基于纳米材料和环糊精的新型DNA电化学生物传感器的研究
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摘要
随着基因的结构与功能的研究不断深入，特别是人类基因组计划(HGP)的发展，基因的分离及分析检测在卫生防疫、医学诊断、药物研究、环境科学及生物工程等领域发挥着越来越重要的作用。许多新的生物技术的开发，为发展高灵敏度、高特异性的生物分析检测方法注入了活力，其中利用DNA分子间的特异性互补配对规律发展起来的各种DNA生物传感技术，引起了国内外生物分析工作者的广泛关注。电化学DNA检测方法以其灵敏度高、轻巧便宜、携带方便、耗能少、能与现代微电子技术联用，易于实现微型化等优点，受到了研究者们的广泛关注，俨然成为当今生物学、医学领域的前沿性课题。
纳米技术的出现为纳米材料在分析化学领域的发展和应用开辟了新的思路。纳米颗粒的比表面积大、表面反应活性高、催化效率高、吸附能力强等优异性质，在催化、光吸收、生物医药、磁介质及新材料等方面得到了广泛的应用，为生物医学研究提供了新的研究途径，同时也推动了化学和生物传感器的迅速发展。纳米粒子的独特性质与生物分子杂交反应和电化学检测方法相结合，使其应用范围更加广阔(例如：纳米生物电子)。纳米粒子生物分子连接可能用于DNA疾病的诊断，并且对生物分析化学产生巨大的影响。
超分子化学是基于分子间的非共价键相互作用而形成的分子聚集体化学，在与材料科学、生命科学、信息科学、纳米科学与技术学科的交叉融合中，超分子化学已发展成为超分子科学。并成为创造新物质、实现新功能的一种新的重要途径，被认为是21世纪新概念和高技术的重要源头之一。环糊精作为超分子化学的重要主体化合物以其独特的性质而倍受关注。对它的研究也逐渐从主客体识别形成包合物的机理转移到对其在分析化学、医药、环境保护和传感器等领域的应用研究中。
本论文的主要创新之处就是将纳米技术、层层组装技术、超分子包合作用等与电化学分析技术相结合用于核酸分子杂交或凝血酶蛋白的分析检测，研制具有高灵敏度高选择性的新型电化学生物传感器，成功地应用于对特定序列DNA片断的选择性测定和对DNA链中的碱基尤其是单个碱基突变的快速、灵敏和准确的识别，为基因的快速分析测定提供了一种简便、快捷、廉价的检测装置。
第一章绪论
首先系统介绍了DNA生物传感器及其研究进展。介绍了DNA生物传感器的原理(包括DNA探针及其分子识别原理和DNA在固体基质表面的固定化)和分类(包括电化学DNA生物传感器，压电DNA生物传感器及光学DNA生物传感器)，其中着重介绍了电化学DNA生物传感器的原理和研究进展，叙述了DNA电化学传感器在基因检测等方面的应用，对今后的发展方向和趋势进行了展望。接着介绍了纳米材料在生物传感器中的一系列应用。最后阐述了本论文的目的和意义，指出论文的创新之处及主要研究内容。
第二章基于纳米颗粒SiO_2包裹Ru(bpy)_3~(2+)标记的DNA电致化学发光生物传感器研究
首次以SiO_2包裹Ru(bpy)_3~(2+)标记DNA分子，制备成高效的电致化学发光探针，实现对目标DNA的高灵敏度特异性识别。我们合成了SiO_2包裹Ru(bpy)_3~(2+)核壳式纳米颗粒，以此作为新型的ECL标记物。利用一个纳米颗粒中可包裹多个Ru(bpy)_3~(2+)分子来达到放大ECL信号的目的，为分析检测更高的灵敏度。根据DNA的碱基互补配对原则、核酸适配体对蛋白质的特异性识别能力，采用Ru(bpy)_3~(2+)-SiO_2纳米颗粒作为标记物设计ECL生物传感器，希望能将ECL方法、纳米颗粒带来的高灵敏度与生物识别的高特异性进行有机的结合，实现对DNA序列以及蛋白质进行高灵敏、高特异性的研究分析。
第三章基于钯纳米粒子/碳纳米管增强的DNA电化学生物传感器研究
首次将钯纳米颗粒与羧基化碳纳米管结合用于DNA生物传感器的研究，借助钯的良好催化活性和碳纳米管的较大的比表面积、极强的导电性等实现超灵敏的DNA检测。合成了直径为3～4nm的钯(Pd)纳米粒子，将其与末端羧基化的多壁碳纳米管(COOH-MWCNT)结合，制得灵敏度增强的电化学DNA生物传感器。首先将一定量的Nafion、COOH-MWCNT及Pd纳米粒子的混合液涂在玻碳电极(GCE)表面，制得MWCNT/Pd修饰电极，对该电极进行了电化学特性的研究。然后通过5’端氨基修饰的寡聚核苷酸(5’-NH_2-DNA)与碳纳米管末端的羧基(—COOH)之间形成酰胺键而将ssDNA固定在MWCNT/Pd修饰电极上。与目标DNA杂交后，以亚甲基蓝(MB)为电化学杂交指示剂，实现对互补序列、非互补序列的识别和电化学测定。在亚甲基蓝的电化学反应中，由于碳纳米管具有很好的电子传递能力同时Pd纳米粒子具有很好的催化活性，可以使电化学DNA生物传感器的灵敏度大大提高。对目标DNA的检测下限可以达到1．2×10~(-13)M。
第四章基于层层组装技术实现DNA放大检测的电化学生物传感器研究
将层层组装技术用于金纳米颗粒标记的DNA生物传感器的研究中，通过电极表面的多次电荷翻转达到富集大量的目标DNA分子的目的，以此获得放大的DNA杂交信息。本文介绍了聚二烯丙基二甲基胺盐酸盐(PDDA)分子与DNA经过层层组装(layer-by-layer,LBL)的方法，以DNA探针分子上标记的金纳米颗粒为电化学检测手段，实现对目标DNA杂交信号的放大。运用交流阻抗技术(EIS)和紫外吸收光谱法(UV-Vis)对LBL的过程进行研究，实验结果表明多层膜能够均匀规则地组装在聚吡咯(PPy)修饰的电极表面，并通过层层组装将杂交信号放大。在优化条件条件下，组装层为6层时，其检测限达到3．20×10~(-14)M，该方法具有高灵敏度和特异性。通过采用干扰序列消除非特异性吸附，这种传感器表现出良好的稳定性和重现性。
