电化学发光DNA和适体生物传感器的研究
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摘要
人类遗传性疾病、传染性疾病、癌症等威胁着人类的生命,这些疾病的早期诊断和治疗都依赖于对病源、基因检测和药物的研究。建立简单、敏感、特异和快速的病源、基因和药物检测方法,对疾病的预防、诊断和治疗具有重要的意义。生物传感器是生物分子识别单元(如酶、抗体或单链DNA)与信号转换元件偶联组成的分析器件,是简单廉价快速免疫检测和核酸检测的重要工具。生物传感器的研究已成为现代分析化学研究的前沿课题之一。在生物传感器生物分子识别元件中,酶和单抗或多抗的制备比较繁琐、固定时易损失活性、活性保存时间有限、使用时对环境和样品条件要求比较高,因此,利用新型高特异性高稳定性生物识别单元,建立高选择型高灵敏度的生物传感新方法,也成为当前分析化学研究一项具有挑战性的研究工作。适体具备类似抗体对靶分子高亲合力和特异性、分子量小、结构简单、易合成和可进行连接性修饰等优点,而且反应速度快、可反复使用和长期保存。因此,适体这些独特的优点使其被认为有望取代抗体或弥补抗体不足而成为新一代生物识别分子,适体传感器的研究已成为生物传感器研究中的研究课题。
电化学发光法兼有电化学和化学发光法的双重优点,具有极低的检测限、极宽的线性范围等优点;相对于荧光法,无光漂白,不需要光源和分光系统等优点;相对于电化学检测,具有检测限低和受电极污染影响小的优点。本论文研究工作旨在基于纳米粒子信号放大作用,结合生物分子识别物质DNA和适体的特异性,研制高灵敏度、高选择性新型电化学发光DNA和适体生物传感器。本论文研究工作是在国家自然科学基金“电化学发光适配体生物传感器”(No.20775046),“微阵列生物传感器信号化学放大基础研究”(No.90607016)和“新型功能纳米材料组装电化学发光生物亲合传感器的研究”(No.20375025)项目的资助和陕西师范大学优秀博士论文资助项目的资助下完成的。本论文研制了一种高灵敏度、高选择性、简单的新型电化学发光DNA杂交生物传感器;研制了一种简单、快速、灵敏的可卡因电化学发光适体生物传感器;研制了三种简单、快速、灵敏的凝血酶电化学发光适体生物传感器;还构建了非标记溶菌酶电化学发光适体传感器。
本论文由五章组成。第一章为引言。引言部分介绍了电化学发光分析的原理、特点和电化学发光反应的机理;重点介绍了DNA与适体生物传感器的构造、原理、特点以及分析应用,总结了适体分子在电极上的几种主要固定方法;介绍了纳米材料作为电极修饰材料和探针载体的优点以及在DNA生物传感器中的应用;还简要介绍了本论文的目的和意义以及主要研究内容。
第二章为电化学发光DNA杂交生物传感器的研究。本章研究工作旨在提高电化学发光DNA杂交检测的灵敏度,基于单壁碳纳米管负载大量钌联吡啶复合物标记,研制了一种超灵敏的电化学发光DNA杂交生物传感器。单链DNA探针(ss-DNA)和钌联吡啶复合物负载到单壁碳纳米管上,作为电化学发光探针。当修饰有巯基的捕获ss-DNA自组装到金电极表面,然后与目标ss-DNA进行杂交,进而与电化学发光探针杂交,形成DNA夹心结构,电化学激发后产生一个强的电化学发光响应信号。该传感器的电化学发光强度与完全互补目标ss-DNA浓度在2.4×10~(-14)mol/L～1.7×10~(-12)mol/L之间呈良好的线性关系,检出限为9×10~(-15)mol/L。该传感器对完全互补目标ss-DNA和两碱基错配ss-DNA有一定识别作用。该工作表明单壁碳纳米管可以负载电化学发光探针,从而建立超灵敏的电化学发光DNA杂交生物传感器。
第三章为可卡因电化学发光适体传感器的研究。以可卡因适体为分子识别物质,可卡因为目标分析物,钌联吡啶衍生物为电化学发光标记物,提出并设计了一种新型的基于适体的电化学发光检测小分子药物可卡因的适体生物传感器。3′末端标记有钌联吡啶衍生物的可卡因适体为电化学发光探针。通过巯基自组装将电化学发光探针固定到电极上制备成为电化学发光适体传感器。当目标物质可卡因存在时,适体折叠,三个双链茎与可卡因结合,适体发生构象转变,钌联吡啶衍生物离电极距离变近,电化学发光强度增强。电化学发光积分强度与可卡因浓度在5.0×10~(-9)mol/L-3.0×10~(-7)mol/L之间呈良好的线性关系,检出限为1×10~(-9)mol/L。
第四章为凝血酶电化学发光适体传感器的研究。本章的研究工作旨在设计基于适体的电化学发光检测蛋白质的适体生物传感器。以凝血酶适体作为分子识别物质,以凝血酶作为目标分析物,研制了三种简单、快速、灵敏的凝血酶电化学发光适体生物传感器。
1.基于二茂铁淬灭钌联吡啶电化学发光设计了一种新型的检测凝血酶电化学发光适体传感器。首先自组装捕获探针到金电极上,捕获探针序列包括凝血酶适体和与DNA标记钌联吡啶(RuDNA)结合部分,随后将与RuDNA和二茂铁标记的DNA(FcDNA)探针依次完全互补单链DNA序列结合在固定化捕获探针序列上,构成传感器。在没有目标物质凝血酶存在时,由于FcDNA和RuDNA接近,产生电化学发光淬灭,得到较低的电化学发光响应信号;存在目标物质凝血酶时,由于FcDNA/凝血酶适体双链变为凝血酶适体/凝血酶复合物,电化学发光淬灭消失,产生一个增强的电化学发光响应信号。该传感器的电化学发光强度与凝血酶浓度在2.0×10~(-10)mol/L～2.0×10~(-7)mol/L范围内呈良好的线性关系,对凝血酶的检出限为6×10~(-11)mol/L。实验结果表明,所设计基于二茂铁淬灭钌联吡啶电化学发光凝血酶适体传感器为信号增强型适体传感器,可有效的降低背景信号,提高检测蛋白质的灵敏度。
