DNA电化学生物传感器中的新方法学研究
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摘要
随着疾病诊断、基因测试、法医鉴证、生化战争预防、环境监测等领域的发展,对特定DNA序列进行准确、简单、快速的检测越显重要。DNA生物传感器主要是利用碱基互补原理对目标DNA进行检测,当已知序列DNA探针与被检的DNA序列发生杂交反应,来辨明DNA的存在与否。其中,电化学DNA生物传感器利用杂交原理及电化学标记物为杂交检测信号,具有操作简便快速、信号灵敏,能与DNA生物芯片兼容等优点,具有非常重要的研究价值。目前电化学DNA检测方法以其轻巧便宜、高灵敏度、方便携带、能耗少、易于实现微型化等优点,受到了广泛的关注,成为当今生物学、医学领域的前沿性课题。
纳米技术的出现为各个科学领域提供新的发展前景。纳米微粒具有的特点有：大比表面积、高活性、高特异物性、极微小性等,与传感器所要求的多功能、微型化相互匹配。作为理想的传感器材料,需要有着高灵敏度、多样功能性、响应高,速度快、检测范围宽、选择性高、稳定性好。纳米微粒能很好地满足上述要求。以纳米材料为原料的化学传感器能够应用于生产、生活、环境监测等各个领域；目前单分子水平的探针制备技术、纳米集成阵列电极、修饰电极等方面的研究取得巨大的进展。
超分子化学是分子之间通过非共价键相互作用而形成的分子聚集体的化学学科,随着与医药科学、生命生物科学、信息科学、纳米材料科学的交叉融合中,超分子化学已发展为应用范围广泛的超分子科学。被认为是21世纪新思路和高科技的重要基础学科之一。环糊精作为典型的超分子识别个体中的重要主体化合物以其独特的识别性质受到广泛的关注。对它的研究从主客体识别形成包合物的机理已经转移到对其在分析化学、医药制备、环境检测和生物传感器等领域的应用研究。
本论文的主要创新之处就是将纳米技术及超分子包合作用相互融合构建了不需要固定探针的新型DNA电化学生物传感器。同时基于生物分子之间的替代作用等与电化学分析技术相结合构建了用于检测DNA及凝血酶蛋白的电化学传感器。这两种传感器具有高特异性,及构建简单,能够成功地应用于对特定序列DNA片断的选择性测定和对目标蛋白的准确识别,为基因及蛋白质分析测定提供了一种简便、便捷、廉价的新理念。
首先介绍了DNA电化学生物传感器的研究进展。着重介绍了DNA生物传感器的原理(包括DNA探针及其分子识别原理和探针DNA在固体基质表面的固定化)和DNA生物传感器中不同的杂交电化学标示剂,叙述了DNA电化学传感器在基因检测等方面的应用。接着介绍了核酸适配体生物传感器和碳纳米管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。
我们基于目标蛋白与其核酸适配体替代机制构建的设计了一种电化学适体传感器。该传感器预先将含有巯基的单链固定DNA(IP)与目标凝血酶(thrombin)核酸适配体(aptamer)通过杂交反应得到双链DNA(dsDNA),通过Au-S键自组装于金电极表面,而另一标记有CdS纳米颗粒的单链DNA(DP-CdS)被用作检测探针。当预先制备好的双链DNA修饰金电极浸入含有凝血酶与DP-CdS的共存的溶液时,dsDNA中的aptamer更倾向与目标thrombin结合形成G-四分体,从而引起dsDNA离解,IP从而能够与DP-CdS碱基互补。将电极捕获的CdS纳米颗粒溶解,使用汞膜电极对溶出的Cd2+离子进行电化学检测,获得灵敏的电化学信号传递。Cd2+离子的峰电流相对thrombin浓度在2.3×10-9-2.3×10-12mol/L范围内有良好的线性响应,检出限为4.3×10-13mol/L。检测具有良好的特异性,BSA,溶菌酶等其他蛋白质共存不会影响thrombin的检测。
我们设计了一种基于DNA之间杂交竞争替代机制的电化学DNA传感器。该传感器通过预先将3’修饰了巯基,5’修饰了二茂铁的发夹探针DNA与识别DNA杂交形成双链DNA,然后通过金硫键将其组装于金电极表面。此时二茂铁位于双链DNA的顶端,远离电极表面,呈现出"Switch-off"状态,仅仅产生一个小的背景信号。目标DNA加入后,由于与识别DNA之间具有更多互补碱基,在杂交的竞争作用下,识别DNA离开探针DNA,与目标结合,探针DNA随之恢复原有的发夹状态,二茂铁靠近电极表面,呈现出"Switch-on"状态,同时获得一个较大的电化学信号。通过目标加入前后电化学信号变化,可实现对目标的检测。本文将适体技术、电化学分子信标技术相结合,实现了对目标DNA和蛋白质的灵敏、高效、方便的检测。此电化学竞争开关生物传感器有望在生物检测领域有更广泛的应用。
