Eudragit S100-coated microbeads of thiolated chitosan/casein for pH-responsive colon-targeted delivery of 6-mercaptopurine
TL;DR
Overall, the Eu-S100@TCh/CS microbead system represents a rationally designed colon-targeted delivery platform with potential to improve local therapeutic efficacy and reduce systemic toxicity.
Abstract
6-Mercaptopurine (6-MP) is a potent chemotherapeutic and immunosuppressive agent; however, its oral administration is limited by poor bioavailability and dose-dependent hepatotoxicity. This study aimed to develop and optimize a colon-targeted, pH-responsive delivery system for 6-MP using Eudragit S100-coated thiolated chitosan/casein microbeads (Eu-S100@TCh/CS) to enhance site-specific release and minimize systemic exposure. The microbeads were fabricated via emulsion cross-linking followed by solvent evaporation and optimized using a central composite design. Physicochemical characterization (FTIR spectroscopy, DSC/TGA, PXRD, and SEM) confirmed efficient drug incorporation in a molecularly dispersed state, thermal stability, and a uniform spherical morphology (541–672 µm). Swelling and dissolution studies demonstrated a clear pH-dependent behavior, with minimal swelling and negligible drug release at pH 1.2 and 6.8, and enhanced release (84.5% at 24 h) at colonic pH 7.4, corresponding to the dissolution of the Eudragit S100 coating and hydration of the polymeric core. Drug-release kinetics indicated Higuchi diffusion for uncoated beads (R2 = 0.9852; n = 0.624) and anomalous (non-Fickian) transport for the coated beads (R2 = 0.9994; n = 0.741), governed by combined diffusion and polymer relaxation mechanisms. Acute oral toxicity studies in rats revealed no significant alterations in the biochemical, hematological, or histopathological parameters, confirming systemic safety. In vitro cytotoxicity studies (MTT assay) showed enhanced antiproliferative activity of the 6-MP-loaded microbeads against HCT-116 cells compared to the free drug, attributed to improved solubility and sustained drug availability following release rather than whole-particle internalization. Blank microbeads exhibited high cell viability, confirming carrier biocompatibility. Overall, the Eu-S100@TCh/CS microbead system represents a rationally designed colon-targeted delivery platform with potential to improve local therapeutic efficacy and reduce systemic toxicity. Further studies are warranted to evaluate selectivity using normal colonic cell lines.