摘要
近年来，生物传感技术的发展大大推动了分析化学在生命科学领域中的应用。由于生物传感技术具有灵敏度高、选择性好、成本较低、分析速度快以及能够进行连续监测等优点，在化学、生物、医学、食品、环境、医药等领域有很高的应用价值。为了进一步提高生物传感技术的性能，使其能够得到更广泛的应用，本研究论文综合文献报道，利用功能核酸与细胞、蛋白质、小分子和离子等的特异性的结合能力，并基于核酸分子的等温信号放大技术在提高生物传感方法的检测灵敏度和检测范围方面，以及在简化实验操作，降低成本，实际样品的应用等方面做了一些工作，具体内容分别如下：
第2章中，构建了一种基于核酸杂交链式反应及酶催化信号放大的电化学适配体传感方法，对干扰素-γ进行了检测。在方法设计中，含有干扰素的核酸适配体序列的识别探针首先与目标蛋白结合，未被结合的识别探针会被捕获到金电极表面，从而启动杂交链式反应。两个分别标记有生物素的发夹型核酸探针将与电极表面的识别探针杂交并且会相互杂交，依次在电极表面打开，形成双链结构。作为报告分子的标记有碱性磷酸酯酶的亲和素与生物素结合后，碱性磷酸酯酶将非电活性物质1-萘磷酸盐转化为具有电活性的1-萘酚，通过电化学方法进行信号放大检测。检测到的电信号与干扰素-γ的浓度呈反向线性相关，该方法具有较高的灵敏度和良好的选择性，其检测范围为0.5-300nM，检测下限为0.3nM。在复杂体系中，该方法也表现出良好的分析性能。
第3章中，设计了一种基于氧化石墨烯的荧光淬灭功能及核酸外切酶III辅助的核酸等温信号放大技术的信号增强型荧光适配体传感策略，用于溶菌酶的识别检测。该体系中设计了一条含有溶菌酶核酸适配体序列的发夹探针和一条荧光素标记的信号探针。当发夹探针与目标蛋白结合后，其茎-环结构打开，露出的茎端部分可以和信号探针杂交。于是开始启动核酸外切酶III的循环酶切功能，从而将标记在信号探针上的荧光基团释放到溶液中，成为自由状态。再加入氧化石墨烯后，自由的荧光素分子不能吸附在石墨烯表面，荧光信号不会被淬灭。相反，没有目标蛋白时，信号探针吸附到氧化石墨烯表面上，检测不到荧光信号。在溶菌酶浓度从0.125μg/ml到1μg/ml范围内，荧光强度与溶菌酶浓度呈线性关系，检测下限为0.08μg/ml。该方法具有检测灵敏度高，成本低，易操作等优点。
第4章中，为了实现对癌症疾病的尽早检测和治疗，提出了一种基于RNA聚合酶的等温信号放大荧光检测方法，对乳腺癌细胞进行了检测。该方法利用含有核酸适配体序列的捕获探针去识别和结合细胞表面的癌症标志物，从而在微孔板内形成夹心结构用于目标细胞的固定。随后结合在细胞表面上的含有T7RNA聚合酶单链启动子序列的识别探针与含有另一半单链启动子序列的模板序列杂交，于是形成了能被RNA聚合酶识别的完整双链启动子序列。最后在RNA聚合酶的转录作用下产生大量的单链RNA分子，再嵌入荧光染料后产生增强的荧光信号。我们以MCF-7乳腺癌细胞为模型，利用提出的方法进行了定量分析检测。在5.0×102到5.0×106cells mL-1的浓度范围内，癌细胞的浓度与荧光信号强度呈线性关系，检测下限为5.0×102cells mL-1。该方法利用基于RNA聚合酶的信号放大技术结合核酸适配体的识别功能，在癌细胞检测方面具有较高的灵敏度和良好的选择性，并初步用于实际样品中的分析。
第5章中，设计了一种基于核酸切刻内切酶的链置换放大荧光传感策略用于磷酸酶活性的检测。该方法以T4PNK酶为模型，设计了一条含有3’端磷酸基团修饰的发夹结构的核酸探针。T4PNK酶的磷酸酶活性能够将该核酸探针的3’端磷酸基团转化成3’端的羟基，之后DNA聚合酶识别此羟基端并进行聚合延伸从而启动核酸切刻内切酶的链置换放大反应。经过不断的循环酶切再聚合延伸进行链置换放大后，产生的大量单链核酸分子与分子信标杂交，将分子信标打开产生荧光信号。通过检测荧光强度的大小达到间接检测磷酸酶活性的目的。当没有磷酸酶作用时，聚合酶和切刻内切酶都不能工作，连置换放大过程就不能发生。该方法操作简单，分析快速并且灵敏度高，检测下限为0.017U/mL。
第6章中，基于DNA连接反应及核酸分子内的G-四链体结构，设计了一种非标记的荧光探针，对辅酶烟酰胺腺嘌呤二核苷酸(NAD+)进行了高灵敏、高选择性的检测。该体系利用DNA聚合酶进行聚合延伸来控制背景信号，利用荧光染料N-甲基卟啉二丙酸IX（NMM）作为信号报告基团。我们注意到NAD+是DNA连接酶的辅酶，NAD+的存在影响着连接酶是否能起到正常的催化作用。所以本章中设计了一条能够自身形成双发夹二级结构的杠铃形DNA探针，其5’端的环结构由富G序列构成，5’端修饰有磷酸基团，与3’端靠近。当目标NAD+分子存在时，加入E.coli DNA连接酶后使核酸探针的末端连接起来，封闭住3’端。阻止聚合酶的延伸作用，之后在一价离子作用下形成G-四链体结构，嵌入染料后产生增强的荧光信号。而没有目标分子时，连接反应不能发生，聚合延伸作用发生后使核酸探针的5’端部分形成完整的双链结构，没有荧光信号生成。该方法具有良好的选择性和灵敏度，其检测下限为0.5nM。
第7章中，提出了一种基于“T-Hg2+-T”特异性结合的非标记荧光传感策略分别对谷胱甘肽（GSH）和半胱氨酸（Cys）进行了检测。该方法设计了两条含有T-T错配碱基的互补DNA链，利用汞离子作为中间调控分子，并利用荧光染料NMM作为信号报告基团。当GSH或Cys存在时，目标分子能够特异性地与Hg2+结合，使DNA双链保持原有的自由状态。其中一条较长的含有富G序列的单链DNA在一价离子作用下形成G-四链体结构，之后荧光染料NMM嵌入到此结构中产生增强的荧光信号。而当没有目标分子时，溶液中有Hg2+存在，通过“T-Hg2+-T”特异性结合作用能够形成稳定的DNA双链结构，从而抑制G-四链体结构形成，于是就没有增强的荧光信号。该方法对GSH的线性检测范围是10-400nM，检测下限为9.6nM，对Cys的线性检测范围是10-500nM，检测下限为10nM。
In recent years, the development of biological sensing technology has greatlypromoted the application of analytical chemistry in life science field. Due to manyadvantages such as high sensitivity, good selectivity, low cost, fast analysis speed,continuous on-line monitoring in complex system and so on, the biological sensingtechnology has a high application value in the chemistry, biology, food, environment,medicine and other fields. In order to further improve the performance of thebiological sensing technology, this