Effect of <i>N</i>-Terminal Peptide Modifications on In Vitro and In Vivo Properties of <sup>177</sup>Lu-Labeled Peptide Analogs Targeting CCK2R
The therapeutic potential of minigastrin (MG) analogs for the treatment of cholecystokinin-2 receptor (CCK2R)-expressing cancers is limited by poor in vivo stability or unfavorable accumulation in non-target tissues. Increased stability against metabolic degradation was achieved by modifying the C-t...
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MDPI AG
2023-02-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/3/796 |
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| author | Anton Amadeus Hörmann Maximilian Klingler Christine Rangger Christian Mair Lieke Joosten Gerben M. Franssen Peter Laverman Elisabeth von Guggenberg |
| author_facet | Anton Amadeus Hörmann Maximilian Klingler Christine Rangger Christian Mair Lieke Joosten Gerben M. Franssen Peter Laverman Elisabeth von Guggenberg |
| author_sort | Anton Amadeus Hörmann |
| collection | DOAJ |
| description | The therapeutic potential of minigastrin (MG) analogs for the treatment of cholecystokinin-2 receptor (CCK2R)-expressing cancers is limited by poor in vivo stability or unfavorable accumulation in non-target tissues. Increased stability against metabolic degradation was achieved by modifying the C-terminal receptor-specific region. This modification led to significantly improved tumor targeting properties. In this study, further <i>N</i>-terminal peptide modifications were investigated. Two novel MG analogs were designed starting from the amino acid sequence of DOTA-MGS5 (DOTA-DGlu-Ala-Tyr-Gly-Trp-(<i>N</i>-Me)Nle-Asp-1Nal-NH<sub>2</sub>). Introduction of a penta-DGlu moiety and replacement of the four <i>N</i>-terminal amino acids by a non-charged hydrophilic linker was investigated. Retained receptor binding was confirmed using two CCK2R-expressing cell lines. The effect on metabolic degradation of the new <sup>177</sup>Lu-labeled peptides was studied in human serum in vitro, as well as in BALB/c mice in vivo. The tumor targeting properties of the radiolabeled peptides were assessed using BALB/c nude mice bearing receptor-positive and receptor-negative tumor xenografts. Both novel MG analogs were found to have strong receptor binding, enhanced stability, and high tumor uptake. Replacement of the four <i>N</i>-terminal amino acids by a non-charged hydrophilic linker lowered the absorption in the dose-limiting organs, whereas introduction of the penta-DGlu moiety increased uptake in renal tissue. |
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| id | doaj.art-cce9ff54695d4e17bf4864ac9c1fe04e |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T06:02:39Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-cce9ff54695d4e17bf4864ac9c1fe04e2023-11-17T13:14:30ZengMDPI AGPharmaceutics1999-49232023-02-0115379610.3390/pharmaceutics15030796Effect of <i>N</i>-Terminal Peptide Modifications on In Vitro and In Vivo Properties of <sup>177</sup>Lu-Labeled Peptide Analogs Targeting CCK2RAnton Amadeus Hörmann0Maximilian Klingler1Christine Rangger2Christian Mair3Lieke Joosten4Gerben M. Franssen5Peter Laverman6Elisabeth von Guggenberg7Department 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 Medical Imaging, Nuclear Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Medical Imaging, Nuclear Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Medical Imaging, Nuclear Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The NetherlandsDepartment of Nuclear Medicine, Medical University of Innsbruck, 6020 Innsbruck, AustriaThe therapeutic potential of minigastrin (MG) analogs for the treatment of cholecystokinin-2 receptor (CCK2R)-expressing cancers is limited by poor in vivo stability or unfavorable accumulation in non-target tissues. Increased stability against metabolic degradation was achieved by modifying the C-terminal receptor-specific region. This modification led to significantly improved tumor targeting properties. In this study, further <i>N</i>-terminal peptide modifications were investigated. Two novel MG analogs were designed starting from the amino acid sequence of DOTA-MGS5 (DOTA-DGlu-Ala-Tyr-Gly-Trp-(<i>N</i>-Me)Nle-Asp-1Nal-NH<sub>2</sub>). Introduction of a penta-DGlu moiety and replacement of the four <i>N</i>-terminal amino acids by a non-charged hydrophilic linker was investigated. Retained receptor binding was confirmed using two CCK2R-expressing cell lines. The effect on metabolic degradation of the new <sup>177</sup>Lu-labeled peptides was studied in human serum in vitro, as well as in BALB/c mice in vivo. The tumor targeting properties of the radiolabeled peptides were assessed using BALB/c nude mice bearing receptor-positive and receptor-negative tumor xenografts. Both novel MG analogs were found to have strong receptor binding, enhanced stability, and high tumor uptake. Replacement of the four <i>N</i>-terminal amino acids by a non-charged hydrophilic linker lowered the absorption in the dose-limiting organs, whereas introduction of the penta-DGlu moiety increased uptake in renal tissue.https://www.mdpi.com/1999-4923/15/3/796cholecystokinin-2 receptorgastrinpeptide receptor radionuclide therapylutetium-177theranostics |
| spellingShingle | Anton Amadeus Hörmann Maximilian Klingler Christine Rangger Christian Mair Lieke Joosten Gerben M. Franssen Peter Laverman Elisabeth von Guggenberg Effect of <i>N</i>-Terminal Peptide Modifications on In Vitro and In Vivo Properties of <sup>177</sup>Lu-Labeled Peptide Analogs Targeting CCK2R Pharmaceutics cholecystokinin-2 receptor gastrin peptide receptor radionuclide therapy lutetium-177 theranostics |
| title | Effect of <i>N</i>-Terminal Peptide Modifications on In Vitro and In Vivo Properties of <sup>177</sup>Lu-Labeled Peptide Analogs Targeting CCK2R |
| title_full | Effect of <i>N</i>-Terminal Peptide Modifications on In Vitro and In Vivo Properties of <sup>177</sup>Lu-Labeled Peptide Analogs Targeting CCK2R |
| title_fullStr | Effect of <i>N</i>-Terminal Peptide Modifications on In Vitro and In Vivo Properties of <sup>177</sup>Lu-Labeled Peptide Analogs Targeting CCK2R |
| title_full_unstemmed | Effect of <i>N</i>-Terminal Peptide Modifications on In Vitro and In Vivo Properties of <sup>177</sup>Lu-Labeled Peptide Analogs Targeting CCK2R |
| title_short | Effect of <i>N</i>-Terminal Peptide Modifications on In Vitro and In Vivo Properties of <sup>177</sup>Lu-Labeled Peptide Analogs Targeting CCK2R |
| title_sort | effect of i n i terminal peptide modifications on in vitro and in vivo properties of sup 177 sup lu labeled peptide analogs targeting cck2r |
| topic | cholecystokinin-2 receptor gastrin peptide receptor radionuclide therapy lutetium-177 theranostics |
| url | https://www.mdpi.com/1999-4923/15/3/796 |
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