MRI with conventional gadolinium (Gd) contrast agents also lacks specificity for detecting inflammatory cells at atherosclerotic sites. 18F-modified polyglucose nanoparticles ( 18F-Macroflor), or the PET tracer 68Ga-DOTATATE (which only binds a subset of macrophage that express the somatostatin receptor subtype-2 (SST 2), allow for quantification of macrophages but not lymphocytes or neutrophils 23, 24. Other limitations of 18F-FDG-PET include radiation doses that limit longitudinal studies and restricted geographic availability of PET tracers. 18F-fluorodeoxyglucose ( 18F-FDG)–based positron emission tomography (PET) imaging can be used to measure inflammation 22 but lacks specificity for inflammatory cells as it is taken up by metabolically active cells in the myocardium 21. Coronary angiography, although the standard technique for imaging arterial anatomy, and contrast-enhanced computed tomography cannot delineate the cellular and molecular composition of plaques 20, 21. Because these cell types are found at the site of culprit lesions and contribute to the weakening of plaques, they are considered critical markers of plaques that are vulnerable to rupture 12, 14, 15, 16, 17 or erosion 18, 19.Ĭurrent clinical diagnostic techniques cannot be used to assess the complete inflammatory cell burden in atherosclerotic plaques. Monocytes/macrophages and lymphocytes make up about half of the cellular components of atherosclerotic plaques 12 neutrophils are present in lower numbers 13. By binding integrin receptors, such as α4β1 on circulating leukocytes, these adhesion molecules facilitate the recruitment and accumulation of leukocytes at inflammatory sites 9, 10, 11. This accumulation results in activation of endothelial cells, which involves upregulating the expression of adhesion molecules, including vascular cell adhesion molecule-1(VCAM-1). Despite our improved understanding of the physiology of atherosclerotic plaque development and progression, no clinically relevant imaging tools are available to identify patients who are at high risk of having an ischemic coronary event.Ītherosclerosis is an inflammatory disease 7 that begins with the subendothelial accumulation of lipoproteins in small- to medium-sized arteries 8. Although therapeutic targeting of risk factors for atherosclerosis, such as high blood pressure and cholesterol levels, has reduced mortality rates, these same risk factors are poor indicators of acute or recurrent events 6. Thrombosis resulting from degradation of atherosclerotic plaques, either through plaque rupture or superficial erosion, is the cause of a majority of acute coronary ischemic events in humans 2, 3, 4, 5. Global mortality rates identify ischemic heart disease as a leading cause of death 1. An inflammatory cell-targeted method that has the specificity and sensitivity to measure the inflammatory burden of a plaque could be used to noninvasively identify patients at risk of an acute ischemic event. These enhanced signals corresponded to the accumulation of monocyte/macrophages in the subendothelial layer of atherosclerotic plaques in vivo, whereas non-targeted liposomal nanoparticles did not demonstrate comparable signal enhancement. We were able to visualize atherosclerotic plaques in various regions of the aorta in atherosclerosis-prone ApoE −/− mice on a 1 Tesla small animal MRI scanner. This liposomal contrast agent has a high T1 relaxivity (~2 × 10 5 mM −1s −1 on a particle basis) resulting in the ability to image liposomes at a clinically relevant MR field strength.
Here, we describe a targeted contrast agent (THI0567-targeted liposomal-Gd) that is suitable for magnetic resonance (MR) imaging and binds with high affinity and selectivity to the integrin α4β1(very late antigen-4, VLA-4), a key integrin involved in recruiting inflammatory cells to atherosclerotic plaques. To address this, we have developed a clinically relevant system to image overall inflammatory cell burden in plaque. Inflammation drives the degradation of atherosclerotic plaque, yet there are no non-invasive techniques available for imaging overall inflammation in atherosclerotic plaques, especially in the coronary arteries.
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