ATRP Fabricated and Short Chain Polyethylenimine Grafted Redox Sensitive Polymeric Nanoparticles for Codelivery of Anticancer Drug and siRNA in Cancer Therapy

摘要

To overcome the limitations of conventional chemotherapy, nanoparticle-mediated combinatorial delivery of siRNA and drugs represents a new approach to overcome its associated side effects. Designing safe and efficient vehicles for their codelivery 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 polyethylenimine modified poly[(poly(ethylene)glycol methacrylate]-s-s-polycaprolactone copolymer synthesized by atom-transfer free-radical polymerization (ATRP), which can deliver doxorubicin and polo-like kinase I (plk1) siRNA, simultaneously for an enhanced chemotherapeutic effect. The nanoparticles were found to be stable at physiological buffer with and without fetal bovine serum (FBS). The developed polymeric nanosystem was found to be biocompatible and hemocompatible in vitro and in vivo at repeated dose administrations. The polymer could easily self-assemble into similar to 100 nm spherical nanoparticles with enhanced doxorubicin loading (similar to 18%) and effective siRNA complexation at a polymer to siRNA weight ratio of 15. The doxorubicin loaded nanoparticles exhibited similar to 4-fold higher drug release in endosomal pH (pH 5) containing 10 mmol of 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 colocalization 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 (EAT, Ehrlich ascites tumor) Swiss albino mice showed a similar to 29-fold decrease in percent tumor volume in comparison to the control group. The results highlight the therapeutic potential of the polyplexes as a combined delivery of doxorubicin and plk1-siRNA in cancer therapy.