Hypoxia-activated prodrug combining site-specific chemotherapy and light-driven photothermal therapy

The development of a highly effective and low toxic drug is very beneficial for precise cancer therapy. Herein, taking advantage of the hypoxic nature of tumors, we carefully designed and synthesized the first hypoxia-activated single-molecule prodrug BDP-CPT-NO2 for fluorescence imaging-guided chemo-photothermal dual-mode therapy. The prodrug contains the chemotherapeutic drug camptothecin (CPT) and a boron dipyrromethene (BDP)-based photothermal agent, which are connected through a nitroreductase (NTR)-responsive linker (a nitro unit), and shows no fluorescence and extremely low cytotoxicity under normoxia. However, the nitro in the prodrug could be reduced to amino by exogenous NTR with nicotinamide adenine dinucleotide (NADH) in PBS buffer solution and endogenous NTR in hypoxic cancer cells, which is followed by a self-immolative reaction that leads to the release of CPT and BDP-COOH. This process is accompanied by significantly enhanced BDP and CPT fluorescence, which are due to NTR-induced ester-to-carboxylate conversion and fluorescence resonance energy transfer (FRET) interruption, respectively. Concomitantly, BDP-CPT-NO2 displays powerful combined chemo-PTT therapeutic efficacy, as evidenced in human cervical cancer HeLa and human liver cancer HepG2 cells, as well as in mice bearing H22 tumors. This study provides a promising strategy for effective and selective cancer treatment by hypoxia-activated prodrugs caged within organic photothermal agents.