以树枝状分子PAMAM为载体的靶向纳米探针的设计与合成
发布时间：2018-07-26 18:05
【摘要】：目前，心血管类慢性疾病已成为危害人类健康的主要因素之一。动脉粥样硬化（Atherosclerosis，，As）是其中一种较为普遍的心血管病变，无创性的研究As斑块的发生、发展过程，已引起了许多学者的广泛关注。对于As发展机制，科学家们提出了几种学说，但大多数的研究学者们支持炎症学说，即炎症破坏As斑块的稳定性，诱发斑块破裂。其中，髓过氧化物酶（Myeloperoxidase，MPO）是由中性粒白细胞、单核细胞、巨噬细胞分泌的白细胞酶，在正常组织中，存在的少量MPO是人体先天免疫的一部分，但在As斑块中，大量的MPO是主要的促炎症酶，参与多阶段的斑块去稳定作用（不稳定过程）。 在本文中，我们选用了树枝状分子聚酰胺-胺（PAMAM）为载体，在这一体系上连接能够在MPO处进行有效聚集的靶向分子5-羟色胺（5-HT），从而实现对MPO靶向的作用和As的识别作用。具体如下： 1.对PAMAM采用磁性氧化铁纳米粒子（IONPs）的修饰，通过配体交换的方法，将第三代树枝状分子（G3.0）交换到IONPs的表面，从而实现IONPs由油溶性向水溶性的转变，得到的纳米粒子简记为G3.0@IONPs。进一步的，通过双羧基聚乙二醇（PEG-(COOH)2）的桥连作用，一端连接能够靶向MPO的靶向分子5-羟色胺（5-HT），另一端接枝到G3.0表面，从而得到了靶向性的磁性纳米探针5-HT-PEG-G3.0@IONPs。并通过一系列的化学表征，如，形貌表征（TEM、DLS），溶液性质表征（UV-Vis），磁性表征（TGA、VSM）等验证纳米探针的成功合成及性能，从而为5-HT-PEG-G3.0@IONPs在靶向As形成早期以及不稳定斑块中均过度表达的MPO创造条件。 2.首先通过PEG--(COOH)2的桥连作用，将靶向分子5-HT连接到G3.0表面，得到靶向性纳米探针G3.0-PEG-5-HT。随后对体系进行造影成像剂Gd的修饰，即通过DTPA的络合作用将Gd螯合在G3.0-PEG-5-HT的表面，得到靶向性纳米探针5-HT-PEG-G3.0-DTPA-Gd，并通过化学表征手段，如，1H NMR、FT-IR、UV-Vis、TGA、DLS等，验证了纳米探针的成功合成。从而实现该纳米探针对As处靶向的潜在应用价值。以PAMAM为载体主要是为了改善低分子的成像造影剂在体内的循环周期短、造影效果差、毒性较高等缺点。 在本文中，我们成功的合成了以PAMAM为载体的两种体系的具有潜在靶向价值的纳米探针，并通过多种化学表征方式验证它们的成功合成。从而为其在As斑块处的MRI成像的实现提供理论依据，并为As早期医学诊断以及不稳定斑块的识别创造条件，同时有望为As这一慢性心血管疾病的预防和治疗提供科学依据。
[Abstract]:At present, cardiovascular chronic diseases have become one of the main factors that harm human health. Atherosclerosis (Atherosclerotic as) is one of the most common cardiovascular diseases. Noninvasive studies on the occurrence and development of as plaques have attracted the attention of many scholars. For the development of as, scientists have proposed several theories, but most researchers support the theory of inflammation, that is, inflammation destroys the stability of as plaques and induces plaque rupture. Myeloperoxidase (MPO) is a leucocyte enzyme secreted by neutrophils, monocytes and macrophages. In normal tissues, a small amount of MPO is a part of human innate immunity, but in as plaque. A large number of MPO are the major pro-inflammatory enzymes involved in multistage plaque de-stabilization (unstable process). In this paper, we select dendritic polyamide-amine (PAMAM) as the carrier to connect the target molecule 5-hydroxytryptamine (5-HT), which can effectively aggregate at the MPO, so as to realize the target effect of MPO and the recognition of as. The details are as follows: 1. The third generation dendritic molecule (G3.0) was exchanged to the surface of PAMAM by ligand exchange with magnetic iron oxide nanoparticles (IONPs). The transition of IONPs from oil-soluble to water-soluble was realized. The obtained nanoparticles were abbreviated as G3.0 IONPs. Furthermore, through the bridging of dicarboxylic polyethylene glycol (PEG- (COOH) 2), one end is connected with the target molecule 5-hydroxytryptamine (5-HT) which can target MPO, and the other end is grafted onto the surface of G3.0, thus the targeted magnetic nano-probe 5-HT-PEG-G3.0 BIONPs are obtained. A series of chemical characterization, such as morphology characterization (TEMN DLS), solution characterization (UV-Vis), magnetic characterization (TGA-VSM) and so on, were used to verify the successful synthesis and properties of the nanoprobes. Thus, the conditions for overexpression of 5-HT-PEG-G3.0@IONPs in target as early as and unstable plaques were established. 2. 2. Firstly, the target molecule 5-HT was connected to the surface of G3.0 by bridging PEG- (COOH) _ 2, and the targeted nano-probe G3.0-PEG-5-HTwas obtained. Then the system was modified with Gd, that is, Gd was chelated on the surface of G3.0-PEG-5-HT by the complexation of DTPA, and the targeted nano-probe 5-HT-PEG-G3.0-DTPA-Gdwas obtained. The successful synthesis of the nanoprobe was verified by chemical characterization, such as 1H NMRFT-IRT-IR UV-VisTGADLS. Thus, the potential application value of the nanoprobe to target as is realized. The main purpose of using PAMAM as carrier is to improve the circulatory period of low molecular weight imaging contrast agent in vivo, poor imaging effect, high toxicity and so on. In this paper, we successfully synthesized the potential targeting nanoprobes of two systems based on PAMAM, and verified their successful synthesis by a variety of chemical characterization methods. Thus it can provide theoretical basis for the realization of MRI imaging in as plaque, create conditions for early medical diagnosis of as and identification of unstable plaque, and provide scientific basis for the prevention and treatment of as, a chronic cardiovascular disease.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：TB383.1;O631.3
