Radiotherapy activates picolinium prodrugs in tumours

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

doi:10.1038/s41557-024-01501-4

Radiotherapy activates picolinium prodrugs in tumours

Nat Chem. 2024 Apr 1. doi: 10.1038/s41557-024-01501-4. Online ahead of print.

Authors

Qunfeng Fu^#^{1

2}, Zhi Gu^#^{1

2}, Siyong Shen^#², Yifei Bai², Xianglin Wang², Mengxin Xu², Pengwei Sun², Junyi Chen², Dongxuan Li², Zhibo Liu^{3

4

5

6}

Affiliations

¹ Changping Laboratory, Beijing, China.
² Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
³ Changping Laboratory, Beijing, China. zbliu@pku.edu.cn.
⁴ Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. zbliu@pku.edu.cn.
⁵ Peking University-Tsinghua University Center for Life Sciences, Peking University, Beijing, China. zbliu@pku.edu.cn.
⁶ Key Laboratory of Carcinogenesis and Translational Research of Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China. zbliu@pku.edu.cn.

^# Contributed equally.

PMID: 38561425
DOI: 10.1038/s41557-024-01501-4

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.

Abstract

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