Switching on prodrugs using radiotherapy

Jin Geng, Yichuan Zhang, Quan Gao, Kevin Neumann, Hua Dong, Hamish Porter, Mark Potter, Hua Ren, David Argyle, Mark Bradley

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
JournalNature Chemistry
Early online date10 Jun 2021
DOIs
Publication statusE-pub ahead of print - 10 Jun 2021

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