【作者】 李瑞雪；

【导师】 赵建青；

【作者基本信息】 华南理工大学 ， 材料学， 2010， 博士

【摘要】 近年来,人们从多学科交叉的角度出发,开发出很多新型的磁性纳米功能材料。其中,磁性靶向药物载体、磁流体、磁性复合纳米材料是较为突出的门类并成为研究中的热点。虽然这几种磁性纳米功能材料的研究正在不断深化,其应用领域也在不断扩展,但仍然存在一些问题值得深入探索。在磁性靶向药物载体方面,如何选取合适的支撑材料以及探索恰当的方法、途径制备性能优异,用途广泛的新型磁性靶向药物载体仍是当前研究中面临的主要问题。在磁流体和磁性纳米复合材料方面,如何实现磁性纳米颗粒在载液和聚合物基质的均匀分散以制备性质稳定、性能优异的磁性纳米功能材料仍是研究中的首要问题和难点。基于以上几点,本文着重设计和开发出了几种新型表面β-环糊精功能化的Fe₃O₄磁性纳米颗粒,并研究了它们作为磁性靶向药物载体应用方面的相关性能;以可聚合表面活性剂马来酸单十八酯对Fe₃O₄磁性纳米颗粒进行表面修饰,将颗粒均匀分散于苯乙烯单体中制备了可聚合磁流体,经本体聚合制备了聚苯乙烯/ Fe₃O₄磁性复合纳米材料,研究了可聚合磁流体和磁性复合纳米材料的相关性能。这些研究不仅为新型磁性纳米功能材料的制备和研究提供了新思路、新方法和新途径,而且还拓宽了其相关应用领域。本文所做的主要研究工作和结果如下:合成了羧基取代度分别为1.2和7.3的羧甲基-β-环糊精,并分别在水介质和DMF介质中制备了羧甲基-β-环糊精修饰Fe₃O₄磁性纳米颗粒。利用TEM、FTIR、XRD、DLS、TG等手段对制备颗粒的结构、形态和成分进行了表征并对其相关性能进行了研究。结果表明,以取代度为1.2的羧甲基-β-环糊精在水介质中对Fe₃O₄磁性纳米颗粒修饰效果较为理想,在此条件下制备的羧甲基-β-环糊精修饰Fe₃O₄磁性纳米颗粒为近球形,粒径在10¹5nm之间,修饰上的羧甲基-β-环糊精约占颗粒总重的8.2%,颗粒为超顺磁性,质量比饱和磁化强度为68.7emu/g,在水中的分散稳定性良好,优化条件下对药物姜黄素的载药量和包封率分别为21.7μg /mg和43.4%。在体外释药实验中,载药颗粒在4小时内具有较强的药物突释效应,随后呈现长达26小时以上的药物缓释状态。将羧甲基-β-环糊精修饰Fe₃O₄磁性纳米颗粒分散于β-环糊精的碱性水溶液中,以环氧氯丙烷为交联剂,通过在羧甲基-β-环糊精修饰Fe₃O₄磁性纳米颗粒表面进行的交联反应制备得到了交联β-环糊精聚合物/Fe₃O₄复合纳米颗粒。利用TEM、SEM、FTIR、XRD、DLS、TG等手段并对制备的颗粒进行了表征并对其相关性能进行了研究。结果表明,制备的交联β-环糊精聚合物/Fe₃O₄复合纳米颗粒为典型的核壳结构,近球形,粒径在20⁴0nm之间,颗粒中形成壳结构的交联β-环糊精聚合物约占颗粒总重的28.0%,颗粒为超顺磁性,质量比饱和磁化强度为52.0emu/g,在水中具有良好的分散稳定性。与羧甲基-β-环糊精修饰Fe₃O₄磁性纳米颗粒相比,交联β-环糊精聚合物/Fe₃O₄复合纳米颗粒对于药物姜黄素的载药量和包封率均明显提高,优化条件下的载药量和包封率分别达到了86.9μg/mg和72.4%,载药后的颗粒具有较好的药物释放性能。采用末端带有可反应性环氧基的硅烷偶联剂γ-缩水甘油丙氧基三甲氧基硅烷（GTMS）对Fe₃O₄磁性纳米颗粒进行表面修饰,然后通过一定条件下β-环糊精羟基与修饰到Fe₃O₄磁性纳米颗粒表面环氧基的化学反应将β-环糊精接枝到GTMS修饰Fe₃O₄磁性纳米颗粒的表面,制备得到了β-环糊精接枝GTMS修饰Fe₃O₄磁性纳米颗粒。利用TEM、FTIR、XRD、DLS、TG等手段对制备的颗粒进行了表征并对其相关性能进行了研究。结果表明,制备的超顺磁性β-环糊精接枝GTMS修饰Fe₃O₄磁性纳米颗粒为近球形,粒径在10¹5nm之间,接枝上的β-环糊精约占颗粒总重的2.2%,质量比饱和磁化强度为67.5 emu/g,在水中具有良好的分散稳定性,优化条件下对药物阿霉素的载药量和包封率分别为5.7μg/mg和47.5%。在体外释药实验中,载药后的颗粒在释药初期具有较强的突释效应,随后呈现长时间的药物缓释状态。合成了丁烯二酸单酯化β-环糊精（MAH-β-CD）,采用带有可聚合双键基团的硅烷偶联剂γ-缩水甘油丙氧基三甲氧基硅烷（MPS）对Fe₃O₄磁性纳米颗粒进行表面修饰,通过在MPS修饰Fe₃O₄磁性纳米颗粒表面进行的丁烯二酸单酯化β-环糊精与丙烯酸（AA）之间的自由基共聚反应,制备了P（MAH-β-CD-co-AA）/Fe₃O₄复合纳米颗粒。利用TEM、FTIR、XRD、DLS、TG等手段并对制备的颗粒进行了表征并对其相关性能进行了研究。结果表明,制备的P（MAH-β-CD-co-AA）/Fe₃O₄复合纳米颗粒为近球形,粒径约在10¹5nm之间。接枝上的P（MAH-β-CD-co-AA）共聚物约占颗粒总重的21.2%,在水中的分散稳定性良好,颗粒为超顺磁性,质量比饱和磁化强度为60.0emu/g。与β-环糊精接枝GTMS修饰Fe₃O₄磁性纳米颗粒相比,优化条件下P（MAH-β-CD-co-AA）/Fe₃O₄复合纳米颗粒对药物阿霉素的载药量和包封率有较明显的提高,分别达到了93.8μg/mg和78.2%。在体外释药实验中,载药后的颗粒在4小时内具有较强的突释效应,随后呈现长时间的药物缓释状态。合成了可聚合表面活性剂马来酸单十八酯,并用其对Fe₃O₄磁性纳米颗粒进行表面修饰。将马来酸单十八酯修饰Fe₃O₄磁性纳米颗粒采用直接转移法由水相分散到苯乙烯单体中,制备了苯乙烯基可聚合磁流体,分别研究了可聚合磁流体的形态、结构、稳定性、流变性和磁性能。通过可聚合磁流体的本体聚合制备了聚苯乙烯/Fe₃O₄磁性纳米复合材料,分别研究了复合材料的形态、结构、热稳定性和磁性能。结果表明,粒径为7nm左右的马来酸单十八酯修饰Fe₃O₄磁性纳米颗粒在磁流体和磁性纳米复合材料中分散均匀,没有产生明显的团聚现象。制备的苯乙烯基磁流体稳定性良好,磁流变效应明显,是符合弱Bingham模型的非牛顿流体,具有典型的超顺磁性。在聚苯乙烯/Fe₃O₄磁性纳米复合材料制备过程中,修饰于Fe₃O₄磁性纳米颗粒表面的马来酸单十八酯和苯乙烯之间发生了共聚反应。与相似条件下聚合得到的纯聚苯乙烯相比,聚苯乙烯/Fe₃O₄磁性纳米复合材料的热稳定性有所提高,是典型的超顺磁性材料。更多还原

