摘要
荧光相关光谱是一种高灵敏的单分子探测方法,被广泛应用于生命科学及其相关的领域,特别是在核酸杂交检测,基因表达分析,生物分子的相互作用及细胞内的一些生物化学过程的研究中发挥着其它方法无可替代的作用。由于大多数化合物特别是生物分子本身没有荧光(或荧光很弱),用荧光方法(如荧光相关光谱)研究这些化合物时通常需要用荧光染料或荧光量子点进行标记。然而,有机荧光染料的化学稳定性和光稳定性较差,在某些生物应用中受到一定的限制。另外,目前制备的荧光量子点大都由Cd, Pb, Hg, Te, Se等有毒元素组成,不能用于生物体内的检测。
金纳米粒子由于其表面效应、体积效应和量子尺寸效应表现出特殊的光学性质,如强的散射特性和吸收特性。另外金纳米粒子生物相容性好、易于与生物分子连接的特性,是一种具有广泛应用前景的生物探针。目前金纳米探针已成功地应用于核酸杂交检测,免疫分析以及细胞成像等领域。现有的检测方法主要有:比色法、紫外光谱法、散射法和动态光散射法,这些方法都有自己的优缺点。主要的缺点在于检测的灵敏度不高,而且都是集合的方法。本论文基于荧光相关光谱基本原理和激光共焦构型,利用金纳米粒子具有非常强的光散射特性,建立了共振散射相关光谱新方法(Resonance Light Scattering Correlation Spectroscopy,RLSCS)。将这一方法成功地应用于金纳米粒子的平动和转动行为的研究,浓度的表征。同时应用于DNA杂交检测和蛋白质的相互作用研究。主要工作包括以下几个方面:
1.共振散射相关光谱是基于纳米粒子(如金纳米粒子)的共振散射特性建立的一种单颗粒探测新方法。我们参照荧光相关光谱理论模型,将金纳米粒子共振散射光近似地按照荧光相关光谱中的荧光来处理,建立了散射相关光谱的理论模型,提出了共振散射相关光谱概念。基于激光共焦构型,建立共振散射相关光谱探测系统。对该系统的基本参数进行了系统的研究和优化。显著地减小了系统的检测体积(小于1飞升),提高检测系统的信/背(信号/背景信号)比。该系统能够获得粒径大于15纳米金颗粒的共振散射相关光谱。建立的模型与实验数据很好的吻合。
2.基于散射相关光谱建立了一种表征金纳米粒子的平动扩散和转动扩散及其浓度的新方法。我们系统的研究了各种因素对金纳米粒子的平动扩散和转动扩散行为的影响。发现当不同波长激光照射时,仅在激光波长处在共振散射峰位置(纳米金的共振散射波长为600纳米附近)时,金纳米粒子的转动扩散可以被共振散射相关光谱探测。为了证实散射相关光谱曲线中快速运动属于转动扩散,设计了改变针孔孔径的实验,我们发现孔径由35微米增大到110微米时,其平动扩散时间由2.39毫秒相应地增大到3.74毫秒;而转动扩散时间却保持6.06微秒不变,这一实验结果与预测相吻合。基于纳米粒子的平动扩散时间计算了纳米金的动力学半径,其动力学半径与电镜测定结果基本相吻合。从共振散射相关光谱中获得检测体积内的粒子个数,用已知扩散系数的荧光染料测定共振散射相关光谱的检测体积,据此,我们建立了金纳米粒子的浓度测定方法,其测定结果与电镜测定方法基本相吻合。研究结果表明共振散射相关光谱是表征纳米粒子的一种有效的新方法。
3.我们将共振光散射相关光谱应用到核酸杂交检测中,建立均相DNA杂交探测新方法。我们首先将两个不同片段的寡核苷酸探针通过巯基引入到纳米金表面,将其与两个片段互补的靶目标DNA加入到体系中,然后用共振光散射相关光谱检测纳米金聚集体的扩散时间和光散射强度来表征纳米金的聚集程度。研究发现随着靶目标DNA的含量不断增加,纳米金聚集体的扩散时间和散射光强度也相应的增加。用单个碱基错配的靶目标DNA加入到体系中,发现其扩散时间和散射光强度也相应的增加,但与完全互补的靶目标DNA相比,其增加的程度要弱一些。该方法检测限达到0.1 nM,与比色法相比,检测限提高了100倍左右。研究结果表明共振光散射相关光谱能够很好的区分DNA碱基序列,同时还可以用于DNA含量的检测,当靶目标DNA的浓度在0-36 nM时,聚集体的扩散时间与核酸浓度有较好的线性关系。与比色法的2-3小时相比,该方法是一种快速检测方法,检测时间也只需要5分钟左右。
4.将纳米金共振光散射相关光谱应用于生物分子的相互作用研究。以过氧化酶-生物素与亲和素相互作用为免疫反应模型,通过监测反应体系中纳米金聚集体的扩散时间来确定纳米金与过氧化酶生物素最佳吸附的pH值以及生物素与亲和素反应的最佳pH值。用辣根过氧化酶-生物素通过化学吸附作用修饰到纳米金的表面,加入链霉亲和素(有四个结合位点)结合生物素使得纳米金偶联在一起,通过监测纳米金聚集体的扩散时间测定纳米金的聚集程度。随着链霉亲和素的浓度增加,实验发现金纳米粒子聚集体的扩散时间也相应的延长,当链霉亲和素的浓度达到65 nM时(恰好链霉亲和素与生物素的化学计量比为1︰4),聚集体的扩散时间达到最大值。当链霉亲和素为260 nM和780 nM时,发现聚集体扩散时间反而随着链霉亲和素浓度的增加而减小。当链霉亲和素大大过量时,链霉亲和素迅速地包覆在生物素化的纳米金表面,从而部分抑制了纳米金的交联。通过对纳米金聚集动力学的研究,证实了辣根过氧化酶生物素与亲和素诱导的纳米金聚集过程符合反应限制模型。
Fluorescence correlation spectroscopy (FCS) has been widely applied in biological and biomedical fields, especially in DNA hybridization detection, gene expression and interaction of bio-molecules. So far, FCS becomes an indispensable tool to study some biological events in cells at single molecular level because of its high sensitivity and very small detection volume. However, most of bio-molecules have no native fluorescence (or very weak), and thus, they need to be labeled with organic dye or inorganic nanocrystal quantum dots when fluorescence methods such as FCS method are used. However, some applications are limited by their bleaching or blinking properties of organic fluorescent dyes. Additionally, quantum dots are not suitable for some applications in vivo because most of quantum dots are composed of toxic elements such as Cd, Pb, Hg, Te and Se.
