A Nitroreductase-Responsive Type I Photosensitizer with Aggregation-Induced Emission Characteristics for Precise Hypoxic Cancer Theranostics

Cancer remains a significant global health challenge, with early and accurate detection being key to improving treatment outcomes. Developing targeted photosensitizers (PS) that selectively image and treat cancer cells is critical for cancer diagnosis, staging, and treatment monitoring. Understanding the hypoxic nature of solid tumors is essential in cancer detection, as hypoxia is associated with tumor aggressiveness and therapy resistance. Nitroreductase (NTR), which is overexpressed in hypoxic tumors, offers a target for selective imaging and treatment. In this study, we developed a type-I PS called TPAPyN, which is responsive to NTR. TPAPyN facilitates the imaging of hypoxic cancer cells and facilitates image-guided photodynamic therapy (PDT). Because of photoinduced electron transfer, TPAPyN does not emit fluorescence in the aqueous environment. However, its fluorescence is restored when NTR cleaves the nitrofuran quencher, forming highly emissive TPAPy aggregates. This characteristic makes TPAPyN a valuable fluorescent probe for specific imaging of NTR-overexpressed cancer cells. Additionally, TPAPy exhibits high efficiency in generating reactive oxygen species, indicating its potential as a PS for cancer treatment via PDT.