NADPH-depletion micelles sensitizing apoptotic and ferroptotic cancer therapy under hypoxia

The heterogeneous characteristics of cancer determine that monotherapeutic strategies is difficult to deal with various sub-populations of cancer cells, leading to tumor recrudescence and dissemination. The combination of reactive oxygen species (ROS) mediated apoptosis in photodynamic therapy (PDT) and lipid peroxides induced ferroptosis exhibits remarkable potential in overcoming tumor heterogeneity-driven therapeutic resistance. However, the intracellular antioxidant systems involve the glutathione (GSH), reduced thioredoxin (Trx(SH) 2 ), and ubiquinol (CoQ 10 H 2 ) can reduce the potency of interactive therapy. Here, we reported a nitroimidazole-bearing hypoxia-responsive polymeric micelles to deliver model photosensitizer Chlorin e6 (Ce6) for selective ROS induced apoptosis in PDT sensitization and ferroptosis boosting. Upon light irradiation, the hypoxia-responsive micelles encapsulated with Ce6 produced ROS for apoptotic cell death. The ROS could also decrease intracellular concentrations of GSH and hence ferroptotic cell death. Leveraging the hypoxic tumor micro-environment characterized by elevated nitroreductase expression, nitroimidazole moieties undergo a reduction process, leading to a marked depletion in nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) levels. This would further decline the intracellular abundance of GSH, Trx(SH) 2 , and CoQ 10 H 2 attributed to NADPH's critical role in regenerating these vital antioxidants, and then boost ferroptotic cell death. The interactive sensitization of apoptosis and ferroptosis induced by ROS and the depletion of NADPH, GSH, Trx(SH) 2 , and CoQ 10 H 2 was subsequently validated in vivo using the 4T1 tumor xenograft murine model. The present study establishes an innovative strategy for the concurrent sensitization of ROS-driven apoptosis and ferroptosis to achieve efficacious cancer treatment.