第五章基于β-环糊精主客体识别作用的DNA电化学生物传感器研究
首次将主客体识别作用应用于DNA生物传感器的研究中，以β-环糊精对客体分子间甲基苯甲酸(mTA)的高效识别性成功地实现了对DNA分子的检测。将β-环糊精采用电化学方法聚合在氮乙酰基苯胺修饰的玻碳电极表面，以mTA作为客体分子标记于5’端氨基修饰寡聚核苷酸片段上，通过电化学交流阻抗对β-环糊精修饰电极捕获mTA标记的DNA进行了表征。其结果显示出该电极对mTA标记的DNA探针分子具有很强的包络作用，能够通过主客体的识别将ssDNA和dsDNA捕获到电极表面。分别采用金纳米颗粒标记探针和以亚甲基兰为杂交指示剂对目标DNA检测，均能通过主客体识别的方法获得良好的检测限。研究表明，β-环糊精修饰电极具有优良的再生性，可重复多次用于DNA的杂交检测。
第六章基于金纳米颗粒聚集体富集亚甲基兰的DNA与蛋白质的电化学生物传感器的研究
首次采用金纳米颗粒标记特定序列的寡聚核苷酸片段，设计了即可用于DNA检测又能实现对特殊蛋白质放大检测的研究方法。采用特殊设计的两段寡聚核苷酸片段，其一端均以金纳米颗粒标记，另外一端均为含有一段可以与凝血酶蛋白产生特异性结合的核酸适配体(适体)片段。当与目标分子(DNA或凝血酶蛋白)产生特异性结合作用时，该探针能与目标分子形成含有多个金纳米颗粒聚集体，将金纳米颗粒聚集体自组装在硫代三聚氢酸修饰的金电极表面，通过探针上的鸟嘌呤富集MB分子，实现对目标物的检测。探针上识别凝血酶的寡聚核苷酸片段含有多个鸟嘌呤碱基，它能与MB有很强的结合作用，因此富含鸟嘌呤的探针能够富集大量的MB分子在纳米颗粒聚集体上，同时，由于金纳米颗粒聚集体能加速MB氧化还原反应过程的电子传递，使得MB的氧化还原反应更容易进行，因此，对目标物的检测具有非常高的灵敏度。
With improved understanding of structure and function of human gene, and the development of the Human Genome Project, DNA separation and analysis has taken a more and more important role in the areas of clinical diagnosis, medicine, epidemic prevention, environmental protection and bioengineering. Wide-scale genetic testing requires the development easy-to-use, fast, inexpensive, miniaturized devices. Many new biological technologies emerged and found their applications in this field. Among them, DNA biosensors are rapidly developed and have received considerable attentions. Electrochemical DNA detection is a novel and developing technique that combining biochemical, electrochemical, medical and electronic techniques with the advantages of being simple, reliable, cheap, sensitive and selective for genetic detection, and has been a hot topic in the field of biochemistry and medicine.
The emergence of nanotechnology is opening new horizons for the application of nanoparticles in analytical chemistry. In particular, nanoparticles are of considerable interest in the world of nanoscience owing to their unique physical and chemical properties. With these unique properties, they are widely used in the fields of catalysis, optical absorption, medicine, magnetic medium, new materials synthesis. Such properties offer excellent prospects for chemical and biological sensing. The power and scope of such nanoparticles can be greatly enhanced by coupling them with biological recognition reactions and electrical processes (i.e. nanobioelectronics). Nanoparticle-biopolymer conjugates offer great potential for DNA diagnostics.
