Preclinical evaluation of [111In]MICA‐401, an activity‐based probe for SPECT imaging of in vivo uPA activity |
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Authors: | Christel Vangestel David Thomae Jeroen Van Soom Johan Ides Leonie wyffels Patrick Pauwels Sigrid Stroobants Pieter Van der Veken Viktor Magdolen Jurgen Joossens Koen Augustyns Steven Staelens |
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Institution: | 1. Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium;2. Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium;3. Department of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium;4. Center for Oncological Research, University of Antwerp, Antwerp, Belgium;5. Department of Pathology, Antwerp University Hospital, Edegem, Belgium;6. Klinische Forschergruppe der Frauenklinik, Klinikum rechts der Isar der TU München, Munich, Germany |
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Abstract: | Urokinase‐type plasminogen activator (uPA) and its inhibitor PAI‐1 are key players in cancer invasion and metastasis. Both uPA and PAI‐1 have been described as prognostic biomarkers; however, non‐invasive methods measuring uPA activity are lacking. We developed an indium‐111 (111In)‐labelled activity‐based probe to image uPA activity in vivo by single photon emission computed tomography (SPECT). A DOTA‐conjugated uPA inhibitor was synthesized and radiolabelled with 111In (111In]MICA‐401), together with its inactive, hydrolysed form (111In]MICA‐402). A biodistribution study was performed in mice (healthy and tumour‐bearing), and tumour‐targeting properties were evaluated in two different cancer xenografts (MDA‐MB‐231 and HT29) with respectively high and low levels of uPA expression in vitro, with either the active or hydrolysed radiotracer. MicroSPECT was performed 95 h post injection followed by ex vivo biodistribution. Tumour uptake was correlated with human and murine uPA expression determined by ELISA and immunohistochemistry (IHC). Biodistribution data with the hydrolysed probe 111In]MICA‐402 showed almost complete clearance 95 h post injection. The ex vivo biodistribution and SPECT data with 111In]MICA‐401 demonstrated similar tumour uptakes in the two models: ex vivo 5.68 ± 1.41%ID/g versus 5.43 ± 1.29%ID/g and in vivo 4.33 ± 0.80 versus 4.86 ± 1.18 for MDA‐MB‐231 and HT‐29 respectively. Human uPA ELISA and IHC showed significantly higher uPA expression in the MDA‐MB‐231 tumours, while mouse uPA staining revealed similar staining intensities of the two tumours. Our data demonstrate non‐invasive imaging of uPA activity in vivo, although the moderate tumour uptake and hence potential clinical translation of the radiotracer warrants further investigation. Copyright © 2016 John Wiley & Sons, Ltd. |
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Keywords: | urokinase‐type plasminogen activator single photon emission computed tomography uPA activity cancer xenografts |
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