Radiotherapy-triggered reduction of platinum-based chemotherapeutic prodrugs in tumours

Qunfeng Fu¹, Shuren Zhang², Siyong Shen¹, Zhi Gu¹, Junyi Chen¹, Dongfan Song², Pengwei Sun¹, Chunhong Wang¹, Zhibin Guo¹, Yunlong Xiao³, Yi Qin Gao³, Zijian Guo⁴, Zhibo Liu^{5

6

7

8}

Affiliations

¹ 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.
² State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, China.
³ Beijing National Laboratory of Molecular Sciences, Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
⁴ State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, China. zguo@nju.edu.cn.
⁵ 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.
⁶ Peking University-Tsinghua University Center for Life Sciences, Peking University, Beijing, China. zbliu@pku.edu.cn.
⁷ Changping Laboratory, Beijing, China. zbliu@pku.edu.cn.
⁸ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), National Medical Products Administration Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China. zbliu@pku.edu.cn.

PMID: 39025943
DOI: 10.1038/s41551-024-01239-x

Radiotherapy-triggered reduction of platinum-based chemotherapeutic prodrugs in tumours

Qunfeng Fu et al. Nat Biomed Eng. 2024 Nov.

. 2024 Nov;8(11):1425-1435.

doi: 10.1038/s41551-024-01239-x. Epub 2024 Jul 18.

Authors

Qunfeng Fu¹, Shuren Zhang², Siyong Shen¹, Zhi Gu¹, Junyi Chen¹, Dongfan Song², Pengwei Sun¹, Chunhong Wang¹, Zhibin Guo¹, Yunlong Xiao³, Yi Qin Gao³, Zijian Guo⁴, Zhibo Liu^{5

6

7

8}

Affiliations

¹ 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.
² State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, China.
³ Beijing National Laboratory of Molecular Sciences, Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
⁴ State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, China. zguo@nju.edu.cn.
⁵ 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.
⁶ Peking University-Tsinghua University Center for Life Sciences, Peking University, Beijing, China. zbliu@pku.edu.cn.
⁷ Changping Laboratory, Beijing, China. zbliu@pku.edu.cn.
⁸ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), National Medical Products Administration Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Beijing, China. zbliu@pku.edu.cn.

PMID: 39025943
DOI: 10.1038/s41551-024-01239-x

Abstract

Pt(II) drugs are a widely used chemotherapeutic, yet their side effects can be severe. Here we show that the radiation-induced reduction of Pt(IV) complexes to cytotoxic Pt(II) drugs is rapid, efficient and applicable in water, that it is mediated by hydrated electrons from water radiolysis and that the X-ray-induced release of Pt(II) drugs from an oxaliplatin prodrug in tumours inhibits their growth, as we show with nearly complete tumour regression in mice with subcutaneous human tumour xenografts. The combination of low-dose radiotherapy with a Pt(IV)-based antibody-trastuzumab conjugate led to the tumour-selective release of the chemotherapeutic in mice and to substantial therapeutic benefits. The radiation-induced local reduction of platinum prodrugs in the reductive tumour microenvironment may expand the utility of radiotherapy.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

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Radiotherapy-triggered reduction of platinum-based chemotherapeutic prodrugs in tumours

Affiliations

Radiotherapy-triggered reduction of platinum-based chemotherapeutic prodrugs in tumours

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

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Grants and funding

LinkOut - more resources

Full Text Sources

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