2.利用适体在目标分子的引入时,使适体原本形成的DNA/DNA双螺旋结构转变为DNA/目标分子的复合物结构,发生构型转换机制,研制了一种用于高灵敏检测凝血酶的电化学发光传感器。首先在金电极表面通过1,6-己二硫醇自组装纳米金,再将巯基修饰的捕获探针组装在纳米金表面,该捕获探针与钌联吡啶衍生物标记的凝血酶适体探针杂交后,即组成传感器。凝血酶的存在使钌联吡啶衍生物标记的适体探针从电极表面脱落而导致电化学发光强度下降。该传感器可对凝血酶进行特异性识别与检测,其电化学发光强度与凝血酶浓度在2.7×10~(-12)mol/L～2.7×10~(-9)mol/L范围内呈良好的线性关系,检出限为8×10~(-13)mol/L。该传感器有较高的灵敏度,可在水中热解后再生,稳定性良好。
3.以碳纳米管作为信号物质载体,结合凝血酶的两段适体,构建了高灵敏的电化学发光适体传感器。将巯基修饰的凝血酶适体Ⅰ通过自组装到金电极表面,形成识别层,特异性“捕捉”目标蛋白质-凝血酶,进而结合电化学发光探针(碳纳米管负载凝血酶适体Ⅱ和钌联吡啶复合物)形成夹心结构,在含有三丙胺的检测液中通过检测电化学发光探针的电化学发光信号对凝血酶进行定量检测。实验证明,此传感器具有优异的特异性和超高的灵敏度,对凝血酶检出限可达3×10~(-15)mol/L。
第五章为非标记溶菌酶电化学发光适体传感器的研究。以溶菌酶适体作为分子识别物质,以溶菌酶作为目标分析物,基于Ru(bpy)_3~(2+)静电结合到修饰有适体探针的电极表面,产生的电化学发光响应,设计了一种灵敏的非标记电化学发光溶菌酶适体传感器。通过表面结合阳离子电化学发光活性物质Ru(bpy)_3~(2+)的电化学发光强度积分值对凝血酶进行识别和定量分析,电化学发光强度积分值与溶菌酶的浓度在6.4×10~(-10)～6.4×10~(-7)mol/L范围内呈良好的线性关系,检出限为1.2×10~(-10)mol/L。探索建立了电化学发光测定溶菌酶适体与溶菌酶结合的解离常数。
本论文所研制的电化学发光DNA和适体生物传感器,为DNA、小分子药物和蛋白质的快速灵敏检测提供了良好的分析器件和分析新方法。金纳米粒子提供相对大的比表面积,可以提高凝血酶适体在电极上的固定量,从而提高电化学发光检测凝血酶的灵敏度。碳纳米管可以负载有多个信号分子,从而使传感器检测DNA和凝血酶的灵敏度大大提高。本论文的研究工作为进一步研制高灵敏度和高选择电化学发光DNA和适体生物传感器提供了基础性研究资料,对此方面的研究工作具有一定的促进作用。
Biosensors are defined as analytical devices incorporating a biological material(e.g.tissue, microorganisms,organelles,cell receptors,enzymes,antibodies,nucleic acids,natural products etc.), a biologically derived material(e.g.recombinant antibodies,engineered proteins) or a biomimic(e.g. synthetic catalysts,combinatorial ligands,imprinted polymers) intimately associated with or integrated within a physicochemical transducer or transducing microsystem,which may be optical, electrochemical,thermometric,piezoelectric,magnetic or micromechanical.The research of biosensors has already become new frontier of modern analytical chemistry.Aptamers have several advantages over traditional antibody-based reagents.Unlike antibodies,aptamers can be synthesized chemically and selected by SELEX(Systematic Evolution of Ligands by Exponential Enrichment) process,undergo ligand-dependent conformational changes,and offer long-term stability,target versatility,and convenient regeneration.Because of their specific binding abilities,aptamers would be extremely useful to make aptamer-based biosensing for the determination of small molecular and protein substances.
Electrogenerated chemiluminescence(also called electrochemiluminescence,abbreviated as ECL) is the process where species generated at electrodes undergo electron-transfer reactions to form excited states that emit light.ECL method has many distinct advantages over fluorescence method because it does not involve a light source and avoids the attendant problems of scattered light and impurities luminescent.Moreover,the specificity of the ECL reaction associated with the ECL label and the