基于金纳米颗粒和核酸的生物传感新方法的研究
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摘要
纳米材料由于具有量子尺寸效应、表面效应、小尺寸效应和宏观量子隧道效应等,表现出一系列独特的力学、光学、电学、磁学及催化性能,因此,在诸多领域中得到日益广泛的应用。而在众多纳米材料中,金纳米材料是各领域应用得最多的纳米材料之一。近年来,金纳米材料在生物传感方面的应用也已经成为研究的热点及焦点。当今世界,生物传感器已经普遍应用于医学诊断、临床检测、生物化工、食品工业以及环境检测等方面,金纳米材料由于其超强的吸附能力、良好的定向能力和生物兼容性,为生物传感器的研究和应用提供了新思路。
     DNA探针作为一种生物传感工具,它能巧妙地利用生物分子的一些特殊的化学性质,如核酸的杂交、蛋白质的特异性结合、酶的生化功能、立体构象转变等,结合分子水平的信号传导机制,将相关的生命信息转变为易于检测的信号,如荧光、拉曼、化学发光、电化学信号等。DNA探针由于其特异性强、背景信号低、易于实现活细胞检测等优点,已成为生物传感研究的热点。本文利用金纳米颗粒与DNA探针,结合本小组已发展的方法和技术,发展了一系列快速、操作简单、成本低的光学及电化学分析的新方法,成功实现了对金属离子、DNA、蛋白质和肿瘤细胞的高选择性、高灵敏度的检测。其主要内容如下:
     (1)第2章中,我们构建了一种简单、快速、免标记的基于DNA构象转换的荧光生物传感方法用于银离子高灵敏的检测。我们设计了一条银离子的特异性DNA,它是一条富含胞嘧啶C的寡核苷酸DNA,在目标物银离子存在的情况下,银离子与其特异性DNA中的胞嘧啶相互作用形成C-Ag+-C的复合结构,使得银离子特异性DNA发生构象转换形成发夹式的双链结构。当我们加入荧光染料Sybr GreenⅠ,它会与双链DNA结合并产生一个增强的荧光信号。而相反,在不存在银离子的情况下,银离子的特异性DNA则不会发生构象转换,加入Sybr Green Ⅰ后,只能产生非常弱的荧光信号。整个的检测过程基本上都在一步完成,并且不需要任何标记,这就为银离子的检测提供了一种简单、快速、免标记的方法,同时也为重金属的检测提供了一个新的思路。
     (2)第3章中,我们建立了一个基于等离激元耦合及表面增强拉曼散射光谱的生物传感平台用于DNA和Hg2+的检测。该方法是利用未进行修饰的金纳米颗粒来进行SERS检测:首先,单链DNA和双链DNA在金纳米颗粒表面的吸附性各不相同。单链DNA能够通过强大的静电吸附作用吸附在金纳米颗粒表面,从而保护金纳米颗粒,使其在一定盐离子的诱导下不发生团聚;但是,双链DNA则没有这一特性,在一定盐离子的诱导下不能阻止金纳米颗粒团聚的发生;其次,当单分散的金纳米颗粒发生团聚时,会产生等离激元耦合,形成许多“拉曼热点”,从而极大地增强了拉曼散射。我们将该传感平台应用于DNA和Hg2+的检测中,分别设计了一条与目标DNA互补的DNA单链和一条能与Hg2+特异性结合的DNA单链,在目标物存在下,目标物与其对应的DNA杂交或结合。当加入金纳米颗粒、拉曼报告分子和NaCl后,由于没有单链DNA的保护,金纳米颗粒发生团聚,从而导致拉曼信号增强。相反,在目标物不存在下,单链DNA通过强烈的静电吸附作用吸附在金纳米颗粒表面,阻止了盐诱导的金纳米颗粒团聚,从而产生一个弱的SERS信号。这种方法在实验中有着高达30倍的信噪比以及良好的选择性,不仅设计简单,而且在操作上相当快速、方便。通过利用寡核苷酸能选择性地结合分析物这一特性,从而延伸到检测各种分析物,例如,其他金属离子、蛋白质、小分子等。
     (3)为了进一步证明第3章中所构建方法的普遍性,在第4章中,我们利用类似的原理发展了一种基于目标诱导的等离激元耦合的SERS方法用于牛奶中三聚氰胺的检测。我们设计了一条聚T的寡核苷酸DNA,它能通过氢键与三聚氰胺结合形成“T-三聚氰胺-T”的结构,首先,通过静电吸附作用,聚T寡核苷酸和拉曼活性染料混合吸附在金纳米颗粒的表面。聚T寡核苷酸能够保证金纳米颗粒很好的分散在反应混合溶液中,并且保护金纳米颗粒在盐离子的诱导下不发生团聚。当三聚氰胺存在时,三聚氰胺能与聚T寡核苷酸在水介质中形成三重氢键,降低了金纳米颗粒表面的负电荷,从而导致金纳米颗粒的不稳定,在加入NaCl溶液后,金纳米颗粒会发生团聚。其结果是,由于金纳米颗粒表面电磁场的显著增强,粒子间强的表面等离激元耦合引发了明显增强的拉曼信号。由于目标物诱导的粒子间的等离激元耦合以及表面增强拉曼信号增强的高效性,我们所发展的这种纳米传感器在三聚氰胺的快速检测中具有很高的灵敏性和选择性,并且在液态牛奶样品的检测中可达到8nM的检测下限。