doctotal thesis uses the specific combining abilityof functional nucleic acid with cells, proteins, small molecules and ions, based onisothermal signal amplification technology of nucleic acid to develop several bioassaysystems for enhancing the detection sensitivity, broadering the assay concentrationrange of biosensors, simplifying experimental operation, and reducing the cost andusing in actual samples. The detailed contents are described as follows.
(1) In chapter2，a novel electrochemical aptasensor based on hybridization chainreaction (HCR) with enzyme-signal amplification was constructed for the detection ofinterferon-gamma (IFN-γ). In this aptasensor, the recognition probes which containedthe sequence of IFN-γ aptamer were initially binded to IFN-γ, and the unboundrecognition probes were captured on the electrode as an initiator to trigger the HCR.The two DNA hairpins bio-H1and bio-H2were opened by the recognition probe, andbound one by one on the electrode. The biotin was used as a tracer in the hairpins andstreptavidin-alkaline phosphatase (SA-ALP) as a reporter molecule. Then, SA-ALPconverted its electro-inactive substrate1-naphthyl phosphate into an electroactivederivative1-naphthol generating amplified electrochemical signal by differential pulsevoltammetry (DPV). The activity of the immobilized enzyme was voltammetricallydetermined by measuring the amount of1-naphthol generated for enzymaticdephosphorylation of1-naphthyl phosphate. The electrochemical signal observed wasinversely related to the concentration of IFN-γ. The proposed approach showed a highsensitivity for IFN-γ in a concentration range of0.5-300nM with a detection limit of0.3nM. The sensing system also provided satisfactory results for the detection ofIFN-γ in the cell media.
(2) In chapter3, based on exonuclease III (Exo III) aided amplification andgraphene oxide (GO) platform for fluorescence quenching, a novel, turn-on fluorescent aptasensor for lysozyme (Lys) protein was constructed. The system contains a hairpinprobe (HP) and a signal probe (SP) labeled with carboxylfluorescein (FAM) at its5'end. HP, which consists of the aptamer sequence of Lys, is partially complementary toSP. Lys can bind with the aptamer region of the HP and facilitated the opening of thehairpin structure of HP, exposing a single-stranded sequence to hybridize with SP. Thistriggered the Exo III aided amplification and caused the degradation of SP, whichliberated the free fluorophore labels. Upon the addition of GO, the releasedfluorophore could not be adsorbed and no fluorescence quenching occured, while theintact SPs could be adsorbed on GO surface with the fluorescence substantiallyquenched. The results revealed that the proposed method displayed fluorescenceresponses in a linear correlation to the concentrations of Lys within the range from0.125μg/ml to1μg/ml and the detection limit is0.08μg/ml. Besides such sensitivity,the proposed strategy is also low-cost and simple due to its homogeneous andfluorescence-based detection format.
