Switching-on Prodrugs Using Radiotherapy

Chemotherapy is a powerful tool in the armoury against cancer, however it is fraught with problems due to 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 chemoradiotherapy 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 ionising 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.