The emergence of drug resistance has been a critical barrier for effective cancer chemotherapy. RNA interference (RNAi) has recently shown promise in suppressing the overexpression of drug resistance-associated proteins, and in treating drug resistant cancers through combination with chemotherapeutic agents. Nevertheless, the safe and effective delivery of RNAi therapeutics (e.g., siRNA) to target cells remains a major hurdle for their clinical applications, and the co-delivery of RNAi and chemotherapeutic agents in a controlled fashion requires specific delivery vehicles.We have developed an innovative nanoparticle (NP) platform to tackle the challenges associated with the delivery of siRNAs and chemotherapeutic drugs, using biodegradable and biocompatible polymers and lipids. The hybrid lipid-polymer NP has a unique hollow core/shell nanostructure which provides the delivery system with three distinct functional features: (i) a positively charged inner hollow core for dense loading of siRNA; (ii) a middle hydrophobic polymer layer for the encapsulation of anti-cancer drugs and the controlled release of both siRNA and drug; and (iii) a polyethylene glycol surface to keep the NP stable and prolong its systematic circulation. The hybrid lipid-polymer NPs show excellent silencing of luciferase (~ 80-95%) at low doses of siRNA. These NPs can also efficiently reduce the expression of drug resistance-associated proteins (e.g., REV1/REV3L and Bcl-2). By co-delivering siREV1/REV3L and cisplatin prodrug, the NPs can effectively inhibit DNA repair activity in LNCaP cancer cells and impair cisplatin-induced mutagenesis, and subsequently dramatically improve the sensitivity of LNCaP cells to concurrent released cisplatin. In vivo results demonstrate that the NPs can sufficiently silence the expression of target genes in tumor tissue after single intratumoral administration, and the NP co-delivery strategy can flat-line the growth of LNCaP xenograft. We expect that the chemo-RNAi nanoparticle co-delivery could be of interest in both fundamental cancer research and clinical applications for cancer treatment.

Nanoparticle-mediated chemo-RNAi combination therapy for cancer treatment

247th National Meeting (2014)

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