     (4)在第5章中,利用适配体辅助靶细胞的捕获及生物催化银沉积反应,构建了一种新颖的电化学生物传感平台用于高灵敏地检测肿瘤细胞。本章中,我们选择Ramos细胞做为目标肿瘤细胞,并且我们设计了两条不同的Ramos细胞核酸适体探针。核酸适体探针1在5’末端共价标记了巯基基团,它能与金面形成Au-S键,从而将探针1固定在金电极表面;核酸适体探针2则在5’末端标记了一个生物素,用来结合SA-ALP并在电极表面产生催化银沉积反应。首先,将巯基标记的捕获探针1固定在金电极表面,用来识别、特异性捕获目标Ramos细胞。接着,引入探针2,与电极表面的Ramos细胞进行特异性结合,并形成“核酸适体-细胞-核酸适体”复合物。由于探针2是有生物素标记的,因此,它能通过生物素和亲和素的相互作用与SA-ALP酶结合,并在电极表面发生酶催化银沉积反应。最后,采用线性扫描伏安法(LSV)检测Ag的电化学信号,从而计算出Ramos细胞的浓度。
     该方法有很高的选择性,具有很宽的线性检测范围(10~106个Ramos细胞),最低能检测到10个Ramos细胞,并且具有相当理想的重现性。该技术平台具有优良兼容性并且符合成本效益的小型化技术,这些特性使得该方法在临床上具有应用潜力。此外,在为每种细胞选择与之特定的核酸适体后,可以实现多种细胞的多元检测。鉴于这些优点,这种新颖的电化学细胞检测方法预计将会为肿瘤细胞的检测和相关研究提供一个具有高特异性和高灵敏度的平台。
     (5)在第6章中,我们构建了一种新型的基于金纳米颗粒和端粒酶扩增反应对信号的双重放大,并结合银沉积增强的电化学免疫检测平台用于蛋白质的检测。本章,我们选择人的IgG做为靶蛋白,并引入了Ab-AuNPs-P1纳米复合物,这是一种在金纳米颗粒上同时修饰了羊抗人IgG二抗和巯基标记的DNA探针1(P1)的复合物,其中巯基标记的P1链为端粒酶的引物链,是用来进行端粒酶扩增反应的。首先,在金电极表面自组装上半胱胺,通过戊二醛的交联将羊抗人IgG抗体固定在金电极表面,用来捕获样品溶液中人的IgG抗原。接着,与Ab-AuNPs-P1纳米复合物在电极上发生免疫夹心反应,当加入端粒酶及混合dNTP后,Ab-AuNPs-P1纳米复合物上的端粒酶引物发生端粒酶扩增反应;然后,将生物素标记的检测探针2(P2)与扩增后的重复单元进行杂交,通过生物素与亲和素的相互作用,SA-ALP酶与P2链结合。在SA-ALP酶的作用下,在电极表面发生酶催化银沉积反应。最后,采用线性扫描伏安法(LSV)检测Ag的电化学信号,从而实现对人的IgG的检测。
     该方法检测目标IgG抗原有着高达35倍的信噪比,检测下限为0.02μg/mL。该电化学免疫传感平台经过金纳米颗粒及端粒酶扩增反应对最后电化学的信号进行了双重信号放大,只有在靶蛋白存在的条件下,才能即时检测到金属银的还原电化学信号。因此,该电化学免疫传感器为检测其他蛋白质构建了一个信号放大的平台,并能用于实际样品的检测。
Nano-materials exhibit a series of unique properties in mechanical, optical,electrical, magnetic and catalytic, due to their quantum size effect, surface effect,small size effect and macroscopic quantum tunneling effect. Therefore, it has beenincreasingly widely used in many areas. Of all the nano-materials, gold nano-materialis among one of the most extensively applied nano-materials in various fields. Inrecent years, the gold nano-material applications has become a hot research and focusin biosensor. And biosensor has been widely used in medical diagnosis, clinical testing,bio-chemical, food industry and environmental testing and other aspect, goldnano-material provides a new idea for biosensor research and application because of itsstrong adsorption capacity, good directional ability and biological compatibility.
