【摘要】：心血管疾病(Cardiovascular disease,CVD)在近些年來已經(jīng)成為人類的首要致死原因,心肌梗死(Myocardial infarction,MI)逐漸成為其中最常見的不良事件,所以亟需高效的心肌梗死診斷和治療的手段。MI是由心肌缺血再灌注之后引起的大量的心肌細(xì)胞壞死和凋亡導(dǎo)致。主要的病理特點(diǎn)是MI后的炎癥反應(yīng),大量巨噬細(xì)胞浸潤。然而過度的炎癥會導(dǎo)致梗死區(qū)域的擴(kuò)張、組織纖維化等不良重構(gòu),引起心衰甚至死亡。基于MI后心梗區(qū)存在大量巨噬細(xì)胞的特點(diǎn),通過心臟巨噬細(xì)胞來診斷和治療心肌梗死將極為有效。核磁共振成像(Magnetic resonance imaging,MRI)以時空分辨率高、無輻射、安全性高等特點(diǎn),在心血管疾病診斷中扮演了重要角色。為提高各類病灶診斷的準(zhǔn)確性,磁共振造影劑進(jìn)而被廣泛應(yīng)用于臨床。傳統(tǒng)的釓系造影劑無法進(jìn)入細(xì)胞。研究表明,磁性氧化鐵納米顆粒作為一種新型磁共振造影劑,具有良好的磁效應(yīng)及生物相容性,可進(jìn)入細(xì)胞用于細(xì)胞成像,是國內(nèi)外研究的熱點(diǎn)�；诖�,本文旨在研制一種以磁性氧化鐵納米立方為基礎(chǔ)的PS呈遞的雙靶向納米診療系統(tǒng),在用于MI區(qū)域磁共振成像的同時,并通過呈遞磷酯酰絲氨酸(PS)模擬細(xì)胞凋亡與巨噬細(xì)胞作用,控制急性炎癥反應(yīng)進(jìn)程和程度,改善不良重構(gòu),從而同時實現(xiàn)針對早期心肌梗死的診斷和治療。主要內(nèi)容包括:1、MIONs的制備及表征。實驗采用高溫?zé)岱纸夥ㄖ苽涓叽彭憫?yīng)性、形貌均一的疏水性磁性氧化鐵納米立方(MIONs)并對其進(jìn)行表征。2、PLA-PCB的合成。開環(huán)聚合法合成聚乳酸(PLA),并在PLA末端修飾上pH敏感性的基于兩性離子的聚合物聚羧基甜菜堿(PCB),得到兩親性高分子聚合物PLA-PCB。3、PP/PS@MIONs的制備與表征。處方優(yōu)化后,經(jīng)薄膜分散法MIONs被包裹在內(nèi)部,兩親性的PLA40-PCB(PP)及PS由于親疏水自組裝包覆在納米立方外表面,制備得到PP/PS@MIONs,粒徑50.6±7.8 nm,具有良好的水溶性、分散性及較強(qiáng)的磁響應(yīng)性,最終體系PS含量為3 mM,Fe濃度為1 mg/mL,弛豫效率達(dá)376.5 mM-1s-1,可用于磁共振成像。4、PP/PS@MIONs的體外活性研究。細(xì)胞學(xué)研究以巨噬細(xì)胞RAW264.7為細(xì)胞模型。結(jié)果顯示PP/PS@MIONs安全性高,對RAW264.7細(xì)胞未表現(xiàn)出明顯毒性作用;PP/PS@MIONs在2 h即可被攝取,PS顯示顯著靶向性。PP/PS@MIONs在攝取12 h后有顯著內(nèi)涵體逃逸行為,釋放鐵顆粒進(jìn)入胞漿。小鼠腹腔巨噬細(xì)胞被用于檢測PP/PS@MIONs調(diào)節(jié)炎癥的活性。結(jié)果顯示,PP/PS@MIONs可以調(diào)節(jié)巨噬細(xì)胞狀態(tài),具有顯著抗炎作用。5、PP/PS@MIONs的體內(nèi)活性研究。以Lewis大鼠左冠脈前降支結(jié)扎為MI動物模型,考察了PP/PS@MIONs在大鼠體內(nèi)的成像及對大鼠MI的治療效果。結(jié)果顯示,在外加磁場和PS靶向巨噬細(xì)胞的雙重作用下,PP/PS@MIONs在梗死部位的分布更明顯,具有良好的成像性能。PP/PS@MIONs在外加磁場作用下能夠顯著降低梗死后心臟的不良重構(gòu),有效促進(jìn)血管新生和心臟功能恢復(fù)。綜合以上研究結(jié)果,本實驗成功構(gòu)建出一種安全有效的心肌梗死納米診療系統(tǒng),為探索新型MI診療方法提供了參考。
[Abstract]:Cardiovascular disease (CVD) has become the leading cause of death in human beings in recent years. Myocardial infarction (Myocardial infarction, MI) has gradually become the most common adverse event. Therefore, high efficient myocardial infarction is urgently needed for the diagnosis and treatment of myocardial infarction..MI is a large number of myocardial fines caused by myocardial ischemia and reperfusion. The main pathological features are inflammatory responses after MI and infiltration of large numbers of macrophages. However, excessive inflammation can lead to dilatation of the infarct area, tissue fibrosis and other bad remodeling, causing heart failure and even death. Based on the characteristics of large macrophages in the infarct area after MI, the diagnosis and treatment of it through cardiac macrophages Myocardial infarction will be very effective. Magnetic resonance imaging (MRI) is an important role in the diagnosis of cardiovascular disease with high spatial resolution, no radiation and high safety. In order to improve the accuracy of diagnosis of all kinds of lesions, magnetic resonance imaging agent is widely used in clinic. As a new type of magnetic resonance contrast agent, magnetic iron oxide nanoparticles, as a new magnetic resonance contrast agent, have good magnetic effect and biocompatibility, and can enter cells for cell imaging. It is a hot spot at home and