Development and characterization of injectable, bioadhesive, pH-responsive hyaluronic acid-based hydrogels for enhanced postoperative cancer therapy

Abstract

Cancer recurrence remains a major challenge in postoperative treatment, often due to incomplete surgical resection and the limited effectiveness of conventional chemotherapy. Traditional drug delivery systems show significant limitations, particularly in ensuring sustained local drug release and effective adhesion to irregular tissue surfaces. To address these issues, this study presents an approach for localized cancer therapy using in situ-forming hydrogels that combine injectability, bioadhesion, self-healing properties, and responsiveness to the tumor microenvironment (TME). The hydrogels are based on hyaluronic acid (HA) derivatives, functionalized to impart distinct properties. A hyaluronic acid aldehyde derivative grafted dopamine (HA-ALD-DOPA), which provides bioadhesive characteristics, ensuring the hydrogel's attachment to postoperative sites and preventing displacement due to physiological movements and a HA aldehyde Doxorubicin derivative (HA-ALD-DOXO) loaded with the anticancer drug doxorubicin were both crosslinked with the HA diethylenetriamine derivative (HA-DETA) forming a dynamic Schiff base based platform that contribute to the hydrogel's self-healing and pH-sensitive drug release behaviors. The hydrogels exhibited shear-thinning behavior for easy injectability while maintaining mechanical integrity. In vitro drug release studies confirmed the pH-responsive nature of the system, with controlled release at physiological pH and fast release under acidic conditions, simulating the TME.