A pH-sensitive cationic lipid facilitates the delivery of liposomal siRNA and gene silencing activity in vitro and in vivo
A pH-sensitive cationic lipid facilitates the delivery of liposomal siRNA and gene silencing activity in vitro and in vivo
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DOI：
10.1016/j.jconrel.2012.09.009
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发表时间：
2012-11-10
影响因子：
10.8
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
--
作者：
Sato, Yusuke;Hatakeyama, Hiroto;Harashima, Hideyoshi
用聚乙二醇修饰脂质体siRNA载体，即聚乙二醇化，是一种普遍接受的实现体内稳定性和向肿瘤组织递送的策略。然而，聚乙二醇化显著抑制细胞摄取和载体的内体逃逸过程。在之前的研究中，我们报道了一种用于siRNA递送的多功能包膜型纳米装置（MEND）和基于肽的功能装置的开发，以克服局限性并成功地将siRNA有效地递送到肿瘤中。在这项研究中，我们合成了一种ph敏感的阳离子脂质，YSK05，以克服局限性。YSK05-MEND比其他含有常规阳离子脂质的mend具有更高的内体逃逸能力。聚乙二醇化的YSK05-MEND诱导了有效的基因沉默，并克服了脂质组成优化后的局限性。此外，与含有常规阳离子脂质的MENDs相比，肿瘤内给药YSK05-MEND导致更有效的基因沉默。总的来说，这些数据证实了YSK05促进了MEND的内体逃逸，从而增强了siRNA递送到细胞质和基因沉默的功效。(c) 2012 Elsevier B.V.版权所有
Modification of liposomal siRNA carriers with polyethylene glycol, i.e., PEGylation, is a generally accepted strategy for achieving in vivo stability and delivery to tumor tissue. However, PEGylation significantly inhibits both cellular uptake and the endosomal escape process of the carriers. In a previous study, we reported on the development of a multifunctional envelope-type nano device (MEND) for siRNA delivery and peptide-based functional devices for overcoming the limitations and succeeded in the efficient delivery of siRNA to tumors. In this study, we synthesized a pH-sensitive cationic lipid, YSK05, to overcome the limitations. The YSK05-MEND had a higher ability for endosomal escape than other MENDs containing conventional cationic lipids. The PEGylated YSK05-MEND induced efficient gene silencing and overcame the limitations followed by optimization of the lipid composition. Furthermore, the intratumoral administration of the YSK05-MEND resulted in a more efficient gene silencing compared with MENDs containing conventional cationic lipids. Collectively, these data confirm that YSK05 facilitates the endosomal escape of the MEND and thereby enhances the efficacy of siRNA delivery into cytosol and gene silencing. (c) 2012 Elsevier B.V. All rights reserved.