Radiotherapy activates picolinium prodrugs in tumours

• Published in: Nature chemistry Vol. 16; no. 8; pp. 1348 - 1356
• Main Authors: Fu, Qunfeng, Gu, Zhi, Shen, Siyong, Bai, Yifei, Wang, Xianglin, Xu, Mengxin, Sun, Pengwei, Chen, Junyi, Li, Dongxuan, Liu, Zhibo
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.08.2024
• Subjects: Animals; Antibodies; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Cancer therapies; Cell Line, Tumor; Chemical compounds; Chemical reactions; Chemotherapy; Conjugates; Electron transfer; Female; Fluorophores; Humans; Immunoconjugates - chemistry; Immunoconjugates - pharmacology; Ionizing radiation; Mice; Neoplasms - drug therapy; Prodrugs; Prodrugs - chemistry; Prodrugs - pharmacology; Protecting groups; Radiation therapy; Side effects; Toxicity; Toxins
• ISSN: 1755-4330; 1755-4349; 1755-4349
• DOI: 10.1038/s41557-024-01501-4

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.