H₂O₂-activated mitochondria-targeting photosensitizer for fluorescence imaging-guided combination photodynamic and radiotherapy

Radiotherapy is a primary modality in cancer treatment but is accompanied by severe side effects to healthy tissues and radiation resistance to some extent. To overcome these limitations, we developed a H₂O₂-responsive photosensitizer, CyBT, which could be activated by the upregulated H₂O₂ induced by radiotherapy, enabling near-infrared fluorescence imaging-guided combination photodynamic and radiotherapy. The synthesis of CyBT began with the covalent linkage of hemicyanine and a free radical TEMPO through the click reaction, which demonstrated superior photodynamic properties. Shielding of fluorescence and photodynamic activity was achieved by incorporating phenylboronic acid pinacol ester. In X-ray irradiated tumor cells, the upregulation of H₂O₂ activated CyBT, thereby restoring its fluorescence and photodynamic activity. Additionally, the positive charge of CyBT facilitated its targeting to the mitochondria within tumor cells for more efficiently triggering cell apoptosis. CyBT was co-assembled with a polymer PEG-<i>b</i>-PDPA to form acid-responsive nanoparticles (NPs-CyBT). This formulation enhanced tumor targeting, improved water solubility of CyBT, and extended <i>in vivo</i> circulation time. Utilizing fluorescence imaging to guide photodynamic and radiotherapy, NPs-CyBT can accurately target solid tumors in mice, and lead to tumor elimination, suggesting that it is a potential strategy for the effective treatment of malignant tumors.