Theranostics 2016; 6(1):104-117. doi:10.7150/thno.13580 This issue

Research Paper

In Vivo Stabilization of a Gastrin-Releasing Peptide Receptor Antagonist Enhances PET Imaging and Radionuclide Therapy of Prostate Cancer in Preclinical Studies

Kristell L.S. Chatalic1,2,3,✉, Mark Konijnenberg1, Julie Nonnekens1,4, Erik de Blois1, Sander Hoeben3, Corrina de Ridder3, Luc Brunel5, Jean-Alain Fehrentz5, Jean Martinez5, Dik C. van Gent4, Berthold A. Nock6, Theodosia Maina6, Wytske M. van Weerden3, Marion de Jong1,2

1. Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
2. Department of Radiology, Erasmus MC, Rotterdam, The Netherlands
3. Department of Urology, Erasmus MC, Rotterdam, The Netherlands
4. Department of Genetics, Erasmus MC, Rotterdam, The Netherlands
5. IBMM, UMR 5247, CNRS, Université Montpellier, ENSCM, France
6. Molecular Radiopharmacy, INRASTES, NCSR Demokritos, Athens, Greece

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See for full terms and conditions.
Chatalic KLS, Konijnenberg M, Nonnekens J, de Blois E, Hoeben S, de Ridder C, Brunel L, Fehrentz JA, Martinez J, van Gent DC, Nock BA, Maina T, van Weerden WM, de Jong M. In Vivo Stabilization of a Gastrin-Releasing Peptide Receptor Antagonist Enhances PET Imaging and Radionuclide Therapy of Prostate Cancer in Preclinical Studies. Theranostics 2016; 6(1):104-117. doi:10.7150/thno.13580. Available from

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Graphic abstract

A single tool for early detection, accurate staging, and personalized treatment of prostate cancer (PCa) would be a major breakthrough in the field of PCa. Gastrin-releasing peptide receptor (GRPR) targeting peptides are promising probes for a theranostic approach for PCa overexpressing GRPR. However, the successful application of small peptides in a theranostic approach is often hampered by their fast in vivo degradation by proteolytic enzymes, such as neutral endopeptidase (NEP). Here we show for the first time that co-injection of a NEP inhibitor (phosphoramidon (PA)) can lead to an impressive enhancement of diagnostic sensitivity and therapeutic efficacy of the theranostic 68Ga-/177Lu-JMV4168 GRPR-antagonist. Co-injection of PA (300 µg) led to stabilization of 177Lu-JMV4168 in murine peripheral blood. In PC-3 tumor-bearing mice, PA co-injection led to a two-fold increase in tumor uptake of 68Ga-/177Lu-JMV4168, 1 h after injection. In positron emission tomography (PET) imaging with 68Ga-JMV4168, PA co-injection substantially enhanced PC-3 tumor signal intensity. Radionuclide therapy with 177Lu-JMV4168 resulted in significant regression of PC-3 tumor size. Radionuclide therapy efficacy was confirmed by production of DNA double strand breaks, decreased cell proliferation and increased apoptosis. Increased survival rates were observed in mice treated with 177Lu-JMV4168 plus PA as compared to those without PA. This data shows that co-injection of the enzyme inhibitor PA greatly enhances the theranostic potential of GRPR-radioantagonists for future application in PCa patients.

Keywords: GRPR, neutral endopeptidase, enzyme inhibition, phosphoramidon, theranostics, PET imaging, radionuclide therapy, prostate cancer.