coreactant species decreases problems with side reactions and is characterized by good spatial and temporal resolution.It has also widely been used in pharmaceutical analysis, bioanalysis,environmental analysis and clinical analysis.In recent years,highly selective and sensitive analytical methods such as DNA hybridization assay and biosensor have been received much attention.The development of a simple,rapid,sensitive and selective ECL biosensor and the fabrication of a simple,cheap and stable analytical detector in ECL analysis have been a long-term goal.
The aim of this thesis is to design and fabricate ECL DNA hybridization and aptamer-based biosensors for the determination of biological molecule with high sensitivity,selectivity and simplify. In this thesis,taking advantages of the unique properties of nanoparticles and the specificity of biological molecular recognition substances,such as DNA,aptamer,we have designed a series of ECL DNA and aptamer-based biosensors for the determination of DNA,cocaine,thrombin and lysozyme.Research work in this thesis is financially supported by the National Natural Science Foundation of China(Grant No.20775046,No.90607016,No.20375025).
The thesis includes two parts.First part,chapter 1,is general introduction while second part consisting of four chapters,is a research report.
In Chapter 1,general introduction to ECL,DNA biosensor and aptamer biosensor including their principles and research development,and the purpose of this research work were presented.
In chapter 2,an ultrasensitive ECL detection method of DNA hybridization based on single-walled carbon-nanotubes(SWNT) carrying a large number of ruthenium complex tags was developed.The probe single strand DNA(ss-DNA) and ruthenium complex were loaded at SWNT, which was taken as an ECL probe.When the capture ss-DNA with a thiol group was self-assembled onto the surface of gold electrode,and then hybridized with target ss-DNA and further hybridized with the ECL probe to form DNA sandwich conjugate,a strong ECL response was electrochemically generated.The ECL intensity was linearly related to the concentration of perfect-matched target ss-DNA in the range from 2.4×10~(-14) to 1.7×10~(-12)mol/L with a detection limit of 9×10~(-15) mol/L.The ECL signal difference permitted to discriminate the perfect-matched target ss-DNA and two-base-mismatched ss-DNA.This work demonstrates that SWNT can provide an amplification platform for carrying a large number of ECL probe and thus resulting in an ultrasensitive ECL detection of DNA hybridization.