abroad. Based on this, the aim of this paper is to develop a kind of PS presentation based on magnetic oxide iron nanometers. The rice diagnosis and treatment system, at the same time used in MI region magnetic resonance imaging, and simulated cell apoptosis and macrophage by presenting phosphonyl serine (PS), control the process and degree of acute inflammation, improve the bad remodeling, and realize the diagnosis and treatment of early myocardial infarction. The main contents include: 1, the preparation and characterization of MIONs The high temperature thermal decomposition method was used to prepare the hydrophobic magnetic iron oxide nano cubic (MIONs) with high magnetic response and homogeneous morphology. The synthesis of.2, PLA-PCB, the synthesis of poly (lactic acid) (PLA) by open loop polymerization, and the pH sensitive polymer polycarboxylic betaine (PCB) based on the pH sensitivity at the end of PLA, obtained two amphibiously high affinity. The preparation and characterization of molecular polymer PLA-PCB.3, PP/PS@MIONs. After the optimization of the formulation, the MIONs was wrapped in the interior by thin film dispersion method, and the two Pro PLA40-PCB (PP) and PS were coated on the surface of the nano cubic surface by hydrophobic self assembly. The particle size was 50.6 + 7.8 NM, with good water solubility, dispersibility and strong magnetic response. The final system PS content is 3 mM, the concentration of Fe is 1 mg/mL and the relaxation efficiency is 376.5 mM-1s-1. It can be used in magnetic resonance imaging.4, PP/PS@MIONs in vitro activity study. The cytological study uses macrophage RAW264.7 as the cell model. The results show that PP/PS@MIONs is high and does not show obvious toxic effect on RAW264.7 cells, PP/PS@MIONs in 2 h. After intake, PS showed significant targeting.PP/PS@MIONs after ingestion of 12 h, a significant endosomal escape behavior, the release of iron particles into the cytoplasm. Mouse peritoneal macrophages were used to detect the activity of PP/PS@MIONs regulating inflammation. The results showed that PP/PS@MIONs could regulate the state of macrophages and had a significant anti-inflammatory effect of.5, PP/PS@MIONs in vivo. Lewis rats were ligated with the left anterior descending branch of the coronary artery as a MI animal model, and the imaging of PP/PS@MIONs in rats and the therapeutic effect on rat MI were investigated. The results showed that the distribution of PP/PS@MIONs was more obvious in the infarct site under the double effect of the applied magnetic field and the PS target macrophage, and the good imaging performance.PP/PS@MIONs was found. The external magnetic field can significantly reduce the bad remodeling of the heart after the infarction, effectively promote the angiogenesis and the recovery of the heart function. In this experiment, a safe and effective nano diagnosis and treatment system for myocardial infarction is successfully constructed, which provides a reference for the exploration of a new MI diagnosis and treatment method.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R943;R96

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本文編號：2149161