RSM optimization of Tetracycline-loaded PLGA nanoparticles in chitosan/HPMC hydrogels for sustained antibacterial delivery

The rising prevalence of antimicrobial resistance and biofilm infections requires innovative drug delivery systems for sustained local antibiotic release with minimal systemic exposure. This study reports the development and characterization of novel nanocomposite hydrogels combining chitosan (CS) and hydroxypropyl methylcellulose (HPMC) matrices embedded with optimized tetracycline (TTC)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for sustained antibacterial delivery. Using a double emulsion solvent evaporation technique, TTC-loaded PLGA NPs were fabricated, and their physicochemical properties—including particle size, encapsulation efficiency % (EE), and drug loading % (DL)—were optimized via Response Surface Methodology (RSM) based on a Box-Behnken design. Optimized NPs exhibited a size of ~ 229 nm, EE of 57.2%, and DL of 0.72%. Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) confirmed successful encapsulation and spherical morphology of the NPs. In vitro release profiles revealed biphasic TTC release from free drug-loaded CS/HPMC hydrogels (95% within 6 h; ~98% by 24 h), whereas NP-loaded nanocomposites exhibited sustained kinetics (initial burst of ~ 48% in 6 h; ~60% at 24 h). Disk diffusion assays confirmed potent antibacterial effects of nanocomposite hydrogels against both E. coli and S. aureus, superior to free drug formulations. Incorporation of optimized NPs into a CS/HPMC hydrogel matrix yielded nanocomposite hydrogels with enhanced mechanical integrity, controlled swelling behavior, and reduced degradation rates compared to hydrogels with free drug or without NPs. This platform leverages hydrogel-NP synergy for prolonged TTC delivery in localized infection management and resistance mitigation.