In chapter 3,a novel ECL aptamer-based biosensor for the determination of a small molecule drug is designed employing cocaine-binding aptamer as molecular recognition element for cocaine as a model analyte and ruthenium complex served as an ECL label.A 5'-terminal cocaine-binding aptarner with the ECL label at 3'-terminal of the aptamer was utilized as an ECL probe.The ECL-AB biosensors were fabricated by immobilizing the ECL probe onto a gold electrode surface via thiol-Au interactions.An enhanced ECL signal is generated upon recognition of the target cocaine, attributed to a change in the conformation of the ECL probe from random coil-like configuration on the probe-modified film to three-way junction structure,in close proximity to the sensor interface. The integrated ECL intensity versus the concentration of cocaine was linear in the range from 5.0×10~(-9) to 3.0×10~(-7) mol/L.The detection limit was 1×10~(-9) mol/L.This work demonstrates that the combination of a highly binding aptamer to analyte with a highly sensitive ECL technique to design ECL aptamer-based biosensor is a great promising approach for the determination of small molecule drugs.
In chapter 4,three aptamer-based ECL biosensors for the determination of thrombin were designed.As a model system,thrombin-binding aptamer was utilized as molecular recognition element and thrombin as a target analyte and tris(2,2'-bipyridyl) ruthenium derivatives as aptamer ECL label.
First one was designed on basis of a structure-switching ECL-dequenching mechanism.The thiolated DNA capture probe,composed of a DNA sequence to adopt two distinct structures-a DNA duplex with a complementary DNA sequence tagged with tris(2,2'-bipyridyl) ruthenium derivatives (RuDNA)-binding motif and a DNA duplex with a complementary DNA sequence tagged with ferrocene(Fc)-DNA probe(FcDNA) with the target for which the aptamer is created,was self-assembled onto surface of a gold electrode.In the presence of thrombin,the aptamer prefers to form the aptamer-target complex and the switch of the binding partners for the aptamer occurs in conjunction with the generation of a strong ECL signal owing to the dissociation of FcDNA.The integrated ECL intensity versus the concentration of thrombin was linear in the range from 2.0×10~(-10) to 2.0×10~(-7) mol/L.The detection limit was 6×10~(-11) mol/L thrombin.
Second one was designed with a "signal off" model.Gold nanoparticles were assembled onto a gold electrode through 1,6-hexanedithiol and then thiolated ss-DNA capture probe was assembled onto the surface of the gold nanoparticles.The ECL aptamer probe was designed to hybridize with capture DNA sequence and specifically recognize thrombin.The introduction of thrombin triggers structure switching of the aptamer and thus the ECL probe is forced to dissociate from the sensing interface,resulting in a decrease in ECL intensity.The decrement of integrated ECL intensity is proportional to the concentration of thrombin in the range from 2.7×10~(-12) to 2.7×10~(-9) mol/L.The detection limit was 8×10~(-13) mol/L.
Third one was designed in sandwich model using the two aptamers(aptamerⅠand aptamerⅡ), which recognize different positions of thrombin.AptamerⅠimmobilized onto a gold electrode can captured the analyte thrombin and then the captured thrombin binds to an ECL probe composed of aptamerⅡand ruthenium complex loaded at SWNT,resulting ECL generation.The detection limit as low as 3×10~(-15) mol/L thrombin was achieved.
In chapter 5,a novel ECL aptamer-based biosensors for label-free determination of lysozyme was developed using aptamer-self-assembly electrodes.Anti-lysozyme DNA aptamers were immobilized on gold surfaces by means of self-assembly,for which the surface concentration of aptamers was determined by ECL studies of Ru(bpy)_3~(2+) bound to the surface via electrostatic interaction with the DNA phosphate backbone.Upon incubation of the electrode with a solution containing lysozyme,the ECL response of surface-bound Ru(bpy)_3~(2+) changed substantially,and the relative decrease in the integrated the ECL intensity can be tabulated as a quantitative measure of the protein concentration 6.4×10~(-10) mol/L to 6.4×10~(-7) mol/L.It is significant that the on-electrode protein/aptamer binding constant and the optimized surface concentration of lysozyme aptamer to achieve the lower detection limit can be evaluated.This biosensor is label-free and offers a sensitive and versatile method for protein detection.
