Huang H Banerjee S Qiu K Zhang P Blacque O Malcomson T Paterson MJ Clarkson GJ Staniforth M Stavros VG Gasser G Chao H Sadler PJ 2019 Hypoxic tumours are a major problem for cancer photodynamic therapy. Here, we show that photoredox catalysis can provide an oxygen-independent mechanism of action to combat this problem. We have designed a highly oxidative Ir(III) photocatalyst, [Ir(ttpy)(pq)Cl]PF6 ([1]PF6, where 'ttpy' represents 4'-(p-tolyl)-2,2':6',2''-terpyridine and 'pq' represents 3-phenylisoquinoline), which is phototoxic towards both normoxic and hypoxic cancer cells. Complex 1 photocatalytically oxidizes 1,4-dihydronicotinamide adenine dinucleotide (NADH)-an important coenzyme in living cells-generating NAD• radicals with a high turnover frequency in biological media. Moreover, complex 1 and NADH synergistically photoreduce cytochrome c under hypoxia. Density functional theory calculations reveal π stacking in adducts of complex 1 and NADH, facilitating photoinduced single-electron transfer. In cancer cells, complex 1 localizes in mitochondria and disrupts electron transport via NADH photocatalysis. On light irradiation, complex 1 induces NADH depletion, intracellular redox imbalance and immunogenic apoptotic cancer cell death. This photocatalytic redox imbalance strategy offers a new approach for efficient cancer phototherapy. application/pdf https://sonar.ch/global/documents/258457 eng info:eu-repo/semantics/altIdentifier/doi/10.1038/s41557-019-0328-4 info:eu-repo/semantics/altIdentifier/pmid/31548671 info:eu-repo/semantics/openAccess Nature chemistry. - 2019 Antineoplastic Agents Biocatalysis Cell Death Coordination Complexes Cytochromes c Density Functional Theory Drug Screening Assays, Antitumor Humans Models, Molecular Molecular Conformation NAD Neoplasms Oxidation-Reduction Photochemical Processes Tumor Hypoxia Targeted photoredox catalysis in cancer cells. http://purl.org/coar/resource_type/c_6501