Hongchuang Xu1, Yanpu Wang2, Jingming Zhang1, Xiaojiang Duan1, Ting Zhang2, Xuekang Cai1, Hyunsoo Ha3, Youngjoo Byun3, Yan Fan1, Zhi Yang4,5, Yiguang Wang6, Zhaofei Liu7,8, Xing Yang9,10,11. 1. Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China. 2. Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. 3. College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019, South Korea. 4. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China. 5. NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Beijing, 100142, China. 6. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China. 7. Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. liuzf@bjmu.edu.cn. 8. NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Beijing, 100142, China. liuzf@bjmu.edu.cn. 9. Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China. yangxing2017@bjmu.edu.cn. 10. NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals, Beijing, 100142, China. yangxing2017@bjmu.edu.cn. 11. Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China. yangxing2017@bjmu.edu.cn.
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.
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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