Supramolecular chemistry has been defined as the "chemistry of molecular assemblies and of the intermolecular bond". Combing with the material science, biological science, information technology and nanometer technology, it has been the supramolecular science and has been employed as a vital method to design, and prepare new materials and obtain novel properties. Therefore, supramolecular chemistry is believed to be the base of new concept and technology in the 21st century. Cyclodextrin (CD), as the most important host, have received considerable attention because of its particular characterization, and the studies on the host-guest interaction based on CD had been transferred from the processes and mechanism of inclusion complex between a pair of host and guest to the application in the fields such as analysis, medicine, environment protection and sensors.
The goal of the present study is to design and optimize new DNA hybridization techniques with high sensitivity and selectivity. This dissertation focuses on fabricating novel electrochemical DNA biosensors based on eletrochemical analysis technique, combining nano-materials, layer-by-layer technology and supramolecular inclusion interaction, thus developing a sensitive, sequence-specific and quantifiable gene detection method, and establishing the bases, especially one base mutation, then for application of electrochemical DNA biosensor to clinic diagnose.
Chapter 1: Preface
Firstly, we introduce the progress of DNA biosensor, including its principle (probe identification principle and immobilization method of ssDNA on solid support) and its classification (electrochemical DNA biosensor, optical DNA biosensor and piezoelectric DNA biosensor). Among these, we emphatically review the principle, progress, the application and development trends of electrochemical DNA biosensors. Second, the application of nano-materials on biosensors was introduced. At last, we pointed out the purpose and significance of the dissertation.
