多金属氧簇在核磁共振造影剂中的应用

发布时间：2018-03-20 09:38

本文选题：多金属氧簇　切入点：核磁共振造影剂　出处：《吉林大学》2015年博士论文　论文类型：学位论文

【摘要】：核磁共振成像技术具备无损伤、无放射性污染、能够获得三维解剖学图谱等优势，逐渐成为了一种不可替代的临床诊断手段。利用顺磁或超顺磁材料作为核磁共振造影剂能够提高核磁共振成像的分辨率及对比度。通过对磁性材料进行合理的选择和修饰，能够获得各种具有靶向性、响应性、长循环时间等特性的新型核磁共振造影剂，有望为核磁共振技术开辟更为广阔的医用前景。多金属氧簇是一类历史悠久的无机材料，其催化、氧化还原及光学特性已经广泛地应用到工业生产当中。近年来，多金属氧簇在医药领域内的独特性质也获得了科研工作者的广泛关注。本论文的的主要研究内容及结论如下：设计并合成了三种框架结构相同的夹心型Gd多金属氧簇结构，分别以磷、硅、硼为杂原子。并以这三种分子作为基础，研究了杂原子种类变化对多金属氧簇的水溶性以及酸碱稳定性的影响。从弛豫效率和细胞毒性的角度评估了三种多金属氧簇作为核磁共振造影剂的可行性。结果表明三种多金属氧簇在水中的溶解度都高于现有的商用Gd配合物造影剂，并且能够在中性及弱酸性溶液中稳定溶解。三种多金属氧簇在水中的纵向弛豫效率与Gd-DTPA相比都有较大程度的增加。杂原子体积不同导致了多金属氧簇体积的变化，使造影剂在水中的翻转相关时间有所差异，最终导致三种多金属氧簇纵向弛豫效率的大小为POM-1≈POM-2POM-3。这种纵向弛豫效率的区别与临床1.5T核磁共振成像仪的测试结果相一致。最后还发现这三种多金属氧簇与蛋白质之间都有比较强的静电相互作用，并且随着多金属氧簇自身所带电荷数的增加，这种静电相互作用的强度逐渐增强，即POM-1POM-2POM-3。而这种多金属氧簇与蛋白质之间的静电相互作用能够减慢多金属氧簇在溶液中的翻转，从而使这三种核磁共振造影剂在蛋白质溶液中的纵向弛豫时间较纯水溶液中均有所增加，增加的幅度随多金属氧簇的电荷的增加而增强，即POM-1POM-2POM-3。但同时也发现，这种静电作用会降低多金属氧簇在生理环境中的稳定性，增加了其生物毒性，导致最终三种造影剂的细胞毒性强度变化为POM-1POM-2POM-3。随后设计并合成了两种体积差异较大的顺磁性多金属氧簇，一种为Keggin型多金属氧簇（POM-4），另一种为两个Keggin型多金属氧簇形成的双扣型多金属氧簇（POM-2），通过两者的对比评价多金属氧簇体积对其溶解度、稳定性、弛豫效率、以及细胞毒性的影响。结果表明，在水溶液中，POM-2具有更大的分子体积，能够增加其在溶液中的翻转时间，从而使POM-2的纵向弛豫效率相对较大。两种多金属氧簇均能够与蛋白质之间发生静电相互作用，使人血清白蛋白溶液的特征荧光信号随着POM-2和POM-4的加入发生明显淬灭。这种静电相互作用使多金属氧簇在溶液中的翻转时间减慢。从而使POM-2和POM-4的纵向弛豫效率都有所增加。其中，POM-2较多的电荷数使其与蛋白质间的静电相互作用相对较强，使POM-2的纵向弛豫效率的增加幅度更大。而进一步的细胞毒性测试则表明，POM-2的细胞毒性较POM-4高。结合两项测试结果，，尽管POM-4的纵向弛豫时间较POM-2相对较低，但是细胞毒性更小，更适合与未来直接的临床应用。
[Abstract]:Magnetic resonance imaging technology has no damage, no radioactive pollution, can obtain the 3D anatomical atlas and other advantages, has become an irreplaceable means of clinical diagnosis. The use of paramagnetic or superparamagnetic materials as magnetic resonance contrast agent can improve the magnetic resonance imaging resolution and contrast. Through the reasonable selection and modification the magnetic material can be obtained with the target response to, and the long cycle time of new MRI contrast agent for magnetic resonance technology is expected to open up a medical prospect. POMS is a long history of inorganic material, its catalytic oxidation, reduction and optical properties have been widely applied to industrial production. In recent years, the unique properties of polyoxometalate in pharmaceutical industry has gained widespread attention of researchers. The main research contents of this thesis. And the conclusions are as follows:
Design and sandwich type Gd three frame structure of the same synthesis of polyoxometalate structure, respectively, phosphorus, silicon, boron atoms. Then these three kinds of molecules as the basis of heteroatom species changes of polyoxometalate water solubility and pH stability. The effect of relaxation efficiency and the view of cytotoxicity evaluation of the three kinds of metal oxygen clusters as the feasibility of magnetic resonance imaging agent. The results show that three kinds of polyoxometalate solubility in water is higher than that of existing commercial complexes of Gd contrast agent, and can be dissolved in neutral and weak acidic