Cargando…

CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer

Background: Molecular targeting remains to be a promising approach in oncology. Overexpression of G protein-coupled receptors (GPCRs) in human cancer is offering a powerful opportunity for tumor-selective imaging and treatment employing nuclear medicine. We utilized novel chemerin-based peptide conj...

Descripción completa

Detalles Bibliográficos
Autores principales: Erdmann, Sarah, Niederstadt, Lars, Koziolek, Eva Jolanthe, Gómez, Juan Daniel Castillo, Prasad, Sonal, Wagener, Asja, von Hacht, Jan Lennart, Reinicke, Sandy, Exner, Samantha, Bandholtz, Sebastian, Beindorff, Nicola, Brenner, Winfried, Grötzinger, Carsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771245/
https://www.ncbi.nlm.nih.gov/pubmed/31588246
http://dx.doi.org/10.7150/thno.34857
_version_ 1783455657882550272
author Erdmann, Sarah
Niederstadt, Lars
Koziolek, Eva Jolanthe
Gómez, Juan Daniel Castillo
Prasad, Sonal
Wagener, Asja
von Hacht, Jan Lennart
Reinicke, Sandy
Exner, Samantha
Bandholtz, Sebastian
Beindorff, Nicola
Brenner, Winfried
Grötzinger, Carsten
author_facet Erdmann, Sarah
Niederstadt, Lars
Koziolek, Eva Jolanthe
Gómez, Juan Daniel Castillo
Prasad, Sonal
Wagener, Asja
von Hacht, Jan Lennart
Reinicke, Sandy
Exner, Samantha
Bandholtz, Sebastian
Beindorff, Nicola
Brenner, Winfried
Grötzinger, Carsten
author_sort Erdmann, Sarah
collection PubMed
description Background: Molecular targeting remains to be a promising approach in oncology. Overexpression of G protein-coupled receptors (GPCRs) in human cancer is offering a powerful opportunity for tumor-selective imaging and treatment employing nuclear medicine. We utilized novel chemerin-based peptide conjugates for chemokine-like receptor 1 (CMKLR1) targeting in a breast cancer xenograft model. Methods: By conjugation with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), we obtained a family of five highly specific, high-affinity tracers for hybrid positron emission tomography/magnetic resonance (PET/MR) imaging. A xenograft model with target-positive DU4475 and negative A549 tumors in immunodeficient nude mice enabled CMKLR1-specific imaging in vivo. We acquired small animal PET/MR images, assessed biodistribution by ex vivo measurements and investigated the tracer specificity by blocking experiments. Results: Five CMKLR1-targeting peptide tracers demonstrated high biological activity and affinity in vitro with EC(50) and IC(50) values below 2 nM. Our target-positive (DU4475) and target-negative (A549) xenograft model could be validated by ex vivo analysis of CMKLR1 expression and binding. After preliminary PET imaging, the three most promising tracers [(68)Ga]Ga-DOTA-AHX-CG34, [(68)Ga]Ga-DOTA-KCap-CG34 and [(68)Ga]Ga-DOTA-ADX-CG34 with best tumor uptake were further analyzed. Hybrid PET/MR imaging along with concomitant biodistribution studies revealed distinct CMKLR1-specific uptake (5.1% IA/g, 3.3% IA/g and 6.2% IA/g 1 h post-injection) of our targeted tracers in DU4475 tumor tissue. In addition, tumor uptake was blocked by excess of unlabeled peptide (6.4-fold, 5.5-fold and 3.4-fold 1 h post-injection), further confirming CMKLR1 specificity. Out of five tracers, we identified these three tracers with moderate, balanced hydrophilicity to be the most potent in receptor-mediated tumor targeting. Conclusion: We demonstrated the applicability of (68)Ga-labeled peptide tracers by visualizing CMKLR1-positive breast cancer xenografts in PET/MR imaging, paving the way for developing them into theranostics for tumor treatment.
format Online
Article
Text
id pubmed-6771245
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Ivyspring International Publisher
record_format MEDLINE/PubMed