Chapter 2: The preparation of Ru(bpy)_3~(2+)-doped nanoparticle and its application in electrogenerated chemiluminescence detection DNA hybridization analysis
A sensitive electrogenerated chemiluminescence (ECL) detection of DNA hybridization, based on tris(2,2'-bipyridyl)ruthenium(Ⅱ) -doped silica nanoparticles (Ru(bpy)_3~(2+)-doped SNPs) as DNA tags, is described. In this protocol, Ru(bpy)_3~(2+)-doped SNPs was used for DNA labeling with trimethoxysilylpropy -diethylenetriamine (DETA) and glutaraldehyde as linking agents. The Ru(bpy)_3~(2+)-doped SNPs labeled DNA probe was hybridized with target DNA immobilized on the surface of PPy modified Pt electrode. The hybridization events were evaluated by ECL measurements and only the complementary sequence could form a double-stranded DNA (dsDNA) with DNA probe and give strong ECL signals. A three-base mismatch sequence and a non-complementary sequence had almost negligible responses. Due to the large number of Ru(bpy)_3~(2+) molecules inside SNPs, the assay allows detection at levels as low as 1.0×10~(-13) mol 1~(-1) of the target DNA. The intensity of ECL was linearly related to the concentration of the complementary sequence in the range of 2.0×10~(-13)-2.0×10~(-9) mol 1~(-1).
Chapter 3: Electrochemical DNA biosensors based on palladium nanoparticles combined with carbon nanotubes
Palladium nanoparticles, in combination with multi-walled carbon nanotubes (MWCNTs), were used to fabricate a sensitivity-enhanced electrochemical DNA biosensor. MWCNTs and palladium nanoparticles were dispersed in Nafion, which were used to modify a glassy carbon electrode (GCE). Oligonucleotides with amino groups at the 5' end were covalently linked onto carboxylic groups of MWCNTs on the electrode. The hybridization events were monitored by differential pulse voltammetry (DPV) measurement using methylene blue (MB) as an indicator. Due to the ability of carbon nanotubes to promote electron-transfer and the high catalytic activities of palladium nanoparticles for electrochemical reaction of methylene blue, the sensitivity of presented electrochemical DNA biosensors was remarkably improved. The detection limit of the method for target DNA was 1.2×10~(-13)M.
Chapter 4: Multilayer membranes via layer-by-Layer deposition of PDDA and DNA with Au nanoparticles as tags for DNA biosensing
A novel Au nanoparticles (Au-NPs)-based protocol for DNA hybridization detection based on assembly of alternating DNA and poly(dimethyldiallylammonium chloride) (PDDA) multilayer films by layer-by-layer (LBL) electrostatic adsorption has been studied. Electrochemical impedance spectroscopy (EIS) and UV-vis absorbance measurements were used to study the film assembly. All the results indicate that the uniform multilayer can be obtained on the polypyrrole (PPy) coated electrode surface and the hybridization reaction can be amplified by the layer-by-layer progress. The hybridization was detected the reductive signal of Au-NPs by direct electrochemical method and nonspecific adsorption was greatly eliminated by an irrelated DNA sequence to the target DNA. Under optimum conditions, a significant sensitivity enhancement had been obtained, and the detection limit was down to 3.20×10~(-14) M when 6 layers assembled. The DNA biosensor has good stability and reproducibility.
Chapter 5: Electrochemical detection of DNA sequence with host-guest recognition onβ-cyclodextrin modified electrode
The electrochemical sensing of DNA is accomplished firstly by the host-guest recognition system according to the very strong inclusion betweenβ-Cyclodextrin (β-CD) and m-toluic acid (mTA).β-CD, as the host molecular, was electropolymorized on the poly(N-acetylaniline) modified glassy carbon electrode by potential sweeping, and mTA, as the guest, was labled on the oligonucleotides with amino groups at the 5' end. The inclusion between P-CD modified electrode and mTA labeled DNA was investigated by CV and EIS, which turned out a strong inclusion interaction between them. Based on the host-guest recognition, introducing Au nanopaticles as tags and MB as indicator to detect DNA hybridization, respectively, has excellent detection limit and reproducibility.
Chapter 6: Bifunctional biosensor based on aggregation methylene blue by cross-linked Au nanoparticles and the functionalized aptamer segmentsWe report here on the construction of a biosensor can detect thrombin or DNA molecules by two functional aptamer segments, which will form Au-NPs/analyte aggregation by adding the analytes, and the redox indicator, MB, that is used to interact specifically with the guanine bases on the aptamer segments. Hybridization for DNA or incubation for thrombin not only result in the binding multi-Au-NPs labeled probe to the analyte for formation of an extended polymeric network, but also in aggregation abundant MB molecules on the aptamer segments which can govern the signals for the analytes. The novel bifunctional apatmer-based biosensing capability is coupled to the enormous amplification feature of the activation for MB through the Au-NPs conductive matrix to yield remarkably low (fmole) detection limits.
