表面引发聚合Fe_3O_4/P（MAA-co-NVP）磁性复合微球的制备、表征与药物释放研究
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摘要
随着生物工程和生物医学相关领域研究的发展,磁性高分子微球作为一种新型功能材料,越来越受到人们的关注。探索磁性高分子微球的智能化、功能化以及将这些微球应用于靶向给药、细胞分离、细胞标记、临床诊断、生物传感和固定化酶等领域是磁性高分子微球研究的热点。磁性高分子微球制备方法很多,比如溶胀法、包埋法、单体聚合法,而单体聚合法又包括悬浮聚合法、乳液聚合法、分散聚合法等,但这些聚合方法都有不尽如人意的地方,一个重要的原因就是无机磁性粒子与有机高分子的结合多是通过氢键以及物理或化学吸附的方式实现的,这种吸附方式容易发生脱附,使两者结合得并不牢固,所以人们在探索新的方法来解决这个问题。本文围绕功能性磁性高分子微球的制备、表征及应用做了两方面的研究工作。第一,采用表面引发自由基分散聚合方法设计并制备了核-壳结构的Fe304/P(MAA-co-NVP)交联磁性复合微球；第二,研究了Fe304/P(MAA-co-NVP)交联磁性复合微球的pH响应性、环境稳定性及咖啡因的药物缓释行为。
1采用化学共沉淀法制备了Fe3O4纳米粒子,然后将Fe3O4表面包一层硅烷偶联剂APTES,使Fe3O4表面氨基化,接着通过Fe3O4表面氨基与4,4’-二环己基甲烷二异氰酸酯(H12MDI)的异氰酸酯键NCO之间发生分子间氢转移反应将H12MDI连接到Fe3O4表面,使Fe3O4表面带有异氰酸酯键NCO,之后利用Fe3O4表面异氰酸酯键NCO与双官能偶氮引发剂2,2'-偶氮[2-甲基-N-(2-羟乙基)丙酰胺(AMNHP)的羟基之间发生分子间氢转移反应将偶氮引发剂AMNHP接到Fe304表面,这样我们就制备了表面带引发剂的Fe3O4。然后采用表面引发自由基聚合法,以甲基丙烯酸和N-乙烯吡咯烷酮为聚合单体制备了核-壳结构的Fe3O4/P(MAA-co-NVP)交联磁性复合微球。通过DSC定量分析接到Fe304表面偶氮引发剂AMNHP的含量。红外光谱(FT-IR)、透射电子显微镜(TEM)、扫描电子显微镜(SEM)、X-射线衍射(XRD)表明P(MAA-co-NVP)成功地包在了Fe3O4纳米粒子表面。通过透射电子显微镜(TEM)、扫描电子显微镜(SEM)我们能够看到Fe3O4是球形,平均粒径12nm左右,团聚现象比较严重。Fe304/P(MAA-co-NVP)交联磁性微球呈现明显的核-壳结构特征,分散性较好。热分析(TGA)表明Fe3O4/P(MAA-co-NVP)交联磁性微球有很好的热稳定性,作为核的Fe3O4与作为壳的P(MAA-co-NVP)之间存在着较强的相互作用,它们之间存在化学键。振动样品磁强计(VSM)分析证明,制备的Fe3O4/P(MAA-co-NVP)交联磁性微球具有超顺磁性。
2用激光粒度分析仪测定Fe3O4/P(MAA-co-NVP)交联磁性微球在不同pH溶液里粒径的变化,分析Fe3O4/P(MAA-co-NVP)交联磁性微球的pH响应性,结果表明,磁性微球有良好的磁响应性。以咖啡因为模拟药物进行的药物释放行为的研究表明,咖啡因在pH=7.4的缓冲溶液中的释放速率较快,约在8小时达到平衡；而在pH=1.4的缓冲溶液中的释放速率较慢,达到平衡需要更长的时间。Fe3O4/P(MAA-co-NVP)交联磁性微球的这种卓越的性能表明其可以应用于对胃有刺激且需要在肠道中吸收的药物,微球在体液中可以保持相结构和磁靶向稳定性。释放动力学表明,药物释放受共聚物的伸展平衡及Fickian扩散定律控制。以上研究表明,Fe3O4/P(MAA-co-NVP)交联磁性微球是一种合适的药物控制释放的载体。
With development of the bio-engineering and biomedical research as well as some related fields, magnetic polymer microspheres as a new functional materials, have attracted more attention. The exploration for intelligentization, functionalization and applications of these microspheresin drug delivery, cell separation, cell markers, clinical diagnosis, biological sensing and the immobilized enzyme has been the hot research subject of magnetic polymer microspheres. Many studies have described methods to prepare the microspheres containing inorganic magnetic nanoparticles such as swelling method, embedding method, monomer polymerization. The monomer polymerization approaches also include suspension polymerization, emulsion polymerization, dispersion polymerization, etc. However, these polymerization methods do not come up to expectations to some extent, One important reason of which is that inorganic magnetic particles combine with organic polymer by the hydrogen bonds and/or other physical or chemical absorption mostly. which is apt to desorption, leading to unstable combination. People