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题名: 叶酸受体介导单壁碳纳米管-异甘草素靶向输运复合体的制备和性能研究
作者: 韩博
答辩日期: 2013-05-29
导师: 阿吉艾克拜尔•艾萨
专业: 有机化学
授予单位: 中国科学院大学
授予地点: 北京
学位: 博士
关键词: 单壁碳纳米管 ; 聚乙二醇 ; 叶酸 ; 生物相容性 ; 异甘草素
摘要:

本文回顾了近年来碳纳米管(carbon nanotubes, CNTs)功能化修饰的方法、生物毒性、进入细胞的机制及其在体内、外肿瘤治疗方面的研究现状。在研究者证明聚乙二醇(polyethylene glycol, PEG)修饰单壁碳纳米管(single-walled carbon nanotubes, SWNTs)后可以提高其生物相容性的前提下,本工作合成并表征了PEG修饰且叶酸(folic acid, FA)介导的SWNTs和异甘草素(isoliquiritigenin, ISL)肿瘤靶向复合物。本工作也考察了碳纳米管-异甘草素(SWNTs-ISL)药物输运体系的血液循环、组织分布和毒性特征。主要研究内容和结论如下:

1 本工作发明了一种新的通过化学转化的方法提取甘草中ISL的方法,实验结果表明,新的提取方法较经典的提取方法ISL的收率提高了27倍,此方法可以有效地提取和分离甘草中的ISL

2.SWNTs进行PEG功能化修饰,考察了合成产物的生物相容性。合成产物的溶血性试验和血小板黏附测试结果表明PEG通过共价接枝或非共价吸附的方式连接到SWNTs上后都可以改善SWNTs的生物相容性。

3. SWNTs在生物医学领域的许多方面都表现出令人瞩目的特性,但是很少有研究者利用拉曼光谱测定体内的SWNTs,本工作测定了PEG与氧化碳纳米管(oxide single-walled carbon nanotubes o-SWNTs)的合成产物(c-PEG-SWNTs)的分散性和生物相容性。相比传统测定方法,新方法的加样回收率从原来的84.2% 提高到102.7%,标准曲线的相关系数从0.7315提高到0.9872,精密度从4.4%降低到3.1%

4. 本工作建立了一种通过同步荧光光谱测定血液和组织中ISL的方法,该方法提供了一种简单有效地测定体内ISL吸收、分布、代谢和排泄的方法,并筛选了同步荧光测定ISL的最佳条件。

5. 为了得到SWNTs在血液中的最长循环时间,本工作考察了SWNTs的氧化程度、PEG的分子量及PEGo-SWNTs连接方式对o-SWNTs长循环时间的影响,并且评价c-PEG-SWNTs可能产生的毒性。结果发现SWNTs氧化30 min后共价连接分子量为3500PEG可以得到最长的SWNTs血液循环时间。但是c-PEG-SWNTs不能延长ISL的血液循环时间,并且我们观察到c-PEG-SWNTs对心脏和肾脏有一定毒性。

6. 合成和表征了PEG修饰且FA介导携带异硫氰酸荧光素(fluorescein isothiocyanate,FITC)的SWNTs-ISL复合物(PEG-SWNTs-FA-FITC-ISL, PSFF-ISL)。结果发现可以通过三步合成的办法合成PSFF-ISL,该合成的顺利完成为ISL提供纳米级的载体。

英文摘要: Firstly, this article has reviewed the recent researches on methods of making functional carbon nanotubes, biotoxicity of CNTs, mechanisms of CNTs crossing the cell membranes, and tumor treatment with CNTs in vitro and in vivo. On the premise of polyethylene glycol (PEG)-modified single-walled carbon nanotubes (SWNTs) can improve the biocompatibility. In this work,folic acid and PEG mediated carbon nanotubes-Isoliquiritigenin tumor targeted drugs was synthesized and characterized. We also sought to determine the circulation profile, biodistribution profile and toxicity profile of PEG mediated carbon nanotubes-Isoliquiritigenin tumor targeted drugs in rats. The main contents and conclusions are listed in the following: 1. A novel procedure of extract isoliquirigenin from Glycyrrhiza uralensis Fisch. is developed. The results demonstrated that the yield of the novel procedure was increased about 27 times compared with the conventional procedure, which indicated that the novel procedure is powerful in separating and purifying isoliquiritigenin. 2. SWNTs was functionalized by PEG, the biocompatibility was investigated of after its functionalization. The results of hemolysis test and platelet adhesion test shown that the biocompatibility of SWNTs was improved after PEG covalently and noncovalently functionalization of single-walled carbon nanotubes. 3. SWNTs have shown great potential in various areas of biomedicine. However, few researches have focu sed on in vivo carbon nanotube detection by Raman spectroscopy. In this work, SWNTs were functionalized by PEGylation covalently (c-PEG-SWNTs) to improve the biocompatibility and dispersibility. A novel application of Raman scattering was used to detect the PEG-o-SWNTs. Compared to the traditional assay method, the recovery rate was improved from 84.2% to 102.7%, the related coefficient of the standard curve increased from 0.7315 to 0.9872, and the degree of precision decreased from 4.4% to 3.1%. 4. A novel method using synchronous fluorescence spectrometry to determine the concentration of isoliquiritigenin (ISL) in mice blood and tissue was developed, which provides a simple but effective analytical way to study the absorption, distribution, metabolism, excretion and in vivo biological effects of ISL. The conditions to determine ISL by synchronous fluorescence was optimized. 5. To obtain single-walled carbon nanotubes (SWNTs) with long blood circulation times, we investigated the influence of oxidation time, PEG molecular weight, and type of PEG linkage (covalent or non-covalent) on the blood circulation time of PEG-modified SWNTs. We also sought to determine the toxicity profile c-PEG-SWNTs in rats. SWNTs oxidized for 30 min and covalently modified with PEG having a molecular weight of 3500 had the longest blood circulation half-lives. However, we found that c-PEG-SWNTs did not extend the ISL blood circulation time and were toxic to the kidneys and the heart. 6. Folic acid (FA) mediated carbon nanotubes-isoliquiritigenin tumor targeted drugs (PSFF-ISL) was synthesized and characterized. PSFF-ISL can be prepared by three-step synthesis method. The synthesis of PEG-SWNTs-FA-FITC (PSFF) provided pharmaceutical carrier for ISL in nano-size.
内容类型: 学位论文
URI标识: http://ir.xjipc.cas.cn/handle/365002/2484
Appears in Collections:资源化学研究室_学位论文

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作者单位: 中国科学院新疆理化技术研究所

Recommended Citation:
韩博. 叶酸受体介导单壁碳纳米管-异甘草素靶向输运复合体的制备和性能研究[D]. 北京. 中国科学院大学. 2013.
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