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Preclinical evaluation of [ 111 In]MICA-401, an activity-based probe for SPECT imaging of in vivo uPA activity.
- Source :
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Contrast media & molecular imaging [Contrast Media Mol Imaging] 2016 Nov; Vol. 11 (6), pp. 448-458. Date of Electronic Publication: 2016 Aug 24. - Publication Year :
- 2016
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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 ( <superscript>111</superscript> In)-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 <superscript>111</superscript> In ([ <superscript>111</superscript> In]MICA-401), together with its inactive, hydrolysed form ([ <superscript>111</superscript> In]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 [ <superscript>111</superscript> In]MICA-402 showed almost complete clearance 95 h post injection. The ex vivo biodistribution and SPECT data with [ <superscript>111</superscript> In]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.<br /> (Copyright © 2016 John Wiley & Sons, Ltd.)
- Subjects :
- Animals
Cell Line, Tumor
HT29 Cells
Heterografts
Humans
Mice
Radionuclide Imaging methods
Radiopharmaceuticals chemical synthesis
Radiopharmaceuticals pharmacokinetics
Tissue Distribution
Indium Radioisotopes
Molecular Imaging methods
Neoplasms diagnostic imaging
Tomography, Emission-Computed, Single-Photon methods
Urokinase-Type Plasminogen Activator analysis
Subjects
Details
- Language :
- English
- ISSN :
- 1555-4317
- Volume :
- 11
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Contrast media & molecular imaging
- Publication Type :
- Academic Journal
- Accession number :
- 27558262
- Full Text :
- https://doi.org/10.1002/cmmi.1706