Hypoxia-triggered singlet oxygen and nitrogen mustard release towards a synergistic therapeutic action

We report an endoperoxide and nitrogen mustard conjugate (Pyd-endo) as a prodrug that can release cytotoxic singlet oxygen and aromatic nitrogen mustard under hypoxic conditions. Cell culture experiments demonstrated the hypoxia-responsiveness of the prodrug and its ability to kill and inhibit the migration and proliferation of various types of cancer cells. Studies using tumor-bearing mice and a liposomal formulation demonstrated its anticancer utility in vivo. Our design not only addresses the challenges of tumor hypoxia and limited light penetration issues of PDT but also presents the power of the combined cytotoxic action of singlet oxygen and a chemotherapy agent.