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 αvβ3 is closely associated with an increased risk of plaque rupture. Herein we evaluated the potential of an αvβ3 integrin-targeting radiotracer, 99mTc-IDA-D-[c(RGDfK)]2, for SPECT/CT imaging of high-risk plaque in murine atherosclerosis models. In vivo uptake of 99mTc-IDA-D-[c(RGDfK)]2 was significantly higher in atherosclerotic aortas than in relatively normal aortas. Comparison with the negative-control peptide, 99mTc-IDA-D-[c(RADfK)]2, proved specific binding of 99mTc-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 99mTc-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 99mTc-IDA-D-[c(RGDfK)]2 showed better imaging performance in comparison with the common monomeric RGD peptide probe 123I-c(RGDyV) and fluorescence tissue assay corroborated this. Our preclinical data demonstrated that 99mTc-IDA-D-[c(RGDfK)]2 SPECT/CT is a sensitive tool to noninvasively gauge atherosclerosis beyond vascular anatomy by assessing culprit plaque neovascularization.
Highlights
D-[c(RGDfK)]2 single photon emission computed tomography (SPECT)/CT is a sensitive tool to noninvasively gauge atherosclerosis beyond vascular anatomy by assessing culprit plaque neovascularization
Previous investigations of imaging neovascular proliferation in plaques are limited to trials using nanoparticle-enhanced molecular magnetic resonance imaging (MRI)[25,26] and to a few recent studies using positron emission tomography (PET) with simple arginyl-glycyl-aspartic acid (RGD) monomer peptides[27,28]
To verify in vivo SPECT/CT imaging data (Fig. 4), we investigated the use of a fluorescently labeled RGD-dimer peptide, QD605-D-[c(RGDfK)]2, for more sensitive targeting of atherosclerotic plaques compared to a fluorophore-conjugated RGD-monomer peptide (i.e., QD605-c(RGDyK)) in the tissue-based assay
Summary
D-[c(RGDfK)]2 SPECT/CT is a sensitive tool to noninvasively gauge atherosclerosis beyond vascular anatomy by assessing culprit plaque neovascularization. Rupture of atherosclerotic plaques (i.e., atheromatous plaques in the inner lining of the arteries) is a critical feature leading to major clinical events such as acute myocardial infarction, sudden cardiac death, and stroke. Current diagnostic strategies predominantly focus on anatomical issues such as myocardial ischemia[5], hemodynamic luminal narrowing, or morphological abnormalities of atheromas, but not on the biological aspects of atherosclerotic lesions. This traditional strategy has proven disappointing in preventing myocardial infarction or prolonging life, except in limited patient groups[6,7,8]. Previous investigations of imaging neovascular proliferation in plaques are limited to trials using nanoparticle-enhanced molecular magnetic resonance imaging (MRI)[25,26] and to a few recent studies using positron emission tomography (PET) with simple arginyl-glycyl-aspartic acid (RGD) monomer peptides[27,28]
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