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Preclinical development of a novel [68Ga]Ga-/[177Lu]Lu-labeled agent for PSMA-targeted imaging and therapy

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Abstract

Prostate-specific membrane antigen (PSMA)-targeted radiolabeled agents have been developed to diagnose and treat prostate cancer. In this study, we developed a novel 68Ga-/177Lu-labeled PSMA-targeted agent for potential for theranostics of prostate cancer. Methods:[68Ga]Ga-/[177Lu]Lu-PSMA-BP were efficiently prepared manually. For in vitro cell experiments 22Rv1 (PSMA+) and PC-3 (PSMA-) cell lines were used. Biodistribution studies, small-animal SPECT imaging, Micro-PET imaging, and therapy studies of [68Ga]Ga-/[177Lu]Lu-PSMA-BP were conducted in mice bearing 22Rv1 and PC-3 xenografted tumors. Results:[68Ga]Ga-/[177Lu]Lu-PSMA-BP were prepared within 30 min. The binding affinity Ki value of PSMA-BP to PSMA was 8.34 ± 2.02 nM. Micro-PET and small-animal SPECT imaging showed accumulation of [68Ga]Ga-/[177Lu]Lu-PSMA-BP mainly in 22Rv1 tumors with a favorable clearance pattern from non-target oragans. Low radioactivity accumulation was observed in PC-3 tumors and PSMA-expressing tissues. The SUVmax for 22Rv1 tumor, PC-3 tumor were 0.77 ± 0.16, 0.09 ± 0.07. The uptake of 68Ga-PSMA-BP in 22Rv1 tumors could be substantially blocked by 2-PMPA (− 81.82%). The mice treated with either low or high dose of 177Lu-PSMA-BP showed delayed tumor growth. Conclusion: Our results demonstrated the promising theranostic potential of [68Ga]Ga-/[177Lu]Lu-PSMA-BP for prostate cancer, while the efficacy warranted further investigation to evaluate the potential for clinical application.

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References

  1. Siegel RL, Miller KD, Jemal A (2020) Cancer statistics. CA Cancer J Clin 70:7–30

    Article  Google Scholar 

  2. Kiess AP, Banerjee SR, Mease RC et al (2015) Prostate-specific membrane antigen as a target for cancer imaging and therapy. Q J Nucl Med Mol Imaging 59:241–268

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Haberkorn U, Eder M, Kopka K et al (2016) New strategies in prostate cancer: Prostate-specific membrane antigen (PSMA) ligands for diagnosis and therapy. Clin Cancer Res 22:9–15

    Article  CAS  Google Scholar 

  4. Osborne JR, Akhtar NH, Vallabhajosula S et al (2013) Prostate-specific membrane antigen-based imaging. Urol Oncol Semin Orig Investig 31:144–154

    CAS  Google Scholar 

  5. Wright GL, Grob BM, Haley C et al (1996) Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology 48:326–334

    Article  Google Scholar 

  6. Bouvet V, Wuest M, Jans HS et al (2016) Automated synthesis of [18F]DCFPyL via direct radiofluorination and validation in preclinical prostate cancer models. EJNMMI Res 6:1–15

    Article  Google Scholar 

  7. Silver DA, Pellicer I, Fair WR et al (1997) Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 3:81–85

    CAS  PubMed  Google Scholar 

  8. Budäus L, Leyh-Bannurah SR, Salomon G et al (2016) Initial experience of 68Ga-PSMA PET/CT imaging in high-risk prostate cancer patients prior to radical prostatectomy. Eur Urol 69:393–396

    Article  Google Scholar 

  9. Maurer T, Gschwend GE, Rauscher I et al (2016) Diagnostic efficacy of 68Gallium-PSMA positron emission tomography compared to conventional imaging for lymph node staging of 130 consecutive patients with intermediate to high risk prostate cancer. J Urol 195:1436–1443

    Article  Google Scholar 

  10. Eder M, Schäfer M, Bauder-Wüst U et al (2012) 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem 23:688–697

    Article  CAS  Google Scholar 

  11. Liu C, Liu T, Zhang N et al (2018) 68Ga-PSMA-617 PET/CT: a promising new technique for predicting risk stratification and metastatic risk of prostate cancer patients. Eur J Nucl Med Mol Imaging 45:1852–1861

    Article  CAS  Google Scholar 

  12. Afshar-Oromieh A, Hetzheim H, Kratochwil C et al (2015) The theranostic PSMA ligand PSMA-617 in the diagnosis of prostate cancer by PET/CT: biodistribution in humans, radiation dosimetry, and first evaluation of tumor lesions. J Nucl Med 56:1697–1706

    Article  CAS  Google Scholar 

  13. Cardinale J, Schäfer M, Benešová M et al (2017) Preclinical evaluation of 18 F-PSMA-1007, a new prostate-specific membrane antigen ligand for prostate cancer imaging. J Nucl Med 58:425–432

    Article  CAS  Google Scholar 

  14. Witkowska-Patena E, Giżewska A, Dziuk M et al (2020) Diagnostic performance of 18F-PSMA-1007 PET/CT in biochemically relapsed patients with prostate cancer with PSA levels ≤ 2.0 ng/ml. Prostate Cancer Prostatic Dis 23:343–348

    Article  CAS  Google Scholar 

  15. Mease RC, Dusich CL, Foss CA et al (2008) N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-L- cysteine, [18F]DCFBC: a new Imaging probe for prostate cancer. Clin Cancer Res 14:3036–3043

    Article  CAS  Google Scholar 

  16. Chen Y, Pullambhatla M, Foss CA et al (2011) 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]- pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer. Clin Cancer Res 17:7645–7653

