Document Detail


A dual magnetic resonance imaging/fluorescent contrast agent for Cathepsin-D detection.
MedLine Citation:
PMID:  23281285     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Currently there are no approved biomarkers for the pre-symptomatic diagnosis of Alzheimer's disease (AD). Cathepsin-D (Cat-D) is a lysosomal protease that is present at elevated levels in amyloid plaques and neurons in patients with AD and is also elevated in some cancers. We have developed a magnetic resonance imaging (MRI)/fluorescent contrast agent to detect Cat-D enzymatic activity. The purpose of this study was to investigate the cellular and tissue uptake of this MRI/fluorescent contrast agent. The agent consists of an MRI probe [DOTA-caged metal ion (Gd(3+) or Tm(3+) )] and a fluorescent probe coupled to a cell-penetrating-peptide sequence by a Cat-D recognition site. The relaxivity of Gd(3+) -DOTA-CAT((cleaved)) was measured in 10% heat-treated bovine serum albumin (BSA) phantoms to assess contrast efficacy at magnetic fields ranging from 0.24 mT to 9.4 T. In vitro, Tm(3+) -DOTA-CAT was added to neuronal SN56 cells over-expressing Cat-D and live-cell confocal microscropy was performed at 30 min. Tm(3+) -DOTA-CAT was also intravenously injected into APP/PS1-dE9 Alzheimer's disease mice (n = 9) and controls (n = 8). Cortical and hippocampal uptake was quantified at 30, 60 and 120 min post-injection using confocal microscopy. The liver and kidneys were also evaluated for contrast agent uptake. The relaxivity of Gd(3+) -DOTA-CAT((cleaved)) was 3.3 (mM s)(-1) in 10% BSA at 9.4 T. In vitro, cells over-expressing Cat-D preferentially took up the contrast agent in a concentration-dependent manner. In vivo, the contrast agent effectively crossed the blood-brain barrier and exhibited a distinct time course of uptake and retention in APP/PS1-dE9 transgenic mice compared with age-matched controls. At clinical and high magnetic field strengths, Gd(3+) -DOTA-CAT produced greater T(1) relaxivity than Gd(3+) -DTPA. Tm(3+) -DOTA-CAT was taken up in a dose-dependent manner in cells over-expressing Cathepsin-D and was shown to transit the blood-brain barrier in vivo. This strategy may be useful for the in vivo detection of enzyme activity and for the diagnosis of Alzheimer's disease. Copyright © 2012 John Wiley & Sons, Ltd.
Authors:
Robert Ta; Mojmir Suchy; Joshua H K Tam; Alex X Li; Francisco S Martinez-Santiesteban; Timothy J Scholl; Robert H E Hudson; Robert Bartha; Stephen H Pasternak
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Contrast media & molecular imaging     Volume:  8     ISSN:  1555-4317     ISO Abbreviation:  Contrast Media Mol Imaging     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-01-02     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101286760     Medline TA:  Contrast Media Mol Imaging     Country:  United States    
Other Details:
Languages:  eng     Pagination:  127-39     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 John Wiley & Sons, Ltd.
Affiliation:
Imaging Research Group, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada; Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada.
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