Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug

Significance The development of acquired chemoresistance is often a clinical problem limiting the successful treatment of cancers. RNAi is showing promising results in human clinical trials. The combination of chemotherapy with RNAi approaches to suppress the expression of proteins involved in the emergence of drug resistance represents a promising synergistic strategy to circumvent or reverse acquired chemoresistance. Such combination therapy approaches require specific delivery vehicles to encapsulate and deliver chemotherapy and siRNA therapeutics simultaneously in a controlled manner. Herein, we describe a nanoparticle technology to codeliver a DNA-damaging chemotherapeutic and siRNAs that impair the cell’s ability to repair the DNA damage. This combination therapeutic approach can sensitize cancer cells to chemotherapeutics and shows superior tumor inhibition compared with monochemotherapy. Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNA-damaging agents. 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 and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNA-based therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1/REV3L-specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide-coglycolide)-b-poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently 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. Quantitative real-time PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy.