Open AccessCMKLR1-targeting peptide tracers for PET/MR imaging of breast cancer
Author(s) -
Sarah Erdmann,
Lars Niederstadt,
Eva Jolanthe Koziolek,
Juan Daniel Castillo Gómez,
Sonal Prasad,
Asja Wagener,
Jan Lennart von Hacht,
Sandy Reinicke,
Samantha Exner,
Sebastian Bandholtz,
Nicola Beindorff,
Winfried Brenner,
Carsten Grötzinger
Publication year - 2019
Publication title -
theranostics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.689
H-Index - 97
ISSN - 1838-7640
DOI - 10.7150/thno.34857
Subject(s) - biodistribution , dota , ex vivo , in vivo , positron emission tomography , molecular imaging , cancer research , breast cancer , cancer , magnetic resonance imaging , preclinical imaging , chemistry , in vitro , medicine , nuclear medicine , biology , biochemistry , microbiology and biotechnology , radiology
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.