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.

Additional Metadata
Keywords Enzyme inhibition, GRPR, Neutral endopeptidase, PET imaging, Phosphoramidon, Prostate cancer, Radionuclide therapy, Theranostics
Persistent URL dx.doi.org/10.7150/thno.13580, hdl.handle.net/1765/89562
Journal Theranostics
Chatalic, K.L.S, Konijnenberg, M, Nonnekens, J, de Blois, E, Hoeben, S, Ridder, C.M.A, … de Jong, M. (2016). In vivo stabilization of a gastrin-releasing peptide receptor antagonist enhances pet imaging and radionuclide therapy of prostate cancer in preclinical studies. Theranostics, 6(1), 104–117. doi:10.7150/thno.13580