【Abstract】 In recent years, many novel magnetic nanostructured functional materials have been developed from the perspective of multi-crossed disciplines. Among which, magnetic targeting drug carrier, magnetic fluid and magnetic nano-composite have become relatively outstanding sorts and research hot spots. Although the research of these materials has been deepened and the application area has been broadened constantly, there still exits some problems worth to be further explored. As to magnetic targeting drug carrier, the main problem still lies in the selection of propping materials and the preparation method of novel sorts with perfect performances and extensive applications. In the respect of magnetic fluid and magnetic nano-composite, how to implement the homogeneous dispersion of magnetic nanoparticles in carrier liquid and polymer matrix in the preparation of stable and exceptional nanostructured functional materials remains to be the primary and difficult point. In this research, some new kinds ofβ-cyclodextrin-functionalized Fe₃O₄ magnetic nanoparticles were designed and developed as magnetic targeting drug carriers and their relative properties were studied. Monooctadecyl maleate as polymerizable surfactant was utilized to modify Fe₃O₄ magnetic nanoparticles. Polymerizable magnetic fluid was obtained by directly dispersing modified Fe₃O₄ magnetic nanoparticles into styrene monomer and PS/Fe₃O₄ magnetic nano-composite was further prepared by the free radical polymerization of the magnetic fluid. The relative properties of both the magnetic fluid and the nano-composite were investigated. The research work offered new ideas and ways on how to exploit novel magnetic nanostructured functional materials and expanded the relative application areas. The main research and results of the contribution are summarized as follows:Carboxymethyl-β-cyclodextrin （CM-β-CD） with carboxyl substitution of 1.2 and 7.3 was synthesized, and utilized to prepare CM-β-CD-modified Fe₃O₄ magnetic nanoparticles in water and DMF medium, respectively. The morphology, structure and component of CM-β-CD-modified Fe₃O₄ magnetic nanoparticles were characterized by TEM, FTIR, XRD, DLS, TG and their relative properties were also studied. It is more ideal for the Fe₃O₄ magnetic nanoparticles to be modified by CM-β-CD with carboxyl substitution of 1.2 in water medium. In such condition, the prepared CM-β-CD-modified Fe₃O₄ nanoparticles are roughly spherical and their diameter rang from 10¹5 nm. The weight percentage of CM-β-CD in CM-β-CD-modified nanoparticles prepared is estimated to be about 8.2%. The prepared CM-β-CD-modified nanoparticle with saturation magnetization of 68.7emu/g exhibit both good superparamagnetic properties and stable dispersibility in water. In optimized condition, the curcumin loading content and entrapment ratio for the prepared