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SPECT/CT Imaging of High-Risk Atherosclerotic Plaques using Integrin-Binding RGD Dimer Peptides.

ABSTRACT: Vulnerable atherosclerotic plaques with unique biological signatures are responsible for most major cardiovascular events including acute myocardial infarction and stroke. However, current clinical diagnostic approaches for atherosclerosis focus on anatomical measurements such as the degree of luminal stenosis and wall thickness. An abundance of neovessels with elevated expression of integrin ?v?3 is closely associated with an increased risk of plaque rupture. Herein we evaluated the potential of an ?v?3 integrin-targeting radiotracer, (99m)Tc-IDA-D-[c(RGDfK)]2, for SPECT/CT imaging of high-risk plaque in murine atherosclerosis models. In vivo uptake of (99m)Tc-IDA-D-[c(RGDfK)]2 was significantly higher in atherosclerotic aortas than in relatively normal aortas. Comparison with the negative-control peptide, (99m)Tc-IDA-D-[c(RADfK)]2, proved specific binding of (99m)Tc-IDA-D-[c(RGDfK)]2 for plaque lesions in in vivo SPECT/CT and ex vivo autoradiographic imaging. Histopathological characterization revealed that a prominent SPECT signal of (99m)Tc-IDA-D-[c(RGDfK)]2 corresponded to the presence of high-risk plaques with a large necrotic core, a thin fibrous cap, and vibrant neoangiogenic events. Notably, the RGD dimer based (99m)Tc-IDA-D-[c(RGDfK)]2 showed better imaging performance in comparison with the common monomeric RGD peptide probe (123)I-c(RGDyV) and fluorescence tissue assay corroborated this. Our preclinical data demonstrated that (99m)Tc-IDA-D-[c(RGDfK)]2 SPECT/CT is a sensitive tool to noninvasively gauge atherosclerosis beyond vascular anatomy by assessing culprit plaque neovascularization.

SUBMITTER: Yoo JS

PROVIDER: S-EPMC4485237 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Project description:Integrin alpha(v)beta(3) plays a significant role in tumor angiogenesis and is a receptor for the extracellular matrix proteins with the exposed arginine-glycine-aspartic (RGD) tripeptide sequence. These include vitronectin, fibronectin, fibrinogen, lamin, collagen, Von Willibrand's factor, osteoponin, and adenovirus particles. Integrin alpha(v)beta(3) is expressed at low levels on epithelial cells and mature endothelial cells, but it is overexpressed on the activated endothelial cells of tumor neovasculature and some tumor cells. The restricted expression of integrin alpha(v)beta(3) during tumor growth, invasion, and metastasis presents an interesting molecular target for both early detection and treatment of rapidly growing solid tumors. Over the past decade, many radiolabeled linear and cyclic RGD peptide antagonists have been evaluated as integrin alpha(v)beta(3)-targeted radiotracers. Significant progress has been made on their use for imaging integrin alpha(v)beta(3)-positive tumors by SPECT or PET. Among the radiotracers evaluated in preclinical tumor-bearing models, [18F]Galacto-RGD (2-[18F]fluoropropanamide c(RGDfK(SAA); SAA = 7-amino-L-glyero-L-galacto-2,6-anhydro-7-deoxyheptanamide) and [18F]-AH111585 are currently under clinical investigation for visualization of integrin alpha(v)beta(3) expression in cancer patients. However, their low tumor uptake, high cost, and lack of preparative modules for routine radiosynthesis will limit their continued clinical application. Thus, there is a continuing need for more efficient integrin alpha(v)beta(3)-targeted radiotracers that are readily prepared from a kit formulation without further postlabeling purification. This article will focus on different approaches to maximize the targeting capability of cyclic RGD peptides and to improve the radiotracer excretion kinetics from noncancerous organs. Improvement of tumor uptake and tumor-to-background ratios is important for early detection of integrin alpha(v)beta(3)-positive tumors and/or noninvasive monitoring of therapeutic efficacy of antiangiogenic therapy.

Project description:INTRODUCTION:Cardiovascular disease is the leading cause of death in the United States. The identification of vulnerable plaque at risk of rupture has been a major focus of research. Hypoxia has been identified as a potential factor in the formation of vulnerable plaque, and it is clear that decreased oxygen plays a role in the development of plaque angiogenesis leading to plaque destabilization. The purpose of this study is to demonstrate the feasibility of copper-64 labeled diacetyl-bis (N(4)-methylthiosemicarbazone) ((64)Cu-ATSM), a positron-emitting radiopharmaceutical taken up in low-oxygen-tension cells, for the identification of hypoxic and potentially unstable atherosclerotic plaque in a mouse model. METHODS:(64)Cu-ATSM PET was performed in 21 atherosclerotic apolipoprotein E knockout (ApoE(-/-)) mice, 6 of which were fed high-fat diet (HFD) while the others received standard-chow diet (SCD), and 13 control wild type mice fed SCD. 4 SCD ApoE(-/-) mice and 4 SCD wild type mice also underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) imaging one day prior to (64)Cu-ATSM PET. RESULTS:(64)Cu-ATSM uptake was increased in the aortic arch in SCD ApoE(-/-) mice (average aortic arch/muscle (A/M) standardized uptake value ratio 7.5-30min post injection: (5.66±0.23) compared to control mice (A/M SUV ratio 7.5-30min post injection (3.87±0.22), p<0.0001). HFD ApoE(-/-) mice also showed similarly increased aortic arch uptake on PET imaging in comparison to control mice. Immunohistochemistry in both HFD and SCD ApoE(-/-) mice revealed noticeable hypoxia by pimonidazole stain in atherosclerosis which was co-localized to macrophage by CD68 staining. Autoradiography assessment demonstrated the presence of hypoxia by (64)Cu-ATSM uptake correlated with pimonidazole uptake within the ex vivo atherosclerotic aortic arch specimens. A significant increase in (18)F-FDG uptake in the SCD ApoE(-/-) mice in comparison to controls was also observed at delayed time points. CONCLUSION:This pre-clinical study suggests that (64)Cu-ATSM is a potential PET tracer for hypoxia imaging in atherosclerosis. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE:While studies in humans are necessary for conclusive data, in the long term, a (64)Cu-ATSM PET imaging strategy could help facilitate the study of plaque biology in human patients.

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SPECT/CT Imaging of High-Risk Atherosclerotic Plaques using Integrin-Binding RGD Dimer Peptides.

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