A ROS responsive nanomedicine with enhanced photodynamic therapy via dual mechanisms: GSH depletion and biosynthesis inhibition.

Reduced glutathione (GSH, containing sulfydryl) inside cancer cells strongly consumes reactive oxygen species (ROS) in photodynamic therapy (PDT) process to reduce PDT effect. Thiol-ene click reaction is a classic method to couple sulfydryl and alkene groups. However, little effort was dedicated to developing medicines for GSH depletion based on this reaction. Our research indicated that GSH could effectively couple with docosahexaenoic acid (DHA, as alkene) in the presence of 2,2-dimethoxy-2-phenylacetophenone (DMPA, as photo-initiator) post 665 nm light irradiation through the thiol-ene click reaction. Based on this result, a ROS responsive nanocarrier (denoted as RSV) was used to load photosensitizer (zinc phthalocyanine, ZnPc), DHA and DMPA (denoted as DDRZ NP). Our research demonstrated that DDRZ NP could effectively accumulate at tumor tissue post tail vein injection. After irradiated by 665 nm light at tumor tissue, RSV was broken by ROS to release the encapsulated drugs. After that, the thiol-ene click reaction was initiated to couple GSH and DHA to deplete intracellular GSH. In addition, DDRZ NP destroyed GSH biosynthesis limiting enzyme, γ-glutamylcysteine synthetase (γ-GCS), to inhibit intracellular GSH biosynthesis. Above dual mechanisms, by GSH depletion and biosynthesis inhibition, could effectively guarantee intracellular GSH concentration decreasing to ensure satisfactory PDT cancer treatment outcome.