本文選題：多金屬氧簇　切入點(diǎn)：核磁共振造影劑　出處：《吉林大學(xué)》2015年博士論文　論文類型：學(xué)位論文

【摘要】：核磁共振成像技術(shù)具備無損傷、無放射性污染、能夠獲得三維解剖學(xué)圖譜等優(yōu)勢，逐漸成為了一種不可替代的臨床診斷手段。利用順磁或超順磁材料作為核磁共振造影劑能夠提高核磁共振成像的分辨率及對比度。通過對磁性材料進(jìn)行合理的選擇和修飾，能夠獲得各種具有靶向性、響應(yīng)性、長循環(huán)時間等特性的新型核磁共振造影劑，有望為核磁共振技術(shù)開辟更為廣闊的醫(yī)用前景。多金屬氧簇是一類歷史悠久的無機(jī)材料，其催化、氧化還原及光學(xué)特性已經(jīng)廣泛地應(yīng)用到工業(yè)生產(chǎn)當(dāng)中。近年來，多金屬氧簇在醫(yī)藥領(lǐng)域內(nèi)的獨(dú)特性質(zhì)也獲得了科研工作者的廣泛關(guān)注。本論文的的主要研究內(nèi)容及結(jié)論如下： 設(shè)計(jì)并合成了三種框架結(jié)構(gòu)相同的夾心型Gd多金屬氧簇結(jié)構(gòu)，分別以磷、硅、硼為雜原子。并以這三種分子作為基礎(chǔ)，研究了雜原子種類變化對多金屬氧簇的水溶性以及酸堿穩(wěn)定性的影響。從弛豫效率和細(xì)胞毒性的角度評估了三種多金屬氧簇作為核磁共振造影劑的可行性。結(jié)果表明三種多金屬氧簇在水中的溶解度都高于現(xiàn)有的商用Gd配合物造影劑，并且能夠在中性及弱酸性溶液中穩(wěn)定溶解。三種多金屬氧簇在水中的縱向弛豫效率與Gd-DTPA相比都有較大程度的增加。雜原子體積不同導(dǎo)致了多金屬氧簇體積的變化，使造影劑在水中的翻轉(zhuǎn)相關(guān)時間有所差異，最終導(dǎo)致三種多金屬氧簇縱向弛豫效率的大小為POM-1≈POM-2POM-3。這種縱向弛豫效率的區(qū)別與臨床1.5T核磁共振成像儀的測試結(jié)果相一致。最后還發(fā)現(xiàn)這三種多金屬氧簇與蛋白質(zhì)之間都有比較強(qiáng)的靜電相互作用，并且隨著多金屬氧簇自身所帶電荷數(shù)的增加，這種靜電相互作用的強(qiáng)度逐漸增強(qiáng)，即POM-1POM-2POM-3。而這種多金屬氧簇與蛋白質(zhì)之間的靜電相互作用能夠減慢多金屬氧簇在溶液中的翻轉(zhuǎn)，從而使這三種核磁共振造影劑在蛋白質(zhì)溶液中的縱向弛豫時間較純水溶液中均有所增加，增加的幅度隨多金屬氧簇的電荷的增加而增強(qiáng)，即POM-1POM-2POM-3。但同時也發(fā)現(xiàn)，這種靜電作用會降低多金屬氧簇在生理環(huán)境中的穩(wěn)定性，增加了其生物毒性，導(dǎo)致最終三種造影劑的細(xì)胞毒性強(qiáng)度變化為POM-1POM-2POM-3。 隨后設(shè)計(jì)并合成了兩種體積差異較大的順磁性多金屬氧簇，一種為Keggin型多金屬氧簇（POM-4），另一種為兩個Keggin型多金屬氧簇形成的雙扣型多金屬氧簇（POM-2），通過兩者的對比評價多金屬氧簇體積對其溶解度、穩(wěn)定性、弛豫效率、以及細(xì)胞毒性的影響。結(jié)果表明，在水溶液中，POM-2具有更大的分子體積，能夠增加其在溶液中的翻轉(zhuǎn)時間，從而使POM-2的縱向弛豫效率相對較大。兩種多金屬氧簇均能夠與蛋白質(zhì)之間發(fā)生靜電相互作用，使人血清白蛋白溶液的特征熒光信號隨著POM-2和POM-4的加入發(fā)生明顯淬滅。這種靜電相互作用使多金屬氧簇在溶液中的翻轉(zhuǎn)時間減慢。從而使POM-2和POM-4的縱向弛豫效率都有所增加。其中，POM-2較多的電荷數(shù)使其與蛋白質(zhì)間的靜電相互作用相對較強(qiáng)，使POM-2的縱向弛豫效率的增加幅度更大。而進(jìn)一步的細(xì)胞毒性測試則表明，POM-2的細(xì)胞毒性較POM-4高。結(jié)合兩項(xiàng)測試結(jié)果，，盡管POM-4的縱向弛豫時間較POM-2相對較低，但是細(xì)胞毒性更小，更適合與未來直接的臨床應(yīng)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.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R91;R914.5

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