A pH-responsive drug delivery system based on phenylboronic acid-conjugated dextran hydrogel for doxorubicin release via dynamic boronate ester bonds

Stimuli-responsive drug carriers based on dynamic covalent bonds, particularly boronate esters, have attracted significant attention for their ability to enable targeted release in specific microenvironments. In this study, an intelligent dextran-based hydrogel was developed through the Hantzsch multicomponent cross-linking strategy integrated with pH-sensitive boronate ester bonding. This hydrogel (DHPD-FPBA) features a dual-network architecture comprising rigid 1,4-dihydropyridine (DHP) covalent networks and dynamic boronate ester cross-links, achieved by employing 4-formylphenylboronic acid (FPBA) as a functional aldehyde component in the Hantzsch reaction. Comprehensive structural and morphological analyses confirmed successful formation, tunable cross-linking density, pronounced pH-dependent swelling and mechanical behavior with rapid framework disintegration under acidic conditions (pH 5.0). Doxorubicin (DOX) was efficiently loaded via boronate ester conjugation and released in a pH-responsive manner, with over 65 % release within 48 h at pH 5.0 compared to less than 25 % at pH 7.4. The release kinetics, which adhered to the Peppas model, indicated a diffusion–erosion coupled mechanism. Furthermore, the hydrogels demonstrated high biocompatibility in cytotoxicity assays, and confocal microscopy revealed efficient cellular internalization of the released DOX. These results underscore the potential of DHPD-FPBA hydrogel as a promising platform for tumor-microenvironment-targeted drug delivery.