北京大学刘志博团队报道了放射治疗激活肿瘤中的甲基砒啶前药。相关研究成果发表在2024年4月1日出版的《自然—化学》。

在癌症治疗中，放射治疗诱导的前药活化为降低化疗的全身毒性提供了理想的解决方案，但放射活化保护集团的范围有限。

该文文，研究人员报道了公认的光诱导电子转移化学，可能为开发多功能可辐射去除的保护基团铺平道路。使用功能报告基因分析，N-烷基-4-吡啶（NAP）被鉴定为通过释放客户端分子对辐射有效反应的笼化基团。当在竞争实验中进行评估时，NAP部分比迄今为止发现的其他可去除辐射的保护基团更有效。

利用这一特性，研究人员开发了一种NAP衍生的氨基甲酸酯连接剂，该连接剂在辐射中释放荧光团和毒素，并将其纳入抗体-药物偶联物（ADCs）中。这些设计的ADCs在活细胞和荷瘤小鼠中具有活性，突出了使用这种可去除辐射的保护基团，开发稳定性和治疗效果更好的下一代ADCs的潜力。

附：英文原文

Title: Radiotherapy activates picolinium prodrugs in tumours

Author: Fu, Qunfeng, Gu, Zhi, Shen, Siyong, Bai, Yifei, Wang, Xianglin, Xu, Mengxin, Sun, Pengwei, Chen, Junyi, Li, Dongxuan, Liu, Zhibo

Issue&Volume: 2024-04-01

Abstract: Radiotherapy-induced prodrug activation provides an ideal solution to reduce the systemic toxicity of chemotherapy in cancer therapy, but the scope of the radiation-activated protecting groups is limited. Here we present that the well-established photoinduced electron transfer chemistry may pave the way for developing versatile radiation-removable protecting groups. Using a functional reporter assay, N-alkyl-4-picolinium (NAP) was identified as a caging group that efficiently responds to radiation by releasing a client molecule. When evaluated in a competition experiment, the NAP moiety is more efficient than other radiation-removable protecting groups discovered so far. Leveraging this property, we developed a NAP-derived carbamate linker that releases fluorophores and toxins on radiation, which we incorporated into antibody–drug conjugates (ADCs). These designed ADCs were active in living cells and tumour-bearing mice, highlighting the potential to use such a radiation-removable protecting group for the development of next-generation ADCs with improved stability and therapeutic effects.

DOI: 10.1038/s41557-024-01501-4

Source: https://www.nature.com/articles/s41557-024-01501-4