Reactive Oxygen Species Sensitive Thioether-Bearing Poly(2-oxazoline)s: Direct and Controlled Polymerization using Initiator Salt.

Reactive oxygen species (ROS)-responsive polymers have attracted significant attention for their potential in biomedical applications, particularly in drug delivery and tissue engineering. This study presents the first direct synthesis and characterization of ROS-responsive thioether-bearing poly(2-oxazoline)s (POx) via controlled cationic ring-opening polymerization (CROP). While typical initiators lead to loss of control over the CROP of 2-(methylthio)-methyl-2-oxazoline, its controlled polymerization was possible via the initiator salt method. The living character was confirmed by kinetic experiments and chain extension, used to synthesize amphiphilic block copolymers. The ROS-responsiveness of the synthesized polymers was evaluated through in vitro studies in the presence of hydrogen peroxide. The amphiphilic self-assemblies disassemble over time, as demonstrated for a triblock copolymer, suggesting a significant change of hydrophilicity of the polymer upon exposure to ROS. Together, the presented synthetic approach has much better atom economy over a previously published approach and enables easy access to ROS-responsive POx with complex architectures.