solution stability. Three kinds of metal oxygen cluster in the longitudinal direction the relaxation of water efficiency compared with Gd-DTPA Henan have increased greatly. Different hybrid atomic volume leads to changes of polyoxometalate volume, the contrast agent has the difference in the turnover related time in water, resulting in three kinds of metal oxygen cluster longitudinal Relaxation efficiency the size difference of POM-1 is POM-2POM-3. the longitudinal relaxation efficiency and clinical 1.5T magnetic resonance imaging test results. Finally it is found that there are strong interactions between these three kinds of electrostatic polyoxometalate and protein, and with the increase of polyoxometalate itself with charge number and the electrostatic interaction strength gradually increased, POM-1POM-2POM-3. and the static between polyoxometalate and protein interactions could slow down the turnover of Polyoxometalates in the solution, so that the three kinds of magnetic resonance imaging agent in the longitudinal relaxation of the protein in solution than the relaxation time were increased in pure water solution, increase the magnitude of the increase with the charge of polyoxometalates, namely POM-1POM-2POM-3. but also found that the electrostatic interaction will reduce the stability of polyoxometalate in physiological environments The cytotoxicity of the final three contrast agents changes to POM-1POM-2POM-3.
Then the design and synthesis of two kinds of volume difference between paramagnetic metal oxygen clusters, a Keggin type polyoxometalate (POM-4), another form of two Keggin type polyoxometalates Shuangkou type polyoxometalate (POM-2), through the contrast of the two evaluation of polyoxometalate the volume of the solubility, stability, relaxation efficiency, and cytotoxic effects. The results showed that in aqueous solution, POM-2 has a larger molecular volume, can increase its turnover in the solution time, so that the longitudinal relaxation of POM-2 efficiency is relatively large. More than two kinds of metal oxygen clusters can occur the electrostatic interaction between the protein and the characteristic fluorescence signal, human serum albumin solution with the addition of POM-2 and POM-4 were quenched. The electrostatic interaction makes the polyoxometalate turnover time slows down in solution. Thus POM-2 and POM-4 longitudinal relaxation The efficiency has increased. Among them, the number of charge more POM-2 with the electrostatic protein-protein interaction is relatively strong, the longitudinal relaxation of POM-2 efficiency increased even more. The cytotoxicity test further showed that the cytotoxicity of POM-2 was higher than that of POM-4. Combined with the two test results, although the longitudinal relaxation POM-4 relaxation time POM-2 is relatively low, but the cytotoxicity of smaller, more suitable for clinical application and future directly.

【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R91;R914.5

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