pH-responsive oxidized sodium alginate–carboxymethyl chitosan hydrogel for locoregional delivery of celastrol in melanoma therapy with reduced systemic toxicity

Melanoma is a highly aggressive malignancy with limited effective and safe therapeutic options. Celastrol (CEL) exhibits potent antitumor activity but its clinical application is restricted by poor druggability and systemic toxicity. Herein, a pH-responsive injectable hydrogel based on oxidized sodium alginate (OSA) and carboxymethyl chitosan (CMCS) was developed for locoregional delivery of celastrol in melanoma therapy. The hydrogel was formed via dynamic Schiff base crosslinking, enabling structural stability under physiological conditions and accelerated degradation under mildly acidic conditions. The OSA-CMCS hydrogel exhibited favorable injectability and shear-thinning behavior, and enabled sustained CEL release that was accelerated at pH 6.5 in vitro. In B16-F10 melanoma-bearing C57BL/6J mice, compared with free CEL at an equivalent dose, peritumoral administration of CEL@Gel significantly suppressed tumor growth, as evidenced by reduced tumor volume and weight, increased tumor apoptosis, and decreased proliferative activity. In vivo fluorescence imaging using Cy5.5 as a surrogate tracer demonstrated prolonged tumor-localized signal retention following hydrogel-mediated delivery. Moreover, hematological analysis and histological examination of major organs revealed no detectable systemic toxicity. Overall, this study demonstrates that pH-responsive hydrogel-mediated locoregional delivery can effectively enhance the antitumor efficacy and safety profile of celastrol, providing a practical locoregional delivery strategy for improving the therapeutic index of celastrol in melanoma.