are exploring new ways to solve this problem. This study contains two areas focusing on preparation, construction and characterization, application of functional magnetic polymer microspheres. First, we design and construct a magnetic composite microsphere consisting of Fe3O4 nanoparticles chemical-covalently encapsulated with poly(methacrylic acid-co-N-vinyl pyrrolidone) (P(MAA-co-NVP)) cross-linked copolymers by a surface-initiated radical dispersion polymerization route. Second, we study pH responsiveness, environmental stability, magnetic rheological and caffeine drug release behavior of the Fe3O4/P(MAA-co-NVP) cross-linked magnetic composite microspheres.
1. We prepared Fe3O4 nanoparticles by chemical coprecipitation and then amino groups were coated on the surface of magnetite nanoparticles via surface modification of 3-amino propyltriethyloxy silane (APTES). Next,1,1-methylene bis-(4-isocyanato-cyclohexane) (H12MDI)) was attached onto the surface of the APTES-modified Fe3O4 nanoparticles through an amide bond linkage formed by a hydrogen transfer chemical reaction between amino groups of the APTES-modified Fe3O4 and isocyanate groups of the H12MDI, introducing isocyanate groups (-NCO). Subsequently,2,2'-azobis[2-methyl-N-(2-hydroxyethyl) propionamide] (AMNHP) was tailored onto the surface of the H12MDI-functionalized Fe3O4 nanoparticles through an ester bond juncture, and Fe3O4 azo initiator was obtained by the treatment of surface isocyanate groups of functionalized magnetic nanoparticles with hydroxyl groups of the AMNHP. Fe3O4/P (MAA-co-NVP) cross-linked magnetic composite microspheres with core-shell structure were prepared by a surface-initiated radical dispersion polymerization route of of methyl methacrylate and N-vinyl pyrrolidone monomer. The content of azo initiator AMNHP introducing to the surface of Fe3O4 was analysised by DSC. observations by FT-IR, SEM, TEM and XRD indicated that the P(MAA-co-NVP)copolymer has successfully covered the Fe3O4 nanoparticles. It can be observed by TEM and SEM that the Fe3O4 particles prepared are of spherical shape and an average particle diameter is about 12 nm under the experimental condition. The distribution of unimproved Fe3O4 nanoparticles assumes an aggregation state. Fe3O4/P(MAA-co-NVP) miceospheres bear an obvious core-shell structure characteristic with good distribution. Thermal analysis (TGA) showed that Fe3O4/P (MAA-co-NVP) crosslinked microspheres have good thennal stability, and there are strong interactions between Fe3O4 as core and P (MAA-co-NVP) as shell, implying chemical bonds between them. The VSM analysis testifies that Fe3O4/P(MAA-co-NVP) magnetic microspheres are superparamagnetic.
