Near Infrared Fluorescence (NIRF) Molecular Imaging of Oxidized LDL with an Autoantibody in Experimental Atherosclerosis.
Near Infrared Fluorescence (NIRF) Molecular Imaging of Oxidized LDL with an Autoantibody in Experimental Atherosclerosis.
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DOI：
10.1038/srep21785
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发表时间：
2016-02-25
影响因子：
4.6
通讯作者：
Haskard DO
中科院分区：
文献类型：
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作者：
Khamis RY;Woollard KJ;Hyde GD;Boyle JJ;Bicknell C;Chang SH;Malik TH;Hara T;Mauskapf A;Granger DW;Johnson JL;Ntziachristos V;Matthews PM;Jaffer FA;Haskard DO
我们的目的是开发一种定量的抗体为基础的近红外荧光（NIRF）的方法在动脉粥样硬化的氧化低密度脂蛋白成像。LO 1是一种充分表征的单克隆自身抗体，可与丙二酰二亚胺缀合的LDL反应，用NIRF染料标记，得到LO 1 -750。LO 1 -750特异性鉴定了离体人冠状动脉病变中的坏死核心。将LO 1 -750注射到高脂肪（HF）喂养的动脉粥样硬化Ldlr−/−小鼠中，导致主动脉弓及其分支内的特异性局灶性定位，如荧光分子断层扫描（FMT）结合显微计算机断层扫描（CT）所检测到的。离体共聚焦显微镜证实LO 1 - 750内皮下定位的LO 1 - 750的动脉粥样硬化的网站，在附近的巨噬细胞。当与MMP活性的NIRF报告物（MMPSense-645-FAST）相比时，两种探针在Ldlr−/−模型中与HF饮食持续时间相关的NIRF信号产生统计学显著增加。在停止HF饮食后，如用LO 1 -750所证明的，oxLDL积累的减少不如对MMP活性的影响显著。在家兔中，使用定制的动脉内NIRF检测导管成功地在主动脉病变中对体内注射的LO 1 -750定位进行了离体成像。部分人源化嵌合LO 1-Fab-Cys在鼠动脉粥样硬化中与亲本抗体类似地定位，显示出未来翻译的前景。
We aimed to develop a quantitative antibody-based near infrared fluorescence (NIRF) approach for the imaging of oxidized LDL in atherosclerosis. LO1, a well- characterized monoclonal autoantibody that reacts with malondialdehyde-conjugated LDL, was labeled with a NIRF dye to yield LO1-750. LO1-750 specifically identified necrotic core in ex vivo human coronary lesions. Injection of LO1-750 into high fat (HF) fed atherosclerotic Ldlr−/− mice led to specific focal localization within the aortic arch and its branches, as detected by fluorescence molecular tomography (FMT) combined with micro-computed tomography (CT). Ex vivo confocal microscopy confirmed LO1-750 subendothelial localization of LO1-750 at sites of atherosclerosis, in the vicinity of macrophages. When compared with a NIRF reporter of MMP activity (MMPSense-645-FAST), both probes produced statistically significant increases in NIRF signal in the Ldlr−/− model in relation to duration of HF diet. Upon withdrawing the HF diet, the reduction in oxLDL accumulation, as demonstrated with LO1-750, was less marked than the effect seen on MMP activity. In the rabbit, in vivo injected LO1-750 localization was successfully imaged ex vivo in aortic lesions with a customised intra-arterial NIRF detection catheter. A partially humanized chimeric LO1-Fab-Cys localized similarly to the parent antibody in murine atheroma showing promise for future translation.