我们基于主客体分子识别技术设计了一种不需要固定探针DNA的电化学检测DNA的新方法。这种传感技术采用了一种新颖的以茎环结构形式存在的双标记DNA探针(DLP),该探针的一端标记了4-4-二甲氨基苯基偶氮苯甲酸(dabcyl)作为客体分子,另一端连接了CdS纳米颗粒作为电化学指示剂指示杂交反应的发生。同时使用环糊精修饰的电极捕获DLP上标记的dabcyl。杂交反应发生前,探针保持茎环结构,迫使dabcyl分子靠近CdS纳米颗粒。由于空间立体效应,阻碍了dabcyl与电极表面β-CD的结合,导致DLP不能被电极捕获。与目标DNA杂交后,DLP的茎环结构展开,使得dabcyl分子易于进入修饰电极表面的β-CD空腔中,进而DLP信号可以被β-CD修饰电极捕获。并且,捕获效应与目标DNA浓度成正比。
在这篇文章中,我们基于主客体分子识别技术构建了电化学检测DNA的新方法。这种传感技术采用了一种新颖的以茎环结构形式存在的双标记DNA探针(DLP),该探针的一端标记了4-4-二甲氨基苯基偶氮苯甲酸(dabcyl)作为客体分子,另一端标记了金胶作为电化学指示剂指示杂交反应的发生。同时采用α-CD/MCNTs/GCE电极捕获杂交反应转换产生的电化学信号。杂交反应发生前,双标记DNA探针保持茎环结构,迫使dabcyl分子靠近金胶。由于金胶的空间立体效应,阻碍了dabcyl与电极表面a-CD的结合,导致DLP不能被电极捕获。与目标DNA杂交后,DLP的茎环结构展开,使得dabcyl分子易于进入修饰电极表面的a-CD空腔中,进而DLP信号可以被a-CD修饰电极捕获。并且,捕获效应与目标DNA浓度成正比。因此,与目标的杂交过程可灵敏地转换并检测DLP标记的金胶AuCl4-的电化学还原电流信号。采用这种新方法,检测目标DNA的浓度可低至2.6×10-10M甚至对单碱基错配也有很好的区分能力。
我们构建了一种基于环糊精修饰的纳米颗粒的电化学DNA传感器,将DNA杂交引起的探针DNA构型变化通过主客体识别技术与纳米颗粒标记结合,并转换为电化学信号。该传感器中,末端标记有4-4-二甲氨基苯基偶氮苯甲酸(dabcyl)和巯基基团的发夹DNA作为探针DNA通过金硫键组装于金电极表面,而表面修饰有β-环糊精的CdS纳米颗粒(CdS-CDs)则被用于电化学信号提供者和主客体识别元件。无目标存在时,固定于电极上的探针DNA保持茎环结构,此时由于空间位阻效应,dabcyl被屏蔽难以触及溶液中的CdS-CDs,而当探针DNA与目标DNA杂交之后,探针DNA发生构型变化,使得最初被屏蔽的dabcyl则得以与CdS-CDs表面的β-环糊精发生主客体识别,从而使得目标杂交事件被转换为CdS-CDs给出的电化学信号。该主客体识别电化学传感器可用于检测pmol的目标DNA,对单碱基错配显示出良好的分辨能力。
With improved understanding of human gene structure and function, 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 of 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. DNA electrochemical biosensor 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.
Nanotechnology is opening new horizons for the application of nanoparticles in analytical chemistry. Owing to unique physical and chemical properties, nanoparticles receive considerable interest and have been 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.
