摘要
荧光探针具有灵敏度高、设计多样化和定量分析能力强等特点,是分析化学的研究热点之一。随着研究工作和荧光技术的不断进步,荧光探针有着越来越广阔的发展前景,在疾病诊断、药物筛选、临床毒理学和环境监测等领域有着较强的应用潜能。核酸适配体是单链的寡聚DNA或RNA,通过体外筛选得到,能选择性的与目标结合,是荧光探针中识别单元的理想选择之一。与抗体相比较,核酸适配体具有两个显著的优势：第一,核酸适配体可以通过仪器在体外自动化高精度合成,批次差异小,且能够稳定地保存备用。第二,核酸的结构灵活多变,能与多种信号放大策略联用,以实现高灵敏度的定量分析,并能用于多种目标的测定,包括金属离子、小分子、蛋白质和细胞等。基于核酸适配体的优良性能,核酸适配体荧光探针的设计成为近年来生化分析中研究热点之一。然而,目前核酸适配体荧光探针仍有许多问题需要解决：1)复杂生物样品中高灵敏生化分析；2)核酸荧光开关的生物兼容性；3)荧光成像信号的不可控性；4)细胞内荧光成像的困难等。
支点介导的DNA链置换是指两条互补的DNA以支点为起点和推动力,通过步进的方式杂交并将另一条互补DNA序列置换下去的过程。该策略在动态DNA纳米技术中得到了广泛应用,能构建多种DNA分子器件,包括分子机器和分子逻辑门等。这种链置换诱导的分子重构过程与核酸适配体荧光探针的设计策略具有相似性,有望成为探针设计中一种新型的信号转换方式。更为重要的是,这种支点介导的DNA链置换可以用于构建一些信号放大策略,且这些策略不需要使用蛋白酶,可以设计出低成本和高稳定性的荧光探针。其中,杂交链反应放大和发夹催化组装是其中的典型代表,它们在多种核酸适配体探针的设计中得到了应用。本论文利用支点介导的DNA链置换的上述优点,将其作为新型的信号转换方式或信号放大策略,用于几种核酸适配体荧光探针的设计,希望有助于解决核酸适配体荧光探针在生化分析领域的一些问题。此外,由于无机纳米材料具有比表面积大、光吸收效率高等特点,本论文还将利用金纳米颗粒和硫化铝纳米片的这些优点构建荧光探针或比色探针,并用于细胞成像或分析测定的研究。具体内容如下：
(1)基于核酸适配体的荧光各向异性分析方法引起了人们广泛关注。但是,该方法不能直接用于小分子的测定,因为小分子与适配体结合后,所引起的分子量的改变太小,而不足以引起荧光各向异性值的显著变化。本章研究工作提出了一种基于DNA-蛋白质复合纳米线的策略,用于小分子的高灵敏测定。在该分析方法中,小分子与适配体结合后,与适配体序列部分互补的DNA会诱发杂交链反应放大,进而组装链酶亲和素,使其与荧光基团靠近。以三磷酸腺苷(ATP)为模型小分子,这一策略的检测下限达到100nM,比单独的杂交链反应放大或链酶亲和素放大策略有显著改进。与之前的去组装方法相比较,本章研究工作所采用的组装策略不易被干扰物质所触发,可以降低假阳性几率进而提高分析结果的可信度。由于荧光各向异性分析方法不依赖于荧光强度变化,它还可以直接用于复杂生物样品中ATP的测定,在细胞培养基、血清及尿液中的可测定的浓度为0.5μM.(第2章)
(2)支点介导的DNA链置换有着许多独特的性质,在DNA分子开关设计中得到了广泛的应用。但是,目前所设计的DNA分子开关有一些缺点,例如它们是由许多独立的DNA片段组合而成,它们也不能直接内吞到细胞内,这些不利于它们在生物体系中的应用。在本章研究中,我们将层状的DNA双链结构组装到了纳米金表面,设计了多种DNA荧光开关。这些分子开关可以形成多种逻辑关系,它们响应的信号变化明显,且互不干扰。此外,这种层状的DNA分子开关可以用于调节纳米金的尺寸,还可以用于多信号方式的多目标检测。更为重要的是,纳米金可以有效地将DNA运输到细胞内,不需要传统转染试剂的辅助,降低了它们对细胞的毒性。因此,这种层状的DNA分子开关的设计将有利于DNA开关在生物体系中的应用,也将有助于DNA纳米技术的发展。(第3章)
(3)核酸适配体是细胞成像探针中识别单元的理想选择之一。但是,目前核酸适配体成像探针大多是采用不可调控型的设计：荧光探针与细胞的目标靶蛋白结合后,它们的荧光信号一般不可以更改。这种不可调控的性质对多种目标蛋白的同时成像是不利的,因为容易产生光谱重叠；对于时空分辨的成像也是不利的,例如研究细胞内吞的过程。为了克服上述缺点,我们设计了一类新型的可编码核酸适配体荧光探针,用于细胞膜表面膜蛋白的成像研究。这类探针主要是基于链置换的动态DNA分子开关来设计的,它们可以用于逻辑控制的成像和可逆荧光标记等。在实验中,我们采用共聚焦成像和流式细胞术研究了荧光探针的响应情况,证实了它们可以实现上述目的。该探针采用了双重荧光标记的内标型设计,它可以避免探针浓度的变化和荧光漂白等原因引起的实验误差,还可以充分地利用两种荧光染料各自的优点,为细胞成像研究提供多样化的选择。(第4章)
