GSH‐Activated Porphyrin Sonosensitizer Prodrug for Fluorescence Imaging‐Guided Cancer Sonodynamic Therapy

Abstract Sonodynamic therapy (SDT), which uses ultrasound to trigger a sonosensitizer to generate reactive oxygen species (ROS), is a promising form of cancer therapy with outstanding tissue penetration depth. However, the sonosensitizer may inevitably spread to surrounding healthy tissue beyond the tumor, resulting in undesired side effects under an ultrasound stimulus. Herein, as glutathione (GSH) is overexpressed in the tumor microenvironment, a GSH‐activatable sonosensitizer prodrug is designed by attaching a quencher to tetraphydroxy porphyrin for tumor therapy. The prodrug exhibits poor fluorescence and low ROS generation capacity under ultrasound irradiation, but it also showed that it can be activated by GSH to simultaneously switch on fluorescence emission and ROS generation capability at the tumor site. Compared with the non‐quenched sonosensitizer, the designed prodrug exhibits significantly higher tumor/healthy organ fluorescence ratios, due to the specific fluorescence and ROS activation by overexpressed GSH in the tumor. Finally, the prodrug exhibits efficient tumor growth inhibition under ultrasound irradiation, further demonstrating its promise as a GSH‐activated sonosensitizer prodrug for highly effective cancer treatment.