Chitosan-Coated PLGA Nanoparticles for Sustained Delivery of Epigallocatechin Gallate and Differential Cytotoxicity in HepG2 and HepaRG Cells

Introduction: Epigallocatechin-3-gallate (EGCG) is a green-tea catechin with well-documented antiproliferative activity, but its short half-life and poor stability in physiological media limit its application. This study aimed to develop chitosan-coated poly(lactic-co-glycolic acid) (PLGA) core-shell nanoparticle carriers for EGCG, with assessing the effect of the chitosan shell on their release kinetics and concentration-response behavior in hepatic carcinoma and non-tumorigenic hepatic cells in vitro. Methods: EGCG-loaded PLGA nanoparticles were prepared by emulsion solvent evaporation at nominal loadings of 0.5, 1, and 1.5 wt% and then coated with chitosan. Morphology and size were characterized by field-emission scanning electron microscopy (FE-SEM), chemical composition by Fourier-transform infrared spectroscopy (FTIR), and EGCG release in phosphate-buffered saline (PBS) up to 30 days by UV-Vis spectroscopy. Release profiles were fitted to the zero-order, first-order, Higuchi and Korsmeyer-Peppas models. Metabolic cell viability was assessed by MTT assay in human hepatocellular carcinoma HepG2 cells and non-tumorigenic hepatic HepaRG cells until 5 days, and the concentration-response data were fitted with a Hill model. Results: The uncoated and chitosan-coated particles had mean diameters of 117 ± 8 and 144 ± 6 nm, respectively, giving an estimated dry shell thickness of 13.5 ± 5.0 nm. The application of the chitosan shell reduced the first 24 h burst release from 25.7 to 10.3– 15.6% and extended the profile to a plateau from 25 to 27 days. Release from the coated formulations was best described by the Higuchi model, with Korsmeyer-Peppas exponents of 0.55– 0.63 indicating anomalous (non-Fickian) transport, against n = 0.46 showing Fickian transport for the uncoated reference. Encapsulation efficiencies were 85.2– 88.8%, corresponding to delivered EGCG doses of 4.26– 12.98 μg mL − 1 at the applied nanoparticle concentration of 1 mg mL − 1 . HepG2 metabolic viability decreased in a concentration-dependent manner to 26.4 ± 1.8% of the untreated control on day 5, corresponding to 73.6% growth inhibition, with a fitted IC50 of 8.2 μg mL − 1 . Over the same dose range, HepaRG viability remained at or above 92.4% and no IC 5 0 was reached (> 13 μg mL − 1 ). The drug-free carrier was non-cytotoxic in both cell lines. Conclusion: A chitosan shell on EGCG-loaded PLGA nanoparticles suppresses burst release and shifts the transport mechanism from Fickian to anomalous, producing sustained release to 27 days. The resulting formulations reduce HepG2 metabolic viability in a concentration-dependent manner, while leaving HepaRG viability above the ISO 10993– 5 cytotoxicity threshold. Keywords: natural anticancer compounds, drug delivery, release kinetics, nanocarriers