Cascade Reactions by Nitric Oxide and Hydrogen Radical for Anti-Hypoxia Photodynamic Therapy Using an Activatable Photosensitizer

Organelle-targeted activatable photosensitizers are attractive to improve the specificity and controllability of photodynamic therapy (PDT), however, they suffer from a big problem in the photoactivity under both normoxia and hypoxia due to the limited diversity of phototoxic species (mainly reactive oxygen species). Herein, by effectively photocaging a pi-conjugated donor-acceptor (D-A) structure with an N-nitrosamine substituent, we established a unimolecular glutathione and light coactivatable photosensitizer, which achieved its high performance PDT effect by targeting mitochondria through both type I and type II (dual type) reactions as well as secondary radicals-participating reactions. Of peculiar interest, hydrogen radical (H center dot) was detected by electron spin resonance technique. The generation pathway of H center dot via reduction of proton and its role in type I reaction were discussed. We demonstrated that the synergistic effect of multiple reactive species originated from tandem cascade reactions comprising reduction of O-2 by H center dot to form O-2(center dot-)/HO2 center dot and downstream reaction of O-2(center dot-) with center dot NO to yield ONOO-. With a relatively large two-photon absorption cross section for photoexcitation in the near-infrared region (166 +/- 22 GM at 800 nm) and fluorogenic property, the new photosensitizing system is very promising for broad biomedical applications, particularly low-light dose PDT, in both normoxic and hypoxic environments.

Automated summary

In this study, a unimolecular glutathione and light coactivatable photosensitizer targeting mitochondria was developed, demonstrating high performance PDT effect through type I, type II reactions, and secondary radicals-participating reactions. With a relatively large two-photon absorption cross section for photoexcitation, the new photosensitizing system shows promising applications in both normoxic and hypoxic environments.