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

Abstract

Background: Despite exhibiting promising anticancer potential, the clinical significance of capecitabine (a potent prodrug of 5-fluorouracil used for 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 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. Capecitabine loading was ranged 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) best fit model was zero order. The extensive toxicity evaluations evidenced 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 pH-responsive system for controlled delivery of anticancer agents.

Anticancer Drugs: Recent Strategies to Improve Stability Profile, Pharmacokinetic and Pharmacodynamic Properties

“…To overcome these limitations, prodrugs have also been incorporated into different controlled delivery systems. As an example, capecitabine has been formulated in co-polymeric hydrogel as a smart pH-responsive network to facilitate its oral administration, reducing its sensitivity to gastric pH [ 118 ]. To overcome some of the therapeutic disadvantages of 6-thioguanine, a supramolecular ternary system, involving the inclusion of the drug in β-cyclodextrins (βCD) and a subsequent interaction of the βCD-thioguanine complex with gold NPs, has been proposed.…”

Polymeric nanoparticles—Promising carriers for cancer therapy

“…Different comonomers give different hydrophobicity to the hydrogels, causing different pHsensitive behaviors. Examples of these are hydrogels based on poly (lactic acid), methoxyl poly (ethylene glycol), and itaconic acid prepared by Ke Wang; pH-responsive co-polymeric hydrogels studied by Umaira Rehman; and polyacrylamide grafted pectin pH-sensitive hydrogel reported by Prashant B. Sutar (Omidia et al, 2019;Sarfraz et al, 2019;Rehman et al, 2021).…”