基于金和四氧化三铁的多功能纳米探针的制备及其生物医学成像应用研究

发布时间：2018-10-25 06:51

【摘要】：随着纳米材料科学领域近年来的不断发展,功能性的纳米材料的控制制备及其生物医学应用越来越受到人们关注。特别是金和四氧化三铁纳米颗粒,因其独特的光学和磁学性质以及良好的生物相容性和安全性,在生物医学领域包括药物传递、免疫分析检测、生物分离、医学成像诊断、多模式诊疗一体化领域等多方面有着极广泛的应用前景。本论文以金和四氧化三铁纳米材料为基础,在形貌可控合成、光学磁学性质调制、表面修饰优化以及生物医学成像应用等方面进行了一系列研究,还设计制备了金、四氧化三铁以及金-四氧化三铁复合的纳米探针,对其各项性能进行了表征,并考察了这些纳米探针的表面增强拉曼光谱(SERS)、磁共振(MRI)和计算机断层扫描(CT)成像方面的应用特性。本论文主要的研究内容包括以下几个方面：(1)利用一种绿色温和及简易的合成策略,制备出多分支的金纳米颗粒,并通过二次生长的策略控制制备分支形貌可调的金纳米颗粒,实现分支金纳米颗粒的局域表面等离子共振在近红外区稳定可调。同时考察了多分支金纳米颗粒的成核生长和二次生长过程中各实验因素对其尺寸、分支形貌和局域表面等离子共振性质的影响。并通过有限时域差分法模拟,研究了多分支金纳米颗粒的分支形貌参数对局域表面等离子共振峰的影响。研究发现,多分支金纳米颗粒的分支越长、分支角度越小,其局域表面等离子共振峰越红移。我们通过对实验参数控制以及利用二次生长的方法来对多分支金纳米颗粒的局域表面等离子共振实现了在近红外区的广泛可调,从而获得一系列的多分支金纳米颗粒,为进一步的研究打下了一定的基础。(2)在已制备的一系列多分支金纳米颗粒的基础上,设计制备了近红外表面增强拉曼光谱纳米探针。并通过研究不同多分支金纳米颗粒及不同量的拉曼活性分子对探针性质的影响,优化了纳米探针的构建。为了深入理解多分支金纳米颗粒在表面增强拉曼光谱信号增强方面的优异表现,利用有限时域差分法模拟分析了不同形貌及多分支金纳米颗粒上不同分支的局域电磁场增强性质。同时,将得到的高性能近红外表面增强拉曼光谱纳米探针用于活细胞(SK-BR-3乳腺癌细胞)的SERS成像。实验表明,近红外SERS纳米探针可以成功地被细胞内在化,并可清晰的看到其在细胞核周围存在。因此,本研究得到的近红外SERS探针不仅具有良好的表面增强拉曼性质,而且还能作为近红外区表面增强拉曼探针,使其在更广泛的生物医学应用领域拥有有巨大的研究潜力。(3)针对于目前热分解方法得到的四氧化三铁纳米颗粒不具有水相分散性,难以实现生物医学应用的问题,本研究采用一种温和高效的反胶束氧化法对油酸包裹的四氧化三铁纳米颗粒进行大规模的水相转移。该方法的机制主要涉及到在反胶束体系中进行四氧化三铁纳米颗粒表面油酸分子的氧化断裂反应。实验结果表明,该方法可以明显缩短反应时间,提高相转移纳米颗粒的产率,可使得到的纳米颗粒具有很好的水相分散性、溶胶稳定性、低的细胞毒性以及良好的磁学性质。同时,进一步的体外和体内的磁共振成像结果证实了该相转移得到的四氧化三铁纳米颗粒可作为良好的T_2造影剂应用于生物成像领域。此外,该方法不仅可以直接得到具有表面羧基官能团的四氧化三铁纳米颗粒,可进行进一步的功能化应用,而且还可推广至其他类型的油酸包覆的纳米颗粒的相转移应用中,具有十分良好的应用前景。(4)在通过相转移过程得到的水相分散的四氧化三铁纳米颗粒的基础上,设计制备了基于金纳米核心、四氧化三铁纳米颗粒外层包覆的新型MRI/CT多功能成像探针。具体途径为,首先制备金纳米颗粒,再将其表面氨基化,然后利用纳米颗粒表面化学分子的缩合反应,将相转移得到的四氧化三铁纳米颗粒结合在金纳米颗粒的表面,得到金-四氧化三铁纳米复合材料。结果显示,该复合材料不仅具有良好的溶胶稳定性、生物相容性,还可同时具备金及四氧化三铁本征的光学、磁学性质。同时,通过进一步将其应用于体内的MRI/CT的双功能成像,证实了该金-四氧化三铁复合纳米探针具有可以同时实现体内T_2-MRI与CT成像的能力。此外,基于金与四氧化三铁共同的优势,该复合纳米材料不仅可以应用于MRI/CT成像领域,还可进一步推广至药物传递、生物标记以及其他成像治疗等领域,以期实现更多的功能化应用。
[Abstract]:With the development of nano-material science field in recent years, the control and preparation of functional nano-materials and their biomedical applications have been paid more and more attention. in particular gold and ferroferric oxide nanoparticles due to its unique optical and magnetic properties and good biocompatibility and safety, including drug delivery, immunoassay detection, biological separation, medical imaging diagnosis, The multi-mode diagnosis and treatment integration field has a wide application prospect. In this paper, based on gold and ferroferric oxide nanomaterials, a series of studies have been carried out in the aspects of morphology controllable synthesis, optical magnetic properties modulation, surface modification optimization and biomedical imaging applications, and gold is also designed. Nano-probes of ferroferric oxide and gold-ferroferric oxide were characterized by characterization of their properties, and the application characteristics of Raman spectroscopy (SERS), magnetic resonance (MRI) and computed tomography (CT) imaging were investigated. The main research contents of this thesis include the following aspects: (1) using a green mild and simple synthesis strategy to prepare multi-branched gold nanoparticles, and controlling the preparation of the gold nanoparticles with adjustable branch morphology through the strategy of secondary growth, and the local surface plasmon resonance of the branched gold nanoparticles can be stably adjusted in the near infrared region. At the same time, the effects of various experimental factors on the size, branch morphology and local surface plasmon resonance properties of multi-branch gold nanoparticles were investigated. The influence of branching morphology parameters on local surface plasmon resonance peaks was studied by finite time-domain difference method. It is found that the longer the branch of the multi-branch gold nanoparticles, the smaller the branch angle, the more red the local surface plasmon resonance peak shifts. The local surface plasmon resonance of the multi-branch gold nanoparticles is widely adjustable in the near infrared region by controlling the experimental parameters and using the method of secondary growth, thus obtaining a series of multi-branch gold nanoparticles and laying a certain foundation for further research. (2) on