(4)硫化钼形貌与石墨烯类似,且有着许多相似的性质,引起了研究人员的广泛关注,在生物医学等领域都有着较好的应用前景。目前硫化钼的研究大多集中在物理器件方面的应用,在生物医学中特别是与核酸适配体相结合领域的研究较少。在本章研究工作中,我们设计了一种基于硫化钼纳米片的药物运载体系：核酸适配体通过共价键与硫化钼结合,作为靶向识别基团,并标记荧光素作为细胞成像的荧光信号；而硫化铝则作为分子药物阿霉素和二氢卟酚的吸附材料。通过流式细胞术和共聚焦成像的结果可以看出,核酸适配体与硫化铝结合后仍然能成功地靶向结合特定癌细胞。此外,由于硫化钼有着较大的比表面积,能够通过范德华作用吸附大量的的分子药物。通过体外细胞毒性实验的数据可以看出,该载药体系可以将药物分子有效地运载到细胞内并杀死癌细胞,从而证实了硫化钼在癌症治疗方面的应用潜能。(第5章)
(5)纳米金比色分析方法有许多优点,在分析化学中得到了广泛应用,检测目标包括核酸和金属离子等。但是,纳米金的比色分析方法还没有用于金离子的测定,因为金离子没有合适的双齿配体。据文献报道,金离子可以将巯基化合物氧化成二硫键的产物,显著改变巯基化合物的结构。基于金离子这一独特的性质,我们报道了一种新型的纳米金比色分析法,用于金离子的无标记定量测定。在该分析方法中,含氟表面活性剂修饰的纳米金作为比色法的信号基团,在半胱氨酸作用下会发生团聚,颜色从红色变为紫色。金离子将半胱氨酸氧化后,抑制了半胱氨酸与纳米金的作用,抑制了其变色过程。此外,通过改变探针分子半胱氨酸的浓度,可以实现对不同浓度范围的金离子实现定量测定。通过优化条件,该探针对金离子的检测下限为50nM,比之前报道的紫外显色试剂要低。该探针还以用于实际水样品中金离子的测定,回收率令人满意。(第6章)
Due to their versatility, sensitivity and quantitative capabilities, the development of sensitive and selective fluorescent probes has become a very active research field in recent years. Fluorescent probes find great potential applications in a wide variety of fields, including disease diagnosis, drug discovery, clinical toxicology, environmental monitoring and so on. With high affinity and specificity to their target molecules, aptamers which are selected in vitro from random pools of DNA or RNA molecules, are ideal recognition elements in the development of fluorescent probes. Compared with antibodies, aptamers offer another two main advantages. First, aptamers can be produced by chemical synthesis with extreme accuracy and reproducibility. Second, aptamers are highly compatible with a variety of signal amplification strategies for highly sensitive bioassay. With these desirable characteristics, aptamer-based fluorescent probes have been developed to detect various targets, including metal ions, small molecules, proteins, cells and so on. However, there are many problems in the area of aptamer fluorescent probes, such as sensitive bioanalysis in complex biological systems, design of fluorescent switchs compatible with biological systems, and fluorescent imaging of cells via an intelligent manner.
