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.

化疗是对抗癌症的有力工具，但由于其全身毒性，它充满了问题。在这里，我们报告了基于化学的策略的概念证明，伽马 / X 射线照射介导了癌症前药的激活，从而使同步放疗与局部激活前药的放疗成为可能。在最初的演示中，我们展示了使用这种方法激活荧光探针。对此进行扩展，我们展示了如何使用临床相关剂量的电离辐射释放帕唑帕尼和多柔比星的磺酰叠氮化物和苯基叠氮化物笼状前药。这种策略不同于传统的化学放疗辐射，在传统的放化疗中，癌症会发生化学增敏作用，从而使后续放疗更加有效。这种方法可以实现定点化疗，而不是全身化疗，在肿瘤部位“实时”药物降解。因此，它开辟了靶向和定向化疗的新纪元。