Abstract 4529: Self-assembled lipid-polymer hybrid nanoparticles for the sustained delivery of siRNA and the treatment of drug-resistant cancers.

Abstract

Abstract RNA interference (RNAi), which can selectively knockdown target genes, has shown great potential in the treatment of various diseases including cancer. Thus far, numerous nanoparticle (NP) platforms such as lipoplex and polyplex have been developed to facilitate the safe and effective delivery of small interfering RNA (siRNA), which represents a major hurdle for the clinical applications of RNAi. Nevertheless, these NP systems lack the sustained siRNA release property, and thus can only induce transient gene silencing due to the short lifetime of siRNA. Therefore, the delivery of siRNA using controlled-release NPs would be necessary for achieving sustained gene silencing. Herein, we will present a novel NP platform for safe and effective siRNA delivery in a sustained manner, which can be developed through the self-assembly of biodegradable and biocompatible polymers and lipids. The lipid-polymer hybrid NPs show excellent in vitro knockdown efficacy at low doses of siRNA, and promising in vivo results for delivering siRNA to xenograft tumors. More importantly, these NPs can control the temporal release of siRNA, with the half-release time of ∼ 9 days, for sustained silencing of target gene expression. Results demonstrate that the luciferase expression is still less than 25% at day 7 when the lucifrease-expressed HeLa cells were transfected with the NPs containing 40 pmol anti-luciferase siRNA. As a comparison, the luciferase expression is largely recovered (∼ 80%) at day 7, after transfection with lipo2000-siRNA complexes. Furthermore, this NP platform has been applied to deliver anti-drug resistance siRNA (e.g., anti-PHB1) and chemotherapeutic drugs (e.g., taxanes) for the effective treatment of drug resistant cancers. We believe that the lipid-polymer hybrid NP platform with the property of sustained siRNA release could hold potential in both fundamental studies and clinical applications. Citation Format: Jinjun Shi, Yingjie Xu, Xiaoyang Xu, Alexander Votruba, Xi Zhu, Eric Pridgen, Zeyu Xiao, Robert Langer, Bruce R. Zetter, Omid C. Farokhzad. Self-assembled lipid-polymer hybrid nanoparticles for the sustained delivery of siRNA and the treatment of drug-resistant cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4529. doi:10.1158/1538-7445.AM2013-4529