Hyaluronic Acid-Coated Isoniazid-Chitosan Nanoparticles forMacrophage-Targeted Drug Delivery in Tuberculosis Therapy

Introduction: Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a global health challenge, with lengthy treatment regimens, drug resistance, and systemic side effects hindering effective therapy. This study aimed to develop and evaluate hyaluronic acidcoated isoniazid-chitosan nanoparticles (HA-coated IS-CNP) as a macrophage-targeted drug delivery system to improve isoniazid bioavailability and reduce systemic exposure. Materials and Methods: Isoniazid-chitosan nanoparticles (IS-CNP) were manufactured using solvent evaporation, optimized using a design of experiments approach, and coated with hyaluronic acid. The nanoparticle formulations were evaluated for particle size, morphology, EE, and zeta potential. The in vitro release investigations of drug-containing nanoparticle formulations were conducted to analyze release kinetics, and macrophage uptake was evaluated in RAW 264.7 cells. Pharmacokinetic studies in Wistar rats were conducted to assess the oral bioavailability of HA-coated IS-CNP in comparison to uncoated nanoparticles and pure isoniazid. Results: The optimized HA-coated IS-CNP formulation displayed a particle size of approximately 512 nm, high EE, and stable zeta potential. FTIR and XRD analyses confirmed successful hyaluronic acid coating. In vitro release studies followed a Higuchi model, suggesting a diffusion-controlled mechanism with a non-Fickian release pattern. Macrophage uptake of HA-coated IS-CNP was significantly higher than uncoated nanoparticles and pure isoniazid. Pharmacokinetic studies indicated a substantial increase in AUC for HA-coated IS-CNP, indicating prolonged systemic circulation and enhanced bioavailability. Discussion: The improved macrophage uptake and extended circulation time of HA-coated IS-CNP underscore the potential of HA as a targeting ligand and stabilizing agent in nanoparticulate drug delivery systems. The diffusion-controlled release mechanism and improved pharmacokinetic profile support the efficacy of this novel formulation. Conclusion: The development of hyaluronic acid-coated isoniazid-chitosan nanoparticles represents significant progress in the field of TB therapy. By enhancing bioavailability and targeting the macrophages while reducing systemic side effects, this new drug delivery approach provides a potential for improving TB treatment.