the basis of a series of multi-branched gold nanoparticles prepared, a near-infrared surface-enhanced Raman spectroscopy nano-probe is designed. The structure of nano-probe was optimized by studying the influence of different multi-branch gold nanoparticles and different amounts of Raman active molecules on the properties of probes. In order to understand the excellent performance of multi-branch gold nanoparticles on surface enhanced Raman spectrum signal enhancement, the local electromagnetic field enhancement properties of different branches in different morphology and multi-branch gold nanoparticles were simulated by finite time domain difference method. Meanwhile, the obtained high-performance near-infrared surface enhanced Raman spectroscopy nano-probe is used for SERS imaging of living cells (SK-BR-3 breast cancer cells). Experiments show that the near-infrared SERS nanometric probe can be successfully internalized by the cells and can clearly see its presence around the nucleus. Therefore, the near-infrared SERS probe obtained by the study not only has a good surface enhancement Raman property, but also can be used as the surface enhancement Raman probe of the near infrared region so as to have great research potential in the wider biomedical application field. (3) solving the problem that the ferroferric oxide nanoparticles obtained by the current thermal decomposition method do not have water phase dispersivity and are difficult to realize biomedical application, In this study, a mild and efficient reverse micelle oxidation method was used to carry out large-scale water phase transfer on ferroferric oxide nanoparticles wrapped by oleic acid. The mechanism of the method mainly relates to the oxidation and fracture reaction of oleic acid molecules on the surface of ferroferric oxide nanoparticles in the reverse micelle system. The experimental results show that the method can obviously shorten the reaction time and improve the yield of the phase-transfer nano-particles, so that the obtained nano-particles have good water-phase dispersivity, sol stability, low cytotoxicity and good magnetic property. Meanwhile, the further in vitro and in vivo magnetic resonance imaging results confirm that the ferroferric oxide nanoparticles obtained by the phase transfer can be used as a good T _ 2 contrast agent in the field of biological imaging. In addition, the method not only can directly obtain ferroferric oxide nanoparticles with surface functional groups, can carry out further functionalization application, but also can be popularized to other types of phase transfer applications of nano-particles coated with oleic acid, and has very good application prospect. (4) on the basis of the water phase dispersed ferroferric oxide nanoparticles obtained by the phase transfer process, a novel MRI/ CT multifunctional imaging probe based on gold nano core and ferroferric oxide nano particle outer layer coating is designed. The method comprises the following steps of: firstly, preparing gold nanoparticles, amination the surfaces thereof, and then utilizing the condensation reaction of the chemical molecules on the surface of the nanoparticles to combine the ferroferric oxide nanoparticles obtained by phase transfer to the surface of the gold nanoparticles to obtain the gold-ferroferric oxide nano composite material. The results show that the composite not only has good sol stability and biocompatibility, but also has the optical and magnetic properties of gold and ferroferric oxide. At the same time, the gold-ferroferric oxide composite nano-probe has the capability of simultaneously realizing the in vivo T _ 2-MRI and CT imaging by further applying the two-functional imaging of MRI/ CT in the body. In addition, based on the advantages of common gold and ferroferric oxide, the composite nano material can be applied not only in the field of MRI/ CT imaging, but also to the fields of drug delivery, biomarker and other imaging treatment, so as to realize more functional applications.
【学位授予单位】：西北大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：TB383.1;R318

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