纳米技术的出现为纳米材料在分析化学领域的发展和应用开辟了新的思路。纳米颗粒的比表面积大、表面反应活性高、催化效率高、吸附能力强等优异性质，在催化、光吸收、生物医药、磁介质及新材料等方面得到了广泛的应用，为生物医学研究提供了新的研究途径，同时也推动了化学和生物传感器的迅速发展。纳米粒子的独特性质与生物分子杂交反应和电化学检测方法相结合，使其应用范围更加广阔(例如：纳米生物电子)。纳米粒子生物分子连接可能用于DNA疾病的诊断，并且对生物分析化学产生巨大的影响。
超分子化学是基于分子间的非共价键相互作用而形成的分子聚集体化学，在与材料科学、生命科学、信息科学、纳米科学与技术学科的交叉融合中，超分子化学已发展成为超分子科学。并成为创造新物质、实现新功能的一种新的重要途径，被认为是21世纪新概念和高技术的重要源头之一。环糊精作为超分子化学的重要主体化合物以其独特的性质而倍受关注。对它的研究也逐渐从主客体识别形成包合物的机理转移到对其在分析化学、医药、环境保护和传感器等领域的应用研究中。
本论文的主要创新之处就是将纳米技术、层层组装技术、超分子包合作用等与电化学分析技术相结合用于核酸分子杂交或凝血酶蛋白的分析检测，研制具有高灵敏度高选择性的新型电化学生物传感器，成功地应用于对特定序列DNA片断的选择性测定和对DNA链中的碱基尤其是单个碱基突变的快速、灵敏和准确的识别，为基因的快速分析测定提供了一种简便、快捷、廉价的检测装置。
第一章绪论
首先系统介绍了DNA生物传感器及其研究进展。介绍了DNA生物传感器的原理(包括DNA探针及其分子识别原理和DNA在固体基质表面的固定化)和分类(包括电化学DNA生物传感器，压电DNA生物传感器及光学DNA生物传感器)，其中着重介绍了电化学DNA生物传感器的原理和研究进展，叙述了DNA电化学传感器在基因检测等方面的应用，对今后的发展方向和趋势进行了展望。接着介绍了纳米材料在生物传感器中的一系列应用。最后阐述了本论文的目的和意义，指出论文的创新之处及主要研究内容。
第二章基于纳米颗粒SiO_2包裹Ru(bpy)_3~(2+)标记的DNA电致化学发光生物传感器研究
首次以SiO_2包裹Ru(bpy)_3~(2+)标记DNA分子，制备成高效的电致化学发光探针，实现对目标DNA的高灵敏度特异性识别。我们合成了SiO_2包裹Ru(bpy)_3~(2+)核壳式纳米颗粒，以此作为新型的ECL标记物。利用一个纳米颗粒中可包裹多个Ru(bpy)_3~(2+)分子来达到放大ECL信号的目的，为分析检测更高的灵敏度。根据DNA的碱基互补配对原则、核酸适配体对蛋白质的特异性识别能力，采用Ru(bpy)_3~(2+)-SiO_2纳米颗粒作为标记物设计ECL生物传感器，希望能将ECL方法、纳米颗粒带来的高灵敏度与生物识别的高特异性进行有机的结合，实现对DNA序列以及蛋白质进行高灵敏、高特异性的研究分析。
第三章基于钯纳米粒子/碳纳米管增强的DNA电化学生物传感器研究
首次将钯纳米颗粒与羧基化碳纳米管结合用于DNA生物传感器的研究，借助钯的良好催化活性和碳纳米管的较大的比表面积、极强的导电性等实现超灵敏的DNA检测。合成了直径为3～4nm的钯(Pd)纳米粒子，将其与末端羧基化的多壁碳纳米管(COOH-MWCNT)结合，制得灵敏度增强的电化学DNA生物传感器。首先将一定量的Nafion、COOH-MWCNT及Pd纳米粒子的混合液涂在玻碳电极(GCE)表面，制得MWCNT/Pd修饰电极，对该电极进行了电化学特性的研究。然后通过5’端氨基修饰的寡聚核苷酸(5’-NH_2-DNA)与碳纳米管末端的羧基(—COOH)之间形成酰胺键而将ssDNA固定在MWCNT/Pd修饰电极上。与目标DNA杂交后，以亚甲基蓝(MB)为电化学杂交指示剂，实现对互补序列、非互补序列的识别和电化学测定。在亚甲基蓝的电化学反应中，由于碳纳米管具有很好的电子传递能力同时Pd纳米粒子具有很好的催化活性，可以使电化学DNA生物传感器的灵敏度大大提高。对目标DNA的检测下限可以达到1．2×10~(-13)M。
第四章基于层层组装技术实现DNA放大检测的电化学生物传感器研究
