title: In Vivo Stabilization of a Gastrin-Releasing Peptide Receptor Antagonist Enhances PET Imaging and Radionuclide Therapy of Prostate Cancer in Preclinical Studies.
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 (68)Ga-/(177)Lu-JMV4168 GRPR-antagonist. Co-injection of PA (300 µg) led to stabilization of (177)Lu-JMV4168 in murine peripheral blood. In PC-3 tumor-bearing mice, PA co-injection led to a two-fold increase in tumor uptake of (68)Ga-/(177)Lu-JMV4168, 1 h after injection. In positron emission tomography (PET) imaging with (68)Ga-JMV4168, PA co-injection substantially enhanced PC-3 tumor signal intensity. Radionuclide therapy with (177)Lu-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 (177)Lu-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.
authors.affiliation: 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.
authors.forename: Kristell L S
authors.initials: KL
authors.lastname: Chatalic
authors.affiliation: 1. Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Konijnenberg
authors.affiliation: 1. Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands ; 4. Department of Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Julie
authors.initials: J
authors.lastname: Nonnekens
authors.affiliation: 1. Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: de Blois
authors.affiliation: 3. Department of Urology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Hoeben
authors.affiliation: 3. Department of Urology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Corrina
authors.initials: C
authors.lastname: de Ridder
authors.affiliation: 5. IBMM, UMR 5247, CNRS, Université Montpellier, ENSCM, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Brunel
authors.affiliation: 5. IBMM, UMR 5247, CNRS, Université Montpellier, ENSCM, France.
authors.forename: Jean-Alain
authors.initials: JA
authors.lastname: Fehrentz
authors.affiliation: 5. IBMM, UMR 5247, CNRS, Université Montpellier, ENSCM, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
authors.affiliation: 4. Department of Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
authors.affiliation: 6. Molecular Radiopharmacy, INRASTES, NCSR Demokritos, Athens, Greece.
authors.forename: Berthold A
authors.initials: BA
authors.lastname: Nock
authors.affiliation: 6. Molecular Radiopharmacy, INRASTES, NCSR Demokritos, Athens, Greece.
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
authors.affiliation: 3. Department of Urology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Wytske M
authors.initials: WM
authors.lastname: van Weerden
authors.affiliation: 1. Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands ; 2. Department of Radiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000628:therapy*; D011868:Radioisotopes / Q000493:pharmacokinetics*; D011878:Radiotherapy / Q000379:methods*; D018004:Receptors, Bombesin / Q000032:analysis* / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D011868:Radioisotopes; D018004:Receptors, Bombesin
keywords: GRPR; PET imaging; enzyme inhibition; neutral endopeptidase; phosphoramidon; radionuclide therapy, prostate cancer.; theranostics