【摘要】：目前，心血管類慢性疾病已成為危害人類健康的主要因素之一。動(dòng)脈粥樣硬化（Atherosclerosis，，As）是其中一種較為普遍的心血管病變，無創(chuàng)性的研究As斑塊的發(fā)生、發(fā)展過程，已引起了許多學(xué)者的廣泛關(guān)注。對(duì)于As發(fā)展機(jī)制，科學(xué)家們提出了幾種學(xué)說，但大多數(shù)的研究學(xué)者們支持炎癥學(xué)說，即炎癥破壞As斑塊的穩(wěn)定性，誘發(fā)斑塊破裂。其中，髓過氧化物酶（Myeloperoxidase，MPO）是由中性粒白細(xì)胞、單核細(xì)胞、巨噬細(xì)胞分泌的白細(xì)胞酶，在正常組織中，存在的少量MPO是人體先天免疫的一部分，但在As斑塊中，大量的MPO是主要的促炎癥酶，參與多階段的斑塊去穩(wěn)定作用（不穩(wěn)定過程）。 在本文中，我們選用了樹枝狀分子聚酰胺-胺（PAMAM）為載體，在這一體系上連接能夠在MPO處進(jìn)行有效聚集的靶向分子5-羥色胺（5-HT），從而實(shí)現(xiàn)對(duì)MPO靶向的作用和As的識(shí)別作用。具體如下： 1.對(duì)PAMAM采用磁性氧化鐵納米粒子（IONPs）的修飾，通過配體交換的方法，將第三代樹枝狀分子（G3.0）交換到IONPs的表面，從而實(shí)現(xiàn)IONPs由油溶性向水溶性的轉(zhuǎn)變，得到的納米粒子簡記為G3.0@IONPs。進(jìn)一步的，通過雙羧基聚乙二醇（PEG-(COOH)2）的橋連作用，一端連接能夠靶向MPO的靶向分子5-羥色胺（5-HT），另一端接枝到G3.0表面，從而得到了靶向性的磁性納米探針5-HT-PEG-G3.0@IONPs。并通過一系列的化學(xué)表征，如，形貌表征（TEM、DLS），溶液性質(zhì)表征（UV-Vis），磁性表征（TGA、VSM）等驗(yàn)證納米探針的成功合成及性能，從而為5-HT-PEG-G3.0@IONPs在靶向As形成早期以及不穩(wěn)定斑塊中均過度表達(dá)的MPO創(chuàng)造條件。 2.首先通過PEG--(COOH)2的橋連作用，將靶向分子5-HT連接到G3.0表面，得到靶向性納米探針G3.0-PEG-5-HT。隨后對(duì)體系進(jìn)行造影成像劑Gd的修飾，即通過DTPA的絡(luò)合作用將Gd螯合在G3.0-PEG-5-HT的表面，得到靶向性納米探針5-HT-PEG-G3.0-DTPA-Gd，并通過化學(xué)表征手段，如，1H NMR、FT-IR、UV-Vis、TGA、DLS等，驗(yàn)證了納米探針的成功合成。從而實(shí)現(xiàn)該納米探針對(duì)As處靶向的潛在應(yīng)用價(jià)值。以PAMAM為載體主要是為了改善低分子的成像造影劑在體內(nèi)的循環(huán)周期短、造影效果差、毒性較高等缺點(diǎn)。 在本文中，我們成功的合成了以PAMAM為載體的兩種體系的具有潛在靶向價(jià)值的納米探針，并通過多種化學(xué)表征方式驗(yàn)證它們的成功合成。從而為其在As斑塊處的MRI成像的實(shí)現(xiàn)提供理論依據(jù)，并為As早期醫(yī)學(xué)診斷以及不穩(wěn)定斑塊的識(shí)別創(chuàng)造條件，同時(shí)有望為As這一慢性心血管疾病的預(yù)防和治療提供科學(xué)依據(jù)。
[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.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：TB383.1;O631.3

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相關(guān)期刊論文 前2條

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