The molecular recognition technology, defined as the supramolecular noncovalent interaction between the "host" and "guest" molecules, has played an important role in the chemical sensing field. 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 novel DNA hybridization detection techniques with high sensitivity and selectivity. This dissertation focuses on fabricating novel electrochemical DNA biosensors based on host-guest recognition technology, combining electrochemical analysis technique and nano-materials, 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. And based on protein-induced strand displacement, we constructed a novel protein electrochemical biosensor.
Firstly, we introduce the DNA biosensor, including its principle (probe identification principle and immobilization method of ssDNA on solid support) and its electrochemical label. Among these, we emphatically review the principle, progress, the application and development trends of electrochemical DNA biosensors. Second, we introduce the principle of aptamer biosensor, including selex technique and application. The application of carbon nano-tube on biosensors was introduced. At last, we pointed out the purpose and significance of the dissertation.
A sensitive electrochemical aptasensor for detection of thrombin based on target protein-induced strand displacement is presented. For this proposed aptasensor, dsDNA which was prepared by the hybridization reaction of the immobilized probe ssDNA (IP) containing thiol group and thrombin aptamer base sequence was initially immobilized on the Au electrode by self-assemble via Au-S bind, and a DNA labeled CdS nanoparticles (DP-CdS) was used as a detection probe. When the so prepared dsDNA modified Au electrode was immersed into a solution containing target protein and DP-CdS, the aptamer in the dsDNA preferred to form G-quarter structure with the present target protein and the dsDNA sequence was released one single strand and returned to IP strand which consequently hybridized with DP-CdS. After dissolving the captured CdS particles from the electrode, a mercury-film electrode was used for electrochemical detection of these Cd2+ ions which offered sensitive electrochemical signal transduction. The peak current of Cd2+ ions had a good linear relationship with the thrombin concentration in the range of 2.3×10-9-2.3×10-12 mol/L and the detection limit was 4.3×10-13 mol/L of thrombin. The detection was also specific for thrombin without being affected by the coexistence of other proteins, such as BSA and lysozyme.
A competitor-switching electrochemical sensor based on a generic displacement strategy was designed for DNA detection. In this strategy, an unmodified single-stranded DNA (cDNA) completely complementary to the target DNA served as the molecular recognition element, while a hairpin DNA (hDNA) labeled with a ferrocene (Fc) and a thiol group at its terminals served as both the competitor element and the probe. This electrochemical sensor was fabricated by self-assembling a dsDNA onto a gold electrode surface. The dsDNA was pre-formed through the hybridization of Fc-labeled hDNA and cDNA with their part complementary sequences. Initially, the labeled ferrocene in the dsDNA was far from surface of the electrode, the electrochemical sensor exhibited a "switch-off" mode due to unfavorable electron transfer of Fc label. However, in the presence of target DNA, cDNA was displaced from hDNA by target DNA, the hairpin-open hDNA restored its original hairpin structure and the ferrocene approached onto the electrode surface, thus the electrochemical sensor exhibited a "switch-on" mode accompanying with a change in the current response. The experimental results showed that as low as 4.4×10-10 mol/L target DNA could be distinguishingly detected, and this method had obvious advantages such as facile operation, low cost and reagentless procedure.
We report on a new electrochemical method to detect the hybridization specificity by using host-guest recognition technique. A hairpin DNA with dabcyl-labeled at its 3' and NH2 group at 5' terminal was combined with CdS nanoparticle to construct a double-labeled probe (DLP), which could selectively hybridize with its target DNA in homogenous solution. Aβ-CD modified Poly(N-acetylaniline) glassy carbon electrode was used for capturing the dabcyl label in DLP. When without binding with target DNA, the DLP kept its stem-loop structure which shielded the dabcyl molecule due to the loop of the hairpin DNA and CdS nanoparticle blocking dabcyl enter into the cavity of theseβ-CD molecules on the electrode. However, in present of complementary sequence, the target-binding DLP was incorporated into double stranded DNA, causing the DLP's loop-stem structure opened and then the dabcyl was easily captured by theβ-CD modified electrode. During electrochemical measurement, the signal from the dissolved Cd2+ was used for target DNA quantitative analysis.
