基于金和四氧化三鐵的多功能納米探針的制備及其生物醫(yī)學(xué)成像應(yīng)用研究
發(fā)布時(shí)間：2018-10-25 06:51
【摘要】：隨著納米材料科學(xué)領(lǐng)域近年來的不斷發(fā)展,功能性的納米材料的控制制備及其生物醫(yī)學(xué)應(yīng)用越來越受到人們關(guān)注。特別是金和四氧化三鐵納米顆粒,因其獨(dú)特的光學(xué)和磁學(xué)性質(zhì)以及良好的生物相容性和安全性,在生物醫(yī)學(xué)領(lǐng)域包括藥物傳遞、免疫分析檢測(cè)、生物分離、醫(yī)學(xué)成像診斷、多模式診療一體化領(lǐng)域等多方面有著極廣泛的應(yīng)用前景。本論文以金和四氧化三鐵納米材料為基礎(chǔ),在形貌可控合成、光學(xué)磁學(xué)性質(zhì)調(diào)制、表面修飾優(yōu)化以及生物醫(yī)學(xué)成像應(yīng)用等方面進(jìn)行了一系列研究,還設(shè)計(jì)制備了金、四氧化三鐵以及金-四氧化三鐵復(fù)合的納米探針,對(duì)其各項(xiàng)性能進(jìn)行了表征,并考察了這些納米探針的表面增強(qiáng)拉曼光譜(SERS)、磁共振(MRI)和計(jì)算機(jī)斷層掃描(CT)成像方面的應(yīng)用特性。本論文主要的研究?jī)?nèi)容包括以下幾個(gè)方面：(1)利用一種綠色溫和及簡(jiǎn)易的合成策略,制備出多分支的金納米顆粒,并通過二次生長(zhǎng)的策略控制制備分支形貌可調(diào)的金納米顆粒,實(shí)現(xiàn)分支金納米顆粒的局域表面等離子共振在近紅外區(qū)穩(wěn)定可調(diào)。同時(shí)考察了多分支金納米顆粒的成核生長(zhǎng)和二次生長(zhǎng)過程中各實(shí)驗(yàn)因素對(duì)其尺寸、分支形貌和局域表面等離子共振性質(zhì)的影響。并通過有限時(shí)域差分法模擬,研究了多分支金納米顆粒的分支形貌參數(shù)對(duì)局域表面等離子共振峰的影響。研究發(fā)現(xiàn),多分支金納米顆粒的分支越長(zhǎng)、分支角度越小,其局域表面等離子共振峰越紅移。我們通過對(duì)實(shí)驗(yàn)參數(shù)控制以及利用二次生長(zhǎng)的方法來對(duì)多分支金納米顆粒的局域表面等離子共振實(shí)現(xiàn)了在近紅外區(qū)的廣泛可調(diào),從而獲得一系列的多分支金納米顆粒,為進(jìn)一步的研究打下了一定的基礎(chǔ)。(2)在已制備的一系列多分支金納米顆粒的基礎(chǔ)上,設(shè)計(jì)制備了近紅外表面增強(qiáng)拉曼光譜納米探針。并通過研究不同多分支金納米顆粒及不同量的拉曼活性分子對(duì)探針性質(zhì)的影響,優(yōu)化了納米探針的構(gòu)建。為了深入理解多分支金納米顆粒在表面增強(qiáng)拉曼光譜信號(hào)增強(qiáng)方面的優(yōu)異表現(xiàn),利用有限時(shí)域差分法模擬分析了不同形貌及多分支金納米顆粒上不同分支的局域電磁場(chǎng)增強(qiáng)性質(zhì)。同時(shí),將得到的高性能近紅外表面增強(qiáng)拉曼光譜納米探針用于活細(xì)胞(SK-BR-3乳腺癌細(xì)胞)的SERS成像。實(shí)驗(yàn)表明,近紅外SERS納米探針可以成功地被細(xì)胞內(nèi)在化,并可清晰的看到其在細(xì)胞核周圍存在。因此,本研究得到的近紅外SERS探針不僅具有良好的表面增強(qiáng)拉曼性質(zhì),而且還能作為近紅外區(qū)表面增強(qiáng)拉曼探針,使其在更廣泛的生物醫(yī)學(xué)應(yīng)用領(lǐng)域擁有有巨大的研究潛力。(3)針對(duì)于目前熱分解方法得到的四氧化三鐵納米顆粒不具有水相分散性,難以實(shí)現(xiàn)生物醫(yī)學(xué)應(yīng)用的問題,本研究采用一種溫和高效的反膠束氧化法對(duì)油酸包裹的四氧化三鐵納米顆粒進(jìn)行大規(guī)模的水相轉(zhuǎn)移。該方法的機(jī)制主要涉及到在反膠束體系中進(jìn)行四氧化三鐵納米顆粒表面油酸分子的氧化斷裂反應(yīng)。實(shí)驗(yàn)結(jié)果表明,該方法可以明顯縮短反應(yīng)時(shí)間,提高相轉(zhuǎn)移納米顆粒的產(chǎn)率,可使得到的納米顆粒具有很好的水相分散性、溶膠穩(wěn)定性、低的細(xì)胞毒性以及良好的磁學(xué)性質(zhì)。同時(shí),進(jìn)一步的體外和體內(nèi)的磁共振成像結(jié)果證實(shí)了該相轉(zhuǎn)移得到的四氧化三鐵納米顆�？勺鳛榱己玫腡_2造影劑應(yīng)用于生物成像領(lǐng)域。此外,該方法不僅可以直接得到具有表面羧基官能團(tuán)的四氧化三鐵納米顆粒,可進(jìn)行進(jìn)一步的功能化應(yīng)用,而且還可推廣至其他類型的油酸包覆的納米顆粒的相轉(zhuǎn)移應(yīng)用中,具有十分良好的應(yīng)用前景。(4)在通過相轉(zhuǎn)移過程得到的水相分散的四氧化三鐵納米顆粒的基礎(chǔ)上,設(shè)計(jì)制備了基于金納米核心、四氧化三鐵納米顆粒外層包覆的新型MRI/CT多功能成像探針。具體途徑為,首先制備金納米顆粒,再將其表面氨基化,然后利用納米顆粒表面化學(xué)分子的縮合反應(yīng),將相轉(zhuǎn)移得到的四氧化三鐵納米顆粒結(jié)合在金納米顆粒的表面,得到金-四氧化三鐵納米復(fù)合材料。結(jié)果顯示,該復(fù)合材料不僅具有良好的溶膠穩(wěn)定性、生物相容性,還可同時(shí)具備金及四氧化三鐵本征的光學(xué)、磁學(xué)性質(zhì)。同時(shí),通過進(jìn)一步將其應(yīng)用于體內(nèi)的MRI/CT的雙功能成像,證實(shí)了該金-四氧化三鐵復(fù)合納米探針具有可以同時(shí)實(shí)現(xiàn)體內(nèi)T_2-MRI與CT成像的能力。此外,基于金與四氧化三鐵共同的優(yōu)勢(shì),該復(fù)合納米材料不僅可以應(yīng)用于MRI/CT成像領(lǐng)域,還可進(jìn)一步推廣至藥物傳遞、生物標(biāo)記以及其他成像治療等領(lǐng)域,以期實(shí)現(xiàn)更多的功能化應(yīng)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.
【學(xué)位授予單位】：西北大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：TB383.1;R318
[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.
【學(xué)位授予單位】：西北大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：TB383.1;R318
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