摘要
DNA检测在医疗诊断、食品安全和生化反恐方面变得日趋重要。尽管传统PCR技术非常灵敏,但是设备成本高、操作复杂而且易受污染,不利于推广到实时检测,因而人们一直在寻求更廉价、更方便的、更灵敏的(检测数个DNA分子)实时检测方法。
纳米材料几乎提供了无限的组分、尺寸、维度和形貌的组合,可以连接各种不同探针分子,从而制备出不同性质的纳米探针。将纳米探针组合可以还产生无数新的放大策略,为DNA检测提供了新的可能。
尽管基于纳米探针的DNA检测已经取得了巨大的进展,该领域依然存在着巨大的挑战:(1)纳米探针的使用经常会引入非均相界面,由此带来一系列问题,如杂交速度缓慢,效率低等问题;(2)许多检测方法需要多步操作,增加了操作复杂性;(3)降低非特异性相互作用对避免背景干扰非常重要,特别在复杂检测体系中;(4)纳米探针的放大效应缺乏一般性,对于不同体系往往需要单个优化。因此发展新的纳米探针、新的检测方法十分重要。
在此基础上,本文完成了以下工作:
(1)制备了具有低于计量比金属含量的金属-有机杂化粒子,这种粒子由反式-4,4'-双(N-(2-氨基苯)氨基)二苯乙烯(EDAPS)和金属离子(Cu(Ⅱ)或Fe(ⅠⅡ))构成,合成时先通过沉淀法制备EDAPS的有机小分子纳米粒子,再加入金属离子,在热辅助下,通过向其中引入配位作用导致了有机小分子粒子向球形金属-有机杂化粒子转化。调节最初沉淀的速度可以调节产物粒子尺寸和其中金属含量,改变反应中投入的金属离子浓度也可以调节产物粒子中金属含量。最终所得粒子金属含量介于有机小分子纳米粒子与金属-有机配合物粒子之间,为通过组分调控粒子性质提供了新的可能。对这种粒子制备过程的研究和性质表征,为揭示性质组分组分迥异的有机小分子粒子和配位聚合物粒子的内在联系提供了重要的线索。
(2)以具有低于计量比金属含量的金属-有机杂化纳米粒子为基础,制备了DNA探针。探针粒子内含大量荧光小分子和少量金属离子,金属离子通过增加表面电荷来稳定粒子。将探针粒子通过DNA杂交附着到DNA修饰的玻璃片表面,将粒子溶解产生荧光信号。相比于小分子荧光基团实现了信号放大,相比于合成条件苛刻的量子点,该粒子合成十分简单快速,同时该探针具有良好的单碱基错配序列区分能力。
(3)合成了表面氨基的聚苯乙烯纳米粒子,对其表面进行DNA修饰制备出表面为正电环境的DNA纳米探针。基于DNA杂交驱动的探针纳米粒子聚集我们发展了一种新的DNA杂交快速分析系统。该系统利用阈值浊度的出现时间对DNA杂交动力学进行表征,有效分析时间甚至能缩短到数分钟,该方法能够成功进行目标DNA序列的定量,并对单碱基错配有良好的区分能力。该系统之所以能进行快速分析,是因为对纳米粒子尺寸和表面官能团的合理选择与设计,纳米粒子表面的正电环境通过屏蔽和削弱了DNA链相互靠近时的排斥作用,从根本上加快了粒子表面的杂交速度。更重要的,该体系的动力学分析方法对于传统基于热力学终点的分析方法做出了有效补充,对于那些热力学终点性质较接近的体系,动力学分析方法是一个优秀选择。
Detection of DNA has become increasingly important in a variety of areas including medical diagnostics, food safety and anti-bioterrorism. Conventional polymerase chain reaction (PCR) is extremely sensitive. However, because of the high cost of equipment, complicated operation and contamination, it is not suitable for wide-spread real-time detection. Much effort has been devoted to the development of more cost-effective, more convenient, more sensitive,(toward the detection of several DNA molecules) real-time detection method.
