Abstract 4590: Cisplatin-RNAi nanotherapeutics for synergistic anti-tumor activity

Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, the development of acquired chemoresistance is a persistent clinical problem limiting the successful treatment of malignancies and considerable work has been done to identify the molecular mechanisms involved. Many possible mechanisms have been suggested for platinum resistance emergence, such as drug efflux, apoptosis inhibition among others. Recent studies have shown that the suppression of crucial gene products (e.g. REV1, REV3L) involved in the error-prone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy. Due to the lack of effective inhibitors and the undruggable feature of some targets, it is not easy to screen and validate the target combinations, especially in vivo. Since synthetic siRNA has emerged as a class of attractive therapeutics for treatment of various cancers by silencing genes that cause diseases. Given the ability to target and silence nearly any gene of interest, specific siRNA can be constructed to target genes encoding proteins involved in DNA repair and the acquisition of multidrug resistance. Although a powerful means to silence the expression of target genes, the safe and effective systemic delivery of siRNA therapeutics remains an important challenge. Herein we have developed an innovative chemo-RNAi nanotherapeutic strategy that can simultaneously deliver platinum drugs and multiple siRNAs. We hypothesize that the NP-mediated delivery of multiple siRNAs against different platinum resistance mechanisms will allow the validation of key targets. We aim to improve the efficacy of chemotherapy through additive or synergistic effects coupled by platinum drug and siRNAs targeting different drug resistance mechanisms. As proof-of-concept, we have used poly(lactide-co-glycolide)-b-poly(ethylene glycol)-lipid hybrid nanocarriers as a delivery platform, translesion DNA polymerases Rev1/3L as model target proteins responsible for platinum resistance, and prostate cancer as a model disease. We have successfully created polymer-lipid NPs that exhibited simultaneous entrapment of siRNA (up to 99%) and cisplatin (around 10%). The size of the NPs ranges from 180 to 220 nm and the drug release profile shows a controlled release of cisplatin and siRNA over 10 days. We demonstrated the potency of the siRNA-containing NPs to efficiently knockdown target genes both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1/REV3L specific siRNAs was further investigated in vitro and in vivo. qRT-PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 days after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in an LNCaP xenograft mouse model that was strikingly more effective than platinum monotherapy. Note: This abstract was not presented at the meeting. Citation Format: Xiaoyang Xu, Xueqing Zhang, Kun Xie, Graham Walker, Omid Farokhzad. Cisplatin-RNAi nanotherapeutics for synergistic anti-tumor activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4590. doi:10.1158/1538-7445.AM2014-4590