Tailoring Drug Release through Thermoresponsive MeHA–NIPA Hydrogels: A 5-Fluorouracil Model System

Methacrylated hyaluronic acid (MeHA) hydrogels combined with poly(N-isopropylacrylamide) (PNIPA) were developed as temperature-responsive carriers for the sustained delivery of 5-fluorouracil (5-FU). MeHA was synthesized via glycidyl methacrylate (GMA) modification and confirmed by Fourier-transform infrared spectroscopy (FTIR) and Proton Nuclear Magnetic Resonance (¹H-NMR) analyses. Four MeHA–NIPA hydrogel compositions (10/90, 20/80, 30/70, and 40/60) were prepared through redox polymerization. Differential scanning calorimetry (DSC) revealed that increasing MeHA content shifted the volume phase transition temperature above the lower critical solution temperature (LCST) of PNIPA, owing to hydrogen bonding and enhanced crosslink density. Swelling studies at 25, 30, and 40 °C showed clear thermo-responsive behavior, with maximum water uptake observed at 25 °C. Drug loading efficiency correlated with swelling, reaching the highest value (85.2 ± 2.1%) for MeHA–NIPA-1, while the hydrogel with the highest crosslink density (MeHA–NIPA-4) exhibited the lowest capacity. In vitro release experiments at 37 °C (pH 7.4) demonstrated distinct composition-dependent profiles. MeHA–NIPA-3 achieved the fastest and highest cumulative release (~90%), while MeHA–NIPA-4 provided the most sustained release (~83–85%) over seven days. Kinetic modeling indicated that the release mechanism followed Fickian diffusion, best described by Weibull (R² = 0.903–0.977) and Korsmeyer–Peppas models (R² = 0.891–0.967). Shape parameter (β < 0.3) values confirmed diffusion-controlled transport. Overall, MeHA–NIPA hydrogels successfully integrated HA’s biocompatibility with PNIPA’s thermal responsiveness, enabling tunable 5-FU delivery. These findings highlight their potential as intelligent systems for controlled chemotherapy applications.