Functionalization of gadolinium metallofullerenes for detecting atherosclerotic plaque lesions by cardiovascular magnetic resonance.
Functionalization of gadolinium metallofullerenes for detecting atherosclerotic plaque lesions by cardiovascular magnetic resonance.
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DOI：
10.1186/1532-429x-15-7
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发表时间：
2013-01-16
期刊：
影响因子：
--
通讯作者：
Kepley CL
中科院分区：
文献类型：
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作者：
Dellinger A;Olson J;Link K;Vance S;Sandros MG;Yang J;Zhou Z;Kepley CL
动脉粥样硬化的标志是斑块在血管壁中的积聚。当单核细胞在高水平致动脉粥样硬化脂蛋白的条件下分化成巨噬细胞泡沫细胞时，该过程开始。易损斑块会脱落，进入血流，导致急性心肌梗死和中风。成像技术，如心血管磁共振（CMR）提供了一个战略，以确定患者的斑块积累。我们合成了一种动脉粥样硬化靶向造影剂（ATCA），其中含钆（Gd）的内面体被功能化并配制成脂质体，其中CD 36配体嵌入脂质双层。使用体外测定来评估ATCA对泡沫细胞的特异性。使用CMR评估ATCA检测体内动脉粥样硬化斑块病变的能力。ATCA能够在体外检测清道夫受体（CD 36）表达泡沫细胞，并通过聚焦离子束/扫描电子显微镜（FIB-SEM）和CD 36受体特异性信号通路的Western印迹分析确定通过CD 36受体特异性内化。使用CMR测定，ATCA在ApoE −/−小鼠动脉粥样硬化斑块病变中表现出时间依赖性蓄积。在野生型（C57/b6）对照的血管中未观察到ATCA蓄积。不含噬斑靶向部分的非靶向对照化合物在体外不被泡沫细胞吸收，并且在体内不结合噬斑。重要的是，ATCA注射剂耐受性良好，在体外或体内均未显示毒性，并且在主要器官中未观察到蓄积。ATCA被动脉粥样硬化斑块上的CD 36受体特异性内化，从而在生理条件下增强病变的可视化。这些ATCA可能为医生提供新的工具，以非侵入性地检测动脉粥样硬化疾病。
The hallmark of atherosclerosis is the accumulation of plaque in vessel walls. This process is initiated when monocytic cells differentiate into macrophage foam cells under conditions with high levels of atherogenic lipoproteins. Vulnerable plaque can dislodge, enter the blood stream, and result in acute myocardial infarction and stroke. Imaging techniques such as cardiovascular magnetic resonance (CMR) provides one strategy to identify patients with plaque accumulation. We synthesized an atherosclerotic-targeting contrast agent (ATCA) in which gadolinium (Gd)-containing endohedrals were functionalized and formulated into liposomes with CD36 ligands intercalated into the lipid bilayer. In vitro assays were used to assess the specificity of the ATCA for foam cells. The ability of ATCA to detect atherosclerotic plaque lesions in vivo was assessed using CMR. The ATCA was able to detect scavenger receptor (CD36)-expressing foam cells in vitro and were specifically internalized via the CD36 receptor as determined by focused ion beam/scanning electron microscopy (FIB-SEM) and Western blotting analysis of CD36 receptor-specific signaling pathways. The ATCA exhibited time-dependent accumulation in atherosclerotic plaque lesions of ApoE −/− mice as determined using CMR. No ATCA accumulation was observed in vessels of wild type (C57/b6) controls. Non-targeted control compounds, without the plaque-targeting moieties, were not taken up by foam cells in vitro and did not bind plaque in vivo. Importantly, the ATCA injection was well tolerated, did not demonstrate toxicity in vitro or in vivo, and no accumulation was observed in the major organs. The ATCA is specifically internalized by CD36 receptors on atherosclerotic plaque providing enhanced visualization of lesions under physiological conditions. These ATCA may provide new tools for physicians to non-invasively detect atherosclerotic disease.