Stimuli-sensitive hyaluronic acid hydrogels for localized and controlled release of antibodies

Stimuli-sensitive hydrogels are utilized in therapeutic applications for their ability to function as controlled drug delivery systems, particularly as delivery platforms for antibodies in cancer treatment. Their adaptive properties, including biocompatibility, high water retention, and tunable mechanical strength, make them well-suited for local and sustained drug release. In this study, redox-sensitive hydrogels based on thiolated hyaluronic acid (HA-SH) were synthetized as tunable platforms for controlled antibody delivery in cancer therapy. HA-SH hydrogels with different degrees of substitution (DS30, DS50 and DS70) exhibited distinct structural and mechanical properties, with HA-SH DS70 forming a denser network and demonstrating greater stability compared to HA-SH DS30 and DS50. Swelling and degradation studies confirmed redox responsiveness of the gels, with DS30 gel degrading faster than DS50 and DS70 gels in reductive environments. Rheological analysis further showed that higher cross-linking density in DS70 gels enhanced viscosity and mechanical strength compared to DS50 and DS30. Immunoglobulin G (IgG), used as a model drug for immunotherapeutic agents, was loaded into DS30 and DS70 hydrogels. The release followed zero-order kinetics at pH 7.4, highlighting the influence of the polysaccharide intrinsic anionic properties. DS30 hydrogels demonstrated sustained release (85 ± 6 % in 9 days), while DS70 exhibited faster release (71 ± 7 % in 5 days). The IgG release kinetics relied on a dual mechanism involving the combination of gel erosion (depending on DS and structural features), as well as IgG poly-charged nature and its ionic interactions with the hyaluronic acid polymeric network, as highlighted by rheological measurements and differential scanning calorimetry (DSC) analysis. Overall, the study highlights the potential of HA-SH hydrogels as customizable and localized immunotherapeutic delivery systems for controlled and precise cancer treatment.