spelling pubmed-67712452019-10-06 CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer Erdmann, Sarah Niederstadt, Lars Koziolek, Eva Jolanthe Gómez, Juan Daniel Castillo Prasad, Sonal Wagener, Asja von Hacht, Jan Lennart Reinicke, Sandy Exner, Samantha Bandholtz, Sebastian Beindorff, Nicola Brenner, Winfried Grötzinger, Carsten Theranostics Research Paper Background: Molecular targeting remains to be a promising approach in oncology. Overexpression of G protein-coupled receptors (GPCRs) in human cancer is offering a powerful opportunity for tumor-selective imaging and treatment employing nuclear medicine. We utilized novel chemerin-based peptide conjugates for chemokine-like receptor 1 (CMKLR1) targeting in a breast cancer xenograft model. Methods: By conjugation with the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), we obtained a family of five highly specific, high-affinity tracers for hybrid positron emission tomography/magnetic resonance (PET/MR) imaging. A xenograft model with target-positive DU4475 and negative A549 tumors in immunodeficient nude mice enabled CMKLR1-specific imaging in vivo. We acquired small animal PET/MR images, assessed biodistribution by ex vivo measurements and investigated the tracer specificity by blocking experiments. Results: Five CMKLR1-targeting peptide tracers demonstrated high biological activity and affinity in vitro with EC(50) and IC(50) values below 2 nM. Our target-positive (DU4475) and target-negative (A549) xenograft model could be validated by ex vivo analysis of CMKLR1 expression and binding. After preliminary PET imaging, the three most promising tracers [(68)Ga]Ga-DOTA-AHX-CG34, [(68)Ga]Ga-DOTA-KCap-CG34 and [(68)Ga]Ga-DOTA-ADX-CG34 with best tumor uptake were further analyzed. Hybrid PET/MR imaging along with concomitant biodistribution studies revealed distinct CMKLR1-specific uptake (5.1% IA/g, 3.3% IA/g and 6.2% IA/g 1 h post-injection) of our targeted tracers in DU4475 tumor tissue. In addition, tumor uptake was blocked by excess of unlabeled peptide (6.4-fold, 5.5-fold and 3.4-fold 1 h post-injection), further confirming CMKLR1 specificity. Out of five tracers, we identified these three tracers with moderate, balanced hydrophilicity to be the most potent in receptor-mediated tumor targeting. Conclusion: We demonstrated the applicability of (68)Ga-labeled peptide tracers by visualizing CMKLR1-positive breast cancer xenografts in PET/MR imaging, paving the way for developing them into theranostics for tumor treatment. Ivyspring International Publisher 2019-09-19 /pmc/articles/PMC6771245/ /pubmed/31588246 http://dx.doi.org/10.7150/thno.34857 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Erdmann, Sarah
Niederstadt, Lars
Koziolek, Eva Jolanthe
Gómez, Juan Daniel Castillo
Prasad, Sonal
Wagener, Asja
von Hacht, Jan Lennart
Reinicke, Sandy
Exner, Samantha
Bandholtz, Sebastian
Beindorff, Nicola
Brenner, Winfried
Grötzinger, Carsten
CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer
title CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer
title_full CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer
title_fullStr CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer
title_full_unstemmed CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer
title_short CMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer
title_sort cmklr1-targeting peptide tracers for pet/mr imaging of breast cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771245/
https://www.ncbi.nlm.nih.gov/pubmed/31588246
http://dx.doi.org/10.7150/thno.34857
work_keys_str_mv AT erdmannsarah cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT niederstadtlars cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT koziolekevajolanthe cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT gomezjuandanielcastillo cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT prasadsonal cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT wagenerasja cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT vonhachtjanlennart cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT reinickesandy cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT exnersamantha cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT bandholtzsebastian cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT beindorffnicola cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT brennerwinfried cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer
AT grotzingercarsten cmklr1targetingpeptidetracersforpetmrimagingofbreastcancer