Glutathione depletion and dual-model oxygen balance disruption for photodynamic therapy enhancement.

Photodynamic therapy (PDT) is a prospective approach to cure tumor diseases. However, tumor micro-environment is notably characterized with severe hypoxia and high expression of glutathione (GSH), which seriously limit its clinical application. Here, based on the characteristics of perfluorocarbon (PFC) to dissolve substantial oxygen (O2) and the sensitivity of reductive GSH to S-NO group, we designed GSH depletion and dual-model O2 supply strategies to promote PDT enhancement. The PFC nanoliposomes (FI@Lip) and biocompatible NO donor S-nitrosated human serum albumin (HSA-SNO) were combined to synergistically combat the obstacle of tumor micro-environment, reducing GSH concentration and increasing singlet oxygen (1O2) generation. In vitro, after irradiation with NIR laser, the PFC in FI@Lip dissolved more O2 to increase 1O2 generation. In addition, with co-delivery of HSA-SNO, it can effectively promote GSH depletion to recover 1O2 level and release NO concurrently to inhibit mitochondrial respiration. This combination strategy of FI@Lip and HSA-SNO obviously relieved intracellular hypoxia and decreased GSH to increase more toxic 1O2 generation for PDT enhancement. The present work will play as an enlightening role in PDT design and clinical application in the near future.