磁性四氧化三铁纳米微球的制备及在药物输送中的应用研究
发布时间：2018-10-31 11:07
【摘要】：超顺磁性氧化铁纳米粒(SPION)因具有良好的生物相容性、生物可降解性、在外磁场作用下能实现靶向治疗等优点,近年来备受研究者关注。作为肿瘤治疗的三大手段之一,化学治疗广泛用于各类肿瘤的治疗,如肺癌、肝癌、胃癌、子宫癌等。但化疗药物大多数都是细胞毒性药物,对肿瘤细胞和正常细胞都有强大的细胞毒性作用,往往导致正常细胞和组织也受到伤害。因此,开发出特异性针对肿瘤细胞起抑制作用的靶向药物传递系统是解决化疗药物全身毒性的一条主要途径。超顺磁性氧化铁纳米粒是目前靶向药物传递系统中常用的材料之一,其高通透性和滞留效应(Enhanced Permeability and Retention,EPR)以及超顺磁性有助于其在肿瘤靶部位大量聚集,实现靶向给药,从而减少化疗药物的全身毒性。超顺磁性氧化铁纳米粒合成工艺很多,如水相共沉淀法、微乳液法、水热/溶剂热法、热分解法、溶胶-凝胶法、超声法、多元醇法和电化学法等。如何找到一条能有效控制纳米粒的形貌、粒径大小与分布,同时使其具有超顺磁性并且能应用于靶向药物传递体系的合成方法,是当前研究的热点。在前期对大量相关文献的调研和预实验的基础上,本课题的研究思路确定为在借鉴前人研究成果的基础上,首先以超声辅助水相共沉淀法制备表面修饰柠檬酸的磁性四氧化三铁纳米粒,在控制其形貌、粒径尺寸与分布及磁性能的基础上,构建以四氧化三铁纳米粒为磁核的靶向药物传递系统,并开展载药与体外释放研究。水相共沉淀法是合成四氧化三铁纳米粒的主要方法之一,相关报道很多,但普遍存在产物粒径大、分布宽、团聚严重的问题。本课题尝试(1)用超声辅助水相共沉淀方法通过调整反应参数来控制产品形貌、粒径大小与分布,同时兼顾其磁性能;(2)以柠檬酸修饰四氧化三铁纳米粒表面,使其呈单分散状态,减少团聚。另外,从文献调研中发现现有的磁靶向药物传递系统存在一些问题,如载药率低、药物释放存在明显突释现象等。β-环糊精作为一种常用的包合材料,是由7个D-葡萄糖分子以1,4-糖苷键连接的环状低聚糖化合物,具有能容纳疏水性药物的空穴结构,其自身毒性很低,适用于提高疏水性药物的水溶性或者延缓药物释放,是一种比较理想的制剂辅料。目前有很多药物如5-氟尿嘧啶、紫杉醇都有包合物制剂已经上市。据此,本课题设计了一条以四氧化三铁@β-环糊精纳米微球包合模型药物多柔比星来提高载药量和实现药物缓释的研究路线。本文的主要工作如下:1.采用超声辅助水相共沉淀法合成了平均粒径84 nm的柠檬酸修饰的Fe3O4纳米粒(Fe3O4@CA),通过查阅文献及预实验,确定了反应条件,即Fe3+∶Fe2+摩尔比为2∶1,反应时间15 min,陈化时间30 min,陈化温度90℃。X射线粉末衍射证明其组成为纯Fe3O4,晶型为反尖晶石;傅里叶变换红外光谱显示其含有柠檬酸;透射电镜下Fe3O4@CA纳米粒外观呈球形,略有团聚;热重分析表明柠檬酸在Fe3O4@CA中的含量为12.1%;磁性能检测显示其具有顺磁性,饱和磁化强度Ms为17.5emu/g,适合用于构建磁靶向药物传递体系。2.利用上一步合成的表面修饰柠檬酸的磁性四氧化三铁纳米粒与β-环糊精偶联,获得了Fe3O4@β-环糊精纳米微球。红外光谱证明β-环糊精与Fe3O4@CA纳米粒偶联成功。透射电镜下,Fe3O4@β-环糊精呈球形或类球型,有部分团聚。粒径分析表明,Fe3O4@β-环糊精纳米微球平均粒径104nm,比Fe3O4@CA平均粒径增大了20nm。以Fe3O4@β-环糊精微球为药物载体,多柔比星为模型药物,借助β-环糊精的分子空穴成功制备了Fe3O4@β-环糊精-多柔比星磁靶向药物传递体系,研究了该药物传递体系在体外的释药过程。建立了多柔比星的浓度-紫外吸收标准曲线,并就Fe3O4@β-环糊精微球对多柔比星的载药量和药物包封率进行了研究。Fe3O4@β-环糊精对多柔比星的载药量可达12%,在超声作用下仅30min就能达到最大载药量,药物包封率30%。Fe3O4@β-环糊精-多柔比星药物传递系统在p H 7.4的磷酸盐缓冲液中释放缓慢,释放时间长达12h,具有缓释效果。
[Abstract]:The superparamagnetic iron oxide nanoparticle (SPION) has the advantages of good biocompatibility, biodegradability and targeted therapy under the action of external magnetic field, and has attracted much attention in recent years. Chemotherapy is widely used in the treatment of various tumors, such as lung cancer, liver cancer, gastric cancer, cancer, etc. But most chemotherapeutic agents are cytotoxic drugs that have strong cytotoxic effects on tumor cells and normal cells, which often result in normal cells and tissues being damaged. Therefore, targeting drug delivery system that specifically targets tumor cells is one of the main ways to solve systemic toxicity of chemotherapeutic drugs. Superparamagnetic iron oxide nanoparticles are one of the most commonly used materials in drug delivery systems. The high permeability and retention effect (EPR) and superparamagnetism contribute to the large aggregation of the target sites of tumor and achieve targeted drug delivery, thus reducing systemic toxicity of chemotherapeutic drugs. There are many synthetic processes of superparamagnetic iron oxide nanoparticles, such as water phase coprecipitation method, microemulsion method, hydrothermal/ solvent thermal method, thermal decomposition method, sol-gel method, ultrasonic method, polyol method and electrochemical method. How to find a synthetic method which can effectively control the morphology, particle size and distribution of the nanoparticles, and