Author:
Leth Julie Maja,Newcombe Estella Anne,Grønnemose Anne Louise,Jørgensen Jesper Tranekjær,Qvist Katrine,Clausen Anne Skovsbo,Knudsen Line Bruhn Schneider,Kjaer Andreas,Kragelund Birthe Brandt,Jørgensen Thomas Jørgen Dyreborg,Ploug Michael
Abstract
AbstractA 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.
Funder
Horizon 2020
Danish National Research Foundation
John and Birthe Meyer Foundation
Research Council of the Capital Region of Denmark
Novo Nordisk Fonden
Publisher
Springer Science and Business Media LLC