基于重组高密度脂蛋白的CEST造影剂的研究

发布时间：2018-06-30 19:47

  本文选题：造影剂 + MRI　； 参考：《中国科学院研究生院(武汉物理与数学研究所)》2014年硕士论文

【摘要】：高密度脂蛋白(HDL)是一种血管中普遍存在的脂质-蛋白复合纳米粒子,其主要作用是将血管壁中和周围器官中的胆固醇等脂质运输回肝脏,对巨噬细胞上丰富表达的SR-BI受体具有特异性。动脉粥样硬化是一种严重影响人类健康的疾病,是引起心血管疾病的主要原因,而心血管疾病已成为发达国家最主要的死因。一般认为动脉粥样硬化与巨噬细胞进入动脉血管壁形成泡沫状细胞有关。因此,实现对巨噬细胞的高灵敏检测,对于动脉粥样硬化形成过程的研究具有十分重要的意义。近年来,人们利用重组HDL (rHDL)颗粒作为载体,发展了MRI, CT和荧光等一系列造影剂,用于巨噬细胞和动脉粥样硬化斑块的检测。顺磁化学交换饱和转移(PARACEST)是新近发展起来的一种磁共振方法。不同于传统的磁共振成像方法,PARACEST主要依靠镧系金属中心上结合水与自由水之间的化学交换。当对结合水施加饱和脉冲照射时,由于化学交换的存在,自由水的磁共振信号发生变化,通过检测自由水信号的变化,实现CEST造影剂的间接检测。相比于传统MRI造影剂,PARACEST造影剂具有对周围环境敏感的特点。但是,PARACEST造影剂具有较低的灵敏度,而发展受到限制。关于提高PARACEST造影剂的灵敏度,主要有两个思路,一种是将多个PARACEST探针连接大分子量分子上,另一种是将小分子探针负载在纳米载体上。基于以上背景,我们设计并制备了一种高灵敏PARACEST MR/荧光双模态造影剂,Eu-Rhod-rHDL,实现了对PARACEST方法灵敏度的提高。发展双模态造影剂的优点在于其可以实现PARACEST和荧光两种成像手段的互补。为了使rHDL造影剂能够具有CEST效果,我们首先合成了一种含有Eu(Ⅲ)基团的磷脂,具有PARACEST的效应。通过多种磷脂和载脂蛋白的自组装,制得了rHDL双模态造影剂。而后对造影剂进行了多种表征以及CEST性质的测定。相比传统小分子PARACEST造影剂,Eu-Rhod-rHDL的灵敏度提高了129倍,从而扩展了PARACEST的应用范围,有利于今后对低浓度物质的检测。同时,通过细胞实验发现Eu-Rhod-rHDL对巨噬细胞具有特异性,可以选择性进入巨噬细胞,从而可以实现对巨噬细胞的检测。这种双模态rHDL还有潜力发展对动脉粥样硬化的PARACEST检测。
[Abstract]:High density lipoprotein (HDL) is a kind of lipide-protein composite nanoparticles widely used in blood vessels. The main function of HDL is to transport cholesterol and other lipids from the walls and surrounding organs of blood vessels back to the liver. It is specific to SR-BI receptors which are expressed on macrophages. Atherosclerosis is a serious disease affecting human health, and is the main cause of cardiovascular disease, which has become the most important cause of death in developed countries. Atherosclerosis is thought to be associated with macrophages entering the arterial wall to form foam cells. Therefore, the highly sensitive detection of macrophages is of great significance for the study of atherosclerosis. In recent years, a series of contrast agents, such as MRI, CT and fluorescence, have been developed using recombinant HDL (rHDL) particles as carriers for the detection of macrophages and atherosclerotic plaques. Paramagnetism exchange saturation transfer (PARACEST) is a newly developed magnetic resonance technique. Unlike the traditional magnetic resonance imaging method, PARACEST mainly depends on the chemical exchange between the bound water and free water on the lanthanide metal center. In the presence of chemical exchange, the magnetic resonance signal of free water changes when the combined water is irradiated with saturated pulse. The indirect detection of CEST contrast agent is realized by detecting the change of free water signal. Compared with conventional MRI contrast agent, PARACEST contrast agent is sensitive to the surrounding environment. However, PARACEST contrast agent has low sensitivity, and its development is limited. There are two main ways to improve the sensitivity of PARACEST contrast agent, one is to attach multiple PARACEST probes to large molecular weight molecules, the other is to load small molecular probes on nano-carriers. Based on the above background, we have designed and prepared a highly sensitive PARACEST MR-Eu-Rhod-rHDL, which can improve the sensitivity of PARACEST method. The advantage of developing bimodular contrast media is that it can complement the two imaging methods of PARACEST and fluorescence. In order to make rHDL contrast agent have CEST effect, we first synthesized a kind of phospholipid containing EU (鈪，

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