Synergistic Photodynamic and Chemodynamic Therapy for Tumor Treatment Using a Glutathione-Activated Photosensitizer with Near-Infrared (NIR) Imaging

Photodynamic therapy (PDT) utilizes photosensitizers (PSs) to generate cytotoxic reactive oxygen species (ROS) upon irradiation, leading to cell death. However, conventional PSs can cause unwanted side effects. Activatable photosensitizers (aPSs) offer a solution by remaining inactive until triggered within tumor microenvironment. Here, we present HFP-SS-Fc, a novel glutathione (GSH) aPS that leverages the high GSH concentration in tumors. HFP-SS-Fc exhibits potent near-infrared (NIR) fluorescence and a robust photodynamic effect upon exposure to tumor-specific GSH levels. A disulfide bond links ferrocene to HFP-SS-Fc, quenching NIR emission and hindering ROS generation. This ferrocene moiety also facilitates •OH production and O 2 release through a Fenton-like reaction, maintaining efficacy in hypoxic tumors. Inspired by its theranostic potential in vitro, HFP-SS-Fc successfully achieves real-time tumor imaging and significant tumor growth inhibition in vivo. This study has presented HFP-SS-Fc as a promising tool for synergistic PDT and CDT with minimized side effects, guided by NIR fluorescence.