Smart pH-responsive Co-polymeric Hydrogels for Controlled Delivery of Capecitabine: Fabrication, Optimization and In Vivo Toxicology Screening

Background: Despite exhibiting promising anticancer potential, the clinical significance of capecitabine (a potent prodrug of 5-fluorouracil used for the treatment of colorectal cancer) is limited owing to its acidic and enzymatic hydrolysis, lower absorption following the oral administration, poor bioavailability, short plasma half-life, and poor patient compliance. Objectives: The present study was aimed to fabricate the capecitabine as a smart pH-responsive hydrogel network to efficiently facilitate its oral delivery while shielding its stability in the gastric media. Methods: The smart pH-sensitive HP-β-CD/agarose-g-poly(MAA) hydrogel network was developed using an aqueous free radical polymerization technique. The developed hydrogels were characterized for drug-loading efficiency, structural and compositional features, thermal stability, swelling behaviour, morphology, physical form, and release kinetics. The pH-responsive behaviour of developed hydrogels was established by conducting the swelling and release behaviour at different pH values (1.2 and 7.4), demonstrating significantly higher swelling and release at pH 7.4 as compared with pH 1.2. The capecitabine-loaded hydrogels were also screened for acute oral toxicity in animals by analysing the body weight, water and food intake, dermal toxicity, ocular toxicity, biochemical analysis, and histological examination. Results: The characteristic evaluations revealed that capecitabine (anticancer agent) was successfully loaded into the hydrogel network. The range of capecitabine loading was from 71.22% to 90.12%. An interesting feature of hydrogel was its pH-responsive behaviour which triggers release at basic pH (94.25%). Optimum swelling (95%)was seen at pH 7.4. Based upon regression coefficient R2(0.96 – 0.99) the best-fit model was zero-order. The extensive toxicity evaluations evidenced a good safety profile with no signs of oral, dermal, or ocular toxicities, as well as no variations in blood parameters and histology of vital organs. Conclusion: Our findings conclusively evinced that the developed hydrogel exhibited excellent pharmaceutical and therapeutic potential and thus can be employed as a pH-responsive system for the controlled delivery of anticancer agents.