Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
J Control Release. 2010 Jul 14;145(2):141-8. doi: 10.1016/j.jconrel.2010.03.019. Epub 2010 Mar 30.
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.
近年来，siRNA 在癌症治疗中的应用成为焦点，但高效 siRNA 递药载体的合理设计仍存在争议，特别是因为载体成分可能具有毒性。此前，一种阳离子聚天冬酰胺衍生物，聚{N-[N-(2-氨基乙基)-2-氨基乙基]天冬酰胺}（PAsp（DET）），被报道对质粒 DNA 具有高转染效率，且细胞毒性可忽略不计。然而，由于聚合物/siRNA 复合物形成不稳定，其直接应用于 siRNA 递送受到很大限制。在这项研究中，为了克服这种不稳定性，将硬脂酸作为疏水性部分与 PAsp（DET）的侧链以不同的取代度进行了连接。硬脂酰基的引入不仅有助于形成具有更高结合数的 siRNA 复合物，而且有助于复合物的稳定。与未修饰的 PAsp（DET）复合物和市售试剂相比，所得硬脂酰 PAsp（DET）/siRNA 复合物在体外显著实现了更高效率的内源性基因（BCL-2 和 VEGF）敲低，这可能是由于细胞内化得到促进。这一发现表明，疏水 PAsp（DET）介导的 siRNA 递药是体内 siRNA 递药的有前途的平台。
