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Exploiting the Concept of Multivalency with (68)Ga- and (89)Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression
Cholecystokinin-2 receptors (CCK2R) are overexpressed in a variety of malignant diseases and therefore have gained certain attention for peptide receptor radionuclide imaging. Among extensive approaches to improve pharmacokinetics and metabolic stability of minigastrin (MG) based radioligands, the c...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914118/ https://www.ncbi.nlm.nih.gov/pubmed/29849512 http://dx.doi.org/10.1155/2018/3171794 |
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author | Summer, Dominik Rangger, Christine Klingler, Maximilian Laverman, Peter Franssen, Gerben M. Lechner, Beatrix E. Orasch, Thomas Haas, Hubertus von Guggenberg, Elisabeth Decristoforo, Clemens |
author_facet | Summer, Dominik Rangger, Christine Klingler, Maximilian Laverman, Peter Franssen, Gerben M. Lechner, Beatrix E. Orasch, Thomas Haas, Hubertus von Guggenberg, Elisabeth Decristoforo, Clemens |
author_sort | Summer, Dominik |
collection | PubMed |
description | Cholecystokinin-2 receptors (CCK2R) are overexpressed in a variety of malignant diseases and therefore have gained certain attention for peptide receptor radionuclide imaging. Among extensive approaches to improve pharmacokinetics and metabolic stability of minigastrin (MG) based radioligands, the concept of multivalency for enhanced tumour targeting has not been investigated extensively. We therefore utilized fusarinine C (FSC) as chelating scaffold for novel mono-, di-, and trimeric bioconjugates for targeting CCK2R expression. FSC-based imaging probes were radiolabelled with positron emitting radionuclides (gallium-68 and zirconium-89) and characterized in vitro (logD, IC(50), and cell uptake) and in vivo (metabolic stability in BALB/c mice, biodistribution profile, and microPET/CT imaging in A431-CCK2R/A431-mock tumour xenografted BALB/c nude mice). Improved targeting did not fully correlate with the grade of multimerization. The divalent probe showed higher receptor affinity and increased CCK2R mediated cell uptake while the trimer remained comparable to the monomer. In vivo biodistribution studies 1 h after administration of the (68)Ga-labelled radioligands confirmed this trend, but imaging at late time point (24 h) with (89)Zr-labelled counterparts showed a clearly enhanced imaging contrast of the trimeric probe compared to the mono- and dimer. Furthermore, in vivo stability studies showed a higher metabolic stability for multimeric probes compared to the monomeric bioconjugate. In summary, we could show that FSC can be utilized as suitable scaffold for novel mono- and multivalent imaging probes for CCK2R-related malignancies with partly improved targeting properties for multivalent conjugates. The increased tumour accumulation of the trimer 24 h postinjection (p.i.) can be explained by slower clearance and increased metabolic stability of multimeric conjugates. |
format | Online Article Text |
id | pubmed-5914118 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-59141182018-05-30 Exploiting the Concept of Multivalency with (68)Ga- and (89)Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression Summer, Dominik Rangger, Christine Klingler, Maximilian Laverman, Peter Franssen, Gerben M. Lechner, Beatrix E. Orasch, Thomas Haas, Hubertus von Guggenberg, Elisabeth Decristoforo, Clemens Contrast Media Mol Imaging Research Article Cholecystokinin-2 receptors (CCK2R) are overexpressed in a variety of malignant diseases and therefore have gained certain attention for peptide receptor radionuclide imaging. Among extensive approaches to improve pharmacokinetics and metabolic stability of minigastrin (MG) based radioligands, the concept of multivalency for enhanced tumour targeting has not been investigated extensively. We therefore utilized fusarinine C (FSC) as chelating scaffold for novel mono-, di-, and trimeric bioconjugates for targeting CCK2R expression. FSC-based imaging probes were radiolabelled with positron emitting radionuclides (gallium-68 and zirconium-89) and characterized in vitro (logD, IC(50), and cell uptake) and in vivo (metabolic stability in BALB/c mice, biodistribution profile, and microPET/CT imaging in A431-CCK2R/A431-mock tumour xenografted BALB/c nude mice). Improved targeting did not fully correlate with the grade of multimerization. The divalent probe showed higher receptor affinity and increased CCK2R mediated cell uptake while the trimer remained comparable to the monomer. In vivo biodistribution studies 1 h after administration of the (68)Ga-labelled radioligands confirmed this trend, but imaging at late time point (24 h) with (89)Zr-labelled counterparts showed a clearly enhanced imaging contrast of the trimeric probe compared to the mono- and dimer. Furthermore, in vivo stability studies showed a higher metabolic stability for multimeric probes compared to the monomeric bioconjugate. In summary, we could show that FSC can be utilized as suitable scaffold for novel mono- and multivalent imaging probes for CCK2R-related malignancies with partly improved targeting properties for multivalent conjugates. The increased tumour accumulation of the trimer 24 h postinjection (p.i.) can be explained by slower clearance and increased metabolic stability of multimeric conjugates. Hindawi 2018-04-10 /pmc/articles/PMC5914118/ /pubmed/29849512 http://dx.doi.org/10.1155/2018/3171794 Text en Copyright © 2018 Dominik Summer et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Summer, Dominik Rangger, Christine Klingler, Maximilian Laverman, Peter Franssen, Gerben M. Lechner, Beatrix E. Orasch, Thomas Haas, Hubertus von Guggenberg, Elisabeth Decristoforo, Clemens Exploiting the Concept of Multivalency with (68)Ga- and (89)Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression |
title | Exploiting the Concept of Multivalency with (68)Ga- and (89)Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression |
title_full | Exploiting the Concept of Multivalency with (68)Ga- and (89)Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression |
title_fullStr | Exploiting the Concept of Multivalency with (68)Ga- and (89)Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression |
title_full_unstemmed | Exploiting the Concept of Multivalency with (68)Ga- and (89)Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression |
title_short | Exploiting the Concept of Multivalency with (68)Ga- and (89)Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression |
title_sort | exploiting the concept of multivalency with (68)ga- and (89)zr-labelled fusarinine c-minigastrin bioconjugates for targeting cck2r expression |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914118/ https://www.ncbi.nlm.nih.gov/pubmed/29849512 http://dx.doi.org/10.1155/2018/3171794 |
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