Dynamic DNA nanotechnology has facilitated the development various DNA devices, which can be engineered to serve as programmable molecular machines, chemical amplifiers and logic gates. Instead of purely classical hybridization mechanisms, these dynamic DNA devices harness a process called toehold mediated DNA strands displacement. In this process, two partial or full complementary DNA strands hybridize to each other by initiating at toeholds domains and then displace another pre-hybridized DNA strands. As a result, such adaptive and reconfigurable DNA molecular devices can be developed as a novel signal transduction format for the design of aptamer-based fluorescent probes in an enzyme-free, isothermal manner. More importantly, this toehold mediated DNA strands displacement can be adapted to engineer several powerful amplification cascades with polynomial or exponential signals amplification ability. Without using protein enzymes, such signal amplification schemes show great potential to develop low-cost and point-of-care diagnostics. Specially, the hybridization chain reaction (HCR) and catalyzed hairpin assembly have been frequently employed in many aptamer-based probes for sensitive detection of numerous targets. Take advantage of the toehold mediated DNA strands displacement mentioned above, several novel aptamer-based fluorescent probes have been designed in this doctoral dissertation to obtain unique signal transduction formats and high sensitivity. In addition, gold nanoparticles and MoS2nanosheets have aslo been imployed in the design of probes for bioimaging or bioanalysis. The texts are summarized in details as follows:
(1) Aptamer-based fluorescence anisotropy (FA) assays have attracted great interest in recent years. However, a key factor that determines FA value is molar mass, thus limiting the utility of this assay for the detection of small molecules. To solve this problem, streptavidin, as a molar mass amplifier, was used in a hybridization chain reaction (HCR) to construct a target-triggered cyclic assembly of DNA-protein hybrid nanowires for highly sensitive detection of small molecules by fluorescence anisotropy. In this assay, one blocking DNA strand could be released by target-aptamer recognition, and then it served as an initiator to trigger enzyme-free autonomous cross-opening of hairpin probes via HCR to form a DNA nanowire for further assembly of streptavidin. Using adenosine triphosphate (ATP) as the model small molecule, this novel dual-amplified, aptamer-based FA assay afforded high sensitivity with a detection limit of100nM, which is much lower than that of the disassembly approach without HCR amplification or the assembly strategy without streptavidin. In contrast to the previous turn-off disassembly approaches based on nonspecific interactions between the aptamer probe and amplification moieties, the proposed aptamer-based FA assay method exhibits a turn-on response to ATP, which can increase sensing reliability and reduce the risk of false hits. Moreover, because of its resistance to environmental interferences, this FA assay has been successfully applied for direct detection of0.5μM ATP in complex biological samples, including cell media, human urine, and human serum, demonstrating its practicality in real complex biological systems.(in chapter2)
(2) DNA strand displacement cascades have been engineered to construct various fascinating DNA circuits. However, their further biological applications are limited by insufficient cellular internalization of naked DNA structures, as well as the separated multicomponent feature. In this work, these problems are addressed through the development of a novel DNA nanodevice, termed intelligent layered nanoflare, which integrates DNA computing at the nanoscale via self-assembly of DNA flares on a single gold nanoparticle. As a "lab-on-a-nanoparticle", the intelligent layered nanoflare could be engineered to perform a variety of Boolean logic gate operations, including three basic logic gates, one three-input AND gate, and two complex logic operations, in a digital, nonleaky way. In addition, the layered nanoflare can serve as a programmable strategy to sequentially tune the size of nanoparticles, as well as a new fingerprint spectrum technique for intelligent multiplex biosensing. More importantly, the nanoflare developed here can also act as a single entity for intracellular DNA logic gate delivery without the need for commercial transfection agents or other auxiliary carriers. By incorporating DNA circuits on nanoparticles, the presented layered nanoflare will broaden the applications of DNA circuits in biological systems and facilitate the development of DNA nanotechnology.(in chapter3)
