单分散磁性纳米粒子/微球的制备、表征与生物医学应用
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摘要
磁场辅助分离技术是基于磁性微球在外磁场作用下的磁泳运动而对目标物进行分离富集的技术,具有高效、快速、非玷污、集分离富集于一体等诸多优点,在核酸提取、基因测序、细胞分离、免疫分析、固定化酶、手性分离等生命科学研究领域获得日益广泛的应用。生物磁分离技术的近期发展趋势是微型化、平行化和自动化,所面临的关键问题在于粒径大小均一、水中分散性好、磁响应性强、超顺磁性磁性微球的制备,以保证生物分离过程的高效性、重现性和可控性。磁性纳米粒子在疾病早期诊断及治疗中具有潜力,在生物医学领域中的发展也颇受关注。磁性纳米粒子和复合微球可通过多种方法制备得到,如化学沉淀法和单体聚合法等,但是这些方法都有一定的局限性,包括粒子粒径不均一、粒径分布宽、制备过程复杂、溶剂毒性大等缺点。因此,探索高质量磁性纳米粒子/微球的简便合成方法,开拓所合成的新材料在生物医药领域中的应用,具有十分重要的科学意义和实用价值。作者以单分散的硅胶微球为模板,通过原位生成法制备了磁性可控的磁性硅胶复合微球,通过对大豆及加工产品的DNA提取及PCR扩增,建立了磁性微球对转基因产品的检测;由于磁性硅胶复合微球的磁响应强度不能满足所有试验样品的实际需求,作者通过溶剂热合成法制备了高磁响应性的Fe_3O_4磁性微球,并将其应用到中药材DNA的提取及真伪鉴别中;将化学沉淀法得到的磁性纳米粒子经过表面处理,以聚苯乙烯为基质制备了核壳型亲和素包覆磁性复合微球,与上述得到的磁性硅胶复合微球及Fe_3O_4磁性微球相比,具有低密度、易悬浮的特点,将其应用于血液样品中细胞分离中获得良好效果;由于化学沉淀制备的磁性纳米粒子不能形成良好的单分散晶体,通过高温分解法,使用无毒的油酸铁复合物作为前驱体,制备了结晶良好的单分散Fe_3O_4磁性纳米粒子并将其成功转入到水相当中,为其在磁共振/磁粒子成像中作为造影剂使用奠定了基础。
本文的研究工作主要分为以下四个部分:
(1)首先采用原位生成法合成了单分散硅胶Fe_3O_4磁性复合微球,通过溶胶-凝胶法用硅烷偶联试剂对磁性微球进行表面官能团修饰。对成球机理和影响因素进行了系统的研究。利用FT-IR、XRD、VSM、TEM、HR-TEM等手段对微球的结构,形貌和磁性进行表征,结果表明,所得微球具有粒径均一、磁性可控、分散性好等优点,为快速分离奠定了基础,且制备简便,有利于实现大规模的生产。用所得到的磁性硅胶复合微球对大豆及加工制品进行了DNA提取及PCR扩增,建立了基于磁分离的转基因产品的检测方法。
(2)以乙二醇为溶剂、多种含氮物质为配体,运用溶剂热合成法制备了高磁响应性Fe_3O_4磁性微球,探讨了体系中含氮物质对成球的影响。所制备的Fe_3O_4磁性微球具有高磁响应性,即便在比较粘稠的溶液体系中也能对外磁场作出快速响应,尤其适合于植物细胞中核酸样品的分离富集。将其用于提取中药材DNA,探讨了对市售中药材进行真伪鉴别和种属鉴别的可能性。
(3)以化学沉淀法制备的磁性纳米粒子为基础,通过层层自组装法制备了核壳型聚苯乙烯磁性微球,该磁性微球具有密度小、容易在溶液中悬浮的特点。探讨了磁性复合微球制备过程中表面包覆的方法对之后生物应用的影响,并将其修饰亲和素蛋白,成为细胞特异性捕获的新型分离载体,研究了该磁性复合微球在细胞分离中的作用,取得了良好的效果。
(4)为了得到单分散超顺磁性的纳米磁性晶体以用于医用检测与治疗,作者用高温分解法分解无毒的油酸钠复合物,制备了单分散Fe_3O_4磁性纳米粒子,探讨了油酸和油酸铁复合物的比例对生成磁性纳米粒子粒径的影响,并将油溶性的磁性纳米粒子通过配体交换分散在水溶液中,得到的水溶性磁性纳米粒子的稳定性良好,有望在磁共振/磁粒子成像中作为造影剂使用。
Magnetically assisted separation is a novel separation technique based on the magnetophoretic movement of magnetic particles under the influence of external magnetic field. Being highly efficient, rapid, non-staining, and versatile with separation and enrichment, the technique has been widely used in immunoassay, nucleic acid extraction, gene sequencing, cell separation, enzyme immobilization and chiral separation. Recent efforts in development of bio-magnetic separation technology are focused on miniaturization, parallelism and automation. One of the key problems to overcome is facile preparation of magnetic microspheres with uniform particle size, excellent dispensability, high responsiveness and superparamagnetic behavior. These properties are important to ensure the efficiency,reproducibility and controllability of the magnetic separation process. Magnetic nanoparticles have generated much interest because they show some potential in diagnosis and treatment of a variety of human diseases. Although nano/micro magnetic particles can be prepared by a variety of methods such as chemical co-precipitation and monomer polymerization, these methods all show some shortcomings, for example, the product with highly uneven particle size distribution, complex and tedious process, expensive raw materials and toxic solvents used. It is therefore of both academic and practical interests to develop methods for the preparation of high-quality monodisperse magnetic nano/microspheres