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. Upon 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.
Highlights
We aimed to develop a quantitative antibody-based near infrared fluorescence (NIRF) approach for the imaging of oxidized LDL in atherosclerosis
To confirm the translational relevance of developing NIRF imaging with LO1 in experimental atherosclerosis, we confirmed with indirect immunohistochemistry (IHC) that LO1 reacts with antigen in human coronary atherosclerosis
We focused on ex vivo intravascular 2D NIRF images of the resected aorta, as the background signal from residual circulating LO1-750 precluded accurate in vivo imaging
Summary
We aimed to develop a quantitative antibody-based near infrared fluorescence (NIRF) approach for the imaging of oxidized LDL in atherosclerosis. It remains clinically challenging to determine which atherosclerotic plaques are prone to rupture and result in acute clinical manifestations, such as myocardial infarction or stroke[2] Intravascular imaging techniques such intravascular ultrasound (IVUS) with virtual histology analysis (IVUS-VH), optical coherence tomography (OCT), and newer non-invasive techniques such as coronary artery CT have made considerable progress in defining atherosclerotic plaque morphology[3,4]. Even in combination, the ability of these techniques to identify plaques that will rupture remains limited[5] In this context, near infrared fluorescence (NIRF) optical molecular imaging offers a new approach to the evaluation of coronary plaque biology, especially in light of the development of intravascular NIRF detectors[6]. Apart from a non-quantitative pilot study using a polyclonal antibody[20], optical molecular imaging of oxLDL in atherosclerosis, alone or in conjunction with other molecular probes, has not yet been reported
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