Targeted imaging of uPAR expression in vivo with cyclic AE105 variants

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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.

TidsskriftScientific Reports
Antal sider17
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We thank Gry E. Rasmussen and Eva C. Østerlund for technical assistance. This work was supported by grants from the Novo Nordisk foundation (NNF18OC0033926 to B.B.K.). NMR spectra were recorded at cOpenNMR, an infrastructure facility funded by the Novo Nordisk Foundation (NNF18OC0032996), the European Union’s Horizon 2020 research and innovation programme under grant agreements no. 670261 (ERC Advanced Grant) and 668532 (Click-It), the Lundbeck Foundation, the Innovation Fund Denmark, the Danish Cancer Society, the Neye Foundation, the Sygeforsikringen Danmark, the Research Foundation of Rigshospitalet, the Danish National Research Foundation (grant 126)—PERSIMUNE, the Research Council of the Capital Region of Denmark, the Danish Health Authority, the John and Birthe Meyer Foundation, and Research Council for Independent Research. Andreas Kjaer is a Lundbeck Foundation Professor.

Publisher Copyright:
© 2023, Springer Nature Limited.

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