Abstract 1955: Simultaneous delivery of siRNA and cisplatin by polymer-lipid hybrid nanoparticles sensitizes resistant cancer to chemotherapy
Authors: Xiaoyang Xu, Kun Xie, Xueqing Zhang, Eric Pridgen, Robert Langer, Graham Walker, Omid Farokhzad
Journal: Cancer Research (2012)

Abstract The development of acquired chemoresistance is a persistent clinical problem limiting the successful treatment of malignant cancer. Acquired resistance can arise from chemotherapy-induced mutations and increase tumor cell capacity to either repair or tolerate DNA damage. RNA interference (RNAi) gene silencing is a potential therapeutic strategy for cancer therapy and the depletion of crucial gene products involved in these pathways (e.g. Rev1 and Rev3) by RNAi may restore tumor chemosensitivity to treatment. Herein, we report a nanotherapeutic approach towards utilizing a nanocarrier platform capable of delivering cisplatin and anti-Rev1/3 siRNAs in order to circumvent or reverse acquired resistance through synergistic effects. Nanoparticles (NPs) were prepared by self-assembling technique using synthesized cationic lipid compounds and poly (lactide-co-glycolide)-b-poly (ethylene glycol) (PLGA-PEG). The differentially charged hollow core/shell nanostructure comprises three distinct components: inner aqueous hollow core, a middle positively charged lipid compound/PLGA hydrophobic shell, and a relatively neutral outer PEG layer. Resultant NPs are highly stable in aqueous solutions and entrap siRNA (360-420 pmol siRNA/mg NP) in the aqueous core via electrostatic interactions. The cisplatin prodrug with linear hexyl chains, c, t, c [Pt(NH3)2(O2CCH2CH2CH2CH2CH3)2Cl2], could be efficiently encapsulated within hydrophobic shell of NPs. These NPs undergo controlled release of both anti-Rev1/3 and cisplatin over a period of 1 week. The optimal NPs have been evaluated for their loading efficiency, release kinetics of payloads, biocompatibility, gene silencing efficacy and tumor cell-toxicity activity. The in vitro bioactivity of the siRNA-containing NPs was first evaluated in Dual-Luc HeLa cells using anti-firefly luciferase siRNA as a reporter gene. Up to 98% silencing efficacy could be achieved with a siRNA dose (2.5 nM), a result which is markedly better than the commercially available Lipo2000-siRNA complex. The NPs encapsulated with anti-Rev1/3 siRNAs could also enable significant Rev1/3 gene silencing in various human cancer cell lines including MCF-7, MBD-MB-231 and LNCaP. RT-PCR results showed that anti Rev1/3 siRNA-containing NPs with a siRNA dose (5 nM) exhibited sustained significant suppression of both genes (up to 90%) for up to 3 days. More importantly, when MCF-7 cells were treated with NPs containing anti Rev 1/3 siRNA and cisplatin, there was a significant enhancement in cell apoptosis as compared to populations without siRNA treatment at equivalent cisplatin dosages. Synergistic efficacy of NP[Rev1/3 siRNA+Pt] is under investigation in tumor-bearing mice. Our results provide a promising strategy toward effective sensitizing resistant cancer to chemotherapy by co-delivering gene-specific siRNAs and anti-cancer drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1955. doi:1538-7445.AM2012-1955