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 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.

Trastuzumab cotreatment improves survival of mice with PC‐3 prostate cancer xenografts treated with the GRPR antagonist 177Lu‐DOTAGA‐PEG2‐RM26

“…As expected, the uptake in GRPR‐expressing organs was also significantly increased, while the uptake in nontarget healthy tissues, particularly the kidneys were not affected. This strategy has been successfully used to enhance the efficacy of other peptide‐based targeting vectors …”

Theranostic Perspectives in Prostate Cancer with the Gastrin-Releasing Peptide Receptor Antagonist NeoBOMB1: Preclinical and First Clinical Results

“…Consequently, lower tumor uptake was achieved in mice, a handicap that could be reversed by in situ neutral endopeptidase inhibition with phosphoramidon (24). However, this promising approach, recently shown to improve the theranostic potential of other GRPR radioantagonists as well, has not yet been translated in humans (22).…”

“…Several studies have shown that noninternalizing radioantagonists can successfully target and be sufficiently retained in GRPR-expressing cancer lesions while rapidly clearing from physiologic organs in both animal models and humans. The superior pharmacokinetics of GRPR radioantagonists over their agonist counterparts in combination with their higher inherent biosafety has shifted current research toward the design of new improved GRPR radioantagonist candidates with clear potential for clinical translation (19)(20)(21)(22)(23).…”

“…For example, replacement of the C-terminal Leu 13 -Met 14 -NH 2 dipeptide by Sta 13 -Leu 14 -NH 2 and coupling of DOTA has recently fostered the development of promising GRPR radioantagonists (20,21,25). We have shown though that such a GRPR radioantagonist, [ 68 Ga/ 177 Lu]JMV4168, can reach its full theranostic potential only after injection of phosphoramidon (22). The latter, by in situ inhibition of the catabolic action of neutral endopeptidase, increased the stability of [ 68 Ga/ 177 Lu]JMV4168 in peripheral blood, leading to notably enhanced tumor uptake.…”

68Ga/177Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology

“…Furthermore, dosimetry calculations resulted in a 1.3-timeshigher tumor dose and a 5-times-lower pancreas dose with 200 pmol 177 Lu-NeoBOMB1 than 10 pmol 177 Lu-NeoBOMB1. When dosimetry data are compared with other radiolabeled GRPR antagonists, such as 177 Lu-JMV4168 (29), estimated absorbed radiation doses to the tumor were higher for 177 LuNeoBOMB1 (29 Gy/50 MBq vs. 11 Gy/50 MBq) even when 177 Lu-JMV4168 was stabilized by coinjection of an enzyme inhibitor (29 Gy/50 MBq vs. 20 Gy/MBq). When we compared the dose to the kidneys and pancreas of the radiotracers, we found a more favorable tumor-to-kidney ratio for 177 LuNeoBOMB1 (10 vs. 1.5) and a similar tumor-to-pancreas ratio (2.2 vs. 2.5).…”