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)....
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/16/2/278 |
| _version_ | 1827755978856071168 |
|---|---|
| author | Taraneh Sadat Zavvar Anton Amadeus Hörmann Maximilian Klingler Dominik Summer Christine Rangger Laurence Desrues Hélène Castel Pierrick Gandolfo Elisabeth von Guggenberg |
| author_facet | Taraneh Sadat Zavvar Anton Amadeus Hörmann Maximilian Klingler Dominik Summer Christine Rangger Laurence Desrues Hélène Castel Pierrick Gandolfo Elisabeth von Guggenberg |
| author_sort | Taraneh Sadat Zavvar |
| collection | DOAJ |
| 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-(<i>N</i>-Me)Nle-Asp-1Nal-NH<sub>2</sub> (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 <sup>111</sup>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 <sup>111</sup>In-labeled conjugates, except [<sup>111</sup>In]In-DOTA-[Phe<sup>8</sup>]MGS5, showed a high resistance against enzymatic degradation. A high receptor affinity with IC<sub>50</sub> 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 [<sup>111</sup>In]In-DOTA-MGS5[NHCH<sub>3</sub>] 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, [<sup>111</sup>In]In-DOTA-[(<i>N</i>-Me)1Nal<sup>8</sup>]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 [<sup>68</sup>Ga]Ga-DOTA-[(<i>N</i>-Me)1Nal<sup>8</sup>]MGS5 and 35.13 ± 6.32% IA/g for [<sup>177</sup>Lu]Lu-DOTA-[(<i>N</i>-Me)1Nal<sup>8</sup>]MGS5. |
| first_indexed | 2024-03-11T08:17:43Z |
| format | Article |
| id | doaj.art-3a432039ee8f46c0a37d73acde50cea6 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T08:17:43Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-3a432039ee8f46c0a37d73acde50cea62023-11-16T22:37:27ZengMDPI AGPharmaceuticals1424-82472023-02-0116227810.3390/ph16020278Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin AnalogsTaraneh Sadat Zavvar0Anton Amadeus Hörmann1Maximilian Klingler2Dominik Summer3Christine Rangger4Laurence Desrues5Hélène Castel6Pierrick Gandolfo7Elisabeth von Guggenberg8Department of Nuclear Medicine, Medical University of Innsbruck, 6020 Innsbruck, AustriaDepartment of Nuclear Medicine, Medical University of Innsbruck, 6020 Innsbruck, AustriaDepartment of Nuclear Medicine, Medical University of Innsbruck, 6020 Innsbruck, AustriaDepartment of Nuclear Medicine, Medical University of Innsbruck, 6020 Innsbruck, AustriaDepartment of Nuclear Medicine, Medical University of Innsbruck, 6020 Innsbruck, AustriaInserm U1245, University Rouen Normandie, 76000 Rouen, FranceInserm U1245, University Rouen Normandie, 76000 Rouen, FranceInserm U1245, University Rouen Normandie, 76000 Rouen, FranceDepartment of Nuclear Medicine, Medical University of Innsbruck, 6020 Innsbruck, AustriaDifferent 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-(<i>N</i>-Me)Nle-Asp-1Nal-NH<sub>2</sub> (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 <sup>111</sup>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 <sup>111</sup>In-labeled conjugates, except [<sup>111</sup>In]In-DOTA-[Phe<sup>8</sup>]MGS5, showed a high resistance against enzymatic degradation. A high receptor affinity with IC<sub>50</sub> 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 [<sup>111</sup>In]In-DOTA-MGS5[NHCH<sub>3</sub>] 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, [<sup>111</sup>In]In-DOTA-[(<i>N</i>-Me)1Nal<sup>8</sup>]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 [<sup>68</sup>Ga]Ga-DOTA-[(<i>N</i>-Me)1Nal<sup>8</sup>]MGS5 and 35.13 ± 6.32% IA/g for [<sup>177</sup>Lu]Lu-DOTA-[(<i>N</i>-Me)1Nal<sup>8</sup>]MGS5.https://www.mdpi.com/1424-8247/16/2/278minigastrincholecystokinin-2 receptormetabolic stabilizationmolecular imagingradiometalstheranostics |
| spellingShingle | Taraneh Sadat Zavvar Anton Amadeus Hörmann Maximilian Klingler Dominik Summer Christine Rangger Laurence Desrues Hélène Castel Pierrick Gandolfo Elisabeth von Guggenberg Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin Analogs Pharmaceuticals minigastrin cholecystokinin-2 receptor metabolic stabilization molecular imaging radiometals theranostics |
| 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 | minigastrin cholecystokinin-2 receptor metabolic stabilization molecular imaging radiometals theranostics |
| url | https://www.mdpi.com/1424-8247/16/2/278 |
| work_keys_str_mv | AT taranehsadatzavvar effectsofsidechainandpeptidebondmodificationsonthetargetingpropertiesofstabilizedminigastrinanalogs AT antonamadeushormann effectsofsidechainandpeptidebondmodificationsonthetargetingpropertiesofstabilizedminigastrinanalogs AT maximilianklingler effectsofsidechainandpeptidebondmodificationsonthetargetingpropertiesofstabilizedminigastrinanalogs AT dominiksummer effectsofsidechainandpeptidebondmodificationsonthetargetingpropertiesofstabilizedminigastrinanalogs AT christinerangger effectsofsidechainandpeptidebondmodificationsonthetargetingpropertiesofstabilizedminigastrinanalogs AT laurencedesrues effectsofsidechainandpeptidebondmodificationsonthetargetingpropertiesofstabilizedminigastrinanalogs AT helenecastel effectsofsidechainandpeptidebondmodificationsonthetargetingpropertiesofstabilizedminigastrinanalogs AT pierrickgandolfo effectsofsidechainandpeptidebondmodificationsonthetargetingpropertiesofstabilizedminigastrinanalogs AT elisabethvonguggenberg effectsofsidechainandpeptidebondmodificationsonthetargetingpropertiesofstabilizedminigastrinanalogs |