also has superparamagnetism and can be applied to the target drug delivery system is the hot spot of the current research. Based on the research and pre-experiment of a large number of related literatures, the research thought of this topic is determined to be based on the previous research achievements, firstly, the magnetic ferroferric oxide nanoparticles with the surface modified citric acid are prepared by the ultrasonic auxiliary water phase coprecipitation method, and the morphology is controlled, On the basis of particle size and distribution and magnetic properties, a targeting drug delivery system with ferroferric oxide nanoparticles as a magnetic core was constructed, and drug-carrying and in vitro release studies were carried out. Water phase co-precipitation method is one of the main methods to synthesize ferroferric oxide nanoparticles. In this paper, the morphology, particle size and distribution of the product are controlled by adjusting the reaction parameters by using the ultrasonic auxiliary water phase coprecipitation method, and the magnetic properties of the product are considered as well; (2) the surface of the ferroferric oxide nanoparticles is modified with citric acid so as to be in a single dispersion state and the agglomeration is reduced. In addition, in the literature research, it is found that there are some problems in the existing magnetic target drug delivery system, such as low drug loading rate, obvious drug release and so on. Cyclodextrin as a commonly used inclusion material is a cyclic oligosaccharide compound linked by 7 D-glucose molecules with 1,4-dioxane, has a hole structure capable of containing hydrophobic drugs, and has low toxicity, It is suitable for improving water solubility of hydrophobic drug or delaying drug release, and is an ideal preparation adjuvant. At present, many drugs such as 5-dimethylaniline and paclitaxel have been marketed. In this paper, we designed a study route to increase the drug loading rate and achieve the sustained release of drug by using ferroferric oxide @ poly-cyclodextrin nanosphere inclusion model. The main work of this paper is as follows: 1. The modified Fe3O4 nanoparticles (Fe3O4 @ CA) with an average particle size of 84 nm were synthesized by ultrasonic assisted water-phase co-precipitation method. The reaction conditions, i.e. Fe3 +: Fe2 + molar ratio of 2: 1, reaction time 15 min, aging time 30 min and aging temperature 90 鈩，
本文编号：2301957
[Abstract]:The superparamagnetic iron oxide nanoparticle (SPION) has the advantages of good biocompatibility, biodegradability and targeted therapy under the action of external magnetic field, and has attracted much attention in recent years. Chemotherapy is widely used in the treatment of various tumors, such as lung cancer, liver cancer, gastric cancer, cancer, etc. But most chemotherapeutic agents are cytotoxic drugs that have strong cytotoxic effects on tumor cells and normal cells, which often result in normal cells and tissues being damaged. Therefore, targeting drug delivery system that specifically targets tumor cells is one of the main ways to solve systemic toxicity of chemotherapeutic drugs. Superparamagnetic iron oxide nanoparticles are one of