We report a new strategy for electrochemical DNA detection in homogeneous solution based on the host-guest molecule recognition technique. In this sensing protocol, a novel dually-labeled DNA probe (DLP) in a stem-loop structure was employed, which was designed with dabcyl labeled at one end as a guest molecule, and with Au nanoparticle labeled at the other end as electrochemical tag to indicate the hybridization occurrence. Oneα-CD/MCNTs/GCE was used for capturing the DNA hybridization and electrochemical signal transduction. Before the hybridization, the DLP remained in the stem-loop structure, which forced the dabcyl molecular to be closed to the Au nanoparticle. Due to the steric effect of the Au nanoparticle, the dabcyl was prevented from conjugating with theα-CD on the electrode and resulting in that the DLP could not be captured by the electrode. After hybridized with the target DNA, the target-binding DLP caused the DLP's loop-stem structure opened and then the dabcyl molecule was easily entering the cavity of the a-CD modified electrode and resulting in that the DLP could be captured by the a-CD modified electrode and the capture efficiency was proportion with the concentration of the target DNA. Therefore, the target hybridization event can be sensitively transduced via detecting the electrochemical reduction current signal of AuCl4- of Au nanoparticles labeled at the DLP. By using this strategy, as low as 2.6×10-10 M DNA target could be detected with excellent differentiation ability for even single mismatch.
We herein constructed a sensor that converts target DNA hybridization-induced conformational transformation of the probe DNA to electrochemical response based on host-guest recognition and nanoparticle label. In the sensor, the hairpin DNA terminal-labeled with 4-((4-(Dimethylamino)phenyl)azo)benzoic acid (dabcyl) and thiol group was immobilized on Au electrode surface as the probe DNA by Au-S bond, and the CdS nanoparticles surface-modified withβ-cyclodextrins (CdS-CDs) were employed as electrochemical signal provider and host-guest recognition element. Initially, the probe DNA immobilized on electrode kept the stem-loop configuration, which shielded dabcyl from docking with the CdS-CDs in solution due to the steric effect. After target hybridization, the probe DNA underwent a significant conformational change, which forced dabcyl away from the electrode. As a result, formerly-shielded dabcyl became accessible to host-guest recognition betweenβ-cyclodextrin (β-CD) and dabcyl, thus the target hybridization event could be sensitively transduced to electrochemical signal provided by CdS-CDs. This host-guest recognition-based electrochemical sensor has been able to detect as low as picomolar DNA target with excellent differentiation ability for even single mismatch.