nanoparticles was detected as 21.7μg/mg and 43.4% respectively. The drug loading nanoparticles exhibited rapid drug release in 4 hours and slow drug release in the followed 26 hours in vitro releasing experiment.Cross-linkedβ-cyclodextrin polymer/Fe₃O₄ composite nanoparticles were prepared via cross-linking reaction on the surface of CM-β-CD-modified Fe₃O₄ magnetic nanoparticles dispersed inβ-cyclodextrin alkaline solution by using epichlorohydrin （EP） as a crosslinking agent. The morphology, structure and component ofβ-cyclodextrin polymer/Fe₃O₄ composite nanoparticles were characterized by TEM, SEM, FTIR, XRD, DLS, TG and their relative properties were also studied. The result indicats that the prepared cross-linkedβ-cyclodextrin polymer/Fe₃O₄ composite nanoparticles with typical core-shell structures are roughly spherical, and their diameter rang from 20⁴0 nm. The weight percentage of cross-linkedβ-cyclodextrin polymer shell in the composite nanoparticles is about 28.0% and the prepared compsite nanoparticles with saturation magnetization of 52.0emu/g possess good superparamagnetic properties as well as stalbe dispersibility in water. Compared with CM-β-CD-modified Fe₃O₄ magnetic nanoparticles, the curcumin loading content and entrapment ratio for the prepared composite nanoparticles was promoted to 86.9μg/mg and 72.4% respectively in optimized condition. The drug loading composite nanoparticles exhibited better drug release properties in vitro releasing experiment.Fe₃O₄ magnetic nanoparticles were modified by 3-glycidoxypropyltrimethoxysilane （GTMS） which have reactive epoxy end groups andβ-cyclodextrin grafted GTMS-modified Fe₃O₄ magnetic nanoparticles were prepared by conjugatingβ-cyclodextrin onto GTMS-modified Fe₃O₄ magnetic nanoparticles via reaction between epoxy groups on the surface of GTMS-modified Fe₃O₄ magnetic nanoparticles and hydroxyl groups ofβ-cyclodextrin. The morphology, structure and component of the prepared Fe₃O₄ magnetic nanoparticles were characterized by TEM, FTIR, XRD, DLS, TG and their relative properties were also studied. The result shows that the prepared nanoparticles are roughly spherical and their diameter rang from 10¹5 nm. The weight percentage of graftedβ-cyclodextrin in the prepared nanoparticles is about 2.2%. The prepared nanoparticles with saturation magnetization of 67.5emu/g possess superparamagnetic properties as well as stable dispersibility in water. In optimized condition, the adriamycin （ADM） loading content and entrapment ratio for the prepared nanoparticles was detected as 5.7μg/mg and 47.5%, respectively. The drug loading nanoparticles exhibited rapid drug release in the initial stage and slow drug release in the followed long time in vitro releasing experiment.MAH-β-CD was synthesized