In conclusion,one ECL DNA hybridization biosensor and five ECL aptamer-based biosensors were fabricated for the determination of biological molecule in this thesis.This thesis work demonstrates that the combination of a highly binding aptamer to analyte with a highly sensitive ECL technique to design ECL aptamer-based biosensor is a great promising approach for the determination of small molecule drugs and proteins.The sensitivity of ECL DNA hybridization and aptamer-based biosensors can be much improved using the nanoparticles modified electrode and nanotubes carrying multiple ECL probes.
电化学发光法兼有电化学和化学发光法的双重优点,具有极低的检测限、极宽的线性范围等优点;相对于荧光法,无光漂白,不需要光源和分光系统等优点;相对于电化学检测,具有检测限低和受电极污染影响小的优点。本论文研究工作旨在基于纳米粒子信号放大作用,结合生物分子识别物质DNA和适体的特异性,研制高灵敏度、高选择性新型电化学发光DNA和适体生物传感器。本论文研究工作是在国家自然科学基金“电化学发光适配体生物传感器”(No.20775046),“微阵列生物传感器信号化学放大基础研究”(No.90607016)和“新型功能纳米材料组装电化学发光生物亲合传感器的研究”(No.20375025)项目的资助和陕西师范大学优秀博士论文资助项目的资助下完成的。本论文研制了一种高灵敏度、高选择性、简单的新型电化学发光DNA杂交生物传感器;研制了一种简单、快速、灵敏的可卡因电化学发光适体生物传感器;研制了三种简单、快速、灵敏的凝血酶电化学发光适体生物传感器;还构建了非标记溶菌酶电化学发光适体传感器。
本论文由五章组成。第一章为引言。引言部分介绍了电化学发光分析的原理、特点和电化学发光反应的机理;重点介绍了DNA与适体生物传感器的构造、原理、特点以及分析应用,总结了适体分子在电极上的几种主要固定方法;介绍了纳米材料作为电极修饰材料和探针载体的优点以及在DNA生物传感器中的应用;还简要介绍了本论文的目的和意义以及主要研究内容。
第二章为电化学发光DNA杂交生物传感器的研究。本章研究工作旨在提高电化学发光DNA杂交检测的灵敏度,基于单壁碳纳米管负载大量钌联吡啶复合物标记,研制了一种超灵敏的电化学发光DNA杂交生物传感器。单链DNA探针(ss-DNA)和钌联吡啶复合物负载到单壁碳纳米管上,作为电化学发光探针。当修饰有巯基的捕获ss-DNA自组装到金电极表面,然后与目标ss-DNA进行杂交,进而与电化学发光探针杂交,形成DNA夹心结构,电化学激发后产生一个强的电化学发光响应信号。该传感器的电化学发光强度与完全互补目标ss-DNA浓度在2.4×10~(-14)mol/L～1.7×10~(-12)mol/L之间呈良好的线性关系,检出限为9×10~(-15)mol/L。该传感器对完全互补目标ss-DNA和两碱基错配ss-DNA有一定识别作用。该工作表明单壁碳纳米管可以负载电化学发光探针,从而建立超灵敏的电化学发光DNA杂交生物传感器。
第三章为可卡因电化学发光适体传感器的研究。以可卡因适体为分子识别物质,可卡因为目标分析物,钌联吡啶衍生物为电化学发光标记物,提出并设计了一种新型的基于适体的电化学发光检测小分子药物可卡因的适体生物传感器。3′末端标记有钌联吡啶衍生物的可卡因适体为电化学发光探针。通过巯基自组装将电化学发光探针固定到电极上制备成为电化学发光适体传感器。当目标物质可卡因存在时,适体折叠,三个双链茎与可卡因结合,适体发生构象转变,钌联吡啶衍生物离电极距离变近,电化学发光强度增强。电化学发光积分强度与可卡因浓度在5.0×10~(-9)mol/L-3.0×10~(-7)mol/L之间呈良好的线性关系,检出限为1×10~(-9)mol/L。
第四章为凝血酶电化学发光适体传感器的研究。本章的研究工作旨在设计基于适体的电化学发光检测蛋白质的适体生物传感器。以凝血酶适体作为分子识别物质,以凝血酶作为目标分析物,研制了三种简单、快速、灵敏的凝血酶电化学发光适体生物传感器。
1.基于二茂铁淬灭钌联吡啶电化学发光设计了一种新型的检测凝血酶电化学发光适体传感器。首先自组装捕获探针到金电极上,捕获探针序列包括凝血酶适体和与DNA标记钌联吡啶(RuDNA)结合部分,随后将与RuDNA和二茂铁标记的DNA(FcDNA)探针依次完全互补单链DNA序列结合在固定化捕获探针序列上,构成传感器。在没有目标物质凝血酶存在时,由于FcDNA和RuDNA接近,产生电化学发光淬灭,得到较低的电化学发光响应信号;存在目标物质凝血酶时,由于FcDNA/凝血酶适体双链变为凝血酶适体/凝血酶复合物,电化学发光淬灭消失,产生一个增强的电化学发光响应信号。该传感器的电化学发光强度与凝血酶浓度在2.0×10~(-10)mol/L～2.0×10~(-7)mol/L范围内呈良好的线性关系,对凝血酶的检出限为6×10~(-11)mol/L。实验结果表明,所设计基于二茂铁淬灭钌联吡啶电化学发光凝血酶适体传感器为信号增强型适体传感器,可有效的降低背景信号,提高检测蛋白质的灵敏度。
