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Organotrifluoroborate enhances tumor targeting of fibroblast activation protein inhibitors for targeted radionuclide therapy

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Fibroblast activation protein (FAP) is a pan-cancer target and now the state-of-the-art to develop radiopharmaceuticals. FAP inhibitors have been of great success in developing imaging tracers. Yet, the overly rapid clearance cannot match with the long half-lives of regular therapeutic radionuclides. Though strategies that aim to elongate the circulation of FAPIs are being developed, here we describe an innovation that uses α-emitters of short half-lives (e.g., 213Bi) to pair the rapid pharmacokinetics of FAPIs.

Methods

An organotrifluoroborate linker is engineered to FAPIs to give two advantages: (1) selectively increases tumor uptake and retention; (2) facile 18F-radiolabeling for positron emission tomography to guide radiotherapy with α-emitters, which can hardly be traced in general.

Results

The organotrifluoroborate linker helps to improve the internalization in cancer cells, resulting in notably higher tumor uptake while the background is clean. In FAP-expressed tumor-bearing mice, this FAPI labeled with 213Bi, a short half-life α-emitter, exhibits almost complete suppression to tumor growth while the side effect is negligible. Additional data shows that this strategy is generally applicable to guide other α-emitters, such as 212Bi, 212Pb, and 149Tb.

Conclusion

The organotrifluoroborate linker may be of importance to optimize FAP-targeted radiopharmaceuticals, and the short half-lived α-emitters may be of choice for the rapid-cleared small molecule-based radiopharmaceuticals.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We acknowledge the facility support from the Analytical Instrumentation Center of Peking University.

Funding

We gratefully acknowledge the Beijing Municipal Natural Science Foundation (Grant No. Z200018), the National Natural Science Foundation of China (Grant No. U1867209), the Ministry of Science and Technology of the People’s Republic of China (Grant Nos. 2021YFA1601400 and 2017YFA0506300), the Special Foundation of Beijing Municipal Education Commission (Grant No. 3500–12020123), and the Li Ge-Zhao Ning Life Science Youth Research Foundation (LGZNQN202004) to Z.L.

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Authors and Affiliations

  1. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China

    Yu Liu & Zhibo Liu

  2. 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

    Haocheng Tang, Tianchi Song, Mengxin Xu, Junyi Chen, Xi-Yang Cui, Yuxiang Han & Zhibo Liu

  3. Changping Laboratory, Beijing, 102206, China

    Xi-Yang Cui & Zhibo Liu

  4. Key Laboratory of Carcinogenesis and Translational Research, Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China

    Zhu Li

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Contributions

Y.L. participated in all the experiments. H.T. and T.S. assisted in cell and animal experiments. M.X. and J.C. provided radionuclides and guided the radiolabeling. Y.L. and XY.C. wrote the manuscipt. Y.H. and Z.L. helped analyze the experimental data. Z.L. designed the study and revised the manuscipt. All authors read and approved the final manuscript.”

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Correspondence to Zhibo Liu.

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Liu, Y., Tang, H., Song, T. et al. Organotrifluoroborate enhances tumor targeting of fibroblast activation protein inhibitors for targeted radionuclide therapy. Eur J Nucl Med Mol Imaging 50, 2636–2646 (2023). https://doi.org/10.1007/s00259-023-06230-3

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