Chemically Cross-Linked Nanocapsules from Terpolymers of Polyethylene Glycol-Polylactide with Cationic Pendent Groups for Pgp-siRNA and Doxorubicin Codelivery in Overcoming Multidrug Resistance in Breast Cancer

Cancer remains one of the leading causes of mortality worldwide. Among current treatment strategies, chemotherapy continues to play a central role; however, its therapeutic efficacy is markedly compromised by the development of multidrug resistance (MDR) in cancer cells. To address this challenge, a new triblock copolymer, poly(ethylene glycol)-b-poly(lactide)-b-poly(cationic polylactide) (PEG-b-PLA-b-CPLA), was first synthesized and converted into biodegradable charged nanocapsules (BCNCs) without the use of surfactants or additives via our developed nanoemulsion interfacial cross-linking technique. With favorable biodegradability, BCNCs exhibit the ability to coload both hydrophobic drugs and hydrophilic genes. Compared with other drug/gene carriers, they feature controllable charge and surface poly(ethylene glycol) (PEG) density, high colloidal stability, and sequential release of the loaded genes and drugs. When loaded with a hydrophobic anticancer drug, dehydrochlorination doxorubicin (Dox), and a hydrophilic P-glycoprotein (Pgp) silencing gene (Pgp-siRNA), the resulting Pgp-siRNA/Dox-coloaded BCNCs successfully demonstrated the ability to overcome MDR in MCF-7/ADR cells, due to enhanced cellular uptake, Pgp silencing efficiency, and effective endosomal/lysosomal escape of the loaded therapeutics.