A GSH-Activatable Theranostic Prodrug Based on Photoinduced Electron Transfer for Cancer Fluorescence Imaging and Therapy

Traditional chemotherapeutic drugs have limitations due to their non-targeted ability toward cancer cells. Stimuli-activatable prodrugs are designed to overcome these obstacles. However, the real-time monitoring of stimuli-activatable theranostic prodrugs still poses challenges. Herein, a prodrug (Fe-SS-HCy), consisting of a ferrocene-modified hemicyanine linked via a disulfide bond, is synthesized for anticancer imaging and therapy. Before activation, the toxicity of Fe-SS-HCy is low. The fluorescence of Fe-SS-HCy is quenched by ferrocene due to photoinduced electron transfer. After being taken up by cancer cells, the intracellular GSH activates Fe-SS-HCy, which releases HCy. The fluorescence of HCy is restored and selectively accumulates in the mitochondria, which further produce reactive oxygen species (ROS) to induce cancer cell death. Thus, this "off-on" fluorogenic HCy presents a new strategy for monitoring prodrug activation in real-time and for enhancing therapeutic efficacy with reduced side effects.