摘要
近年来，功能化的纳米材料（如碳纳米管，硅纳米线，贵金属纳米材料等）在物理学、化学和生物学等方面的广泛应用，引起了研究人员极大的关注。其中，金纳米材料由于其独特的光学性质成为研究工作的热点。目前，随着对金纳米材料的合成方法的不断改进和表征技术的探索，各种形状、各种尺寸、多种特性的金纳米材料层出不穷，使得它们在催化、传感、成像和生物医学等领域都扮演着重要的角色。尽管现在它们的应用范围已经很宽，然而，许多重要的问题仍然悬而未决。比如，当纳米材料作为载体时如何提高它们的载药效率，如何在生理环境下保持纳米胶体材料的稳定性，如何在较复杂的环境中（如活细胞体系中）去分辨哪些是纳米粒子等。为了解决这些问题，我们如果开发出一种简便但却功能强大的成像方法，对于研究和分析在高的时空分辨率下单个纳米颗粒的动态运动过程等现象则很有帮助。为此，在本论文中：
（1）首先，我们选择了适合的方法分别合成了18nm,40nm和60nm的球形金纳米颗粒。由于球形的金纳米颗粒是一种等离子体共振的材料，所以它对于不同的波长的光有着不同的响应，尤其是在它的最大吸收波长处有着很高的散射截面积。利用这样的特性，在接下来的工作中，我们将金纳米颗粒作为一个模板粒子，分析探讨了前面所述的这些动态过程。
（2）基于传统的暗场成像技术，我们开发了一个双波长的暗场显微系统。在这里，我们仅仅是把显微镜的传统光源替换成了两束不同波长的激光，其中一束是所要观察颗粒的最大吸收波长，另一束作为参比波长。利用这个系统，我们在复杂体系中能够实现将金纳米颗粒轻松地分辨出来，并用不同的生物分子修饰后的金纳米颗粒进行了成像，充分验证了该方法的可靠性（第二章）。除此以外，我们还利用了该方法详细地研究了纳米颗粒与细胞之间的作用状态，探讨分析了金纳米颗粒在细胞膜表面的扩散运动模式并合理解释了细胞内吞金纳米颗粒的动态过程（第三章）。另外，我们依旧使用双波长的暗场成像技术对单个的金纳米棒进行了成像。金纳米棒是具有各向异性的纳米材料，通过分析其长轴和短轴的振荡模式，我们实现了对单个金纳米棒在三维空间内的位置和角度的信息的获得（第四章）。接下来，我们应用该方法研究了金纳米棒在细胞膜表面的运动行为，发现修饰后的金纳米棒与细胞膜表面受体间的结合过程是独立的，与金纳米棒的横向扩散模式无关（第五章）。
（3）细胞穿膜肽是一种有效的能够将颗粒带入细胞内部的生物分子。而人工磷脂双分子膜作为模拟活细胞膜的模型，来研究修饰了细胞穿膜肽的纳米颗粒在磷脂双分子膜上的运动行为十分具有意义。在这个工作中，我们发现，修饰了细胞穿膜肽的金纳米颗粒在磷脂膜上的吸附过程是十分缓慢的，但是一旦发生吸附，其扩散模式是运动受限的。我们又根据其他的一些实验现象推测，金纳米颗粒之所以有这样的运动行为是因为它在磷脂膜的表面形成了小的区域范围，并且我们用金纳米棒在磷脂双分子膜上的空间构型分析的实验也间接地证明了这一点（第六章）。
（4）金纳米团簇由于具有很好的荧光效应，容易制备，低毒性等优点被逐渐地应用到多个方面。在这里，我们利用非常温和的反应条件，制备了能发出荧光的金纳米团簇，并将其修饰上了叶酸分子，来对肿瘤细胞进行特异性的识别。实验结果表明，利用普通的荧光显微镜，我们就非常容易地对金纳米团簇进行成像。这对于肿瘤细胞的标记是一个很好的应用。此外，我们又用同样的方法制备了银纳米团簇，它对于肿瘤细胞具有同样的标记效果（第七章）。
Recently, functional nanomaterials (e.g. carbon nanotubes, silica nanowires, noblemetal nanostructures and so on) have received great attention in physics, chemistry andbiology. Among those nanomaterials, the gold nanostructure has become a “hot-spot”due to its unique photo-physical properties. Along with the enormous exploration ofnew synthesis and characterization methods, variety of novel gold nanostructures withdifferent shape and size have been synthesized and they are playing important role incatalysis, biosensing, optical imaging, biomedicine and so on. Despite their significantapplications, some important questions have to be addressed in advance before theirfurther usage in these areas. For example, how to improve the drug-loading efficiencywhen they are served as functional nanocarrier? How to control the colloidal stabilityin physiological solutions? How to elucidate the interaction mechanism between goldnanostructures and cellular membrane for the improvement of translocation efficiency?How to discriminate the target nanoparticle from the interfering signals inside livingcells? In order to provide insightful information to these questions, we have to developrobust and convenient methods for the characterization and exploration of thosedynamic processes at single nanoparticle level with high spatial and temporalresolution. In this regard, we performed extensive researches as described in thefollowing four parts:
(1) Firstly, we synthesized gold nanoparticles with different size (18nm,40nmand60nm, gold nanospheres) and shape (gold nanorod). Due to the extremely largescattering cross-section at the plasmon resonance frequency, the scattered light willrepresent distinct color when illuminated by white light. Therefore, these nanoparticlescan be adopted as efficient imaging contrast agent based on scattering detectionmodality to investigate those dynamic processes as described above.