the most commonly used materials in drug delivery systems. The high permeability and retention effect (EPR) and superparamagnetism contribute to the large aggregation of the target sites of tumor and achieve targeted drug delivery, thus reducing systemic toxicity of chemotherapeutic drugs. There are many synthetic processes of superparamagnetic iron oxide nanoparticles, such as water phase coprecipitation method, microemulsion method, hydrothermal/ solvent thermal method, thermal decomposition method, sol-gel method, ultrasonic method, polyol method and electrochemical method. How to find a synthetic method which can effectively control the morphology, particle size and distribution of the nanoparticles, and also has superparamagnetism and can be applied to the target drug delivery system is the hot spot of the current research. Based on the research and pre-experiment of a large number of related literatures, the research thought of this topic is determined to be based on the previous research achievements, firstly, the magnetic ferroferric oxide nanoparticles with the surface modified citric acid are prepared by the ultrasonic auxiliary water phase coprecipitation method, and the morphology is controlled, On the basis of particle size and distribution and magnetic properties, a targeting drug delivery system with ferroferric oxide nanoparticles as a magnetic core was constructed, and drug-carrying and in vitro release studies were carried out. Water phase co-precipitation method is one of the main methods to synthesize ferroferric oxide nanoparticles. In this paper, the morphology, particle size and distribution of the product are controlled by adjusting the reaction parameters by using the ultrasonic auxiliary water phase coprecipitation method, and the magnetic properties of the product are considered as well; (2) the surface of the ferroferric oxide nanoparticles is modified with citric acid so as to be in a single dispersion state and the agglomeration is reduced. In addition, in the literature research, it is found that there are some problems in the existing magnetic target drug delivery system, such as low drug loading rate, obvious drug release and so on. Cyclodextrin as a commonly used inclusion material is a cyclic oligosaccharide compound linked by 7 D-glucose molecules with 1,4-dioxane, has a hole structure capable of containing hydrophobic drugs, and has low toxicity, It is suitable for improving water solubility of hydrophobic drug or delaying drug release, and is an ideal preparation adjuvant. At present, many drugs such as 5-dimethylaniline and paclitaxel have been marketed. In this paper, we designed a study route to increase the drug loading rate and achieve the sustained release of drug by using ferroferric oxide @ poly-cyclodextrin nanosphere inclusion model. The main work of this paper is as follows: 1. The modified Fe3O4 nanoparticles (Fe3O4 @ CA) with an average particle size of 84 nm were synthesized by ultrasonic assisted water-phase co-precipitation method. The reaction conditions, i.e. Fe3 +: Fe2 + molar ratio of 2: 1, reaction time 15 min, aging time 30 min and aging temperature 90 鈩，
本文编号：2301957
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