and Fe₃O₄ magnetic nanoparticles were modified byγ-methacryloxypropyltrimethoxy （MPS） which have reactive double carbon bonds. P（MAH-β-CD-co-AA）/Fe₃O₄ composite nanoparticles were prepared via free radical copolymerization of MAH-β-CD and acrylic acid on the surface of MPS-modified Fe₃O₄ magnetic nanoparticles. The morphology, structure and component of P（MAH-β-CD-co-AA）/Fe₃O₄ composite nanoparticles were characterized by TEM, FTIR, XRD, DLS, TG and their relative properties were also studied. The result indiates that the prepared composite nanoparticles with diameter ranged from 10-15 nm are roughly spherical. The weight percentage of grafted P（MAH-β-CD-co-AA） copolymer in the prepared nanoparticles is about 28%. The prepared composite nanoparticles with saturation magnetization of 60.0emu/g exhibited superparamagnetism as well as stable dispersibility in water. Compared withβ-cyclodextrin grafted GTMS-modified Fe₃O₄ magnetic nanoparticles, the curcumin loading content and entrapment ratio for the prepared composite nanoparticles was promoted to 93.8μg/mg and 78.2% in optimized condition. The drug loading composite nanoparticles exhibited rapid drug release in the initial stage and slow drug release in the followed long time in vitro releasing experiment.Monooctadecyl maleate as polymerizable surfactant was synthesized utilized to surface-modify Fe₃O₄ magnetic nanoparticles. A stable polymerizable magnetic fluid was obtained by directly transferring modified Fe₃O₄ magnetic nanoparticles from aqueous phase to styrene monomer. Polystyrene/Fe₃O₄ nano-composite was prepared via bulk polymerization of polymerizable magnetic fluid. The morphology, structure, stability, rheological and magnetic properties of prepared magnetic fluid and the morphology, structure, thermal stability as well as magnetic properties of prepared polystyrene/Fe₃O₄ nano-composite were studied, respectively. Result shows that Fe₃O₄ magnetic nanoparticles modified by monooctadecyl maleate with the diameter of about 7 nm can be homogeneously dispersed in the styrene monomer and fixed in the nano-composite without apparent aggregation during the procedure of polymerization. The prepared polymerizable magnetic fluid with good stability and magnetic rheology property is a sort of typical superparamagnetic materials according with inferior Bingham fluid pattern. Copolymerization occurred between styrene monomer and monooctadecyl maleate modified on the surface of Fe₃O₄ magnetic nanoparticles during the preparation of polystyrene/Fe₃O₄ nano-composite. Compared with polystyrene prepared under almost the same polymerization conditions, the thermal stability of polystyrene/Fe₃O₄ nano-composite is obviously improved and the composite is also a sort of superparamagnetic materials.更多还原