    Article  CAS  Google Scholar 

  17. Heidenreich A, Bellmunt J, Bolla M et al (2011) EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol 59:61–71

    Article  Google Scholar 

  18. Heidenreich A, Bastian PJ, Bellmunt J et al (2014) EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 65:467–479

    Article  CAS  Google Scholar 

  19. Heidenreich A, Porres D (2014) Prostate cancer: treatment sequencing for CRPC - What do we know? Nat Rev Urol 11:189–190

    Article  Google Scholar 

  20. Parker C, Nilsson S, Heinrich D et al (2013) Alpha emitter Radium-223 and Survival in metastatic prostate cancer. N Engl J Med 369:213–223

    Article  CAS  Google Scholar 

  21. Tagawa ST, Milowsky MI, Morris M et al (2013) Phase II study of lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer. Clin Cancer Res 19:5182–5191

    Article  CAS  Google Scholar 

  22. Chatalic KLS, Heskamp S, Konijnenberg M et al (2016) Towards personalized treatment of prostate cancer : PSMA I & T, a promising prostate-specific membrane antigen-targeted theranostic agent. Theranostics 6:849–861

    Article  CAS  Google Scholar 

  23. Kulkarni HR, Singh A, Schuchardt C et al (2016) PSMA-based radioligand therapy for metastatic castration-resistant prostate cancer: the bad berka experience since 2013. J Nucl Med 57:97S-104S

    Article  CAS  Google Scholar 

  24. Rahbar K, Ahmadzadehfar H, Kratochwil C et al (2017) German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. J Nucl Med 58:85–90

    Article  CAS  Google Scholar 

  25. Weineisen M, Schottelius M, Simecek J et al (2015) 68Ga-and 177Lu-labeled PSMA I&T: optimization of a PSMA-targeted theranostic concept and first proof-of-concept human studies. J Nucl Med 56:1169–1176

    Article  CAS  Google Scholar 

  26. Schwarzenboeck SM, Rauscher I, Bluemelet C et al (2017) PSMA ligands for PET imaging of prostate cancer. J Nucl Med 58:1545–1552

    Article  CAS  Google Scholar 

  27. Weineisen M, Schottelius M, Simecek J et al (2015) Ga- and 177 Lu-labeled PSMA I&T: optimization of a PSMA-targeted theranostic concept and first proof-of-concept human studies. J Nucl Med 56:1169–1177

    Article  CAS  Google Scholar 

  28. Baum RP, Kulkarni HR, Schuchardt C et al (2016) 177Lu-labeled prostate-specific membrane antigen radioligand therapy of metastatic castration-resistant prostate cancer: Safety and efficacy. J Nucl Med 57:1006–1013

    Article  CAS  Google Scholar 

  29. Benesová M, Schäfer M, Bauder-Wüst U et al (2015) Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer. J Nucl Med 56:914–920

    Article  Google Scholar 

  30. Sinnes J-P, Bauder-Wüst U, Schäfer M et al (2020) 68Ga, 44Sc and 177Lu-labeled AAZTA5-PSMA-617: synthesis, radiolabeling, stability and cell binding compared to DOTA-PSMA-617 analogues. EJNMMI Radiopharm Chem 5:28

    Article  Google Scholar 

  31. Liu T, Liu C, Liu F et al (2019) Synthesis and preclinical evaluation of 68Ga-PSMA-BCH for prostate cancer imaging. Bioorganic Med Chem Lett 29:933–937

    Article  CAS  Google Scholar 

  32. Liu T, Liu C, Xu X et al (2019) Preclinical evaluation and pilot clinical study of Al 18F-PSMA-BCH for prostate cancer imaging. J Nucl Med 60:1284–1292

    Article  CAS  Google Scholar 

  33. Banerjee SR, Kumar V, Lisok A et al (2019) 177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy. Eur J Nucl Med Mol Imaging 46:2545–2557

    Article  CAS  Google Scholar 

  34. Umbricht CA, Benešová M, Schibli R et al (2018) Preclinical development of novel PSMA-targeting radioligands: modulation of albumin-binding properties to improve prostate cancer therapy. Mol Pharm 15:2297–2306

    Article  CAS  Google Scholar 

  35. Choy CJ, Ling X, Geruntho JJ et al (2017) 177Lu-labeled phosphoramidate-based PSMA inhibitors: the effect of an albumin binder on biodistribution and therapeutic efficacy in prostate tumor-bearing mice. Theranostics 7:1928–1939

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Prof. Xing Yang and Dr. Xiaojiang Duan (Department of Nuclear Medicine, Peking University First Hospital) for providing the 22Rv1 tumor-bearing mice and technical assistance.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Chinese PLA General Hospital, No. 28 Fu-Xing Rd., Beijing, 100853, China

    Yitian Wu, Xiaojun Zhang, Haoxi Zhou & Jinming Zhang

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  1. Yitian Wu
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  2. Xiaojun Zhang
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  3. Haoxi Zhou
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  4. Jinming Zhang
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Contributions

JZ and YW conceived and designed the experiments. YW and XZ performed the experiments. YW and HZ analyzed the data. JZ contributed reagents, materials, and analysis tools. YW wrote the paper.

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Correspondence to Jinming Zhang.

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Wu, Y., Zhang, X., Zhou, H. et al. Preclinical development of a novel [68Ga]Ga-/[177Lu]Lu-labeled agent for PSMA-targeted imaging and therapy. J Radioanal Nucl Chem 331, 2705–2717 (2022). https://doi.org/10.1007/s10967-022-08301-5

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  • DOI: https://doi.org/10.1007/s10967-022-08301-5

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