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

Kristell Chatalic, Mark Konijnenberg, Julie Nonnekens, Erik de Blois, Sander Hoeben, Corrina de Ridder, L Brunel, JA Fehrentz, J Martinez, Dik van Gent, BA Nock, T Maina, Wytske van Weerden, Marion Jong

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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 mu g) led to stabilization of Lu-177-JMV4168 in murine peripheral blood. In PC-3 tumor-bearing mice, PA co-injection led to a two-fold increase in tumor uptake of Ga-68-/Lu-177-JMV4168, 1 h after injection. In positron emission tomography (PET) imaging with Ga-68-JMV4168, PA co-injection substantially enhanced PC-3 tumor signal intensity. Radionuclide therapy with Lu-177-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 Lu-177-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.
Original languageUndefined/Unknown
Pages (from-to)104-117
Number of pages14
Issue number1
Publication statusPublished - 2016

Research programs

  • EMC MGC-01-12-03
  • EMC MM-01-40-01
  • EMC MM-03-49-01
  • EMC NIHES-03-30-01
  • EMC NIHES-03-30-03

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