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Theranostics 2019; 9(22):6719-6733. doi:10.7150/thno.34857 This issue Cite

Research Paper

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

Sarah Erdmann¹, Lars Niederstadt¹, Eva Jolanthe Koziolek^2,3,4, Juan Daniel Castillo Gómez², Sonal Prasad^2,3, Asja Wagener¹, Jan Lennart von Hacht¹, Sandy Reinicke¹, Samantha Exner¹, Sebastian Bandholtz¹, Nicola Beindorff³, Winfried Brenner^2,3,5, Carsten Grötzinger^{1,4,5,6 ✉}

1. Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
2. Department of Nuclear Medicine, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
3. Berlin Experimental Radionuclide Imaging Center (BERIC), Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin
4. German Cancer Research Center (DKFZ) Heidelberg, Germany
5. German Cancer Consortium (DKTK), partner site Berlin, Germany
6. Molecular Cancer Research Center (MKFZ), Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany

✉ Corresponding author: Dr. Carsten Grötzinger. Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Department of Hepatology and Gastroenterology and Molecular Cancer Research Center (MKFZ). Augustenburger Platz 1, D-13353 Berlin, Germany. Phone: +49 30 450559488; Fax: +49 30 45055997; Email: carsten.groetzingerde More

Abstract

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 EC₅₀ and IC₅₀ 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 [⁶⁸Ga]Ga-DOTA-AHX-CG34, [⁶⁸Ga]Ga-DOTA-KCap-CG34 and [⁶⁸Ga]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 ⁶⁸Ga-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.

Keywords: Tumor targeting, PET tracer, Chemokine-like receptor 1, peptide ligand, breast cancer

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