纳米技术的出现为各个科学领域提供新的发展前景。纳米微粒具有的特点有：大比表面积、高活性、高特异物性、极微小性等,与传感器所要求的多功能、微型化相互匹配。作为理想的传感器材料,需要有着高灵敏度、多样功能性、响应高,速度快、检测范围宽、选择性高、稳定性好。纳米微粒能很好地满足上述要求。以纳米材料为原料的化学传感器能够应用于生产、生活、环境监测等各个领域；目前单分子水平的探针制备技术、纳米集成阵列电极、修饰电极等方面的研究取得巨大的进展。
超分子化学是分子之间通过非共价键相互作用而形成的分子聚集体的化学学科,随着与医药科学、生命生物科学、信息科学、纳米材料科学的交叉融合中,超分子化学已发展为应用范围广泛的超分子科学。被认为是21世纪新思路和高科技的重要基础学科之一。环糊精作为典型的超分子识别个体中的重要主体化合物以其独特的识别性质受到广泛的关注。对它的研究从主客体识别形成包合物的机理已经转移到对其在分析化学、医药制备、环境检测和生物传感器等领域的应用研究。
本论文的主要创新之处就是将纳米技术及超分子包合作用相互融合构建了不需要固定探针的新型DNA电化学生物传感器。同时基于生物分子之间的替代作用等与电化学分析技术相结合构建了用于检测DNA及凝血酶蛋白的电化学传感器。这两种传感器具有高特异性,及构建简单,能够成功地应用于对特定序列DNA片断的选择性测定和对目标蛋白的准确识别,为基因及蛋白质分析测定提供了一种简便、便捷、廉价的新理念。
首先介绍了DNA电化学生物传感器的研究进展。着重介绍了DNA生物传感器的原理(包括DNA探针及其分子识别原理和探针DNA在固体基质表面的固定化)和DNA生物传感器中不同的杂交电化学标示剂,叙述了DNA电化学传感器在基因检测等方面的应用。接着介绍了核酸适配体生物传感器和碳纳米管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。
我们基于目标蛋白与其核酸适配体替代机制构建的设计了一种电化学适体传感器。该传感器预先将含有巯基的单链固定DNA(IP)与目标凝血酶(thrombin)核酸适配体(aptamer)通过杂交反应得到双链DNA(dsDNA),通过Au-S键自组装于金电极表面,而另一标记有CdS纳米颗粒的单链DNA(DP-CdS)被用作检测探针。当预先制备好的双链DNA修饰金电极浸入含有凝血酶与DP-CdS的共存的溶液时,dsDNA中的aptamer更倾向与目标thrombin结合形成G-四分体,从而引起dsDNA离解,IP从而能够与DP-CdS碱基互补。将电极捕获的CdS纳米颗粒溶解,使用汞膜电极对溶出的Cd2+离子进行电化学检测,获得灵敏的电化学信号传递。Cd2+离子的峰电流相对thrombin浓度在2.3×10-9-2.3×10-12mol/L范围内有良好的线性响应,检出限为4.3×10-13mol/L。检测具有良好的特异性,BSA,溶菌酶等其他蛋白质共存不会影响thrombin的检测。
我们设计了一种基于DNA之间杂交竞争替代机制的电化学DNA传感器。该传感器通过预先将3’修饰了巯基,5’修饰了二茂铁的发夹探针DNA与识别DNA杂交形成双链DNA,然后通过金硫键将其组装于金电极表面。此时二茂铁位于双链DNA的顶端,远离电极表面,呈现出"Switch-off"状态,仅仅产生一个小的背景信号。目标DNA加入后,由于与识别DNA之间具有更多互补碱基,在杂交的竞争作用下,识别DNA离开探针DNA,与目标结合,探针DNA随之恢复原有的发夹状态,二茂铁靠近电极表面,呈现出"Switch-on"状态,同时获得一个较大的电化学信号。通过目标加入前后电化学信号变化,可实现对目标的检测。本文将适体技术、电化学分子信标技术相结合,实现了对目标DNA和蛋白质的灵敏、高效、方便的检测。此电化学竞争开关生物传感器有望在生物检测领域有更广泛的应用。
我们基于主客体分子识别技术设计了一种不需要固定探针DNA的电化学检测DNA的新方法。这种传感技术采用了一种新颖的以茎环结构形式存在的双标记DNA探针(DLP),该探针的一端标记了4-4-二甲氨基苯基偶氮苯甲酸(dabcyl)作为客体分子,另一端连接了CdS纳米颗粒作为电化学指示剂指示杂交反应的发生。同时使用环糊精修饰的电极捕获DLP上标记的dabcyl。杂交反应发生前,探针保持茎环结构,迫使dabcyl分子靠近CdS纳米颗粒。由于空间立体效应,阻碍了dabcyl与电极表面β-CD的结合,导致DLP不能被电极捕获。与目标DNA杂交后,DLP的茎环结构展开,使得dabcyl分子易于进入修饰电极表面的β-CD空腔中,进而DLP信号可以被β-CD修饰电极捕获。并且,捕获效应与目标DNA浓度成正比。
在这篇文章中,我们基于主客体分子识别技术构建了电化学检测DNA的新方法。这种传感技术采用了一种新颖的以茎环结构形式存在的双标记DNA探针(DLP),该探针的一端标记了4-4-二甲氨基苯基偶氮苯甲酸(dabcyl)作为客体分子,另一端标记了金胶作为电化学指示剂指示杂交反应的发生。同时采用α-CD/MCNTs/GCE电极捕获杂交反应转换产生的电化学信号。杂交反应发生前,双标记DNA探针保持茎环结构,迫使dabcyl分子靠近金胶。由于金胶的空间立体效应,阻碍了dabcyl与电极表面a-CD的结合,导致DLP不能被电极捕获。与目标DNA杂交后,DLP的茎环结构展开,使得dabcyl分子易于进入修饰电极表面的a-CD空腔中,进而DLP信号可以被a-CD修饰电极捕获。并且,捕获效应与目标DNA浓度成正比。因此,与目标的杂交过程可灵敏地转换并检测DLP标记的金胶AuCl4-的电化学还原电流信号。采用这种新方法,检测目标DNA的浓度可低至2.6×10-10M甚至对单碱基错配也有很好的区分能力。
我们构建了一种基于环糊精修饰的纳米颗粒的电化学DNA传感器,将DNA杂交引起的探针DNA构型变化通过主客体识别技术与纳米颗粒标记结合,并转换为电化学信号。该传感器中,末端标记有4-4-二甲氨基苯基偶氮苯甲酸(dabcyl)和巯基基团的发夹DNA作为探针DNA通过金硫键组装于金电极表面,而表面修饰有β-环糊精的CdS纳米颗粒(CdS-CDs)则被用于电化学信号提供者和主客体识别元件。无目标存在时,固定于电极上的探针DNA保持茎环结构,此时由于空间位阻效应,dabcyl被屏蔽难以触及溶液中的CdS-CDs,而当探针DNA与目标DNA杂交之后,探针DNA发生构型变化,使得最初被屏蔽的dabcyl则得以与CdS-CDs表面的β-环糊精发生主客体识别,从而使得目标杂交事件被转换为CdS-CDs给出的电化学信号。该主客体识别电化学传感器可用于检测pmol的目标DNA,对单碱基错配显示出良好的分辨能力。
With improved understanding of human gene structure and function, 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 of 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. DNA electrochemical biosensor 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.