The gold nanoparticles (GNPs) have been regarded as an ideal nano-probe with potential applications in diagnosis and bio-assay due to their unique optical and chemical properties. The labeling procedure of GNPs method is fair simple. The GNPs can conjugate to most of biomolecules such as nucleotides and proteins by adsorption. Meanwhile, the bioactivity of biomolecules was no significant change during labeling process, and GNPs conjugates with biomolecule are fairly stable and have no toxicity. To date, GNPs have been widely applied in the DNA detection and immunoassay detection. In this dissertation, we first build a resonance light scattering correlation spectroscopy (RLSCS) system based on the principle of fluorescence correlation spectroscopy and laser confocal configuration. All kinds of parameters in the RLSCS system were systematically optimized. The confocal detection volume in RLSCS was about 1 fl. And then, RLSCS method was successfully applied for characterizing translational and rotational diffusion, particles size and concentration of GNPs. Finally, RLSCS method also was applied in DNA hybridization detection and interaction of proteins using GNPs as probes. The main work includes as following:
(1) RLSCS is a new single particle method, which is based on the resonance light scattering properties of gold nanoparticles. Following the principle of FCS, we consider resonance scattering light in RLSCS as fluorescence in FCS and build a theoretical model of RLSCS. The setup of RLSCS is built on the laser confocal configuration. All kinds of parameters are studied and optimized systematically. The detection volume obtained was about 1 fL. The RLSCS of gold nanoparticles for particles size larger than 15 nm can be obtained by this method. Our theoretical model of RLSCS is very well in agreement with experimental data.
(2) We developed a new method to characterize concentration, translational and rotational diffusion of GNPs with RLSCS technology. We systematically studied the effects of some parameters on translational and rotational diffusion. We discovered that the intensity of scattering light and the polarization anisotropy of GNPs were significantly dependent on the illumination wavelength of laser and shape of GNPs. In the resonance scattering band, the polarization anisotropy and the scattering light intensity are very strong to successfully obtain the rotational information of GNPs by RLSCS. Far from the resonance scattering band, the rotational information of GNPs can not be tracked. The RLSCS method was successfully used to characterize the rotational and translational behaviors of GNPs and gold nanorods in solution using 632.8 nm He-Ne laser as light source. Meanwhile, the concentration of GNPs was characterized by RLSCS according to the particle numbers in the known illumination volume. The numbers of GNPs in the confocal detection volume were obtained from the resonance light scattering autocorrelation function and the confocal detection volume was determined by the translational diffusion coefficient of a known fluorescent dye.
(3) The RLSCS technology was successfully applied in DNA hybridization. In this experiment, the two different oligo-DNA was introduced onto the surface of GNPs with thiol functional group. The aggregation of GNPs was formed by adding complementary target DNA. The diffusion time and intensity of scattering-light from GNPs can be monitored by RLSCS. The degree of aggregation became larger with the concentration increase of target oligo DNA. RLSCS discriminated complementary target DNA and single-base mismatch DNA through the diffusion time and intensity of scattering light from GNPs. The limit of detection for target oligonucleotides reach 0.1 nM using 21 nm gold nanoparticles modified with oligonucleotides as probes. Meanwhile, it can offer quantitative analysis for DNA concentration range from 0-48 nM.
(4) The interaction between HRP-biotin and streptavidin was characterized by RLSCS with GNPs as probes. This interaction was regard as an immune assay model. The optimal environment pH value 8.4 for HRP-biotin covalent conjugation to the surface of GNPs was obtained by RLSCS as well as the pH value in the reaction system. The degree of aggregation was increasing with increase of the concentrations of streptavidin. It is interesting that the average translational diffusion time reached the maximum value when streptavidin concentration is 65 nM. However, the average translation diffusion time will gradually decrease when the concentration of streptavidin will be increased continually from 65 nM to 780 nM. It found that it reached the optimum stoichimetric ratio when the streptavidin concentration was 65 nM. The surface of HRP-biotinylated GNPs was rapidly occupied by large quantity of streptavidin molecules when streptavidin concentration was over 65 nM, which inhibit the cross link between GNPs. The RLSCS was applied in studying the dynamic of reaction. We found the aggregation of GNPs induced by interaction of HRP-biotin and streptavidin coincided with the reaction-limited aggregation modeling.
引文
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