(3) Owning a series of advantages over antibodies, aptamers provide the basis for the design of excellent imaging probes with high specificity under complex biologic environments. However, most of the aptamers-based fluorescent probes were in an uncontrolled way, in which the fluorescence signal couldn't be altered after the recognition of aptamer to its target. This uncontrolled characteristic is unfavorable for multiplex imaging, as well as temporal and spatial imaging with specific need, such as the research of probes'internalization. To overcome the limitations of previous aptamer probes, we adapted a new class of dynamic DNA complexes as programmable aptamer probes for imaging cell-surface marker. It allowed AND-logic controlled imaging and reiterative fluorescence labeling. Both confocal imaging and flow cytometry have been employed to confirm the response and features of each imaging probes. The two-label approach in these probes offers the opportunity to study a single binding event by different fluorescence signals, and provides a flexibility choice of fluorophores to overcome the shortcomings and utilize the advantages of individual ones. Specifically, one of the fluorescence labels could be used as an internal control for another one, thus improving imaging by accounting for cell-to-cell variations in probe binding amount and background,(in chapter4)
(4) Similar to graphene's morphology and properties, MoS2has received much attention from researchers, and it may find great potential applications in many areas including biomedicine. However, to our best knowledge, the possibility of using aptamer as targeting moiety for MoS2-based drug delivery platforms has not been demonstrated until now. In this study, a new MoS2-based nanosystem was developed to facilitate the application of MoS2in biomedical applications. In this nanosystem, the chemical exfoliated MoS2nanosheets were used as a drug carrier, while the aptamer served as a targeting moiety for cancer cells. Due to the defect sites in the surface of MoS2nanosheets, the Aptamer Sgc8, targeting leukemia T cells, could be easily conjugated via a thiol-based covalent bond and was also labeled with FITC as fluorescent signal for cell imaging. Form the results of flow cytometry and confocal imaging, the Aptamer Sgc8could greatly and specifically bind to its target cell due to a multivalent effect. In addition, the exceptional surface-area-to-mass ratio of MoS2nanosheets makes it a promising class of nano-carriers for molecule drugs, doxorubicin (DOX) and chlorin e6(Ce6), with high loading capacities. Further results from in vitro cytotoxicity experiments showed that MoS2nanosheets could be used for deliver therapeutic molecules into cell to effectively kill target cells, thus demonstrating the potential application of MoS2nanosheets in cancer therapeutics.(in chapter5)
(5) Gold nanoparticles-based colorimetric assay possesses several unique advantages, and has been applied for a wide range of targets, varying from nucleic acids to different metal ions. However, due to the lack of proper coordinating ligand, gold nanoparticles-based colorimetric sensing system for Au3+has not been developed so far. It is well-known that Au3+could induce the oxidation transition of thiol compounds to disulfide compounds. In this article, we for the first time converted such thiol masking reaction into colorimetric sensing system for label-free detection of Au3+via a target-controlled aggregation of nanoparticles strategy. In the new proposed sensing system, fluorosurfactant-capped gold nanoparticles were chosen as signal reporter units, while an Au3+-triggered oxidation of cysteine (Cys), which inhibited the aggregation of gold nanoparticles, acted as the recognition unit. By varying the amount of Cys, a tunable response range accompanied with different windows of color change could be obtained for Au3+, illustrating the universality of the sensing system for Au3+samples with different sensitivity requirements. Under optimized condition, the proposed sensing system exhibits a high sensitivity towards Au3+with a detection limit of50nM, which is lower than previously reported spectroscopic methods. It has also been applied for detection of Au3+in practical water samples with satisfactory result,(in chapter6)
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