Polysaccharide hydrogels regulate macrophage polarization and enhance the anti-tumor efficacy of melanoma

Chemotherapy occupies a prominent position in combination treatments of melanoma. However, the severe systemic side effects and the pro-tumorigenic microenvironment limited its therapeutic efficacy. In the present study, polysaccharide hydrogels (SCOD) were constructed by N-succinyl chitosan and oxidized dextran through Schiff-base formation to deliver doxorubicin (Dox) locally. The gelation time and mechanical properties of SCOD hydrogels could be fine-tuned by varying concentration of precursor solutions. Rheological data revealed that SCOD hydrogels possessed injectable shear-shinning property and remarkable self-healing capability. It also could be degraded by lysozyme widely present in body fluids. Moreover, SCOD hydrogels were readily loaded with Dox in precursor solutions and released drug over 1 week in a pH-dependent manner. The ability of Dox-loaded SCOD hydrogels to inhibit the growth of murine B16 and human A375 melanoma was verified by in vitro assays. Strikingly, Dox-loaded SCOD hydrogels were found to efficiently induce polarization of tumor-associated macrophages towards M1 phenotype that favors an anti-tumorigenic tumor microenvironment. Notably, in vivo experiments demonstrated that locally injected Dox-loaded SCOD hydrogels exhibited excellent anti-tumor activity against B16 melanoma, outperforming Dox at equivalent doses administrated intravenously. Therefore, the injectable and self-healing polysaccharide hydrogels are a promising strategy to improve locoregional control in melanoma.