2. We analysis pH response of Fe3O4/P(MAA-co-NVP) crosslinked microspheres by the change in particle size of Fe3O4/P(MAA-co-NVP) crosslinked microspheres at different pH solution with a laser particle size analyzer. The results show that the magnetic microspheres bear good magnetic response. The invitro controlled release examination based on caffiene as the model drug exhibited that the release rate in pH 7.4 buffer solution was faster than in pH 1.4 buffer solution, corresponding to their pH swelling. This superior performance of Fe3O4/P(MAA-co-NVP) crosslinked microspheres can be applied to the drugs which stimulate the stomach and is absorpted in the intestinal.The kinetic modeling demonstrated that the drug release is controlled by a balance between copolymer chain relaxation and Fickian diffusion process, and the proposed carrier is suitable for a magnetic targeting drug delivery system.
1采用化学共沉淀法制备了Fe3O4纳米粒子,然后将Fe3O4表面包一层硅烷偶联剂APTES,使Fe3O4表面氨基化,接着通过Fe3O4表面氨基与4,4’-二环己基甲烷二异氰酸酯(H12MDI)的异氰酸酯键NCO之间发生分子间氢转移反应将H12MDI连接到Fe3O4表面,使Fe3O4表面带有异氰酸酯键NCO,之后利用Fe3O4表面异氰酸酯键NCO与双官能偶氮引发剂2,2'-偶氮[2-甲基-N-(2-羟乙基)丙酰胺(AMNHP)的羟基之间发生分子间氢转移反应将偶氮引发剂AMNHP接到Fe304表面,这样我们就制备了表面带引发剂的Fe3O4。然后采用表面引发自由基聚合法,以甲基丙烯酸和N-乙烯吡咯烷酮为聚合单体制备了核-壳结构的Fe3O4/P(MAA-co-NVP)交联磁性复合微球。通过DSC定量分析接到Fe304表面偶氮引发剂AMNHP的含量。红外光谱(FT-IR)、透射电子显微镜(TEM)、扫描电子显微镜(SEM)、X-射线衍射(XRD)表明P(MAA-co-NVP)成功地包在了Fe3O4纳米粒子表面。通过透射电子显微镜(TEM)、扫描电子显微镜(SEM)我们能够看到Fe3O4是球形,平均粒径12nm左右,团聚现象比较严重。Fe304/P(MAA-co-NVP)交联磁性微球呈现明显的核-壳结构特征,分散性较好。热分析(TGA)表明Fe3O4/P(MAA-co-NVP)交联磁性微球有很好的热稳定性,作为核的Fe3O4与作为壳的P(MAA-co-NVP)之间存在着较强的相互作用,它们之间存在化学键。振动样品磁强计(VSM)分析证明,制备的Fe3O4/P(MAA-co-NVP)交联磁性微球具有超顺磁性。
2用激光粒度分析仪测定Fe3O4/P(MAA-co-NVP)交联磁性微球在不同pH溶液里粒径的变化,分析Fe3O4/P(MAA-co-NVP)交联磁性微球的pH响应性,结果表明,磁性微球有良好的磁响应性。以咖啡因为模拟药物进行的药物释放行为的研究表明,咖啡因在pH=7.4的缓冲溶液中的释放速率较快,约在8小时达到平衡；而在pH=1.4的缓冲溶液中的释放速率较慢,达到平衡需要更长的时间。Fe3O4/P(MAA-co-NVP)交联磁性微球的这种卓越的性能表明其可以应用于对胃有刺激且需要在肠道中吸收的药物,微球在体液中可以保持相结构和磁靶向稳定性。释放动力学表明,药物释放受共聚物的伸展平衡及Fickian扩散定律控制。以上研究表明,Fe3O4/P(MAA-co-NVP)交联磁性微球是一种合适的药物控制释放的载体。
With development of the bio-engineering and biomedical research as well as some related fields, magnetic polymer microspheres as a new functional materials, have attracted more attention. The exploration for intelligentization, functionalization and applications of these microspheresin drug delivery, cell separation, cell markers, clinical diagnosis, biological sensing and the immobilized enzyme has been the hot research subject of magnetic polymer microspheres. Many studies have described methods to prepare the microspheres containing inorganic magnetic nanoparticles such as swelling method, embedding method, monomer polymerization. The monomer polymerization approaches also include suspension polymerization, emulsion polymerization, dispersion polymerization, etc. However, these polymerization methods do not come up to expectations to some extent, One important reason of which is that inorganic magnetic particles combine with organic polymer by the hydrogen bonds and/or other physical or chemical absorption mostly. which is apt to desorption, leading to unstable combination. People are exploring new ways to solve this problem. This study contains two areas focusing on preparation, construction and characterization, application of functional magnetic polymer microspheres. First, we design and construct a magnetic composite microsphere consisting of Fe3O4 nanoparticles chemical-covalently encapsulated with poly(methacrylic acid-co-N-vinyl pyrrolidone) (P(MAA-co-NVP)) cross-linked copolymers by a surface-initiated radical dispersion polymerization route. Second, we study pH responsiveness, environmental stability, magnetic rheological and caffeine drug release behavior of the Fe3O4/P(MAA-co-NVP) cross-linked magnetic composite microspheres.
