Targeted photoredox catalysis in cancer cells

Huang, Huaiyi and Banerjee, Samya and Qiu, Kangqiang and Zhang, Pingyu and Blacque, Olivier and Malcomson, Thomas and Paterson, Martin J. and Clarkson, Guy J. and Staniforth, Michael and Stavros, Vasilios G. and Gasser, Gilles and Chao, Hui and Sadler, Peter J. (2019) Targeted photoredox catalysis in cancer cells. Nature Chemistry, 11 (11). pp. 1041-1048. ISSN 1755-4330

Abstract

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.