Nanotechnology is opening new horizons for the application of nanoparticles in analytical chemistry. Owing to unique physical and chemical properties, nanoparticles receive considerable interest and have been 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.
The molecular recognition technology, defined as the supramolecular noncovalent interaction between the "host" and "guest" molecules, has played an important role in the chemical sensing field. 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 novel DNA hybridization detection techniques with high sensitivity and selectivity. This dissertation focuses on fabricating novel electrochemical DNA biosensors based on host-guest recognition technology, combining electrochemical analysis technique and nano-materials, 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. And based on protein-induced strand displacement, we constructed a novel protein electrochemical biosensor.
Firstly, we introduce the DNA biosensor, including its principle (probe identification principle and immobilization method of ssDNA on solid support) and its electrochemical label. Among these, we emphatically review the principle, progress, the application and development trends of electrochemical DNA biosensors. Second, we introduce the principle of aptamer biosensor, including selex technique and application. The application of carbon nano-tube on biosensors was introduced. At last, we pointed out the purpose and significance of the dissertation.
A sensitive electrochemical aptasensor for detection of thrombin based on target protein-induced strand displacement is presented. For this proposed aptasensor, dsDNA which was prepared by the hybridization reaction of the immobilized probe ssDNA (IP) containing thiol group and thrombin aptamer base sequence was initially immobilized on the Au electrode by self-assemble via Au-S bind, and a DNA labeled CdS nanoparticles (DP-CdS) was used as a detection probe. When the so prepared dsDNA modified Au electrode was immersed into a solution containing target protein and DP-CdS, the aptamer in the dsDNA preferred to form G-quarter structure with the present target protein and the dsDNA sequence was released one single strand and returned to IP strand which consequently hybridized with DP-CdS. After dissolving the captured CdS particles from the electrode, a mercury-film electrode was used for electrochemical detection of these Cd2+ ions which offered sensitive electrochemical signal transduction. The peak current of Cd2+ ions had a good linear relationship with the thrombin concentration in the range of 2.3×10-9-2.3×10-12 mol/L and the detection limit was 4.3×10-13 mol/L of thrombin. The detection was also specific for thrombin without being affected by the coexistence of other proteins, such as BSA and lysozyme.
