A sodium alginate-based injectable hydrogel system for locoregional treatment of colorectal cancer by eliciting pyroptosis and apoptosis.

Effective delivery of sufficient doxorubicin (DOX) molecules in tumors is hindered by the complex biological barriers. Herein, a DOX-loaded sodium alginate-based injectable hydrogel (DOX@MHB-conj-SA) was designed by the Michael addition reactions between the sulfydryl in cross-linkers and the double bonds in a derivative of sodium alginate. DOX@MHB-conj-SA was administrated to CT26 tumor-bearing mice via peritumoral injection for locoregional treatment of colorectal cancer by inducing apoptosis and pyroptosis. The released DOX molecules were localized within tumors, resulting in pronounced anti-tumor effects as evidenced by reduced tumor volumes (29.6 ± 43.7 mm), less tumor weights (58.4 ± 48.4 mg), higher inhibition rate (92.7 ± 4.9 %), and diminished Ki67 staining (2.15 ± 0.4 %). Meanwhile, DOX triggered pyroptosis in CT26 cells through the activation of caspase-3 to cleave gasdermin E, promoting potent anti-tumor immunity. The pyroptosis in CT26 cells was verified by characteristic cellular changes, including cell swelling, membrane blebbing, and cell rupture. Additionally, the immunogenicity of CT26 cells triggered by pyroptosis was demonstrated by the immunofluorescence imaging of GSDME, CD3, CD4, CD8 T cells, and CD31 in tumor sections. The hydrogel-based locoregional therapy represents a novel platform that combines the pyroptosis and apoptosis of DOX, thereby enhancing the therapeutic efficacy against colorectal cancer.