     As a biosensing tool, DNA probe can convert relevant information of life intoeasily detected signal (fluorescence, Raman, chemiluminescence and electrochemicalfor example), skilfully using some specific chemical properties of biological molecules,such as nucleic acid hybridization, the specific bingding of protein, enzymebiochemical function and structure-switching, and combining with signal transductionmechanism of molecular level. Now, because of its high specificity, low backgroundsignal and easy to realize detection of living cells, DNA probe has become a hotreseach biosensing. In this paper, we have developed a series of novel, fast,easy-operation, low-cost optical and electrochemical analysis method for selective andsensitive detection of metal ions, DNA, proteins and cancer cells, utilizing Au NPs andDNA probe, combined with the developed methods and techniques in our group. Thedetailed contents are described as follows:
     (1) In chapter2, we constructed a simple, rapid, label-free fluorescencebiosensing method for sensitive deteciton of silver ions based on structure-switchingDNA. In this method, we designed a silver ion specific DNA, which is a C-richoligonucleotide DNA. In the presence of Ag+, silver-mediate base pairs (C-Ag+-C) ofsilver ion specific DNA could be formed between cytosine residues from two Ag+-binding sequences to give rise to a hairpin structure. In the hairpin structure, the SybrGreen Ⅰ binds to the silver ion specific DNA hairpin to achieve the high Sybr GreenⅠ emission intensity. In the absence of Ag+, the silver ion specific DNA exists as arandom coil which showed a very weak fluorescence. The whole detection process was basically done in a single step, and did not require any tags, which was not onlyprovides a simple, fast, label-free method for the detection of silver ions, but alsoprovides a new way of thinking for the detection of metal.
     (2) In chapter3, we exploited a label-free, homogeneous biosensing platformbased on plasmonic coupling and surface-enhanced Raman scattering. This method iscarried out by unmodified gold nanoparticles for SERS detection: first, there aredifferences in adsorption properties of ssDNA and dsDNA on citrate-coated Au NPs.The ssDNA adsorbs efficiently on the Au NPs surface through strong electrostaticattraction while dsDNA does not, which results in ssDNA that can protect the Au NPsfrom salt-induced aggregation, but dsDNA cannot. Secondly, the aggregation ofmonodis-persed Au NPs into discrete clusters can give rise to the plasmonic couplingand the formation of many SERS ‘‘hot spots’’, resulting in the enormous enhancementof Raman scattering. We designed two ssDNA probes for this sensor platform indetection of DNA and Hg2+respectively: one was perfected complementary to a targetDNA, and the other one was a specific DNA to Hg2+. In the presence of target, thetarget was hybridized or binded with its corresponding ssDNA probe. After theaddition of unmodified Au NPs, Raman reporter molecules and NaCl, the aggregationof Au NPs occurs due to lack of the protection of ssDNA, resulting in a strong SERSsignal. On the contrary, in the absence of target, the ssDNA adsorbs on the Au NPssurface and protects Au NPs from salt-induced aggregation, leading to a weak SERSsignal. This assay possesses the superior signal-to-background ratio as high as~30andexcellent selectivity, and not only simple in design but also quick, easy in operation.Factually, this method can in principle be extended to detect various analytes, such asother metal ions, proteins and small molecules by using the oligonucleotides that canselectively bind the analytes.
     (3) In order to further demonstrate the generality of the strategy in chapter3, weused the same principle to develop a target-controlled plasmonic coupling andSERS-based biosensing technique for the detection of Melamine using unmodifiedAuNPs in chapter4. In this strategy, we designed a poly-T oligonucleotide DNA,which can combine with melamine through hydrogen bonds to form a T-melamine-Tstructure. First, AuNPs are decorated through mixed self-assembly with polythymineand Raman-active dye via electrostatic attraction. By adsorbing polythymine onto thesurfaces of AuNPs, the negative charges of polythymine can maintain AuNPswell-dispersed in the reaction mixture and protect AuNPs from salt-inducedaggregation owing to the repulsion force of the neighboring nanoparticles. Then, the present melamine decreases the negative charges of the surface of AuNPs by formingtriple H-bonds with polythymine in aqueous medium, thus leading to thedestabilization of AuNPs and the aggregation of AuNPs with the addition of NaCl. Asa result, strong interparticle plasmonic coupling between AuNPs can be induced withremarkable enhancement of the Raman signal, due to dramatically enhancedelectromagnetic fields near the particle surface. Due to the high efficiency oftarget-controlled interparticle plasmonic coupling and SERS enhancement, thisnanosensor exhibits high sensitivity and selectivity in rapid melamine assay, with aquite low detection limit of8nM for real liquid milk samples.