A competitor-switching electrochemical sensor based on a generic displacement strategy was designed for DNA detection. In this strategy, an unmodified single-stranded DNA (cDNA) completely complementary to the target DNA served as the molecular recognition element, while a hairpin DNA (hDNA) labeled with a ferrocene (Fc) and a thiol group at its terminals served as both the competitor element and the probe. This electrochemical sensor was fabricated by self-assembling a dsDNA onto a gold electrode surface. The dsDNA was pre-formed through the hybridization of Fc-labeled hDNA and cDNA with their part complementary sequences. Initially, the labeled ferrocene in the dsDNA was far from surface of the electrode, the electrochemical sensor exhibited a "switch-off" mode due to unfavorable electron transfer of Fc label. However, in the presence of target DNA, cDNA was displaced from hDNA by target DNA, the hairpin-open hDNA restored its original hairpin structure and the ferrocene approached onto the electrode surface, thus the electrochemical sensor exhibited a "switch-on" mode accompanying with a change in the current response. The experimental results showed that as low as 4.4×10-10 mol/L target DNA could be distinguishingly detected, and this method had obvious advantages such as facile operation, low cost and reagentless procedure.
We report on a new electrochemical method to detect the hybridization specificity by using host-guest recognition technique. A hairpin DNA with dabcyl-labeled at its 3' and NH2 group at 5' terminal was combined with CdS nanoparticle to construct a double-labeled probe (DLP), which could selectively hybridize with its target DNA in homogenous solution. Aβ-CD modified Poly(N-acetylaniline) glassy carbon electrode was used for capturing the dabcyl label in DLP. When without binding with target DNA, the DLP kept its stem-loop structure which shielded the dabcyl molecule due to the loop of the hairpin DNA and CdS nanoparticle blocking dabcyl enter into the cavity of theseβ-CD molecules on the electrode. However, in present of complementary sequence, the target-binding DLP was incorporated into double stranded DNA, causing the DLP's loop-stem structure opened and then the dabcyl was easily captured by theβ-CD modified electrode. During electrochemical measurement, the signal from the dissolved Cd2+ was used for target DNA quantitative analysis.
We report a new strategy for electrochemical DNA detection in homogeneous solution based on the host-guest molecule recognition technique. In this sensing protocol, a novel dually-labeled DNA probe (DLP) in a stem-loop structure was employed, which was designed with dabcyl labeled at one end as a guest molecule, and with Au nanoparticle labeled at the other end as electrochemical tag to indicate the hybridization occurrence. Oneα-CD/MCNTs/GCE was used for capturing the DNA hybridization and electrochemical signal transduction. Before the hybridization, the DLP remained in the stem-loop structure, which forced the dabcyl molecular to be closed to the Au nanoparticle. Due to the steric effect of the Au nanoparticle, the dabcyl was prevented from conjugating with theα-CD on the electrode and resulting in that the DLP could not be captured by the electrode. After hybridized with the target DNA, the target-binding DLP caused the DLP's loop-stem structure opened and then the dabcyl molecule was easily entering the cavity of the a-CD modified electrode and resulting in that the DLP could be captured by the a-CD modified electrode and the capture efficiency was proportion with the concentration of the target DNA. Therefore, the target hybridization event can be sensitively transduced via detecting the electrochemical reduction current signal of AuCl4- of Au nanoparticles labeled at the DLP. By using this strategy, as low as 2.6×10-10 M DNA target could be detected with excellent differentiation ability for even single mismatch.
We herein constructed a sensor that converts target DNA hybridization-induced conformational transformation of the probe DNA to electrochemical response based on host-guest recognition and nanoparticle label. In the sensor, the hairpin DNA terminal-labeled with 4-((4-(Dimethylamino)phenyl)azo)benzoic acid (dabcyl) and thiol group was immobilized on Au electrode surface as the probe DNA by Au-S bond, and the CdS nanoparticles surface-modified withβ-cyclodextrins (CdS-CDs) were employed as electrochemical signal provider and host-guest recognition element. Initially, the probe DNA immobilized on electrode kept the stem-loop configuration, which shielded dabcyl from docking with the CdS-CDs in solution due to the steric effect. After target hybridization, the probe DNA underwent a significant conformational change, which forced dabcyl away from the electrode. As a result, formerly-shielded dabcyl became accessible to host-guest recognition betweenβ-cyclodextrin (β-CD) and dabcyl, thus the target hybridization event could be sensitively transduced to electrochemical signal provided by CdS-CDs. This host-guest recognition-based electrochemical sensor has been able to detect as low as picomolar DNA target with excellent differentiation ability for even single mismatch.
引文
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