Sensitizing ferroptotic and apoptotic cancer therapy via tailored micelles-mediated coenzyme and ATP depletion under hypoxia

Concurrent induction of apoptosis and ferroptosis is promising in handling heterogenous cancers. We report a tailored polymeric micellar nanoplatform for the combinational anti-tumor therapy. Two stimuli-responsive amphiphlic block copolymers were synthesized, bearing three functional moieties, i.e. azobenzene, nitroimidazole and 3-fluorophenylboronic acid. Azobenzene could enhance the cellular uptake of micelles. Nitroimidazole and 3-fluorophenylboronic acid could deplete the reduced nicotinamide adenine dinucleotide phosphate (NADPH), glucose and adenosine triphosphate (ATP) under hypoxia, sensitizing ferroptotic and apoptotic cell death. The proof-of-concept was demonstrated in a triple-negative breast cancer cell line (MDA-MB-231). Irrespective of the free or encapsulated form, doxorubicin and auranofin showed a synergistic action, evidenced by a low combination index (< 1). The co-delivery micelles showed improved potency than the single drug-loaded micelles in terms of the biomarkers of apoptosis ( e.g. caspase 3/9, cytochrome c and ATP) and ferroptosis ( e.g. thioredoxin reductase, thioredoxin, glutathione, NADPH, malondialdehyde and lipid peroxides). The apoptosis and ferroptosis induction ability of cargo-free micelles was proved. The in vivo efficacy was verified in the MDA-MB 231 tumor-bearing nude mice model. The current work offers a promising strategy of combinational anti-tumor drug delivery for potent induction of ferroptosis and apoptosis via the sensitization effect of vehicle in the hypoxic tumor.