Advances in Physically Crosslinked Thermoresponsive Nanocomposite Hydrogels for Prolonged Drug Delivery

ABSTRACT In this study, we synthesized and characterized thermoresponsive poly( N ‐isopropylacrylamide), pNIPAAm, hydrogels physically crosslinked with unmodified and acid‐activated Laponite (Lap) XLG nanoparticles to evaluate their potential for developing drug delivery systems with prolonged release. Specifically, we studied the effect of Lap incorporation on the absorption and release profiles of the widely used anticancer drug doxorubicin (DOXO). We also investigated the effect of sulfuric acid concentrations used for Lap activation on the physicochemical properties of the nanocomposite hydrogels, including their morphology, swelling behavior, and phase transitions. We showed that acid activation of Lap significantly increased the swelling capacity (up to a threefold to sevenfold increase in equilibrium water content) and shifted the phase transition temperatures (PTTs) closer to physiological conditions at lower acid concentrations (from 30.4°C to 32.1°C), whereas at acid concentrations above 4 N, the PTTs were decreased to 26.9°C for Lap treated with 16 N acid. Moderate acid activation with 2–4 N sulfuric acid produced hydrogels that achieved an optimal balance between high DOXO loading and sustained release, thereby mitigating the initial burst release and prolonging drug release over several days. This work highlights the role of acid‐activated Lap nanoparticles in modifying and adjusting the physicochemical and drug‐release properties of pNIPAAm‐based nanocomposite hydrogels, while identifying challenges in optimizing their performance for targeted cancer therapies.