Introduction of stearoyl moieties into a biocompatible cationic polyaspartamide derivative, PAsp(DET), with endosomal escaping function for enhanced siRNA-mediated gene knockdown

JOURNAL OF CONTROLLED RELEASE

卷:145

Article

Kim, Hyun Jin¹  Ishii, Atsushi²  Miyata, Kanjiro^3,4  Lee, Yan^3,4  Wu, Shourong¹  Oba, Makoto⁵  Nishiyama, Nobuhiro^3,4  Kataoka, Kazunori^1,3,4 

[1] Univ Tokyo, Dept Mat Engn, Grad Sch Engn, Bunkyo Ku, Tokyo 1138656, Japan

[2] NanoCarrier Co Ltd, Kashiwa, Chiba 2770882, Japan

[3] Univ Tokyo, Ctr NanoBio Integrat, Bunkyo Ku, Tokyo 1138656, Japan

[4] Univ Tokyo, Ctr Dis Biol & Integrat Med, Grad Sch Med, Bunkyo Ku, Tokyo 1130033, Japan

[5] Univ Tokyo, Dept Clin Vasc Regenerat, Grad Sch Med, Bunkyo Ku, Tokyo 1130033, Japan

关键词: RNAi;    siRNA delivery;    Polyplex;    Stearoylation;    Polyaspartamide;   

DOI  :  10.1016/j.jconrel.2010.03.019

来源: Elsevier

【 摘 要 】

Applications of siRNA for cancer therapy have been spotlighted in recent years, but the rational design of efficient siRNA delivery carriers is still controversial, especially because of possible toxicity of the carrier components. Previously, a cationic polyaspartamide derivative, poly{N-[N-(2-aminoethyl)-2-aminoethyl] aspartamide} (PAsp(DET)), was reported to exert high transfection efficacy for plasmid DNA with negligible cytotoxicity. However, its direct application for siRNA delivery was fairly limited due to the unstable polymer/siRNA complex formation. In this study, to overcome such instability, stearic acid as a hydrophobic moiety was conjugated to the side chain of PAsp(DET) with various substitution degrees. The stearoyl introduction contributed not only to siRNA complex formation with higher association numbers but also to complex stabilization. The obtained stearoyl PAsp(DET)/siRNA complex significantly accomplished more efficient endogenous gene (BCL-2 and VEGF) knockdown in vitro against the human pancreatic adenocarcinoma (Panc-1) cells than did the unmodified PAsp(DET) complex and commercially available reagents, probably due to the facilitated cellular internalization. This finding suggests that the hydrophobic PAsp(DET)-mediated siRNA delivery is a promising platform for in vivo siRNA delivery. (C) 2010 Elsevier B.V. All rights reserved.

【 授权许可】

Free