将层层组装技术用于金纳米颗粒标记的DNA生物传感器的研究中，通过电极表面的多次电荷翻转达到富集大量的目标DNA分子的目的，以此获得放大的DNA杂交信息。本文介绍了聚二烯丙基二甲基胺盐酸盐(PDDA)分子与DNA经过层层组装(layer-by-layer,LBL)的方法，以DNA探针分子上标记的金纳米颗粒为电化学检测手段，实现对目标DNA杂交信号的放大。运用交流阻抗技术(EIS)和紫外吸收光谱法(UV-Vis)对LBL的过程进行研究，实验结果表明多层膜能够均匀规则地组装在聚吡咯(PPy)修饰的电极表面，并通过层层组装将杂交信号放大。在优化条件条件下，组装层为6层时，其检测限达到3．20×10~(-14)M，该方法具有高灵敏度和特异性。通过采用干扰序列消除非特异性吸附，这种传感器表现出良好的稳定性和重现性。
第五章基于β-环糊精主客体识别作用的DNA电化学生物传感器研究
首次将主客体识别作用应用于DNA生物传感器的研究中，以β-环糊精对客体分子间甲基苯甲酸(mTA)的高效识别性成功地实现了对DNA分子的检测。将β-环糊精采用电化学方法聚合在氮乙酰基苯胺修饰的玻碳电极表面，以mTA作为客体分子标记于5’端氨基修饰寡聚核苷酸片段上，通过电化学交流阻抗对β-环糊精修饰电极捕获mTA标记的DNA进行了表征。其结果显示出该电极对mTA标记的DNA探针分子具有很强的包络作用，能够通过主客体的识别将ssDNA和dsDNA捕获到电极表面。分别采用金纳米颗粒标记探针和以亚甲基兰为杂交指示剂对目标DNA检测，均能通过主客体识别的方法获得良好的检测限。研究表明，β-环糊精修饰电极具有优良的再生性，可重复多次用于DNA的杂交检测。
第六章基于金纳米颗粒聚集体富集亚甲基兰的DNA与蛋白质的电化学生物传感器的研究
首次采用金纳米颗粒标记特定序列的寡聚核苷酸片段，设计了即可用于DNA检测又能实现对特殊蛋白质放大检测的研究方法。采用特殊设计的两段寡聚核苷酸片段，其一端均以金纳米颗粒标记，另外一端均为含有一段可以与凝血酶蛋白产生特异性结合的核酸适配体(适体)片段。当与目标分子(DNA或凝血酶蛋白)产生特异性结合作用时，该探针能与目标分子形成含有多个金纳米颗粒聚集体，将金纳米颗粒聚集体自组装在硫代三聚氢酸修饰的金电极表面，通过探针上的鸟嘌呤富集MB分子，实现对目标物的检测。探针上识别凝血酶的寡聚核苷酸片段含有多个鸟嘌呤碱基，它能与MB有很强的结合作用，因此富含鸟嘌呤的探针能够富集大量的MB分子在纳米颗粒聚集体上，同时，由于金纳米颗粒聚集体能加速MB氧化还原反应过程的电子传递，使得MB的氧化还原反应更容易进行，因此，对目标物的检测具有非常高的灵敏度。
With improved understanding of structure and function of human gene, and the development of the Human Genome Project, DNA separation and analysis has taken a more and more important role in the areas of clinical diagnosis, medicine, epidemic prevention, environmental protection and bioengineering. Wide-scale genetic testing requires the development easy-to-use, fast, inexpensive, miniaturized devices. Many new biological technologies emerged and found their applications in this field. Among them, DNA biosensors are rapidly developed and have received considerable attentions. Electrochemical DNA detection is a novel and developing technique that combining biochemical, electrochemical, medical and electronic techniques with the advantages of being simple, reliable, cheap, sensitive and selective for genetic detection, and has been a hot topic in the field of biochemistry and medicine.
