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
  • 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.

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