Multiresponsive Random Terpolymers Based on Phenylboronic Acid for Smart Controlled Insulin Delivery

ABSTRACT pH‐ and glucose‐responsive random terpolymers based on 4‐carboxyphenylboronic acid‐modified 2‐hydroxyethyl methacrylate, 2‐hydroxyethyl methacrylate and 2‐(dimethylamino) ethyl methacrylate, p(HEMA‐PBA‐ co ‐HEMA‐ co ‐DMAEMA), are synthesized via reversible addition‐fragmentation chain transfer (RAFT) polymerization. The terpolymers are prepared with three different DMAEMA contents (20, 30, and 40 mol. %) and phenylboronic acid moieties (20, 15, and 10 mol. %) to investigate the effect of composition on physicochemical and responsive behavior. FT‐IR, 1 HNMR, and GPC confirmed the successful synthesis of well‐defined terpolymers with a narrow molecular weight distribution (M w /M n ∼1.18‐1.19). The p K a values obtained from pH titration and spectral difference analyses decreased as the DMAEMA content increased, likely due to the presence of amino groups that altered the local environment and enhanced the apparent acidity of the terpolymers. Dynamic light scattering (DLS) demonstrated pH‐dependent aggregation and glucose‐sensitive disassembly driven by reversible diol‐boronate complexation. Insulin encapsulation in all samples exhibited high loading efficiencies over 91%. Furthermore, cytotoxicity evaluation using HFF‐2 fibroblast cells confirmed excellent biocompatibility, with cell viability maintained at ∼75% even at high concentrations for both unloaded and insulin‐loaded terpolymers.