Stimuli-Responsive Polymer–Prodrug Hybrid Nanoplatform for Multistage siRNA Delivery and Combination Cancer Therapy

Abstract

Nanoparticles (NPs) formulated with cationic lipids and/or polymers have shown substantial potential for systemic delivery of RNA therapeutics such as small interfering RNA (siRNA) for the treatment of cancer and other diseases. While both cationic lipids and polymers have demonstrated the promise to facilitate siRNA encapsulation and endosomal escape, they could also hamper cytosolic siRNA release due to charge interaction and induce potential toxicities. Herein, a unique polymer–prodrug hybrid NP platform was developed for multistage siRNA delivery and combination cancer therapy. This NP system is composed of (i) a hydrophilic polyethylene glycol (PEG) shell, (ii) a hydrophobic NP core made with a tumor microenvironment (TME) pH-responsive polymer, and (iii) charge-mediated complexes of siRNA and amphiphilic cationic mitoxantrone (MTO)-based prodrug that are encapsulated in the NP core. After intravenous administration, the long-circulating NPs accumulate in tumor tissues and then rapidly release the siRNA–prodrug complexes via TME pH-mediated NP disassociation for subsequent tissue penetration and cytosolic transport. With the overexpressed esterase in tumor cells to hydrolyze the amphiphilic structure of the prodrug and thereby induce destabilization of the siRNA–prodrug complexes, the therapeutic siRNA and anticancer drug MTO can be efficiently released in the cytoplasm, ultimately leading to the combinational inhibition of tumor growth via concurrent RNAi-mediated gene silencing and MTO-mediated chemotherapy.