Targeted imaging of uPAR expression in vivo with cyclic AE105 variants
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Targeted imaging of uPAR expression in vivo with cyclic AE105 variants. / 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.
I: Scientific Reports, Bind 13, 17248, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Targeted imaging of uPAR expression in vivo with cyclic AE105 variants
AU - Leth, Julie Maja
AU - Newcombe, Estella Anne
AU - Grønnemose, Anne Louise
AU - Jørgensen, Jesper Tranekjær
AU - Qvist, Katrine
AU - Clausen, Anne Skovsbo
AU - Knudsen, Line Bruhn Schneider
AU - Kjaer, Andreas
AU - Kragelund, Birthe Brandt
AU - Jørgensen, Thomas Jørgen Dyreborg
AU - Ploug, Michael
N1 - Publisher Copyright: © 2023, Springer Nature Limited.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1038/s41598-023-43934-w
DO - 10.1038/s41598-023-43934-w
M3 - Journal article
C2 - 37821532
AN - SCOPUS:85173907660
VL - 13
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 17248
ER -
ID: 370480361