2. Academic Validation
  3. Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

  • Sci Rep. 2023 Oct 11;13(1):17248. doi: 10.1038/s41598-023-43934-w.
Julie Maja Leth 1 2,  Estella Anne Newcombe 3 4 5,  Anne Louise Grønnemose 1 2 6,  Jesper Tranekjær Jørgensen 7 8,  Katrine Qvist 7 8,  Anne Skovsbo Clausen 7 8,  Line Bruhn Schneider Knudsen 7 8,  Andreas Kjaer 7 8,  Birthe Brandt Kragelund 3 4 5,  Thomas Jørgen Dyreborg Jørgensen 6,  Michael Ploug 9 10
Affiliations

Affiliations

  • 1 Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, 2200, Copenhagen N, Denmark.
  • 2 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200, Copenhagen N, Denmark.
  • 3 Structural Biology and NMR Laboratory, Copenhagen N, Denmark.
  • 4 REPIN, Copenhagen N, Denmark.
  • 5 The Linderstrøm Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200, Copenhagen N, Denmark.
  • 6 Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230, Odense M, Denmark.
  • 7 Department of Clinical Physiology and Nuclear Medicine and Cluster for Molecular Imaging, Copenhagen University Hospital - Rigshospitalet, Copenhagen N, Denmark.
  • 8 Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark.
  • 9 Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, 2200, Copenhagen N, Denmark. [email protected].
  • 10 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200, Copenhagen N, Denmark. [email protected].
PMID: 37821532 DOI: 10.1038/s41598-023-43934-w
Abstract

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.

Figures
Products