Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Peking University-Tsinghua University Center for Life Sciences, Peking University, Beijing 100871, China.
J Am Chem Soc. 2022 Jun 1;144(21):9458-9464. doi: 10.1021/jacs.2c02521. Epub 2022 May 20.
Precisely activating chemotherapeutic prodrugs in a tumor-selective manner is an ideal way to cure cancers without causing systemic toxicities. Although many efforts have been made, developing spatiotemporally controllable activation methods is still an unmet challenge. Here, we report a novel prodrug activation strategy using radiotherapy (X-ray). Due to its precision and deep tissue penetration, X-ray matches the need for altering molecules in tumors through water radiolysis. We first demonstrated that -oxides can be effectively reduced by hydrated electrons (e) generated from radiation both in tubes and living cells. A screening is performed to investigate the structure-reduction relationship and mechanism of the e-mediated reductions. We then apply the strategy to activate -oxide prodrugs The anticancer drug camptothecin (CPT)-based -oxide prodrug shows a remarkable anticancer effect upon activation by radiotherapy. This radiation-induced chemistry may enable versatile designs of radiotherapy-activated prodrugs, which are of remarkable clinical relevance, as over 50% of cancer patients take radiotherapy.
精确地以肿瘤选择性方式激活化疗前药是一种治愈癌症而不引起全身毒性的理想方法。尽管已经做了很多努力，但开发时空可控的激活方法仍然是一个未满足的挑战。在这里，我们报告了一种使用放射治疗（X 射线）的新的前药激活策略。由于其精确性和深组织穿透性，X 射线符合通过水辐射解改变肿瘤中分子的需求。我们首先证明了-氧化物可以通过辐射产生的水合电子（e）在管中和活细胞中有效还原。进行了筛选以研究 e 介导的还原的结构还原关系和机制。然后，我们将该策略应用于激活-氧化物前药。基于喜树碱（CPT）的-氧化物前药在放射治疗激活后表现出显著的抗癌作用。这种辐射诱导的化学可能能够实现多种放射治疗激活前药的设计，这具有显著的临床相关性，因为超过 50%的癌症患者接受放射治疗。
