Hypoxia-Responsive Photosensitizer Prodrug for Bimodal Chemo-Photodynamic Therapy

The tumor hypoxic environment and photodynamic therapy (PDT) induced hypoxia could severely limit the therapeutic efficacy of traditional PDT. The integration of hypoxia-responsive prodrug with photosensitizer (PS) might solve this problem in the hypoxic environment of solid tumors. Here in we design and synthesize a novel prodrug functionalized PS TPA-Py-NM, in which the AIE-based PS and nitrogen mustard (NM), a chemotherapy drug, were linked by the hypoxia-responsive azo linker. TPA-Py-NM exhibits AIE-based red emission at 726 nm, and produces 1O2 (type II ROS) and O2•– (type I ROS) under white light irritation. In hypoxic tumors, the azo group of TPA-Py-NM was reduced to no fluorescent aniline derivative and drug NM, which enhance cancer cells killing efficiency both in light or darkness for synergistic PDT and chemotherapy effect. In contrast, the control PS TPA-Py-DM without NM components exhibited weaker cancer cell killing ability under hypoxic conditions.