2.利用适体在目标分子的引入时,使适体原本形成的DNA/DNA双螺旋结构转变为DNA/目标分子的复合物结构,发生构型转换机制,研制了一种用于高灵敏检测凝血酶的电化学发光传感器。首先在金电极表面通过1,6-己二硫醇自组装纳米金,再将巯基修饰的捕获探针组装在纳米金表面,该捕获探针与钌联吡啶衍生物标记的凝血酶适体探针杂交后,即组成传感器。凝血酶的存在使钌联吡啶衍生物标记的适体探针从电极表面脱落而导致电化学发光强度下降。该传感器可对凝血酶进行特异性识别与检测,其电化学发光强度与凝血酶浓度在2.7×10~(-12)mol/L～2.7×10~(-9)mol/L范围内呈良好的线性关系,检出限为8×10~(-13)mol/L。该传感器有较高的灵敏度,可在水中热解后再生,稳定性良好。
3.以碳纳米管作为信号物质载体,结合凝血酶的两段适体,构建了高灵敏的电化学发光适体传感器。将巯基修饰的凝血酶适体Ⅰ通过自组装到金电极表面,形成识别层,特异性“捕捉”目标蛋白质-凝血酶,进而结合电化学发光探针(碳纳米管负载凝血酶适体Ⅱ和钌联吡啶复合物)形成夹心结构,在含有三丙胺的检测液中通过检测电化学发光探针的电化学发光信号对凝血酶进行定量检测。实验证明,此传感器具有优异的特异性和超高的灵敏度,对凝血酶检出限可达3×10~(-15)mol/L。
第五章为非标记溶菌酶电化学发光适体传感器的研究。以溶菌酶适体作为分子识别物质,以溶菌酶作为目标分析物,基于Ru(bpy)_3~(2+)静电结合到修饰有适体探针的电极表面,产生的电化学发光响应,设计了一种灵敏的非标记电化学发光溶菌酶适体传感器。通过表面结合阳离子电化学发光活性物质Ru(bpy)_3~(2+)的电化学发光强度积分值对凝血酶进行识别和定量分析,电化学发光强度积分值与溶菌酶的浓度在6.4×10~(-10)～6.4×10~(-7)mol/L范围内呈良好的线性关系,检出限为1.2×10~(-10)mol/L。探索建立了电化学发光测定溶菌酶适体与溶菌酶结合的解离常数。
本论文所研制的电化学发光DNA和适体生物传感器,为DNA、小分子药物和蛋白质的快速灵敏检测提供了良好的分析器件和分析新方法。金纳米粒子提供相对大的比表面积,可以提高凝血酶适体在电极上的固定量,从而提高电化学发光检测凝血酶的灵敏度。碳纳米管可以负载有多个信号分子,从而使传感器检测DNA和凝血酶的灵敏度大大提高。本论文的研究工作为进一步研制高灵敏度和高选择电化学发光DNA和适体生物传感器提供了基础性研究资料,对此方面的研究工作具有一定的促进作用。
Biosensors are defined as analytical devices incorporating a biological material(e.g.tissue, microorganisms,organelles,cell receptors,enzymes,antibodies,nucleic acids,natural products etc.), a biologically derived material(e.g.recombinant antibodies,engineered proteins) or a biomimic(e.g. synthetic catalysts,combinatorial ligands,imprinted polymers) intimately associated with or integrated within a physicochemical transducer or transducing microsystem,which may be optical, electrochemical,thermometric,piezoelectric,magnetic or micromechanical.The research of biosensors has already become new frontier of modern analytical chemistry.Aptamers have several advantages over traditional antibody-based reagents.Unlike antibodies,aptamers can be synthesized chemically and selected by SELEX(Systematic Evolution of Ligands by Exponential Enrichment) process,undergo ligand-dependent conformational changes,and offer long-term stability,target versatility,and convenient regeneration.Because of their specific binding abilities,aptamers would be extremely useful to make aptamer-based biosensing for the determination of small molecular and protein substances.
