Alginate-based dual-drug bridging hydrogels harnessing dynamic PtO coordination for programmed drug delivery and efficient cancer combination therapy.

Abstract

Although hydrogel-based drug delivery shows promise for localized cancer therapy, effective combination strategies remain needed. Herein, a dual-drug bridging hydrogel was engineered using cisplatin (CDDP) and hematoporphyrin (HP) as crosslinking agents to improve combination therapy for tumors. This hydrogel platform facilitates the codelivery of aCTLA-4 antibodies and exhibits potent antitumor efficacy in a melanoma model. PtO coordination bonds among CDDP, HP, and sodium alginate stabilize the scaffold and reduce the burst release of HP, thereby enhancing photodynamic therapy. Under 630 nm laser irradiation, HP produces cytotoxic reactive oxygen species, and the hydrogel matrix breaks down in response to environmental triggers, enabling sustained drug release and resulting in prolonged therapeutic effects. This process induces cell apoptosis and releases tumor antigens and damage-associated molecular patterns. In a subcutaneous B16-F10 melanoma model, aCTLA-4@HP-SC-Gel with laser irradiation achieved exceeding 97% tumor growth inhibition and prolonged 50-day survival, with no obvious systemic toxicity. It increased intratumoral CD8⁺ T cells by 11-fold and promoted M1 macrophage polarization. By integrating chemotherapy, photodynamic therapy, and immunotherapy, this dual-drug bridging hydrogel offers a hopeful strategy for localized treatment of superficial tumors.