ATRP fabricated and short chain polyethyleneimine grafted redox sensitive polymeric nanoparticles for co-delivery of anticancer drug and siRNA in cancer therapy.

To overcome the limitations of conventional chemotherapy, nanoparticle mediated combinatorial delivery of siRNA and drug represents a new approach to overcome its associated side effects. Designing safe and efficient vehicles for their co-delivery has emerged as a potential challenge in the clinical translation of these formulations. Herein, we have demonstrated a novel "two in one" polyplex nanosystem developed from redox sensitive, short chain polyethyleneimine modified poly[(poly(ethylene)glycol methacrylate]-s-s-polycaprolactone copolymer synthesised by ATRP, which can deliver doxorubicin and polo like kinase I siRNA, simultaneously for enhanced chemotherapeutic effect. The nanoparticles were found to be stable at physiological buffer with and without FBS. The developed polymeric nanosystem was found to be biocompatible and hemocompatible in vitro and in vivo at repeated dose administration. The polymer could easily self-assemble into ~100 nm spherical nanoparticles with enhanced doxorubicin loading (~18%) and effective siRNA complexation at polymer to siRNA weight ratio of 15. The doxorubicin loaded nanoparticles exhibited ~ 4 fold higher drug release in endosomal pH (pH 5) containing 10 mmol GSH compared to pH 7.4, depicting their redox sensitive behavior. The polyplexes were capable of delivering both cargos simultaneously to cancer cells in vitro as observed by their excellent co-localization in the cytoplasm of MDA-MB-231 and HeLa cells using confocal laser microscopy. Moreover, in vitro transfection of the cells with polyplexes exhibited 50-70 % knockdown of plk1 mRNA expression in both cell lines. In vivo administration of the drug loaded polyplexes to EAT tumor bearing Swiss albino mice depicted ~ 29 fold decrease in percent tumor volume in comparison to control group. The results highlight the therapeutic potential of the polyplexes as combined delivery of doxorubicin and plk1 siRNA in cancer therapy.