磁性氧化铁纳米立方的制备及其在心脏疾病应用的研究
发布时间：2018-07-27 21:17
【摘要】：心血管疾病(Cardiovascular disease,CVD)在近些年来已经成为人类的首要致死原因,心肌梗死(Myocardial infarction,MI)逐渐成为其中最常见的不良事件,所以亟需高效的心肌梗死诊断和治疗的手段。MI是由心肌缺血再灌注之后引起的大量的心肌细胞坏死和凋亡导致。主要的病理特点是MI后的炎症反应,大量巨噬细胞浸润。然而过度的炎症会导致梗死区域的扩张、组织纤维化等不良重构,引起心衰甚至死亡。基于MI后心梗区存在大量巨噬细胞的特点,通过心脏巨噬细胞来诊断和治疗心肌梗死将极为有效。核磁共振成像(Magnetic resonance imaging,MRI)以时空分辨率高、无辐射、安全性高等特点,在心血管疾病诊断中扮演了重要角色。为提高各类病灶诊断的准确性,磁共振造影剂进而被广泛应用于临床。传统的钆系造影剂无法进入细胞。研究表明,磁性氧化铁纳米颗粒作为一种新型磁共振造影剂,具有良好的磁效应及生物相容性,可进入细胞用于细胞成像,是国内外研究的热点。基于此,本文旨在研制一种以磁性氧化铁纳米立方为基础的PS呈递的双靶向纳米诊疗系统,在用于MI区域磁共振成像的同时,并通过呈递磷酯酰丝氨酸(PS)模拟细胞凋亡与巨噬细胞作用,控制急性炎症反应进程和程度,改善不良重构,从而同时实现针对早期心肌梗死的诊断和治疗。主要内容包括:1、MIONs的制备及表征。实验采用高温热分解法制备高磁响应性、形貌均一的疏水性磁性氧化铁纳米立方(MIONs)并对其进行表征。2、PLA-PCB的合成。开环聚合法合成聚乳酸(PLA),并在PLA末端修饰上pH敏感性的基于两性离子的聚合物聚羧基甜菜碱(PCB),得到两亲性高分子聚合物PLA-PCB。3、PP/PS@MIONs的制备与表征。处方优化后,经薄膜分散法MIONs被包裹在内部,两亲性的PLA40-PCB(PP)及PS由于亲疏水自组装包覆在纳米立方外表面,制备得到PP/PS@MIONs,粒径50.6±7.8 nm,具有良好的水溶性、分散性及较强的磁响应性,最终体系PS含量为3 mM,Fe浓度为1 mg/mL,弛豫效率达376.5 mM-1s-1,可用于磁共振成像。4、PP/PS@MIONs的体外活性研究。细胞学研究以巨噬细胞RAW264.7为细胞模型。结果显示PP/PS@MIONs安全性高,对RAW264.7细胞未表现出明显毒性作用;PP/PS@MIONs在2 h即可被摄取,PS显示显著靶向性。PP/PS@MIONs在摄取12 h后有显著内涵体逃逸行为,释放铁颗粒进入胞浆。小鼠腹腔巨噬细胞被用于检测PP/PS@MIONs调节炎症的活性。结果显示,PP/PS@MIONs可以调节巨噬细胞状态,具有显著抗炎作用。5、PP/PS@MIONs的体内活性研究。以Lewis大鼠左冠脉前降支结扎为MI动物模型,考察了PP/PS@MIONs在大鼠体内的成像及对大鼠MI的治疗效果。结果显示,在外加磁场和PS靶向巨噬细胞的双重作用下,PP/PS@MIONs在梗死部位的分布更明显,具有良好的成像性能。PP/PS@MIONs在外加磁场作用下能够显著降低梗死后心脏的不良重构,有效促进血管新生和心脏功能恢复。综合以上研究结果,本实验成功构建出一种安全有效的心肌梗死纳米诊疗系统,为探索新型MI诊疗方法提供了参考。
[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.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943;R96
本文编号：2149161
[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.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943;R96
【参考文献】
相关期刊论文 前4条
1 朱皓;高凯;张连峰;;三种正常大鼠磁共振成像心功能基础数据采集和分析[J];中国比较医学杂志;2013年02期
2 李慧;王大新;顾健;;超顺磁性纳米颗粒治疗肿瘤的应用进展[J];中国组织工程研究与临床康复;2009年51期
3 刘迎春,许妙琼,朱文祥;医疗诊断新技术——磁共振成像术[J];化学教育;2005年05期
4 俞开潮,王国平,丁尚武,叶朝辉;用于磁共振成像对比增强的造影剂研发进展[J];波谱学杂志;2004年04期
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