Fabrication of GSH‐Responsive Poly(Tertiary Amine‐Oxide)‐Based Nanomedicines for Enhanced Anticancer Drug Release

Abstract Poly(tertiary amine‐oxide)‐based polymeric nanocarriers have showed more functionalities than stealthy PEG‐based analogs due to the structure of phospholipid affinitive N ‐oxides groups, which has attracted considerable attention to the synthesis of various zwitterionic copolymers with tertiary amine‐oxide grafts for enhanced anticancer drug delivery. However, poly(tertiary amine‐oxide)‐based amphiphilic copolymers with tumor intracellular microenvironment sensitivities, to the knowledge, have been rarely reported likely due to the lack of a controlled synthetic strategy. Herein, a reducible zwitterionic copolymer, poly( ε ‐caprolactone) 25 ‐SS‐poly(2‐( N ‐oxide‐ N , N ‐diethylamino)ethyl methacrylate) 30 (PCL 25 ‐SS‐OPDEA 30 ) is designed and synthesized successfully via combination of controlled polymerization techniques and post polymerization modification. Specifically, postoxidation of poly(tertiary amine) is confirmed to be a better synthetic strategy toward a well‐defined polymer structure relative to direct polymerization of N , N ‐diethylaminoethyl methacrylate (ODEA). The effect of disulfide bridges on the self‐assembly behaviors, in vitro drug loading and drug release properties is investigated in detail. Notablely, the resulting micelles self‐assembled from PCL 25 ‐SS‐OPDEA 30 show much greater colloidal stability, higher drug loading content (DLC), and better in vitro tumor cell inhibition than the reduction‐insensitive counterparts. Overall, this study reports a robust strategy toward zwitterionic nanomedicines for on‐demand anticancer drug delivery.