Nanomaterials provide almost unlimited combinations of various compositions, sizes, dimensions and shapes of materials, which can be tailored to couple different biomolecules in order to develop nanoprobes with desired properties. Recombination of different methods based on various nanoprobes will provide more amplification strategies, thus new chance for DNA detection.
Despite tremendous progress, there remain several challenges for nanoprobe-based DNA detection technologies:(1) the use of nanomaterials always introduces heterogeneous interfaces in bioassays that are usually in homogenous solution, which might result in several problems (e.g. slow binding kinetics and low recognition efficiency);(2) many ultrasensitive assays require multiple steps that significantly increase the operation complexity;(3) elimination of non-specific binding is critically important to avoid interferences, particularly for detection in complex biological matrixes;(4) the ultrahigh amplification offered by nanomaterials often lacks generality, therefore bioassay reactions should be individually optimized. Therefore, design of new nanoprobes and new detection strategies is critical.
Based on these conditions, we started our research in the development of new nanoprobes in DNA detection:
(1) We have prepared metal-organic hybrid particles (MOHPs) with sub-stoichiometric metal contents. MOHPs are constructed by an organic molecule (E-4,4'-di(N-(2-aminophenyl)amino)stilbene, ED APS) and metal ions (Cu(Ⅱ) or Fe(Ⅲ)). Organic molecule particles (OMPs) of EDAPS were first prepared by precipitation in the preparation of MOHPs. Then metal ions were added. The introduction of coordination interaction resulted in a heat-assisted morphology transformation to sphere-shaped MOHPs. The size of MOHPs could be tuned by the tuning of precipitation speed, while the metal contents in MOHPs is tunable through both the initial precipitation speed and the initial concentration of metal ions. The final yielded MOHPs contained sub-stoichiometric metal contents, which is between that of OMPs and coordination polymer particles (CPPs). MOHPs provide new opportunity toward the control of particle properties through the tuning of particle composition. The characterization of MOHPs and MOHP preparation process also provides important insight into the inter-relationship between the seemingly disparate classes of particles (OMPs and CPPs).
(2) DNA probe based on MOHPs (DNA-modified MOHPs, DNA-MOHPs) have been prepared. Every DNA-MOHP contained many EDAPS molecules and relatively less metal ions. Aqueous suspension of DNA-MOHP is stabilized by the increase of surface charge from metal ions. In a typical assay, hybridization with target DNA could bind DNA-MOHPs to the surface of DNA-modified glass slide. Then, blue fluorescence could be observed through the dissolving of DNA-MOHPs. Compared with organic fluorescent dyes, better sensitivity was achieved. While compared with the harsh synthetic condition of quantum dots, the preparation of MOHP was much easier. Additionally, the detection system based on DNA-MOHPs could differentiate complementary DNA strand with DNA strands containing single-base mismatches.
(3) Aminated polystyrene nanospheres (APSNSs) were synthesized and used for the preparation of positively charged DNA-modified APSNSs (DNA-APSNSs). Based on hybridization-driven agglutination of DNA nanoprobes (DNA-APSNSs), we developed an ultrafast kinetic DNA hybridization assay system. In this system, the onset time of a visually identifiable, turbidity-definitive, and kinetic threshold state (state of threshold turbidity) was employed in the characterization of DNA hybridization kinetics, and a fast DNA assay within the timeframe of minutes was achieved. By the onset time of threshold turbidity, DNA quantification could be performed. Additionally, DNA strands with single-base mismatches could be differentiated with complementary target DNA. The judicious selection of the size and surface groups of APSNSs ensured the ultrafast DNA hybridization assay. The positive surface charge fundamentally improved the hybridization kinetics caused by the screening and reducing of the electrostatic repulsion between negatively charged DNA strands. More importantly, the kinetic visual protocol complements conventionally used thermodynamic strategies and provides an entry point for the circumvention of assay issues associated with ill-defined thermodynamic endpoints.
引文
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