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To mitigate off-target drug toxicity, hypoxia-activated prodrugs have been designed for precise tumor treatment. However, their therapeutic efficiency is often constrained by limited drug release and the development of anticancer drug resistance. In this study, we combined hypoxia-activated chemotherapy with photodynamic therapy (PDT) to develop a new hypoxia-activated cationic iridium(III) complex prodrug, Ir-azo-Cl, for enhancing drug release with robust synergistic chemo-photodynamic therapy of tumors. Ir-azo-Cl can be selectively activated by tumor hypoxia to release a cationic iridium(III) complex photosensitizer and chemotherapeutic drug. Two-photon PDT-induced self-immolation of Ir-azo-Cl further accelerates drug release, amplifying the therapeutic effect. To enhance tumor targeting and accumulation, Ir-azo-Cl was encapsulated into folate-functionalized phospholipids, resulting in the formation of a nanoprodrug (DPF@Ir-azo-Cl). DPF@Ir-azo-Cl exhibited strong tumor-accumulation capability and high therapeutic efficiency in melanoma-bearing mice. Overall, the present study presents a novel strategy for developing hypoxia-activated prodrugs to enhance drug release and improve synergistic chemo-photodynamic cancer therapy.
Liu et al. (2025) studied this question.