One-Pot Synthesis of Enzyme and GSH Dual-Responsive Zwitterionic Copolymers with Cross-Linked Shells for Enhanced Anticancer Drug Delivery

Cross-linked polymeric micelles capable of undergoing de-cross-linking triggered by tumor microenvironment (TME) provide a solution to the extracellular stability vs intracellular destabilization dilemma of nanomedicine. Herein, we reported a simple yet effective strategy for the one-pot construction of enzyme and glutathione (GSH) dual-responsive zwitterionic copolymer micelles consisting of hydrophobic enzyme-degradable polytyrosine (PTyr) cores and cross-linked zwitterionic poly(oligo(ethylene glycol)monomethyl ether methacrylate- co -sulfobetaine methacrylate- co -disulfide dimethacrylate) ( P (OEGMA- co -SBMA- co -DSDMA)) shells. Notably, the development of unimolecular zwitterionic copolymer micelles could be achieved simultaneously in the polymer synthesis process via regulating the feed ratio of a functionalized monomer, DSDMA, as a cross-linker. The optimized polymer construct could form stable unimolecular micelles with a drug-loading content (DLC) of 14.9% and an entrapment efficiency (EE) of 87.7% for DOX, along with promoted in vitro drug release and tumor inhibition ratio (TIR). The simple synthetic strategy developed herein provides a widespread approach for the production of multifunctional cross-linked polymeric delivery systems for efficient anticancer drug transportation.