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 (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.
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The data that support the findings of this study are available within the paper and its Supplementary Information files, or from the corresponding authors on reasonable request. Crystallographic data for the complex PF6·(1.5 toluene) reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (under deposition number CCDC 1840366). After the Open Access agreement has been established, underpinning datasets will be deposited in Warwick’s Institutional Repository—Warwick Research Archive Portal, according to the Open Access Agreement.
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We thank the EPSRC (grants EP/G006792, EP/F034210/1 and EP/P030572/1 to P.J.S.; platform grant EP/P001459/1 to M.J.P.; EPSRC DTP studentship to T.M.; EP/N010825/1 to M.S.; and EP/N010825 to V.G.S.), MRC (grant G0701062 to P.J.S.), The Royal Society (Newton International Fellowship NF160307 to H.H.; and Newton-Bhahba International Fellowship NF151429 to S.B.), Leverhulme Trust (Senior Research Fellowship to V.G.S.), National Science Foundation of China (NSFC grant 21701113 to P.Z.; and 21525105, 21471164 and 21778079 to H.C.), 973 Program (2015CB856301 to H.C.), The Fundamental Research Funds for the Central Universities (to H.C.), ERC (Consolidator Grant GA 681679 PhotoMedMet to G.G.), French Government (Investissements d’Avenir grant ANR-10-IDEX-0001-02 PSL to G.G.) and the Sun Yat-sen University Startup fund (75110-18841213 to H.H.). We also thank W. Zhang, L. Song and P. Aston for assistance with mass spectrometry, J. P. C. Coverdale for assistance with ICP-MS experiments, and I. Prokes for assistance with NMR spectroscopy.
The authors declare no competing interests.
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Huang, H., Banerjee, S., Qiu, K. et al. Targeted photoredox catalysis in cancer cells. Nat. Chem. 11, 1041–1048 (2019). https://doi.org/10.1038/s41557-019-0328-4
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