A PET-activated photosensitizer based on ROS-sensitive Trolox for tumor microenvironment-responsive imaging and therapy

Abstract

We designed a dormant photosensitizer, EtNBS-2C-Tro, featuring a Trolox-modified benzo[a]phenoxazinium scaffold for ROS-responsive activation. In normal cells, both fluorescence and photodynamic therapy effects are effectively quenched via photoinduced electron transfer (PET). In the tumor microenvironment, elevated levels of ROS, including peroxyl radicals (ROO˙) and singlet oxygen (¹O₂), oxidize the chromanol ring, therefore deactivating PET and restoring both fluorescence and photosensitizing activity. EtNBS-2C-Tro enables NIR fluorescence imaging of endogenous ROS in tumor-bearing mice and demonstrates potent tumor inhibition with minimal side effects.