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嵌段共聚物修饰的纳米磁性药物载体的制备和载药研究
Alternative TitleMagnetic nanoparticles (MNPs) covalently coated by PEO–PPO–PEO block copolymer for drug delivery
王宁
Subtype硕士
Thesis Advisor刘会洲 ; 郭晨
2013-05-01
Degree Grantor中国科学院研究生院
Degree Discipline化学工程
Keyword磁性纳米颗粒   嵌段共聚物   稳定药物载体   温度响应性   姜黄素   药物运输系统
Abstract磁性纳米颗粒因其具有磁性,可在外加磁场的作用下方便地分离,同时兼具纳米材料的结构特性和良好的生物相容性。一方面,磁性颗粒可通过物理化学作用来结合酶、细胞和抗体等生物活性物质;另一方面因其具有“在外界磁场存在下能定向运动”这一特殊性能,可对外加磁场表现出强烈的磁响应性,因此它被用作酶、细胞、药物等的载体,广泛地应用到生物医学、细胞学和生物工程等领域。 聚氧乙烯–聚氧丙烯–聚氧乙烯 (PEO–PPO–PEO)嵌段共聚物在选择性溶剂中可以自组装形成形貌和性质丰富的介观结构,具有生物相容、结构可控和温度敏感等优点,因此是制备纳米材料的理想元件,在生物医药领域也有着非常广泛的应用。本论文围绕着磁性纳米颗粒的外加磁场响应性和PEO-PPO-PEO嵌段共聚物的自组装性质,在深入研究磁性颗粒的溶液稳定性和PEO-PPO-PEO 嵌段共聚物胶团形成机理的基础上,将这两种纳米材料的结构和性能优势结合起来,制备了用嵌段共聚物共价修饰的磁性纳米药物载体,并应用到疏水性药物(实验中以姜黄素为例)的负载之中,以达到提高药物载体稳定性,增加疏水性药物的生物利用程度的目的。实验中利用各种光谱技术和体内环境模拟药物释放,表征了该药物载体的物理生化特性,证实了其应用于疏水性药物体内负载的可行性。 研究内容主要包括以下三个方面: (1) 利用二维相关光谱的处理手段,得到不同无机盐浓度下的水溶液中嵌段共聚物的二维红外光谱,对水溶液中嵌段共聚物的胶束形成机理做了进一步的探讨,证明无机盐离子促进了嵌段共聚物胶束的形成,在此过程中嵌段共聚物各基团的变化顺序为水化的甲基→形成氢键的水化C-O醚键→反式构象的EO嵌端的亚甲基→去水化的甲基→去水化状态的C-O醚键→EO嵌端的旁氏构象。对于胶束形成机理的探讨为接下来的实验中利用嵌段共聚物的胶束行为负载药物做了理论上的铺垫; (2) 对嵌段共聚物(实验中以Pluronic P85为例)进行了端基活化,利用琥珀酸酐通过有机化学反应使得其两端羟基活化为羧基,提高其化学活性,以便更加牢固的修饰到磁颗粒表面。活化反应前后的红外谱图结果对比证明了活化实验的成功实现; (3) 利用成肽反应,以水溶性的碳二亚胺族化合物EDC(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)为催化剂,将活化后带有羧基的嵌段共聚物共价连接在带有羧基的磁性纳米颗粒表面,通过调控反应物比例,浓度,温度以及pH,实现较大负载率。红外光谱,动态光散射和热重分析等表征实验的结果都证明了嵌段共聚物对磁性纳米颗粒的成功修饰,修饰后的纳米颗粒尺度较为均一(绝对直径15 nm左右,水力直径100 nm左右),在水溶液中(包括PBS缓冲液和pH 13.5碱性溶液)分散性较好; (4) 利用姜黄素分子的疏水性基团与嵌段共聚物的疏水嵌段(PPO)之间的疏水相互作用,利用合成的载体负载姜黄素分子,得到了81.3%的包封率。在模拟体内环境(温度,pH等)进行的药物释放研究中,在100 h内释药量达到70%以上,证明了磁性载体的稳定性和缓释性。
Other AbstractMagnetite nanoparticles (MNPs) have been widely applied in biomedical fields due to low toxicity and good compatibility. MNPs with high magnetization values and ultrafine particle sizes can be manipulated by external magnetic field (MF) by which human issues can be penetrated, indicating the possibility of applying them for targetable drug delivery. Poly (ethylene oxide)–poly (propylene oxide)–poly (ethylene oxide) (PEO–PPO–PEO) block copolymers could self-assemble into several types of meso-structure with various morphologies and properties in selective solvents. The PEO-PPO-PEO block copolymers have many attractive advantages including temperature-response and biocompatibility which make them ideal building blocks of nanomaterials, and the self-assembled structures could be well controlled by varying the copolymer composition or adding additives. Therefore, PEO-PPO-PEO block copolymers also have widespread applications in biomedical field. This thesis aims at studying the agglomeration mechanism of magnetic nanoparticles (MNPs) as well as the micelle formation of PEO-PPO-PEO block copolymers in aqueous solutions, and taking advantage of the superparamagnetism of MNPs and temperature-response of block copolymers to develop a kind of stable drug carrier. This carrier has been prepared by covalently coating magnetic nanoparticles (MNPs) with PEO–PPO–PEO block copolymer Pluronic P85. The carrier was then applied to deliver the hydrophobic model drug curcumin to increase its solubility and bioavailability. By using several spectroscopic techniques including TEM, XRD, DLS, VSM, FTIR and TGA, as well as drug release experiments in simulated in vivo conditions, the physical and biochemical properties of this carrier has been characterized, and its function in delivery of hydrophobic drugs has been proved feasible. The main results are as follows: (1) Taking advantage of two-dimensional Infrared Spectrum which is initiated by Isao Noda, micellization mechanism of block copolymer in aqueous solution with different salt concentrations has been investigated. It proved that the existence of salt ions contributes to the formation of micelles. The changing sequence of various groups of Pluronics is as follows - hydrated methyl groups→hydrogen bonded C-O band→EO methylene groups belonging to the trans conformation→dehydrated methyl groups→dehydrated state C-O band→gauche conformation of EO segments. The result laid foundation for usage of micellization behavior of block copolymer in controlled drug delivery; (2) The end-group functionalization of Pluronic block copolymer used in the experiments (P85) has been achieved by reacting with succinic anhydride in toluene. End-group functionalization makes Pluronic molecules more chemically active and is favorable for the modification of MNPs. FTIR results of reactants in this process certifies the successful functionalization of Pluronics; (3) Taken as a water-soluble crosslinking agent, EDC?HCl has successfully linked MNPs with functionalized Pluronic P85 by peptide formation. Adjustments of reagents ratio, concentration and pH have been explored to achieve a better modification efficiency. The carriers acquired presented narrow size distribution (15 nm in TEM image and 100 nm in DLS data) and good aqueous stability (including in PBS and pH 13.5 solution); (4) The carrier has been applied to deliver the hydrophobic drug model curcumin via hydrophobic interaction between curcumin molecules and PPO block of Pluronic P85. The drug loading experiment proved the high loading capacity of this carrier (EE 81.3%), and the drug release experiment tested in simulated in vivo conditions (more than 70% released in 100 h) confirmed the stability and sustained release of the carrier.
Pages88
Language中文
Document Type学位论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/8348
Collection研究所(批量导入)
Recommended Citation
GB/T 7714
王宁. 嵌段共聚物修饰的纳米磁性药物载体的制备和载药研究[D]. 中国科学院研究生院,2013.
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