The emergence of nanotechnology is opening new horizons for the application of nanoparticles in analytical chemistry. In particular, nanoparticles are of considerable interest in the world of nanoscience owing to their unique physical and chemical properties. With these unique properties, they are widely used in the fields of catalysis, optical absorption, medicine, magnetic medium, new materials synthesis. Such properties offer excellent prospects for chemical and biological sensing. The power and scope of such nanoparticles can be greatly enhanced by coupling them with biological recognition reactions and electrical processes (i.e. nanobioelectronics). Nanoparticle-biopolymer conjugates offer great potential for DNA diagnostics.
Supramolecular chemistry has been defined as the "chemistry of molecular assemblies and of the intermolecular bond". Combing with the material science, biological science, information technology and nanometer technology, it has been the supramolecular science and has been employed as a vital method to design, and prepare new materials and obtain novel properties. Therefore, supramolecular chemistry is believed to be the base of new concept and technology in the 21st century. Cyclodextrin (CD), as the most important host, have received considerable attention because of its particular characterization, and the studies on the host-guest interaction based on CD had been transferred from the processes and mechanism of inclusion complex between a pair of host and guest to the application in the fields such as analysis, medicine, environment protection and sensors.
The goal of the present study is to design and optimize new DNA hybridization techniques with high sensitivity and selectivity. This dissertation focuses on fabricating novel electrochemical DNA biosensors based on eletrochemical analysis technique, combining nano-materials, layer-by-layer technology and supramolecular inclusion interaction, thus developing a sensitive, sequence-specific and quantifiable gene detection method, and establishing the bases, especially one base mutation, then for application of electrochemical DNA biosensor to clinic diagnose.
Chapter 1: Preface
Firstly, we introduce the progress of DNA biosensor, including its principle (probe identification principle and immobilization method of ssDNA on solid support) and its classification (electrochemical DNA biosensor, optical DNA biosensor and piezoelectric DNA biosensor). Among these, we emphatically review the principle, progress, the application and development trends of electrochemical DNA biosensors. Second, the application of nano-materials on biosensors was introduced. At last, we pointed out the purpose and significance of the dissertation.
Chapter 2: The preparation of Ru(bpy)_3~(2+)-doped nanoparticle and its application in electrogenerated chemiluminescence detection DNA hybridization analysis
A sensitive electrogenerated chemiluminescence (ECL) detection of DNA hybridization, based on tris(2,2'-bipyridyl)ruthenium(Ⅱ) -doped silica nanoparticles (Ru(bpy)_3~(2+)-doped SNPs) as DNA tags, is described. In this protocol, Ru(bpy)_3~(2+)-doped SNPs was used for DNA labeling with trimethoxysilylpropy -diethylenetriamine (DETA) and glutaraldehyde as linking agents. The Ru(bpy)_3~(2+)-doped SNPs labeled DNA probe was hybridized with target DNA immobilized on the surface of PPy modified Pt electrode. The hybridization events were evaluated by ECL measurements and only the complementary sequence could form a double-stranded DNA (dsDNA) with DNA probe and give strong ECL signals. A three-base mismatch sequence and a non-complementary sequence had almost negligible responses. Due to the large number of Ru(bpy)_3~(2+) molecules inside SNPs, the assay allows detection at levels as low as 1.0×10~(-13) mol 1~(-1) of the target DNA. The intensity of ECL was linearly related to the concentration of the complementary sequence in the range of 2.0×10~(-13)-2.0×10~(-9) mol 1~(-1).
