Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

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 disseminat...

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Bibliographic Details
Published in:	Scientific reports Vol. 13; no. 1; pp. 17248 - 17
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 11-10-2023 Nature Publishing Group Nature Portfolio
Subjects:	631/45 631/535 631/57 631/67 692/4028 692/53 Affinity Biology Cancer surgery Cell adhesion & migration Cell Line, Tumor Chelating agents Chemical bonds Crystal structure Cytotoxicity Humanities and Social Sciences Humans Mass spectrometry multidisciplinary NMR Nuclear magnetic resonance Peptides Peptides - chemistry Positron emission tomography Positron-Emission Tomography - methods Proteins Receptors, Urokinase Plasminogen Activator - metabolism Science Science (multidisciplinary) Scientific imaging Tomography Tomography, X-Ray Computed U-Plasminogen activator Urokinase-Type Plasminogen Activator
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-023-43934-w