Electrogenerated chemiluminescence(also called electrochemiluminescence,abbreviated as ECL) is the process where species generated at electrodes undergo electron-transfer reactions to form excited states that emit light.ECL method has many distinct advantages over fluorescence method because it does not involve a light source and avoids the attendant problems of scattered light and impurities luminescent.Moreover,the specificity of the ECL reaction associated with the ECL label and the coreactant species decreases problems with side reactions and is characterized by good spatial and temporal resolution.It has also widely been used in pharmaceutical analysis, bioanalysis,environmental analysis and clinical analysis.In recent years,highly selective and sensitive analytical methods such as DNA hybridization assay and biosensor have been received much attention.The development of a simple,rapid,sensitive and selective ECL biosensor and the fabrication of a simple,cheap and stable analytical detector in ECL analysis have been a long-term goal.
The aim of this thesis is to design and fabricate ECL DNA hybridization and aptamer-based biosensors for the determination of biological molecule with high sensitivity,selectivity and simplify. In this thesis,taking advantages of the unique properties of nanoparticles and the specificity of biological molecular recognition substances,such as DNA,aptamer,we have designed a series of ECL DNA and aptamer-based biosensors for the determination of DNA,cocaine,thrombin and lysozyme.Research work in this thesis is financially supported by the National Natural Science Foundation of China(Grant No.20775046,No.90607016,No.20375025).
The thesis includes two parts.First part,chapter 1,is general introduction while second part consisting of four chapters,is a research report.
In Chapter 1,general introduction to ECL,DNA biosensor and aptamer biosensor including their principles and research development,and the purpose of this research work were presented.
In chapter 2,an ultrasensitive ECL detection method of DNA hybridization based on single-walled carbon-nanotubes(SWNT) carrying a large number of ruthenium complex tags was developed.The probe single strand DNA(ss-DNA) and ruthenium complex were loaded at SWNT, which was taken as an ECL probe.When the capture ss-DNA with a thiol group was self-assembled onto the surface of gold electrode,and then hybridized with target ss-DNA and further hybridized with the ECL probe to form DNA sandwich conjugate,a strong ECL response was electrochemically generated.The ECL intensity was linearly related to the concentration of perfect-matched target ss-DNA in the range from 2.4×10~(-14) to 1.7×10~(-12)mol/L with a detection limit of 9×10~(-15) mol/L.The ECL signal difference permitted to discriminate the perfect-matched target ss-DNA and two-base-mismatched ss-DNA.This work demonstrates that SWNT can provide an amplification platform for carrying a large number of ECL probe and thus resulting in an ultrasensitive ECL detection of DNA hybridization.
