Nitroxide-Containing Poly(2-oxazoline)s Show Dual-Stimuli-Responsive Behavior and Radical-Trapping Activity.

2,2,6,6-Tetramethylpiperidine-N-oxyl (TEMPO) structures possess potent antioxidant activities for biomedical applications. TEMPO immobilization on hydrophilic polymers is a powerful strategy to improve its properties; however, it is mostly limited to reversible-deactivation radical polymerizations or postpolymerization approaches. Here, we immobilized TEMPO units on a hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx) backbone through cationic ring-opening polymerization (CROP) of a new 2-oxazoline monomer bearing a methoxy-protected TEMPO 2-substituent with 2-ethyl-2-oxazoline (EtOx). The ratios of EtOx/TempOx were adjusted to optimize the nitroxide content while maintaining suitable water solubility of the resulting P(EtOxx-stat-TempOx-Oy•) copolymers upon deprotection. P(EtOx40-stat-TempOx-O10•) and P(EtOx33-stat-TempOx-O17•) showed a dual stimuli-responsive behavior and demonstrated significant radical-trapping activities in aqueous media. Particularly, a meaningful augmentation in the activity of TempOx-O• was observed when it was immobilized as P(EtOxx-stat-TempOx-Oy•). The P(EtOx40-stat-TempOx-O10•) system exhibited a longer-lasting activity in water, statistically comparable to that of the antioxidant ferrostatin-1 (Fer-1). Overall, this study introduces a biocompatible polymeric platform for TEMPO immobilization that augments its radical-trapping activity and offers controllable stimuli-responsive properties.