Hypoxia-selective prodrug restrains tumor cells through triggering mitophagy and inducing apoptosis

Hypoxia is a common feature of various solid tumors, which reduces the sensitivity of tumor cells to both radiotherapy and chemotherapy. However, hypoxia also presents an opportunity for tumor-selective therapy. The prodrug strategy, leveraging the hypoxic nature of the tumor microenvironment, shows significant potential for clinical application. Here we present CHD-1, a hypoxia-activated antitumor prodrug that activates in hypoxic environments, effectively inhibiting hypoxic tumor cells while exhibiting no toxicity to normoxic cells. CHD-1 impairs mitochondrial morphology and membrane potential of hypoxic tumor cells, further triggers excessive mitophagy and induces apoptosis. Moreover, prodrug CHD-1 significantly inhibits HeLa xenograft growth in vivo, and shows lower toxicity than parent molecule in an acute toxicity assessment in animal models. This study introduces a promising hypoxia-activated antitumor prodrug with strong potential for further development in hypoxic tumor therapy.