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 analogues 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 our 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 (PCL₂₅‐SS‐OPDEA₃₀) was designed and synthesized successfully via combination of controlled polymerization techniques and post polymerization modification. Specifically, post‐oxidation of poly(tertiary amine) was 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 was investigated in detail. Notablely, the resulting micelles self‐assembled from PCL₂₅‐SS‐OPDEA₃₀ 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.

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