Near Infrared Fluorescence (NIRF) Molecular Imaging of Oxidized LDL with an Autoantibody in Experimental Atherosclerosis

Khamis, Ramzi; Woollard, Kevin J.; Hyde, Gareth; Boyle, Joseph J.; Bicknell, Colin; Chang, Shang‐Hung; Malik, Talat H.; Hara, Tetsuya; Mauskapf, Adam; Granger, David; Johnson, Jason L.; Ntziachristos, Vasilis; Matthews, Paul M.; Jaffer, Farouc A.; Haskard, Dorian O.

doi:10.1038/srep21785

Cited by 41 publications

(48 citation statements)

References 33 publications

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“…OxLDL, acetylated LDL, MMPs). Recently for example, Khamis et al (67) developed an antibody-based NIRF approach for targeting oxLDL in vivo – providing new potential avenues for exploring molecular compositions of atheroma longitudinally with intravascular NIRF imaging.. In addition, FDA-approved indocyanine green is a promising translational NIR fluorophore for plaque imaging (68), and has recently been shown to report on impaired endothelial barrier function in human plaques (69).…”

Section: Introductionmentioning

confidence: 99%

Molecular Imaging of Atherosclerosis: a Clinical Focus

Chowdhury

Tawakol

Jaffer

2017

Curr Cardiovasc Imaging Rep

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Molecular imaging of cardiovascular disease is a powerful clinical and experimental approach that can inform our understanding of atherosclerosis biology. Complementing cross-sectional imaging techniques that provide detailed anatomical information, molecular imaging can further detect important biological changes occurring within atheroma, and refine the prediction of vascular complications. In addition, molecular imaging of atherosclerosis can illuminate underlying pathophysiology and serve as a surrogate end-point in clinical trials of new drugs. This review showcases promising molecular approaches for imaging atherosclerosis, with a focus on PET, MRI, and intravascular near-infrared fluorescence (NIRF) imaging methods that are in the clinic or close-to-clinical usage.

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Section: Introductionmentioning

confidence: 99%

Molecular Imaging of Atherosclerosis: a Clinical Focus

Chowdhury

Tawakol

Jaffer

2017

Curr Cardiovasc Imaging Rep

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“…They represent danger-associated molecular patterns and induce a proinflammatory response (14,15). Additionally, prior work has shown that OSEs can be imaged in zebrafish, mice, and rabbit lipid/atherosclerosis models with murine or human OSE-targeted antibodies using nuclear and magnetic resonance (MR) imaging techniques (16–22). However, the potential immunogenicity of these approaches may limit clinical application (23,24).…”

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confidence: 99%

PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis

Senders

Que

Cho

et al. 2018

Journal of the American College of Cardiology

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BACKGROUND Oxidation-specific epitopes (OSEs) are proinflammatory, and elevated levels in plasma predict cardiovascular events. OBJECTIVES The purpose of this study was to develop novel positron emission tomography (PET) probes to noninvasively image OSE-rich lesions. METHODS An antigen-binding fragment (Fab) antibody library was constructed from human fetal cord blood. After multiple rounds of screening against malondialdehyde-acetaldehyde (MAA) epitopes, the Fab LA25 containing minimal nontemplated insertions in the CDR3 region was identified and characterized. In mice, pharmacokinetics, biodistribution, and plaque specificity studies were performed with Zirconium-89 (89Zr)-labeled LA25. In rabbits, 89Zr-LA25 was used in combination with an integrated clinical PET/magnetic resonance (MR) system. 18F-fluorodeoxyglucose PET and dynamic contrast-enhanced MR imaging were used to evaluate vessel wall inflammation and plaque neovascularization, respectively. Extensive ex vivo validation was carried out through a combination of gamma counting, near infrared fluorescence, autoradiography, immunohistochemistry, and immunofluorescence. RESULTS LA25 bound specifically to MAA epitopes in advanced and ruptured human atherosclerotic plaques with accompanying thrombi and in debris from distal protection devices. PET/MR imaging 24 h after injection of 89Zr-LA25 showed increased uptake in the abdominal aorta of atherosclerotic rabbits compared with nonatherosclerotic control rabbits, confirmed by ex vivo gamma counting and autoradiography. 18F-fluorodeoxyglucose PET, dynamic contrast-enhanced MR imaging, and near-infrared fluorescence signals were also significantly higher in atherosclerotic rabbit aortas compared with control aortas. Enhanced liver uptake was also noted in atherosclerotic animals, confirmed by the presence of MAA epitopes by immunostaining. CONCLUSIONS 89Zr-LA25 is a novel PET radiotracer that may allow noninvasive phenotyping of high-risk OSE-rich lesions.

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“… 7 Near-infrared fluorescence (NIRF) optical molecular imaging offers a new approach to the evaluation of coronary plaque biology, especially helped by the development of intravascular NIRF detectors. 8 , 9 Compared to the use of radionuclear reporters, intravascular NIRF targeting would have the advantage of not adding radiation as well as providing better spatial resolution compared to whole-body approaches. The ultimate goal of NIRF molecular targeting is to integrate specific multi-agent biological information with morphological imaging obtained by existing catheter-based technologies (ie, IVUS and OCT), thereby providing a much needed extra dimension for improving the prediction of individual plaque progression and instability.…”

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confidence: 99%

“… 19 , 20 As yet, we are the only group to report quantitative optical molecular imaging of oxLDL in atherosclerosis in conjunction with other molecular probes. 9 …”

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confidence: 99%

“… 21 We labeled LO1 with the NIRF dye VivoTag-S 750 (and designated this LO1-750), and this specifically reacted with determinants in the necrotic core in human coronary lesions ex vivo. 9 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 FMT combined with micro-CT. Ex vivo confocal microscopy confirmed LO1-750 subendothelial localization at sites of atherosclerosis, in the vicinity of macrophages. When compared with an NIRF reporter of metalloprotease (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, with a better target to background ratio (TBR) for LO1-750 (LO1-750 19.8; MMPSense 2.8).…”

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confidence: 99%

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Developing a Strategy for Interventional Molecular Imaging of Oxidized Low-Density Lipoprotein in Atherosclerosis

2017

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The identification of vulnerable coronary artery atherosclerotic plaques offers the prospect of either localized or systematic therapeutic targeting in order to prevent myocardial infarction. Molecular imaging of atherosclerosis adds to morphological imaging by focusing on the immunobiology hidden in and behind the endothelium and therefore may be able to improve the identification of prospective culprit lesions. Our focus has been on identifying arterial accumulation of oxidized low-density lipoprotein (oxLDL) by exploiting advances in knowledge of vascular pathobiology. Here, we reflect on our work developing near-infrared fluorescence imaging of oxLDL using LO1, a monoclonal autoantibody generated in our laboratory. We detail progress to date and discuss our vision on taking the work through the early translational pipeline toward a multitargeted approach in imaging rupture-prone atherosclerotic plaques. Ultimately, molecular imaging of coronary arteries should be able to assess the regional risk that is specific to a lesion, which can then be used in concert with global risk factors to personalize the therapeutic strategy for patients in a way that goes beyond generalized population-based therapies.

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Near Infrared Fluorescence (NIRF) Molecular Imaging of Oxidized LDL with an Autoantibody in Experimental Atherosclerosis

Cited by 41 publications

References 33 publications

Molecular Imaging of Atherosclerosis: a Clinical Focus

Molecular Imaging of Atherosclerosis: a Clinical Focus

PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis

Developing a Strategy for Interventional Molecular Imaging of Oxidized Low-Density Lipoprotein in Atherosclerosis

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