TY - JOUR

T1 - Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

AU - Leth, Julie Maja

AU - Newcombe, Estella Anne

AU - Grønnemose, Anne Louise

AU - Jørgensen, Jesper Tranekjær

AU - Qvist, Katrine

AU - Clausen, Anne Skovsbo

AU - Knudsen, Line Bruhn Schneider

AU - Kjaer, Andreas

AU - Kragelund, Birthe Brandt

AU - Jørgensen, Thomas Jørgen Dyreborg

AU - Ploug, Michael

N1 - Publisher Copyright: © 2023, Springer Nature Limited.

PY - 2023

Y1 - 2023

N2 - A comprehensive literature reports on the correlation between elevated levels of urokinase-type plasminogen activator receptor (uPAR) and the severity of diseases with chronic inflammation including solid cancers. Molecular imaging is widely used as a non-invasive method to locate disease dissemination via full body scans and to stratify patients for targeted treatment. To date, the only imaging probe targeting uPAR that has reached clinical phase-II testing relies on a high-affinity 9-mer peptide (AE105), and several studies by positron emission tomography (PET) scanning or near-infra red (NIR) fluorescence imaging have validated its utility and specificity in vivo. While our previous studies focused on applying various reporter groups, the current study aims to improve uPAR-targeting properties of AE105. We successfully stabilized the small uPAR-targeting core of AE105 by constraining its conformational landscape by disulfide-mediated cyclization. Importantly, this modification mitigated the penalty on uPAR-affinity typically observed after conjugation to macrocyclic chelators. Cyclization did not impair tumor targeting efficiency of AE105 in vivo as assessed by PET imaging and a trend towards increased tracer uptake was observed. In future studies, we predict that this knowledge will aid development of new fluorescent AE105 derivatives with a view to optical imaging of uPAR to assist precision guided cancer surgery.

AB - A comprehensive literature reports on the correlation between elevated levels of urokinase-type plasminogen activator receptor (uPAR) and the severity of diseases with chronic inflammation including solid cancers. Molecular imaging is widely used as a non-invasive method to locate disease dissemination via full body scans and to stratify patients for targeted treatment. To date, the only imaging probe targeting uPAR that has reached clinical phase-II testing relies on a high-affinity 9-mer peptide (AE105), and several studies by positron emission tomography (PET) scanning or near-infra red (NIR) fluorescence imaging have validated its utility and specificity in vivo. While our previous studies focused on applying various reporter groups, the current study aims to improve uPAR-targeting properties of AE105. We successfully stabilized the small uPAR-targeting core of AE105 by constraining its conformational landscape by disulfide-mediated cyclization. Importantly, this modification mitigated the penalty on uPAR-affinity typically observed after conjugation to macrocyclic chelators. Cyclization did not impair tumor targeting efficiency of AE105 in vivo as assessed by PET imaging and a trend towards increased tracer uptake was observed. In future studies, we predict that this knowledge will aid development of new fluorescent AE105 derivatives with a view to optical imaging of uPAR to assist precision guided cancer surgery.

U2 - 10.1038/s41598-023-43934-w

DO - 10.1038/s41598-023-43934-w

M3 - Journal article

C2 - 37821532

AN - SCOPUS:85173907660

VL - 13

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 17248

ER -