In chapter 3,a novel ECL aptamer-based biosensor for the determination of a small molecule drug is designed employing cocaine-binding aptamer as molecular recognition element for cocaine as a model analyte and ruthenium complex served as an ECL label.A 5'-terminal cocaine-binding aptarner with the ECL label at 3'-terminal of the aptamer was utilized as an ECL probe.The ECL-AB biosensors were fabricated by immobilizing the ECL probe onto a gold electrode surface via thiol-Au interactions.An enhanced ECL signal is generated upon recognition of the target cocaine, attributed to a change in the conformation of the ECL probe from random coil-like configuration on the probe-modified film to three-way junction structure,in close proximity to the sensor interface. The integrated ECL intensity versus the concentration of cocaine was linear in the range from 5.0×10~(-9) to 3.0×10~(-7) mol/L.The detection limit was 1×10~(-9) mol/L.This work demonstrates that the combination of a highly binding aptamer to analyte with a highly sensitive ECL technique to design ECL aptamer-based biosensor is a great promising approach for the determination of small molecule drugs.
In chapter 4,three aptamer-based ECL biosensors for the determination of thrombin were designed.As a model system,thrombin-binding aptamer was utilized as molecular recognition element and thrombin as a target analyte and tris(2,2'-bipyridyl) ruthenium derivatives as aptamer ECL label.
First one was designed on basis of a structure-switching ECL-dequenching mechanism.The thiolated DNA capture probe,composed of a DNA sequence to adopt two distinct structures-a DNA duplex with a complementary DNA sequence tagged with tris(2,2'-bipyridyl) ruthenium derivatives (RuDNA)-binding motif and a DNA duplex with a complementary DNA sequence tagged with ferrocene(Fc)-DNA probe(FcDNA) with the target for which the aptamer is created,was self-assembled onto surface of a gold electrode.In the presence of thrombin,the aptamer prefers to form the aptamer-target complex and the switch of the binding partners for the aptamer occurs in conjunction with the generation of a strong ECL signal owing to the dissociation of FcDNA.The integrated ECL intensity versus the concentration of thrombin was linear in the range from 2.0×10~(-10) to 2.0×10~(-7) mol/L.The detection limit was 6×10~(-11) mol/L thrombin.
Second one was designed with a "signal off" model.Gold nanoparticles were assembled onto a gold electrode through 1,6-hexanedithiol and then thiolated ss-DNA capture probe was assembled onto the surface of the gold nanoparticles.The ECL aptamer probe was designed to hybridize with capture DNA sequence and specifically recognize thrombin.The introduction of thrombin triggers structure switching of the aptamer and thus the ECL probe is forced to dissociate from the sensing interface,resulting in a decrease in ECL intensity.The decrement of integrated ECL intensity is proportional to the concentration of thrombin in the range from 2.7×10~(-12) to 2.7×10~(-9) mol/L.The detection limit was 8×10~(-13) mol/L.
Third one was designed in sandwich model using the two aptamers(aptamerⅠand aptamerⅡ), which recognize different positions of thrombin.AptamerⅠimmobilized onto a gold electrode can captured the analyte thrombin and then the captured thrombin binds to an ECL probe composed of aptamerⅡand ruthenium complex loaded at SWNT,resulting ECL generation.The detection limit as low as 3×10~(-15) mol/L thrombin was achieved.
In chapter 5,a novel ECL aptamer-based biosensors for label-free determination of lysozyme was developed using aptamer-self-assembly electrodes.Anti-lysozyme DNA aptamers were immobilized on gold surfaces by means of self-assembly,for which the surface concentration of aptamers was determined by ECL studies of Ru(bpy)_3~(2+) bound to the surface via electrostatic interaction with the DNA phosphate backbone.Upon incubation of the electrode with a solution containing lysozyme,the ECL response of surface-bound Ru(bpy)_3~(2+) changed substantially,and the relative decrease in the integrated the ECL intensity can be tabulated as a quantitative measure of the protein concentration 6.4×10~(-10) mol/L to 6.4×10~(-7) mol/L.It is significant that the on-electrode protein/aptamer binding constant and the optimized surface concentration of lysozyme aptamer to achieve the lower detection limit can be evaluated.This biosensor is label-free and offers a sensitive and versatile method for protein detection.
In conclusion,one ECL DNA hybridization biosensor and five ECL aptamer-based biosensors were fabricated for the determination of biological molecule in this thesis.This thesis work demonstrates that the combination of a highly binding aptamer to analyte with a highly sensitive ECL technique to design ECL aptamer-based biosensor is a great promising approach for the determination of small molecule drugs and proteins.The sensitivity of ECL DNA hybridization and aptamer-based biosensors can be much improved using the nanoparticles modified electrode and nanotubes carrying multiple ECL probes.
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