Abstract 5616: Enhancing tumor cell response to chemotherapy by simultaneous delivery of siRNA and cisplatin using polymeric nanoparticles.
Authors: Xu Xiaoyang , Zhang Xueqing , Xie Kun , Pridgen Eric , Langer Robert , Walker Graham , Farokhzad Omid 
Published: August 2014

Cisplatin and other DNA adduct-forming chemotherapeutics are widely used for the treatment of a broad spectrum of malignancies. However, their application is limited by the emergence of tumor chemoresistance and relapse. It is generally believed that acquired resistance can arise from cisplatin-induced mutations which increase tumor cell capacity to either repair or tolerate DNA damage. Recent studies have shown that the suppression of crucial genes products (e.g. Rev1 and Rev3) involved in the error-prone translesion DNA synthesis (TLS) could inhibit cisplatin-induced mutagenesis and restore tumor chemosensitivity to treatment. In this context, the combination of conventional chemotherapeutics with small interfering RNA (siRNA)-based therapeutics represents a promising strategy for treating patients with chemoresistant tumors. Thus, it is necessary to develop a versatile delivery system capable of accommodating the diverse physicochemical characteristics of multiple therapeutic agents. Towards this end, we have developed a nanoparticle (NP) platform to simultaneously deliver cisplatin and siRNA targeting specific genes encoding Rev1 and Rev3, essential TLS proteins, to the same tumor cells. NPs are formulated through self-assembly of a biodegradable copolymer and a self-synthesized cationic lipid. Both siRNA and cisplatin prodrug can be co-encapsulated within the resultant NPs at high loading efficiencies (up to 11%) and sustainably released over 10 days. The in vitro and in vivo gene silencing capacities of siRNA-containing NPs was first evaluated using anti-firefly luciferase siRNA as a reporter gene. Up to 98% silencing efficacy could be achieved in Dual-Luc HeLa cells with a small siRNA dose (2.5 nM), a result which is markedly better than the commercially available Lipo2000-siRNA complex. Twenty-four hours after siRNA-NP administration, the bioluminescence images of mice bearing luciferase-expressing tumor showed approximately 80% less luminescence intensity compared to the control group. The therapeutic efficacy of NPs containing both cisplatin and anti Rev1/3 siRNA was also evaluated in vitro and in vivo. The sensitivity of LNCaP cells to cisplatin increased up to 10-fold after treatment with NPs carrying anti Rev1/3 siRNA and cisplatin prodrug. RT-PCR results showed that anti Rev1/3 siRNA-NPs exhibited sustained suppression of both genes (up to 90%) in tumors for up to 3 days. We further demonstrated that administration of NPs loaded with both anti Rev1/3 siRNA and cisplatin prodrug can induce a synergistic tumor suppression effect in a prostate cancer (PCa) xenograft mouse model. This work presents a promising “two-in-one” nanomedicine approach for cancer therapy.

Citation Format: Xiaoyang Xu, Xueqing Zhang, Kun Xie, Eric Pridgen, Robert Langer, Graham Walker, Omid Farokhzad. Enhancing tumor cell response to chemotherapy by simultaneous delivery of siRNA and cisplatin using polymeric nanoparticles. [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 5616. doi:10.1158/1538-7445.AM2013-5616