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Switching on prodrugs using radiotherapy

Abstract

Chemotherapy is a powerful tool in the armoury against cancer, but it is fraught with problems due to its global systemic toxicity. Here we report the proof of concept of a chemistry-based strategy, whereby gamma/X-ray irradiation mediates the activation of a cancer prodrug, thereby enabling simultaneous chemo-radiotherapy with radiotherapy locally activating a prodrug. In an initial demonstration, we show the activation of a fluorescent probe using this approach. Expanding on this, we show how sulfonyl azide- and phenyl azide-caged prodrugs of pazopanib and doxorubicin can be liberated using clinically relevant doses of ionizing radiation. This strategy is different to conventional chemo-radiotherapy radiation, where chemo-sensitization of the cancer takes place so that subsequent radiotherapy is more effective. This approach could enable site-directed chemotherapy, rather than systemic chemotherapy, with ‘real time’ drug decaging at the tumour site. As such, it opens up a new era in targeted and directed chemotherapy.

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Fig. 1: Drug/probe decaging via X-ray irradiation.
Fig. 2: Model reactions of 1, 4 and 6 under X-ray irradiation.
Fig. 3: X-ray irradiation-mediated activation of azido coumarin.
Fig. 4: Synthesis of the pazopanib prodrug 11 and analysis of the irradiation reaction in vivo.
Fig. 5: Doxorubicin prodrug activation by X-ray irradiation.

Data availability

All relevant data supporting the findings of this study are available within the paper and its Supplementary Information files.

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Acknowledgements

We thank the ERC (ERC-2013-ADG 340469 ADREEM) for funding M.B., J.G., K.N. and Y.Z. J.G. acknowledges support from the National Natural Science Foundation of China (22071263), the Natural Science Foundation of Guangdong Province, China (2020A1515010994), Guangdong Province Zhujiang Talents Program (2019QN01Y127), Shenzhen Fundamental Research Program (JCYJ20200109110215774) and ‘Hundred Talents Program’ of the Chinese Academy of Sciences. Y.Z. acknowledges support from the National Natural Science Foundation of China (22001261) and the China Postdoctoral Science Foundation (2020M672873). Q.G. acknowledges support from the China Postdoctoral Science Foundation (2020M682976).

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Contributions

M.B. and J.G. conceived, designed and directed the project. Y.Z., K.N., H.D. and H.P. conducted the compound syntheses, X-ray activation and characterizations. Y.Z. and J.G. conducted the MTT, flow cytometry, transwell and wound healing assays. Y.Z. and Q.G. conducted the in vivo experiments. J.G., Y.Z., M.P., H.R., D.A. and M.B. co-wrote the manuscript. All authors analysed the data, contributed to the scientific discussion and revised the manuscript.

Corresponding authors

Correspondence to Jin Geng or Mark Bradley.

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Peer review information Nature Chemistry thanks Peng Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Geng, J., Zhang, Y., Gao, Q. et al. Switching on prodrugs using radiotherapy. Nat. Chem. 13, 805–810 (2021). https://doi.org/10.1038/s41557-021-00711-4

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