本文编号：2146858
[Abstract]:At present, cardiovascular chronic diseases have become one of the main factors that harm human health. Atherosclerosis (Atherosclerotic as) is one of the most common cardiovascular diseases. Noninvasive studies on the occurrence and development of as plaques have attracted the attention of many scholars. For the development of as, scientists have proposed several theories, but most researchers support the theory of inflammation, that is, inflammation destroys the stability of as plaques and induces plaque rupture. Myeloperoxidase (MPO) is a leucocyte enzyme secreted by neutrophils, monocytes and macrophages. In normal tissues, a small amount of MPO is a part of human innate immunity, but in as plaque. A large number of MPO are the major pro-inflammatory enzymes involved in multistage plaque de-stabilization (unstable process). In this paper, we select dendritic polyamide-amine (PAMAM) as the carrier to connect the target molecule 5-hydroxytryptamine (5-HT), which can effectively aggregate at the MPO, so as to realize the target effect of MPO and the recognition of as. The details are as follows: 1. The third generation dendritic molecule (G3.0) was exchanged to the surface of PAMAM by ligand exchange with magnetic iron oxide nanoparticles (IONPs). The transition of IONPs from oil-soluble to water-soluble was realized. The obtained nanoparticles were abbreviated as G3.0 IONPs. Furthermore, through the bridging of dicarboxylic polyethylene glycol (PEG- (COOH) 2), one end is connected with the target molecule 5-hydroxytryptamine (5-HT) which can target MPO, and the other end is grafted onto the surface of G3.0, thus the targeted magnetic nano-probe 5-HT-PEG-G3.0 BIONPs are obtained. A series of chemical characterization, such as morphology characterization (TEMN DLS), solution characterization (UV-Vis), magnetic characterization (TGA-VSM) and so on, were used to verify the successful synthesis and properties of the nanoprobes. Thus, the conditions for overexpression of 5-HT-PEG-G3.0@IONPs in target as early as and unstable plaques were established. 2. 2. Firstly, the target molecule 5-HT was connected to the surface of G3.0 by bridging PEG- (COOH) _ 2, and the targeted nano-probe G3.0-PEG-5-HTwas obtained. Then the system was modified with Gd, that is, Gd was chelated on the surface of G3.0-PEG-5-HT by the complexation of DTPA, and the targeted nano-probe 5-HT-PEG-G3.0-DTPA-Gdwas obtained. The successful synthesis of the nanoprobe was verified by chemical characterization, such as 1H NMRFT-IRT-IR UV-VisTGADLS. Thus, the potential application value of the nanoprobe to target as is realized. The main purpose of using PAMAM as carrier is to improve the circulatory period of low molecular weight imaging contrast agent in vivo, poor imaging effect, high toxicity and so on. In this paper, we successfully synthesized the potential targeting nanoprobes of two systems based on PAMAM, and verified their successful synthesis by a variety of chemical characterization methods. Thus it can provide theoretical basis for the realization of MRI imaging in as plaque, create conditions for early medical diagnosis of as and identification of unstable plaque, and provide scientific basis for the prevention and treatment of as, a chronic cardiovascular disease.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：TB383.1;O631.3
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相关期刊论文 前2条
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2 武军驻,洪嘉玲;低密度脂蛋白诱导巨噬细胞髓过氧化物酶活性的研究[J];中国免疫学杂志;2003年01期
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