Chapter 3: Electrochemical DNA biosensors based on palladium nanoparticles combined with carbon nanotubes
Palladium nanoparticles, in combination with multi-walled carbon nanotubes (MWCNTs), were used to fabricate a sensitivity-enhanced electrochemical DNA biosensor. MWCNTs and palladium nanoparticles were dispersed in Nafion, which were used to modify a glassy carbon electrode (GCE). Oligonucleotides with amino groups at the 5' end were covalently linked onto carboxylic groups of MWCNTs on the electrode. The hybridization events were monitored by differential pulse voltammetry (DPV) measurement using methylene blue (MB) as an indicator. Due to the ability of carbon nanotubes to promote electron-transfer and the high catalytic activities of palladium nanoparticles for electrochemical reaction of methylene blue, the sensitivity of presented electrochemical DNA biosensors was remarkably improved. The detection limit of the method for target DNA was 1.2×10~(-13)M.
Chapter 4: Multilayer membranes via layer-by-Layer deposition of PDDA and DNA with Au nanoparticles as tags for DNA biosensing
A novel Au nanoparticles (Au-NPs)-based protocol for DNA hybridization detection based on assembly of alternating DNA and poly(dimethyldiallylammonium chloride) (PDDA) multilayer films by layer-by-layer (LBL) electrostatic adsorption has been studied. Electrochemical impedance spectroscopy (EIS) and UV-vis absorbance measurements were used to study the film assembly. All the results indicate that the uniform multilayer can be obtained on the polypyrrole (PPy) coated electrode surface and the hybridization reaction can be amplified by the layer-by-layer progress. The hybridization was detected the reductive signal of Au-NPs by direct electrochemical method and nonspecific adsorption was greatly eliminated by an irrelated DNA sequence to the target DNA. Under optimum conditions, a significant sensitivity enhancement had been obtained, and the detection limit was down to 3.20×10~(-14) M when 6 layers assembled. The DNA biosensor has good stability and reproducibility.
Chapter 5: Electrochemical detection of DNA sequence with host-guest recognition onβ-cyclodextrin modified electrode
The electrochemical sensing of DNA is accomplished firstly by the host-guest recognition system according to the very strong inclusion betweenβ-Cyclodextrin (β-CD) and m-toluic acid (mTA).β-CD, as the host molecular, was electropolymorized on the poly(N-acetylaniline) modified glassy carbon electrode by potential sweeping, and mTA, as the guest, was labled on the oligonucleotides with amino groups at the 5' end. The inclusion between P-CD modified electrode and mTA labeled DNA was investigated by CV and EIS, which turned out a strong inclusion interaction between them. Based on the host-guest recognition, introducing Au nanopaticles as tags and MB as indicator to detect DNA hybridization, respectively, has excellent detection limit and reproducibility.
Chapter 6: Bifunctional biosensor based on aggregation methylene blue by cross-linked Au nanoparticles and the functionalized aptamer segmentsWe report here on the construction of a biosensor can detect thrombin or DNA molecules by two functional aptamer segments, which will form Au-NPs/analyte aggregation by adding the analytes, and the redox indicator, MB, that is used to interact specifically with the guanine bases on the aptamer segments. Hybridization for DNA or incubation for thrombin not only result in the binding multi-Au-NPs labeled probe to the analyte for formation of an extended polymeric network, but also in aggregation abundant MB molecules on the aptamer segments which can govern the signals for the analytes. The novel bifunctional apatmer-based biosensing capability is coupled to the enormous amplification feature of the activation for MB through the Au-NPs conductive matrix to yield remarkably low (fmole) detection limits.
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