Sato Yusuke, Hatakeyama Hiroto, Hyodo Mamoru, Akita Hidetaka, Harashima Hideyoshi
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Yakugaku Zasshi. 2012;132(12):1355-63. doi: 10.1248/yakushi.12-00234-2.
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.
用于递送小干扰RNA（siRNA）的载体的开发是实现RNA干扰（RNAi）疗法的一个因素。用聚乙二醇修饰siRNA载体，即聚乙二醇化，是在血流中稳定颗粒并将其递送至组织或细胞的常用策略。然而，众所周知，当载体通过聚乙二醇化进行修饰时，会导致细胞摄取和内体逃逸过程均受到显著抑制。在之前的一项研究中，我们报道了一种用于递送siRNA的多功能包膜型纳米装置（MEND）以及用于克服聚乙二醇化所带来影响的基于肽的功能装置，并成功地将siRNA递送至肿瘤组织。在本研究中，我们注意到pH敏感特性，即随着pH降低从中性转变为阳离子性，可避免聚乙二醇化引起的抑制作用，并成功合成了一种pH敏感的阳离子脂质YSK05。与含有传统阳离子脂质的其他MEND相比，YSK05-MEND具有更高的融合性和内体逃逸能力。聚乙二醇化的YSK05-MEND在优化脂质组成后诱导了有效的基因沉默，并避免了聚乙二醇化引起的内体逃逸抑制。此外，与含有传统阳离子脂质的MEND相比，瘤内注射聚乙二醇化的YSK05-MEND导致了更有效的基因沉默。因此，YSK05-MEND是一种有前景的siRNA载体，可避免在体外和体内由聚乙二醇化引起的细胞内运输抑制。
