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Am J Nucl Med Mol Imaging 2013;3(5):446-455
Original Article
Molecular MRI of atherosclerotic plaque progression in an ApoE-/- mouse model
with a CLT1 peptide targeted macrocyclic Gd(III) chelate
Xueming Wu, Niranjan Balu, Wen Li, Yong Chen, Xiaoyue Shi, China M Kummitha, Xin Yu, Chun Yuan, Zheng-Rong Lu
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Radiology,
University of Washington, Seattle, Washington 98019, USA
Received August 8, 2013; Accepted September 2, 2013; Epub September 19, 2013; Published September 30, 2013
Abstract: Molecular imaging of atherosclerotic biomarkers is critical for non-invasive detection and diagnosis of atherosclerotic
plaques and therapeutic management. Fibrin and fibronectin accumulate at elevated levels in atherosclerotic plaques and are
associated with atherogenesis and disease progression. Molecular imaging of these biomarkers has the potential to non-invasively
characterize plaque burden. In this work, we investigated the effectiveness of a peptide-targeted macrocyclic Gd(III) chelate,
CLT1-dL-(DOTA-Gd)4, specific to fibrin-fibronectin complexes for molecular MRI of atherosclerosis. Atherosclerotic plaques were
induced in Apolipoprotein E-knockout (ApoE-/-) mice by feeding with high fat and cholesterol-enriched diet (HFD) for up to 30 weeks.
MRI of the vessel wall in the arch aorta was performed at 10, 20 and 30 weeks after the onset of HFD. High spatial-resolution MRI
was performed prior and up to 35 minutes after i.v. injection of CLT1-dL-(DOTA-Gd)4 or a nonspecific control agent at a dose of 0.1
mmol-Gd/kg. CLT1-dL-(DOTA-Gd)4 produced stronger enhancement in the atherosclerotic lesions of the aortic wall than the control
at all time points in the mice. Cross sectional MR images of the aortic arch revealed progressive thickening of the atherosclerotic
vessel wall in the mice on HFD for up to 30 weeks. This progression correlated well to histological staining, as well as fibrin and
fibronectin immunochemical stained images. Molecular MRI with CLT1-dL-(DOTA-Gd)4 has a potential for detecting atherosclerosis
and non-invasive monitoring of the progression of the plaques. (ajnmmi1308001).
Keywords: Molecular MRI, atherosclerosis, CLT1 peptide, targeted contrast agent, macrocyclic Gd(III) chelate
Address correspondence to: Dr. Zheng-Rong Lu, Department of Biomedical Engineering, Case Western Reserve University, Room
427, Wickenden Building, 10900 Euclid Avenue, Cleveland, OH 44106-7207, USA. Tel: 216-368-0187; E-mail: zxl125@case.edu
Original Article
Molecular MRI of atherosclerotic plaque progression in an ApoE-/- mouse model
with a CLT1 peptide targeted macrocyclic Gd(III) chelate
Xueming Wu, Niranjan Balu, Wen Li, Yong Chen, Xiaoyue Shi, China M Kummitha, Xin Yu, Chun Yuan, Zheng-Rong Lu
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Radiology,
University of Washington, Seattle, Washington 98019, USA
Received August 8, 2013; Accepted September 2, 2013; Epub September 19, 2013; Published September 30, 2013
Abstract: Molecular imaging of atherosclerotic biomarkers is critical for non-invasive detection and diagnosis of atherosclerotic
plaques and therapeutic management. Fibrin and fibronectin accumulate at elevated levels in atherosclerotic plaques and are
associated with atherogenesis and disease progression. Molecular imaging of these biomarkers has the potential to non-invasively
characterize plaque burden. In this work, we investigated the effectiveness of a peptide-targeted macrocyclic Gd(III) chelate,
CLT1-dL-(DOTA-Gd)4, specific to fibrin-fibronectin complexes for molecular MRI of atherosclerosis. Atherosclerotic plaques were
induced in Apolipoprotein E-knockout (ApoE-/-) mice by feeding with high fat and cholesterol-enriched diet (HFD) for up to 30 weeks.
MRI of the vessel wall in the arch aorta was performed at 10, 20 and 30 weeks after the onset of HFD. High spatial-resolution MRI
was performed prior and up to 35 minutes after i.v. injection of CLT1-dL-(DOTA-Gd)4 or a nonspecific control agent at a dose of 0.1
mmol-Gd/kg. CLT1-dL-(DOTA-Gd)4 produced stronger enhancement in the atherosclerotic lesions of the aortic wall than the control
at all time points in the mice. Cross sectional MR images of the aortic arch revealed progressive thickening of the atherosclerotic
vessel wall in the mice on HFD for up to 30 weeks. This progression correlated well to histological staining, as well as fibrin and
fibronectin immunochemical stained images. Molecular MRI with CLT1-dL-(DOTA-Gd)4 has a potential for detecting atherosclerosis
and non-invasive monitoring of the progression of the plaques. (ajnmmi1308001).
Keywords: Molecular MRI, atherosclerosis, CLT1 peptide, targeted contrast agent, macrocyclic Gd(III) chelate
Address correspondence to: Dr. Zheng-Rong Lu, Department of Biomedical Engineering, Case Western Reserve University, Room
427, Wickenden Building, 10900 Euclid Avenue, Cleveland, OH 44106-7207, USA. Tel: 216-368-0187; E-mail: zxl125@case.edu
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