and explore their applications in biomedical fields. In this thesis, the work aimed at development of methods for preparation of magnetic nano/micro particles with improved properties is described, which starts with the in-situ synthesis of magnetic silica composite microspheres using porous silica microspheres as templates. The magnetic microspheres obtained were used to extract DNA templates from soybeans and foodstuffs followed by PCR amplification for detection of genomic modified organisms in soy products. Because of their relatively weak response to magnetic field, they are less ideal for application in extraction of DNA from viscous solutions. Efforts were made to prepare magnetic Fe_3O_4 microspheres with strong magnetization and to explore their application in extraction of DNA from traditional Chinese medicinal herbs for identification and authentication. Application of magnetic particles to cell sorting requires the particles of good dispensability. Therefore core-shell polystyrene composite magnetic microspheres with low density and good suspension were prepared and conjugated with avidin for capturing specific cells from a cell mixture. Finally, to overcome the shortcoming with chemical precipitation for preparation of magnetic nanoparticles, a new thermolysis procedure was introduced in which a non-toxic ferric oleate complex was used as precurcor and the highly monodiperse magnetic nanoparticles produced were then converted to hydrophilic nanoparticles which are essential for using as contract agents for MRI/MPI.
The details of this thesis are outlined as follows:
1. A facile method for the preparation of such magnetic composite particles was developed, which entails impregnation of porous silica microspheres with iron salts, followed by calcination and reduction treatments. The samples were characterized using powder X-ray diffractometry (XRD), scanning electron microscopy (SEM), nitrogen adsorption/desorption isotherms, and vibrating sample magnetometry (VSM). The magnetic silica composite microspheres coated with silica shells were tested as adsorbents for rapid extraction of genomic DNA from soybean-derived products. The purified DNA templates were amplified by PCR for screening of genetically modified organisms (GMOs). The preliminary results confirm that the DNA extraction protocols using magnetite-loaded silica microspheres are capable of producing DNA templates which are inhibitor-free and ready for downstream analysis.
2. Using ethylene glycol as solvent, a variety of nitrogen-containing substances as ligands, Fe_3O_4 magnetic microspheres of high magnetic responsiveness were prepared by solvothermal method. The as-prepared Fe_3O_4 magnetic microspheres show quick response for applied magnetic field even in a relatively viscous solution, which made them ideal separation tool for plant cell nucleic acid sample separation and enrichment. The Fe_3O_4 magnetic microspheres of high magnetic responsiveness were applied in DNA extraction of Chinese medical herbs and the possibility of identification and species identification.was discussed.
