Near Infrared Fluorescence (NIRF) Molecular Imaging of Oxidized LDL with an Autoantibody in Experimental Atherosclerosis
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Author(s)
Type
Journal Article
Abstract
We aimed to develop a quantitative antibody-based near infrared fluorescence (NIRF) approach
for the imaging of oxidized LDL in atherosclerosis. LO1, a well- characterized monoclonal
autoantibody that reacts with malondialdehyde-conjugated LDL, was labeled with a NIRF dye to
yield LO1-750. LO1-750 specifically identified necrotic core in ex vivo human coronary lesions.
Injection of LO1-750 into high fat (HF) fed atherosclerotic Ldlr
-/-
mice led to specific focal
localization within the aortic arch and its branches, as detected by fluorescence molecular
tomography (FMT) combined with micro-computed tomography (CT). Ex vivo confocal
microscopy confirmed LO1-750 subendothelial localization of LO1-750 at sites of
atherosclerosis, in the vicinity of macrophages. When compared with a NIRF reporter of MMP
activity (MMPSense-645-FAST), both probes produced statistically significant increases in
NIRF signal in the Ldlr-/- model in relation to duration of HF diet. When withdrawing the HF
diet, the reduction in oxLDL accumulation, as demonstrated with LO1-750, was less marked
than the effect seen on MMP activity. In the rabbit, in vivo injected LO1-750 localization was
successfully imaged ex vivo in aortic lesions with a customised intra-arterial NIRF detection
catheter. A partially humanized chimeric LO1-Fab-Cys localized similarly to the parent
antibody in murine atheroma showing promise for future translation.
for the imaging of oxidized LDL in atherosclerosis. LO1, a well- characterized monoclonal
autoantibody that reacts with malondialdehyde-conjugated LDL, was labeled with a NIRF dye to
yield LO1-750. LO1-750 specifically identified necrotic core in ex vivo human coronary lesions.
Injection of LO1-750 into high fat (HF) fed atherosclerotic Ldlr
-/-
mice led to specific focal
localization within the aortic arch and its branches, as detected by fluorescence molecular
tomography (FMT) combined with micro-computed tomography (CT). Ex vivo confocal
microscopy confirmed LO1-750 subendothelial localization of LO1-750 at sites of
atherosclerosis, in the vicinity of macrophages. When compared with a NIRF reporter of MMP
activity (MMPSense-645-FAST), both probes produced statistically significant increases in
NIRF signal in the Ldlr-/- model in relation to duration of HF diet. When withdrawing the HF
diet, the reduction in oxLDL accumulation, as demonstrated with LO1-750, was less marked
than the effect seen on MMP activity. In the rabbit, in vivo injected LO1-750 localization was
successfully imaged ex vivo in aortic lesions with a customised intra-arterial NIRF detection
catheter. A partially humanized chimeric LO1-Fab-Cys localized similarly to the parent
antibody in murine atheroma showing promise for future translation.
Date Issued
2016-02-25
Date Acceptance
2016-02-03
Citation
Scientific Reports, 2016, 6
ISSN
2045-2322
Publisher
Nature Publishing Group
Journal / Book Title
Scientific Reports
Volume
6
Copyright Statement
This work is licensed under a Creative Commons Attribution 4.0 International License. The images
or other third party material in this article are included in the article’s Creative Commons license,
unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material. To view a copy of this
license, visit http://creativecommons.org/licenses/by/4.0/
or other third party material in this article are included in the article’s Creative Commons license,
unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material. To view a copy of this
license, visit http://creativecommons.org/licenses/by/4.0/
License URL
Sponsor
British Heart Foundation
Wellcome Trust
Grant Number
CH/1992009/6772
095034/Z/10/Z
Publication Status
Published
Article Number
21785