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A self-triggered radioligand therapy agent for fluorescence imaging of the treatment response in prostate cancer

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

Abstract

Purpose

Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is emerging as an effective treatment option for metastatic castration-resistant prostate cancer (mCRPC). An imaging-based method to quantify early treatment responses can help to understand and optimize RLT.

Methods

We developed a self-triggered probe 2 targeting the colocalization of PSMA and caspase-3 for fluorescence imaging of RLT-induced apoptosis.

Results

The probe binds to PSMA potently with a Ki of 4.12 nM, and its fluorescence can be effectively switched on by caspase-3 with a Km of 67.62 μM. Cellular and in vivo studies demonstrated its specificity for imaging radiation-induced caspase-3 upregulation in prostate cancer. To identify the detection limit of our method, we showed that probe 2 could achieve 1.79 times fluorescence enhancement in response to 177Lu-RLT in a medium PSMA-expressing 22Rv1 xenograft model.

Conclusion

Probe 2 can potently bind to PSMA, and the fluorescence signal can be sensitively switched on by caspase-3 both in vitro and in vivo. This method may provide an effective tool to investigate and optimize PSMA-RLT.

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Funding

This work was financially supported by the National Natural Science Foundation of China (92059101, 21877004, 81873907, and 81920108020), National Key R&D Program of China (2018YFE0205300 and 2018YFC1313300), Beijing Natural Science Foundation (JQ19026), Clinical Medicine Plus X-Young Scholars Project of Peking University (PKU2020LCXQ029), and the Fundamental Research Funds for the Central Universities (BMU2021RCZX018 and PKU2019LCXQ023). This work was in part supported by the National Research Foundation of Korea (2019R1A6A1A03013807 and 2020R1A2C2005919).

Author information

Author notes

  1. Hongchuang Xu and Yanpu Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China

    Hongchuang Xu, Jingming Zhang, Xiaojiang Duan, Xuekang Cai, Yan Fan & Xing Yang

  2. Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Yanpu Wang, Ting Zhang & Zhaofei Liu

  3. College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019, South Korea

    Hyunsoo Ha & Youngjoo Byun

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

    Zhi Yang

  5. NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Beijing, 100142, China

    Zhi Yang, Zhaofei Liu & Xing Yang

  6. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China

    Yiguang Wang

  7. Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China

    Xing Yang

Authors
  1. Hongchuang Xu
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Contributions

Xing Yang and Zhaofei Liu conceived and designed research. Hongchuang Xu performed the chemical synthesis. Hongchuang Xu and Xuekang Cai measured the absorption and emission spectrum. Jingming Zhang performed in vitro caspase-3 protein assay and PSMA inhibition experiments. Hyunsoo Ha and Youngjoo Byun performed the docking study. Xiaojiang Duan and Yanpu Wang performed radiolabeling experiments. Xiaojiang Duan performed cell uptake experiments. Yanpu Wang and Ting Zhang designed and performed live cell imaging experiments and SPECT/CT imaging experiments. Yanpu Wang performed the mouse imaging. Hongchuang Xu, Yanpu Wang, Jingming Zhang, Xing Yang, and Zhaofei Liu analyzed data. Xing Yang, Zhaofei Liu, Jingming Zhang, Hongchuang Xu, Yanpu Wang, and Xuekang Cai wrote the original draft. Xing Yang, Zhaofei Liu, Yanpu Wang, Yan Fan, and Zhi Yang reviewed and edited the draft. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Zhaofei Liu or Xing Yang.

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All animal studies were carried out in conformity to regulations on laboratory animals of the Beijing municipality and approved by the Animal Ethics Committee at Peking University Frist Hospital (Beijing, China), approval number J202163.

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Xu, H., Wang, Y., Zhang, J. et al. A self-triggered radioligand therapy agent for fluorescence imaging of the treatment response in prostate cancer. Eur J Nucl Med Mol Imaging 49, 2693–2704 (2022). https://doi.org/10.1007/s00259-022-05743-7

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