3. Magnetic nanoparticles prepared by chemical precipitation method were modified and coated on the surface of polystyrene microspheres to form core-shell polystyrene magnetic composite microspheres by layer-by-layer method. The as-prepared magnetic composite microspheres are characterized of lower density and better suspension in aqueous solution compared with as-prepared magnetic silica composite microspheres and Fe_3O_4 magnetic microspheres. The effects of methods of surface modification on subsequent biological applications were discussed. The magnetic composite microspheres were modified with avidin protein to form new separation carriers for specific cells. The ability of specific capture of cells was studied and shown to produce good results.
4. In order to obtain monodisperse superparamagnetic nano-magnetic crystals to be used for medical testing and treatment, monodisperse Fe_3O_4 nanoparticles by pyrolysis, using non-toxic Fe oleate complex as precursor. The ratio of oleic acid to Fe oleate complex were studied on the effects in particle size. The oil-soluble magnetic nanoparticles were dispersed in aqueous solution by ligand exchange. The resulting water-soluble magnetic nanoparticles showed good stability in aqueous solution and were considered to be ideal candidate as contrast agent to be used in magnetic resonance and magnetic particle imaging.
本文的研究工作主要分为以下四个部分:
(1)首先采用原位生成法合成了单分散硅胶Fe_3O_4磁性复合微球,通过溶胶-凝胶法用硅烷偶联试剂对磁性微球进行表面官能团修饰。对成球机理和影响因素进行了系统的研究。利用FT-IR、XRD、VSM、TEM、HR-TEM等手段对微球的结构,形貌和磁性进行表征,结果表明,所得微球具有粒径均一、磁性可控、分散性好等优点,为快速分离奠定了基础,且制备简便,有利于实现大规模的生产。用所得到的磁性硅胶复合微球对大豆及加工制品进行了DNA提取及PCR扩增,建立了基于磁分离的转基因产品的检测方法。
(2)以乙二醇为溶剂、多种含氮物质为配体,运用溶剂热合成法制备了高磁响应性Fe_3O_4磁性微球,探讨了体系中含氮物质对成球的影响。所制备的Fe_3O_4磁性微球具有高磁响应性,即便在比较粘稠的溶液体系中也能对外磁场作出快速响应,尤其适合于植物细胞中核酸样品的分离富集。将其用于提取中药材DNA,探讨了对市售中药材进行真伪鉴别和种属鉴别的可能性。
(3)以化学沉淀法制备的磁性纳米粒子为基础,通过层层自组装法制备了核壳型聚苯乙烯磁性微球,该磁性微球具有密度小、容易在溶液中悬浮的特点。探讨了磁性复合微球制备过程中表面包覆的方法对之后生物应用的影响,并将其修饰亲和素蛋白,成为细胞特异性捕获的新型分离载体,研究了该磁性复合微球在细胞分离中的作用,取得了良好的效果。
(4)为了得到单分散超顺磁性的纳米磁性晶体以用于医用检测与治疗,作者用高温分解法分解无毒的油酸钠复合物,制备了单分散Fe_3O_4磁性纳米粒子,探讨了油酸和油酸铁复合物的比例对生成磁性纳米粒子粒径的影响,并将油溶性的磁性纳米粒子通过配体交换分散在水溶液中,得到的水溶性磁性纳米粒子的稳定性良好,有望在磁共振/磁粒子成像中作为造影剂使用。
Magnetically assisted separation is a novel separation technique based on the magnetophoretic movement of magnetic particles under the influence of external magnetic field. Being highly efficient, rapid, non-staining, and versatile with separation and enrichment, the technique has been widely used in immunoassay, nucleic acid extraction, gene sequencing, cell separation, enzyme immobilization and chiral separation. Recent efforts in development of bio-magnetic separation technology are focused on miniaturization, parallelism and automation. One of the key problems to overcome is facile preparation of magnetic microspheres with uniform particle size, excellent dispensability, high responsiveness and superparamagnetic behavior. These properties are important to ensure the efficiency,reproducibility and controllability of the magnetic separation process. Magnetic nanoparticles have generated much interest because they show some potential in diagnosis and treatment of a variety of human diseases. Although nano/micro magnetic particles can be prepared by a variety of methods such as chemical co-precipitation and monomer polymerization, these methods all show some shortcomings, for example, the product with highly uneven particle size distribution, complex and tedious process, expensive raw materials and toxic solvents used. It is therefore of both academic and practical interests to develop methods for the preparation of high-quality monodisperse magnetic nano/microspheres and explore their applications in biomedical fields. In this thesis, the work aimed at development of methods for preparation of magnetic nano/micro particles with improved properties is described, which starts with the in-situ synthesis of magnetic silica composite microspheres using porous silica microspheres as templates. The magnetic microspheres obtained were used to extract DNA templates from soybeans and foodstuffs followed by PCR amplification