     (4) In chapter5, we presented a novel electrochemical platform for sensitivedetection of cancer cells by using Aptamer-aided target capturing with biocatalyticmetal deposition. In this chapter, we chose Ramos cell as a model case, and designdtwo Aptamer probes with different sequences and binding sites of the same cancer cell:Aptamer probe1is thiolated at the5’ end and via covalent binding, its thiolated endcan be immobilized onto the surface of the gold electrode. Aptamer2is a probebiotinylated at its5’ end for the silver deposition reaction on the electrode surface bybinding with SA-ALP. First, the thiolated probe1immobilized on the surface ofworking electrode, which is also the Aptamer for the target cell, recognises andspecifically captures the target cell close to the electrode. In the presence of probe2, itfurther specifically binds with the captured cancer cell, forming “Aptamer-Ramoscell-Aptamer” composites. As probe2is biotinylated, it can conjugate with theSA–ALP through the biotin–streptavidin interaction. Thus, it allows the nonreductivesubstrate of alkaline phosphatase, ascorbic acid2-phosphate, to be converted intoreducing agent ascorbic acid on the electrode surface. Hence, the silver ions arereduced and deposited on the electrode surface. Furthermore, as the Aptamer sensorutilizes the enzymatic silver deposition procedure for electrochemical quantifcation ofthe target cell, it permits the accumulation of the enzymatic product at the electrodesurface for a highly sensitive LSV readout.
     The developed strategy was demonstrated to display high selectivity indiscriminating Ramos cells, detection limit as low as10cells, and a wide linearresponse range10to106cells with desirable reproducibility. The technique platformwas proved to be cost-efficient with excellent compatibility to miniaturizationtechnologies. These properties support its potential in clinical applications. Moreover,multiplex detection of multiple cells can be implemented in densely packed arrayformat with specific Aptamers selected for each kind of cell. In view of these advantages, this new electrochemical cell detection strategy is expected to provide anintrinsically specific and sensitive platform for cancer cell assay and associatedstudies.
     (5) In chapter6, we developed a novel electrochemical immunoassay for thedetection of human IgG by using AuNPs and telomerase extension reaction as dualsignal amplification and coupling biocatalytic silver deposition. In this assay, weselected human IgG as a target protein, and introduced a Ab-Au NPs-P1nanocomplex,which were Au NPs modified with telomerase primer DNA probe1and goatanti-human IgG (Ab). Firstly, goat anti-human IgG (Ab) is immobilized on goldelectrode through cysteamine and glutaraldehyde reaction. After electrode surfaceblocked by BSA, analyte human IgG antigen is bonded with Ab specifically. ThenAb-AuNPs-P1nanocomplex is used as a secondary antibody to combine human IgGantigen to form a sandwich structure. In the presence of telomerase, telomeraseextension reaction is initiated to add TTAGGG tandem repeat unites to the3’-end ofthe primer by adding nucleotide mixture dNTPs. DNA probe P2is designed forhybridization with telomerase extension product. Then streptavidin labeled alkalinephosphatase (SA-ALP) is employed to connect ALP onto electrode surface via specificbinding between biotin and streptavin. After washing steps, the modified goldelectrode is incubated with ascorbic acid2-phosphate (AA-P) and silver ions. The ALPconverts AA-P to ascorbic acid, a reducing reagent which reduces silver ions to form ametallic silver layer on the electrode surface. The amount of deposited silver iscorrelated with analyte human IgG concentration and can be determined by linearsweep voltammetry (LSV). The deposited silver layer can only be obtained in thepresence of human IgG.
     This assay possesses the superior signal-to-background ratio as high as~35, andthe detection limited was as low as0.02μg/mL. Hence, this strategy held the potentialto be extended to a common electrochemical immunoassay platform for differentproteins assay. The real human serum analysis results demonstrated the developedapproach could be used for quantitative analysis of practical and clinical samples.
引文
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