(2) Inspired from the traditional dark-field imaging technology, we developed anew optical imaging system named dual-wavelength dark field microscopy (DWD) forthe selective detection of plasmon nanoparticles in noisy surroundings. By replacingthe regular light source with two different wavelength lasers (one at the resonancefrequency, the other one is shifted away from that wavelength), gold nanoparticles canbe readily distinguished in complex environment by two wavelength differenceimaging.(chapter2). Besides, with this method, we further studied the interactionsbetween gold nanoparticles and cancer cells by DWD method. We analyzed the diffusion mode of gold nanoparticles on live cell membrane and explained the dynamiccellular uptake process (chapter3). Moreover, we also investigated the localizationand orientation of single gold nanorod in3D by dual-wavelength dark-field microscopy.Gold nanorods split their surface plasmon resonance into transverse and longitudinalmodes due to theirs inherent morphological anisotropy. By capturing the dynamicmovement of single gold nanorod in solution, we elucidated the translationallocalization information and rotational dynamics in3D (chapter4). Then, thediffusion dynamics of protein functionalized gold nanorods were studied on livingHela cell membrane with this imaging mode. We found that the conjugation processbetween gold nanorod and receptor on living cellular surface was independent anduncorrelated with their lateral diffusion mode (chapter5).
(3) Cell penetrating peptides have been extensively applied as efficientintracellular delivery platform for drug and gene delivery. By using lipid bilayer as asimplified model, we can deduce basic interaction mechanisms occurred on living cellsystem. In this work, we discussed the motion of gold nanoparticles coupled with acommon cell penetrating peptide (Tat) on neutral lipid bilayer by total internalreflection technology. We found that the adsorption process of Tat functionalized goldnanoparticles on lipid bilayer was very slow. The diffusion motion of these particleswas confined once the adsorption occurs. Based on dynamic information, we foundthat the gold nanoparticles could form a small domain on lipid bilayer. This processwas further validated by the gold nanorod orientational information on lipid bilayer(chapter6).
(4) Gold nanocluster has emerged as a robust fluorescent contrast agent recently.They exhibit many advantages like facile fabrication process, low cellular toxicity,highly quantum yield and so on. In this part, we fabricated gold nanoclusters under agentle condition. These nanoclusters were able to target tumor cells by conjugatingwith folic acid. With a regular fluorescent microscope, we successfully detectednanoclusters labeled tumor cells with high efficiency. In addition, we also developedanother kind of cluster with different color (i.e. silver nanoclusters) which alsoexhibited good targeting capability for tumor cells (chapter7).
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