for detection of genomic modified organisms in soy products. Because of their relatively weak response to magnetic field, they are less ideal for application in extraction of DNA from viscous solutions. Efforts were made to prepare magnetic Fe_3O_4 microspheres with strong magnetization and to explore their application in extraction of DNA from traditional Chinese medicinal herbs for identification and authentication. Application of magnetic particles to cell sorting requires the particles of good dispensability. Therefore core-shell polystyrene composite magnetic microspheres with low density and good suspension were prepared and conjugated with avidin for capturing specific cells from a cell mixture. Finally, to overcome the shortcoming with chemical precipitation for preparation of magnetic nanoparticles, a new thermolysis procedure was introduced in which a non-toxic ferric oleate complex was used as precurcor and the highly monodiperse magnetic nanoparticles produced were then converted to hydrophilic nanoparticles which are essential for using as contract agents for MRI/MPI.
The details of this thesis are outlined as follows:
1. A facile method for the preparation of such magnetic composite particles was developed, which entails impregnation of porous silica microspheres with iron salts, followed by calcination and reduction treatments. The samples were characterized using powder X-ray diffractometry (XRD), scanning electron microscopy (SEM), nitrogen adsorption/desorption isotherms, and vibrating sample magnetometry (VSM). The magnetic silica composite microspheres coated with silica shells were tested as adsorbents for rapid extraction of genomic DNA from soybean-derived products. The purified DNA templates were amplified by PCR for screening of genetically modified organisms (GMOs). The preliminary results confirm that the DNA extraction protocols using magnetite-loaded silica microspheres are capable of producing DNA templates which are inhibitor-free and ready for downstream analysis.
2. Using ethylene glycol as solvent, a variety of nitrogen-containing substances as ligands, Fe_3O_4 magnetic microspheres of high magnetic responsiveness were prepared by solvothermal method. The as-prepared Fe_3O_4 magnetic microspheres show quick response for applied magnetic field even in a relatively viscous solution, which made them ideal separation tool for plant cell nucleic acid sample separation and enrichment. The Fe_3O_4 magnetic microspheres of high magnetic responsiveness were applied in DNA extraction of Chinese medical herbs and the possibility of identification and species identification.was discussed.
3. Magnetic nanoparticles prepared by chemical precipitation method were modified and coated on the surface of polystyrene microspheres to form core-shell polystyrene magnetic composite microspheres by layer-by-layer method. The as-prepared magnetic composite microspheres are characterized of lower density and better suspension in aqueous solution compared with as-prepared magnetic silica composite microspheres and Fe_3O_4 magnetic microspheres. The effects of methods of surface modification on subsequent biological applications were discussed. The magnetic composite microspheres were modified with avidin protein to form new separation carriers for specific cells. The ability of specific capture of cells was studied and shown to produce good results.
4. In order to obtain monodisperse superparamagnetic nano-magnetic crystals to be used for medical testing and treatment, monodisperse Fe_3O_4 nanoparticles by pyrolysis, using non-toxic Fe oleate complex as precursor. The ratio of oleic acid to Fe oleate complex were studied on the effects in particle size. The oil-soluble magnetic nanoparticles were dispersed in aqueous solution by ligand exchange. The resulting water-soluble magnetic nanoparticles showed good stability in aqueous solution and were considered to be ideal candidate as contrast agent to be used in magnetic resonance and magnetic particle imaging.
引文
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