Localization of Tc-GRP Analogs in GRPR-Expressing Tumors: Effects of Peptide Length and Neprilysin Inhibition on Biological Responses

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2019 Mar 23

PMID 30897789

Citations 5

Authors

Aikaterini Kaloudi

Emmanouil Lymperis

Panagiotis Kanellopoulos

Beatrice Waser

Marion de Jong

Eric P Krenning

Jean Claude Reubi

Berthold A Nock

Theodosia Maina

Affiliations

Soon will be listed here.

Abstract

The overexpression of gastrin-releasing peptide receptors (GRPRs) in frequently occurring human tumors has provided the opportunity to use bombesin (BBN) analogs as radionuclide carriers to cancer sites for diagnostic and therapeutic purposes. We have been alternatively exploring human GRP motifs of higher GRPR selectivity compared to frog BBN sequences aiming to improve pharmacokinetic profiles. In the present study, we compared two differently truncated human endogenous GRP motifs: GRP(14⁻27) and GRP(18⁻27). An acyclic tetraamine was coupled at the N-terminus to allow for stable binding of the SPECT radionuclide Tc. Their biological profiles were compared in PC-3 cells and in mice without or with coinjection of phosphoramidon (PA) to induce transient neprilysin (NEP) inhibition in vivo. The two Tc-N₄-GRP(14/18⁻27) radioligands displayed similar biological behavior in mice. Coinjection of PA exerted a profound effect on in vivo stability and translated into notably improved radiolabel localization in PC-3 experimental tumors. Hence, this study has shown that promising Tc-radiotracers for SPECT imaging may indeed derive from human GRP sequences. Radiotracer bioavailability was found to be of major significance. It could be improved during in situ NEP inhibition resulting in drastically enhanced uptake in GRPR-expressing lesions.

Citing Articles

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Mansi R, Nock B, Dalm S, Busstra M, van Weerden W, Maina T Cancers (Basel). 2021; 13(22).

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Ga-PET-imaging of GRPR-expression in prostate cancer: production and characterization of [Ga]Ga-NOTA-PEG-RM26.

Rinne S, Abouzayed A, Gagnon K, Tolmachev V, Orlova A Sci Rep. 2021; 11(1):3631.

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One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [Tc]Tc-DB4 and [In]In-SG4 in Mice Treated with Entresto.

Kanellopoulos P, Kaloudi A, Rouchota M, Loudos G, de Jong M, Krenning E Pharmaceutics. 2020; 12(12).

PMID: 33256013 PMC: 7760338. DOI: 10.3390/pharmaceutics12121145.

[Tc]Tc-DB1 Mimics with Different-Length PEG Spacers: Preclinical Comparison in GRPR-Positive Models.

Kanellopoulos P, Lymperis E, Kaloudi A, de Jong M, Krenning E, Nock B Molecules. 2020; 25(15).

PMID: 32731473 PMC: 7435657. DOI: 10.3390/molecules25153418.

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