Targeted photoredox catalysis in cancer cells


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.

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Fig. 1: Structures of compounds.
Fig. 2: DFT calculations and stability of complex 1.
Fig. 3: Photoredox reaction between NADH and complex 1 under 463 nm blue-light irradiation.
Fig. 4: Cellular localization and cellular response after irradiation.
Fig. 5: Photocatalytic cycle for oxidation of NADH by complex 1, showing the production of NAD radicals, involvement of oxygen, and reduction of cyt c.

Data availability

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 [1]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.

Author information




All authors were involved with the design and interpretation of the experiments, and with the writing of the manuscript. Chemical and biological experiments were carried out by H.H., S.B., K.Q. and P.Z. X-ray crystallography was carried out by S.B. and G.J.C. DFT calculations were carried by O.B., T.M. and M.J.P. M.S. and V.G.S. carried out the excited-state photochemistry experiments and analysed the data. H.H., S.B., H.C., G.G. and P.J.S analysed the data and co-wrote the paper. All authors discussed the results and commented on the manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Gilles Gasser or Hui Chao or Peter J. Sadler.

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Supplementary Information

Supplementary Tables 1–9, Figs. 1–36 and references.

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Crystallographic data for compound 1 (CCDC reference 1840366).

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Huang, H., Banerjee, S., Qiu, K. et al. Targeted photoredox catalysis in cancer cells. Nat. Chem. 11, 1041–1048 (2019).

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