In vivo detection of oxidation-specific epitopes in atherosclerotic lesions using biocompatible manganese molecular magnetic imaging probes.
In vivo detection of oxidation-specific epitopes in atherosclerotic lesions using biocompatible manganese molecular magnetic imaging probes.
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DOI：
10.1016/j.jacc.2011.10.881
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发表时间：
2012-02-07
影响因子：
24
通讯作者：
Tsimikas, Sotirios
中科院分区：
文献类型：
--
作者：
Briley-Saebo, Karen C.;Tuyen Hoang Nguyen;Saeboe, Alexander M.;Cho, Young-Seok;Ryu, Sung Kee;Volkava, Eugenia;Dickson, Stephen;Leibundgut, Gregor;Weisner, Philipp;Green, Simone;Casanada, Florence;Miller, Yury I.;Shaw, Walter;Witztum, Joseph L.;Fayad, Zahi A.;Tsimikas, Sotirios
目的评价氧化特异性表位(OSE)靶向锰(Mn(II))分子成像探针的体内磁共振(MR)成像效果。OSE在动脉粥样硬化斑块的发生、发展和去稳定化过程中起关键作用。以Gd(III)为基础的磁共振成像剂可能与全身毒性有关。锰是一种内源性、生物相容的顺磁性金属离子，在螯合时MR效果不佳，但在细胞内释放时效果很强。制备了含有罗丹明的多峰锰胶束，用于共聚焦显微镜，并与靶向丙二醛(MDA)-赖氨酸表位的鼠单抗IgG抗体MDA2或靶向于类MDA表位的人单链抗体片段IK17(靶向胶束)连接。胶束制剂在体外和体内进行了表征，并在apoE−/−和LDLr−/−小鼠(所有实验共120只小鼠)上评估了它们的MR效率(9.4特斯拉)。进行体内竞争性抑制研究，以评估靶点特异性。未靶向胶束、MDA2-Gd胶束和IK17-Gd胶束(0.075 mmolGd/kg)作为对照。体外研究表明，当预先暴露于丙二醛-低密度脂蛋白时，靶向锰胶束在巨噬细胞中积累，纵向相关性增加约10倍。静脉注射后，注射靶向MN胶束后48-72小时可观察到强烈的MR信号增强，并共存于斑块内巨噬细胞内。将游离的MDA2与MDA2-MN胶束共同注射，可完全抑制动脉壁内的MR信号，从而证实靶点特异性。在伴有动脉粥样硬化的载脂蛋白E−/−和低密度脂蛋白受体−/−小鼠中也观察到了类似的MR效果。靶向Mn和Gd胶束之间的MR效果没有显著差异。这项研究表明，生物兼容的多模式锰基分子成像探针可以检测动脉粥样硬化斑块中的OSE，并可能有助于临床翻译人类动脉粥样硬化的非侵入性成像。
To evaluate the in vivo magnetic resonance (MR) imaging efficacy of manganese (Mn(II)) molecular imaging probes targeted to oxidation-specific epitopes (OSE). OSE are critical in the initiation, progression and de-stabilization of atherosclerotic plaques. Gadolinium (Gd(III)) based MR imaging agents can be associated with systemic toxicity. Mn is an endogenous, bio-compatible, paramagnetic metal ion that has poor MR efficacy when chelated, but strong efficacy when released within cells. Multimodal Mn-micelles were generated to contain rhodamine for confocal microscopy and conjugated with either the murine monoclonal IgG antibody MDA2 targeted to malondialdehyde (MDA)-lysine epitopes or the human single-chain Fv antibody fragment IK17 targeted to MDA-like epitopes (‘targeted micelles”). Micelle formulations were characterized in vitro and in vivo and their MR efficacy (9.4 Tesla) evaluated in apoE−/− and LDLR−/− mice (0.05 mmol Mn/Kg dose) (total of 120 mice for all experiments). In vivo competitive inhibition studies were performed to evaluate target specificity. Untargeted, MDA2-Gd and IK17-Gd micelles (0.075 mmol Gd/Kg) were included as controls. In vitro studies demonstrated that targeted Mn-micelles accumulate in macrophages when pre-exposed to MDA-LDL with ~10X increase in longitudinal relativity. Following intravenous injection, strong MR signal enhancement was observed 48–72 hours after administration of targeted Mn-micelles, with co-localization within intraplaque macrophages. Co-injection of free MDA2 with the MDA2-Mn micelles resulted in full suppression of MR signal in the arterial wall confirming target specificity. Similar MR efficacy was noted in apoE−/− and LDLR−/− mice with aortic atherosclerosis. No significant differences in MR efficacy were noted between targeted Mn and Gd micelles. This study demonstrates that bio-compatible multimodal Mn-based molecular imaging probes detect OSE within atherosclerotic plaques and may facilitate clinical translation of non-invasive imaging of human atherosclerosis.
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影响因子：
3.2
作者：
Rovetta, F.;Catalani, S.;Mazzoleni, G.
通讯作者：
Mazzoleni, G.
影响因子：
158.5
作者：
Tsimikas, S;Brilakis, ES;Berger, PB
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作者：
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Griffioen, AW
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3.3
作者：
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