Dual pH‐ and Temperature‐Responsive P(AAc‐co‐C16A) Shape‐Memory Hydrogels for Controlled Drug Release

ABSTRACT This study presents an amphiphilic shape‐memory hydrogel (SMH) based on poly(acrylic acid‐co‐n‐hexadecyl acrylate) [P(AAc‐co‐C16A)] that integrates pH and temperature responsiveness within a single molecular network. The hydrophobic C16 side chains form reversible crystalline domains that act as physical cross‐links, imparting thermal shape‐memory and mechanical strength, while ionizable acrylic acid units provide pH‐dependent swelling and charge regulation. An optimal composition containing 30 mol % C16A exhibited a balanced combination of mechanical robustness ( E ≈ 15 MPa), a high shape‐recovery ratio (>93 %), and a thermoresponsive transition near physiological temperature (37°C–39°C). Ibuprofen‐loaded SMHs demonstrated strongly pH‐dependent and thermally accelerated drug release, with enhanced release under mildly acidic conditions and further acceleration upon shape recovery. Cytocompatibility assays confirmed the hydrogels’ safety for normal fibroblasts, while selective cytotoxicity toward MDA‐MB‐231 breast cancer cells underscored their therapeutic potential. Overall, P(AAc‐co‐C16A) SMHs provide a molecularly tunable platform that couples shape‐memory functionality with controlled, dual‐stimulus drug delivery. Their combination of reversibility, biocompatibility, and mechanical resilience offers new opportunities for localized and on‐demand release systems in cancer therapy and next‐generation 4D‐printed biomedical devices.