title: Preclinical evaluation of [111In]MICA-401, an activity-based probe for SPECT imaging of in vivo uPA activity.
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 with111In ([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.
authors: Molecular Imaging Center Antwerp, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, B-2650, Edegem, Belgium.
authors: Christel
authors: C
authors: Vangestel
authors: Molecular Imaging Center Antwerp, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.|Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
authors: David
authors: D
authors: Thomae
authors: Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
authors: Jeroen
authors: J
authors: Van Soom
authors: Center for Oncological Research, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
authors: Johan
authors: J
authors: Ides
authors: Molecular Imaging Center Antwerp, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, B-2650, Edegem, Belgium.
authors: Leonie
authors: L
authors: Wyffels
authors: Center for Oncological Research, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.|Department of Pathology, Antwerp University Hospital, Wilrijkstraat 10, B-2650, Edegem, Belgium.
authors: Patrick
authors: P
authors: Pauwels
authors: Molecular Imaging Center Antwerp, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.|Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, B-2650, Edegem, Belgium.
authors: Sigrid
authors: S
authors: Stroobants
authors: Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
authors: Pieter
authors: P
authors: Van der Veken
authors: Klinische Forschergruppe der Frauenklinik, Klinikum rechts der Isar der TU München, 81675, Munich, Germany.
authors: Viktor
authors: V
authors: Magdolen
authors: Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
authors: Jurgen
authors: J
authors: Joossens
authors: Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
authors: Koen
authors: K
authors: Augustyns
authors: Molecular Imaging Center Antwerp, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
authors: Steven
authors: S
authors: Staelens
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019073:HT29 Cells; D064593:Heterografts; D006801:Humans; D007205:Indium Radioisotopes; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D009369:Neoplasms / Q000000981:diagnostic imaging*; D011877:Radionuclide Imaging / Q000379:methods; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis*
chemical_list: D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D014568:Urokinase-Type Plasminogen Activator
keywords: cancer xenografts; single photon emission computed; tomography; uPA activity; urokinase-type plasminogen activator