(3) Cancer is one of the most serious and lethal diseases around the world. Itsearly detection has become a challenging goal. To address this challenge, in chapter4,we developed a novel sensing platform using aptamer and RNA polymerase-basedamplification for the detection of cancer cells. The assay uses the aptamer as a captureprobe to recognise and bind the tumor marker on the surface of the cancer cells, andform an aptamer-based sandwich structure for collection of the cells in the microplatewells, then it uses SYBR Green II dye as a tracer to produce strong fluorescence signal.The tumor marker interacts first with the recognition probes which were composed ofthe aptamer and single-stranded T7RNA polymerase promoter. Then, the recognitionprobe hybridized with template probes to form a double-stranded T7RNA polymerasepromoter. This dsDNA region is extensively transcribed by T7RNA polymerase toproduce large amounts of RNAs, which are easily monitored using the SYBR Green IIdye and a fluorometer, resulting in the amplification of the fluorescence signal. UsingMCF-7breast cancer cell as the model cell, the present sensing platform showed alinear range from5.0×102to5.0×106cells mL-1with a detection limit of5.0×102cellsmL-1. This work suggested a strategy to use RNA signal amplification combiningaptamer recognition to develop a highly sensitive and selective method for cancer cellsdetection.
(4) In chapter5, we developed a novel fluorescence assay for DNA phosphataseactivity based on the strand displacement amplification of nicking enzyme. Thismethod took T4polynucleotide kinase phosphatase (PNKP) as the model analyte and aimed at the detection of DNA3'-phosphatase activity. The designed3'-phosphoryl ofhairpin probe could be dephosphorylated by T4PNKP into a3'-hydroxyl end, leadingto the initiation of DNA polymerase extension and triggering the strand displacementamplification of nicking enzyme. The process resulted in many“polymerization-nicking” cycles and displaced plenty of single strand DNA. Afterhybridizing with molecular beacons, the single strand DNA opened the loop struactureof molecular beacons and yielded significant fluorescence signal. The detection ofDNA phosphatase activity can be accomplished by monitoring the fluorescenceintensity change. This proposed assay is convenient, fast and highly sensitive with thelimit of detection of0.17U/mL.
(5) In chapter6, a simple lable-free fluorescent sensing scheme for sensitive andselective detection of nicotinamide adenine dinucleotide (NAD+) has been developedbased on DNA ligation reaction with ligand-responsive quadruplex formation. Wenoticed that the E. coli ligase specifically employed NAD+as cofactor and its catalyticactivity is cofactor-dependent. We employed Klenow fragment (exo-) which couldsuppress the blank signal and N-methyl mesoporphyrin IX (NMM) as the signalreporter. The DNA probe was designed as a single-strand molecule that formedself-complementary structure at both ends and a quadruplex-forming sequence wasdesigned as the loop close to5’-end. The5’-end was modified with a phosphate groupand the3’-end was exposed. In the presence of E. coli DNA ligase, together with thecofactor NAD+, the ends of DNA probe can be ligated to block the extension reactionfrom the3’-end and ensure the quadruplex-forming sequence reserved. This G-richoligomer fold into a quadruplex structure with monovalent ions. The strong interactionbetween the “activated” quadruplex and NMM, brings about a great fluorescenceenhancement. This approach can detect0.5nM NAD+with high selectivity againstother NAD+analogs.
(6) In chapter7, we designed a novel lable-free fluorescent strategy for detectionof glutathione (GSH) and cysteine (Cys). The system consisted of two single strandDNA (ssDNA) containing thymine-thymine (T-T) mismatches and used Hg2+as amediator, N-Methyl mesoporphyrin IX (NMM) as the signal reporter. The assay isbased on a competitive reaction of Hg2+by GSH/Cys and by T-Hg2+-T double strandDNA (dsDNA) complexes. In the abcence of target, two ssDNA containing T-Tmismatches react with Hg2+to form a T-Hg2+-T dsDNA structure in the solution, whichhampers the formation of G-quadruplex structure. However, in the presence of target,GSH/Cys react with Hg2+to keep DNA probes in a free single state. This process results in the effective formation of G-quadruplex structure of DNA probe (GP).Subsequently, because of the strong interaction between the “activated” G-quadruplexand NMM, a great fluorescence enhancement was obtained. The concentration rangesof the strategy are10-400nM for GSH detection and10-500nM for Cys detection withthe limit of detection (LOD) of9.6nM for GSH and10nM for Cys.
引文
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