Activatable theranostic prodrug scaffold with tunable drug release rate for sequential photodynamic and chemotherapy

Abstract

Glutathione (GSH)‐activated prodrugs are promising for overcoming the limitations of conventional anti‐tumor drugs. However, current GSH‐responsive disulfide groups exhibit unregulated reactivity, making it impossible to precisely control the drug release rate. We herein report a series of GSH‐responsive prodrugs with a “three‐in‐one” molecular design by integrating a fluorescence report unit, stimuli‐responsive unit and chemodrug into one scaffold with tunable aromatic nucleophilic substitution (SNAr) reactivity. The drug release rate of these prodrugs is tailored by modification of substituent groups with different electron‐withdrawing or ‐donating abilities on the BODIPY core. Furthermore, the prodrugs self‐assemble in water to form nanoparticles that serve as photosensitizers to produce reactive oxygen species upon irradiation for photodynamic therapy (PDT). The PDT process also increases the concentration of GSH in cells, further promoting the release of drugs for chemotherapy. This strategy provides a powerful platform for sequential photodynamic and chemotherapy with tunable drug release rates and synergistic therapeutic effects.

Charge-reversal polymeric nanomodulators for ferroptosis-enhanced photodynamic therapy

“…9 In addition, tumor cells have strong antioxidant defense systems, including antioxidant enzymes that produce antioxidant proteins and substances. 10,11 Among others, glutathione peroxidase 4 (GPX4), an antioxidant enzyme with reduced glutathione as a cofactor, is an important protectant against ferroptosis, which could eliminate oxidized phospholipids in cell membranes. 12,13 The PDT efficiency is inherently weakened because the reductive TME can scavenge therapeutically generated ROS.…”