Injectable responsive chemodynamic hydrogel for the sustained and localized delivery of a ferroptosis inducer to improve anticancer therapy

Ferroptosis is a promising strategy for cancer therapy because of its distinct reaction mechanism and potential for overcoming cancer drug resistance. However, the efficient tumor-specific delivery of ferroptosis inducers remains a challenge. To address this challenge, we developed a chemodynamic chitosan hydrogel loaded with the ferroptosis inducer ML210 to facilitate sustained and localized drug delivery for effective anticancer therapy. This study is the first to report the integration of ML210, which is a glutathione peroxidase 4 inhibitor, and a Cu-based Fenton nanocatalyst into an in-situ-forming injectable chitosan hydrogel for anticancer therapy. The ML210 encapsulated within the matrix of the developed hydrogel is released in response to reactive oxygen species and an acidic tumor microenvironment, causing localized cytotoxicity to tumor cells by inducing ferroptosis. Furthermore, the chemodynamic property of the developed hydrogel enhances its therapeutic efficacy through a Cu-catalyzed Fenton reaction, with the CaO2 in the hydrogel acting as a H2O2 generator. Moreover, Ca2+ is released from the hydrogel, which induces intracellular Ca2+ overloading in cancer cells, thus synergistically intensifying the ferroptotic effect. An in-vivo evaluation revealed significant tumor growth inhibition and minimal systemic toxicity following intratumoral injection of the developed hydrogel. Overall, our findings highlight the potential of the hydrogel as a promising platform for tumor-site-specific delivery of ML210, hydroxyl radicals, and Ca2+. The synergistic mechanism of this hydrogel—which involves Ca2+ overloading, chemodynamic therapy, and ferroptosis—offers a new avenue for developing cancer therapies with improved efficacy and safety profiles.