Pre-clinical evaluation of eight DOTA coupled gastrin-releasing peptide receptor (GRP-R) ligands for in vivo targeting of receptor-expressing tumors

Abstract

BackgroundOverexpression of the gastrin-releasing peptide receptor (GRP-R) has been documented in several human neoplasms such as breast, prostate, and ovarian cancer. There is growing interest in developing radiolabeled peptide-based ligands toward these receptors for the purpose of in vivo imaging and radionuclide therapy of GRP-R-overexpressing tumors. A number of different peptide sequences, isotopes, and labeling methods have been proposed for this purpose. The aim of this work is to perform a direct side-by-side comparison of different GRP-R binding peptides utilizing a single labeling strategy to identify the most suitable peptide sequence.MethodsSolid-phase synthesis of eight derivatives (BN1-8) designed based on literature analysis was carried out. Peptides were coupled to the DOTA chelator through a PEG4 spacer at the N-terminus. Derivatives were characterized for serum stability, binding affinity on PC-3 human prostate cancer cells, biodistribution in tumor-bearing mice, and gamma camera imaging at 1, 6, and 24 h after injection.ResultsSerum stability was quite variable among the different compounds with half-lives ranging from 16 to 400 min at 37 °C. All compounds tested showed Kd values in the nanomolar range with the exception of BN3 that showed no binding. Biodistribution and imaging studies carried out for compounds BN1, BN4, BN7, and BN8 showed targeting of the GRP-R-positive tumors and the pancreas. The BN8 compound (DOTA-PEG-DPhe-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH2) showed high affinity, the longest serum stability, and the highest target-to-background ratios in biodistribution and imaging experiments among the compounds tested.ConclusionsOur results indicate that the NMeGly for Gly substitution and the Sta-Leu substitution at the C-terminus confer high serum stability while maintaining high receptor affinity, resulting in biodistribution properties that outperform those of the other peptides.

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“…This would have potentially rendered our study irreproducible, more expensive (our study was self-funded), and moreover a single receptor-specific radiopharmaceutical might have highlighted only one feature of the receptor expression profile of the cancers. However, we are aware that other radiopharmaceuticals showed potential to characterise breast cancer better that FDG (van de Wiele et al , 2002; Van Den Bossche et al , 2006; Siwowska and Muller, 2015; Accardo et al , 2016; Park et al , 2016). …”

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New Insights in the Design of Bioactive Peptides and Chelating Agents for Imaging and Therapy in Oncology

“…Other amino acids sensitive to endopeptidases, such as His-12/Leu-13 and Gly-11/His-12, have been substituted with non-natural Cha or statin (Sta) and N -methylglycine, respectively, to increase the in vivo stability [ 38 ]. Finally, the introduction of d -Phe at the N-terminus and Sta-13 in place of Leu-13 conferred antagonistic properties superior to the agonistic features in terms of higher tumor targeting, retention, and tumor-to-tissue ratios [ 54 ].…”