1. We prepared Fe3O4 nanoparticles by chemical coprecipitation and then amino groups were coated on the surface of magnetite nanoparticles via surface modification of 3-amino propyltriethyloxy silane (APTES). Next,1,1-methylene bis-(4-isocyanato-cyclohexane) (H12MDI)) was attached onto the surface of the APTES-modified Fe3O4 nanoparticles through an amide bond linkage formed by a hydrogen transfer chemical reaction between amino groups of the APTES-modified Fe3O4 and isocyanate groups of the H12MDI, introducing isocyanate groups (-NCO). Subsequently,2,2'-azobis[2-methyl-N-(2-hydroxyethyl) propionamide] (AMNHP) was tailored onto the surface of the H12MDI-functionalized Fe3O4 nanoparticles through an ester bond juncture, and Fe3O4 azo initiator was obtained by the treatment of surface isocyanate groups of functionalized magnetic nanoparticles with hydroxyl groups of the AMNHP. Fe3O4/P (MAA-co-NVP) cross-linked magnetic composite microspheres with core-shell structure were prepared by a surface-initiated radical dispersion polymerization route of of methyl methacrylate and N-vinyl pyrrolidone monomer. The content of azo initiator AMNHP introducing to the surface of Fe3O4 was analysised by DSC. observations by FT-IR, SEM, TEM and XRD indicated that the P(MAA-co-NVP)copolymer has successfully covered the Fe3O4 nanoparticles. It can be observed by TEM and SEM that the Fe3O4 particles prepared are of spherical shape and an average particle diameter is about 12 nm under the experimental condition. The distribution of unimproved Fe3O4 nanoparticles assumes an aggregation state. Fe3O4/P(MAA-co-NVP) miceospheres bear an obvious core-shell structure characteristic with good distribution. Thermal analysis (TGA) showed that Fe3O4/P (MAA-co-NVP) crosslinked microspheres have good thennal stability, and there are strong interactions between Fe3O4 as core and P (MAA-co-NVP) as shell, implying chemical bonds between them. The VSM analysis testifies that Fe3O4/P(MAA-co-NVP) magnetic microspheres are superparamagnetic.
2. We analysis pH response of Fe3O4/P(MAA-co-NVP) crosslinked microspheres by the change in particle size of Fe3O4/P(MAA-co-NVP) crosslinked microspheres at different pH solution with a laser particle size analyzer. The results show that the magnetic microspheres bear good magnetic response. The invitro controlled release examination based on caffiene as the model drug exhibited that the release rate in pH 7.4 buffer solution was faster than in pH 1.4 buffer solution, corresponding to their pH swelling. This superior performance of Fe3O4/P(MAA-co-NVP) crosslinked microspheres can be applied to the drugs which stimulate the stomach and is absorpted in the intestinal.The kinetic modeling demonstrated that the drug release is controlled by a balance between copolymer chain relaxation and Fickian diffusion process, and the proposed carrier is suitable for a magnetic targeting drug delivery system.
引文
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