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Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin Analogs
Different attempts have been made in the past two decades to develop radiolabeled peptide conjugates with enhanced pharmacokinetic properties in order to improve the application for tumor imaging and peptide receptor radionuclide therapy (PRRT), which targets the cholecystokinin-2 receptor (CCK2R)....
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9959130/ https://www.ncbi.nlm.nih.gov/pubmed/37052226 http://dx.doi.org/10.3390/ph16020278 |
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author | Zavvar, Taraneh Sadat Hörmann, Anton Amadeus Klingler, Maximilian Summer, Dominik Rangger, Christine Desrues, Laurence Castel, Hélène Gandolfo, Pierrick von Guggenberg, Elisabeth |
author_facet | Zavvar, Taraneh Sadat Hörmann, Anton Amadeus Klingler, Maximilian Summer, Dominik Rangger, Christine Desrues, Laurence Castel, Hélène Gandolfo, Pierrick von Guggenberg, Elisabeth |
author_sort | Zavvar, Taraneh Sadat |
collection | PubMed |
description | Different attempts have been made in the past two decades to develop radiolabeled peptide conjugates with enhanced pharmacokinetic properties in order to improve the application for tumor imaging and peptide receptor radionuclide therapy (PRRT), which targets the cholecystokinin-2 receptor (CCK2R). In this paper, the influence of different side chain and peptide bond modifications has been explored for the minigastrin analog DOTA-DGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH(2) (DOTA-MGS5). Based on this lead structure, five new derivatives were synthesized for radiolabeling with trivalent radiometals. Different chemical and biological properties of the new derivatives were analyzed. Receptor interaction of the peptide derivatives and cell internalization of the radiolabeled peptides were studied in A431-CCK2R cells. The stability of the radiolabeled peptides in vivo was investigated using BALB/c mice. Tumor targeting of all (111)In-labeled peptide conjugates, and of a selected compound radiolabeled with gallium-68 and lutetium-177, was evaluated in BALB/c nude mice xenografted with A431-CCK2R and A431-mock cells. All (111)In-labeled conjugates, except [(111)In]In-DOTA-[Phe(8)]MGS5, showed a high resistance against enzymatic degradation. A high receptor affinity with IC(50) values in the low nanomolar range was confirmed for most of the peptide derivatives. The specific cell internalization over time was 35.3–47.3% for all radiopeptides 4 h after incubation. Only [(111)In]In-DOTA-MGS5[NHCH(3)] exhibited a lower cell internalization of 6.6 ± 2.8%. An overall improved resistance against enzymatic degradation was confirmed in vivo. Of the radiopeptides studied, [(111)In]In-DOTA-[(N-Me)1Nal(8)]MGS5 showed the most promising targeting properties, with significantly increased accumulation of radioactivity in A431-CCK2R xenografts (48.1 ± 9.2% IA/g) and reduced accumulation of radioactivity in stomach (4.2 ± 0.5% IA/g). However, in comparison with DOTA-MGS5, a higher influence on the targeting properties was observed for the change of radiometal, resulting in a tumor uptake of 15.67 ± 2.21% IA/g for [(68)Ga]Ga-DOTA-[(N-Me)1Nal(8)]MGS5 and 35.13 ± 6.32% IA/g for [(177)Lu]Lu-DOTA-[(N-Me)1Nal(8)]MGS5. |
format | Online Article Text |
id | pubmed-9959130 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99591302023-02-26 Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin Analogs Zavvar, Taraneh Sadat Hörmann, Anton Amadeus Klingler, Maximilian Summer, Dominik Rangger, Christine Desrues, Laurence Castel, Hélène Gandolfo, Pierrick von Guggenberg, Elisabeth Pharmaceuticals (Basel) Article Different attempts have been made in the past two decades to develop radiolabeled peptide conjugates with enhanced pharmacokinetic properties in order to improve the application for tumor imaging and peptide receptor radionuclide therapy (PRRT), which targets the cholecystokinin-2 receptor (CCK2R). In this paper, the influence of different side chain and peptide bond modifications has been explored for the minigastrin analog DOTA-DGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH(2) (DOTA-MGS5). Based on this lead structure, five new derivatives were synthesized for radiolabeling with trivalent radiometals. Different chemical and biological properties of the new derivatives were analyzed. Receptor interaction of the peptide derivatives and cell internalization of the radiolabeled peptides were studied in A431-CCK2R cells. The stability of the radiolabeled peptides in vivo was investigated using BALB/c mice. Tumor targeting of all (111)In-labeled peptide conjugates, and of a selected compound radiolabeled with gallium-68 and lutetium-177, was evaluated in BALB/c nude mice xenografted with A431-CCK2R and A431-mock cells. All (111)In-labeled conjugates, except [(111)In]In-DOTA-[Phe(8)]MGS5, showed a high resistance against enzymatic degradation. A high receptor affinity with IC(50) values in the low nanomolar range was confirmed for most of the peptide derivatives. The specific cell internalization over time was 35.3–47.3% for all radiopeptides 4 h after incubation. Only [(111)In]In-DOTA-MGS5[NHCH(3)] exhibited a lower cell internalization of 6.6 ± 2.8%. An overall improved resistance against enzymatic degradation was confirmed in vivo. Of the radiopeptides studied, [(111)In]In-DOTA-[(N-Me)1Nal(8)]MGS5 showed the most promising targeting properties, with significantly increased accumulation of radioactivity in A431-CCK2R xenografts (48.1 ± 9.2% IA/g) and reduced accumulation of radioactivity in stomach (4.2 ± 0.5% IA/g). However, in comparison with DOTA-MGS5, a higher influence on the targeting properties was observed for the change of radiometal, resulting in a tumor uptake of 15.67 ± 2.21% IA/g for [(68)Ga]Ga-DOTA-[(N-Me)1Nal(8)]MGS5 and 35.13 ± 6.32% IA/g for [(177)Lu]Lu-DOTA-[(N-Me)1Nal(8)]MGS5. MDPI 2023-02-13 /pmc/articles/PMC9959130/ /pubmed/37052226 http://dx.doi.org/10.3390/ph16020278 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zavvar, Taraneh Sadat Hörmann, Anton Amadeus Klingler, Maximilian Summer, Dominik Rangger, Christine Desrues, Laurence Castel, Hélène Gandolfo, Pierrick von Guggenberg, Elisabeth Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin Analogs |
title | Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin Analogs |
title_full | Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin Analogs |
title_fullStr | Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin Analogs |
title_full_unstemmed | Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin Analogs |
title_short | Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin Analogs |
title_sort | effects of side chain and peptide bond modifications on the targeting properties of stabilized minigastrin analogs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9959130/ https://www.ncbi.nlm.nih.gov/pubmed/37052226 http://dx.doi.org/10.3390/ph16020278 |
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