の制御によるがんへの遺伝子・核酸デリバリー
- 著者
- 畠山 浩人 原島 秀吉
- 出版者
- 日本DDS学会
- 雑誌
- Drug Delivery System (ISSN:09135006)
- 巻号頁・発行日
- vol.31, no.4, pp.293-299, 2016-07-25 (Released:2016-12-25)
- 参考文献数
- 30
- 被引用文献数
- 2
核酸医薬のがん治療への応用にはDDSが必要不可欠である。血中投与後のがんへの送達には、DDSへのPEG修飾による血中滞留性向上とEPR効果が重要であるが、これは同時に標的細胞における著しい活性の低下を引き起こす。この体内動態と細胞内動態に対する相反するPEGの性質を「PEGのジレンマ」として提唱し、この問題の解決が、効率的なDDS開発にとって最も重要な課題であると考えている。本稿ではこのPEGのジレンマの解決にむけた筆者らの戦略や取り組みについて紹介したい。
- 著者
- 佐藤 悠介 畠山 浩人 兵藤 守 秋田 英万 原島 秀吉
- 出版者
- 公益社団法人 日本薬学会
- 雑誌
- YAKUGAKU ZASSHI (ISSN:00316903)
- 巻号頁・発行日
- vol.132, no.12, pp.1355-1363, 2012-12-01 (Released:2012-12-01)
- 参考文献数
- 19
- 被引用文献数
- 5 7
The development of a carrier for the delivery of siRNA is a factor in the realization of RNA interference (RNAi) therapeutics. Modification of siRNA carriers with polyethylene glycol, i.e., PEGylation, is a general strategy for stabilizing a particle in the blood stream and delivering it to tissue or cells. However, it is well-known that, when a carrier is modified by PEGylation, it results in a significant inhibition of both cellular uptake and the endosomal escape process. In a previous study, we reported on the development of a multifunctional envelope-type nano device (MEND) for delivering siRNA and peptide-based functional devices for overcoming the effects conferred by PEGylation and succeeded in the delivery of siRNA to tumor tissue. In this study, we noticed that the pH-sensitive property, changing from neutral to cationic in response to a decrease in pH, could avoid the inhibition caused by PEGylation and succeeded in synthesizing a pH-sensitive cationic lipid, YSK05. The YSK05-MEND had a higher fusogenicity and potency for endosomal escape than other MENDs containing conventional cationic lipids. The PEGylated YSK05-MEND induced efficient gene silencing and avoided the inhibition of endosomal escape caused by PEGylation followed by optimization of the lipid composition. Furthermore, the intratumoral injection of the PEGylated YSK05-MEND resulted in a more efficient gene silencing compared with MENDs containing conventional cationic lipids. Thus, the YSK05-MEND is a promising siRNA carrier for avoiding the inhibition in intracellular trafficking caused by PEGylation both in vitro and in vivo.