摘要
荧光标记物研究的核心是寻找灵敏度高、稳定性好的荧光物质或荧光试剂。目前,最为常用的是有机荧光染料。这类荧光试剂具有荧光强度高、种类多样化等特点,但同时也存在光学稳定性较差、激发光谱范围窄、发射光谱较宽、与生物分子的背景荧光难以区分等不可忽视的弱点,导致在应用中灵敏度下降。而量子点作为一种新型的荧光纳米材料,弥补了有机染料的上述缺点,引起分析化学和生命科学领域的广泛关注。荧光材料在获得广泛应用之前,必须具有普遍使用的制备方法。无论在国内还是国际领域,量子点绝大部分是采用三辛基膦/三辛基氧膦(TOP/TOPO)体系在300℃左右高温合成的。由这种方法制得的量子点具有较好的光学性质和较高的荧光产率。然而,采用TOP/TOPO体系合成量子点时,要求在试剂储存和制备过程中绝对无氧,合成条件苛刻。同时,纵观国内外市场,量子点作为一种荧光试剂,价格非常昂贵。因此,研究工作者开始寻求绿色、环保、更为有效的合成路线,以满足不同领域应用的需要。其中,水相合成法和绿色有机合成法最引人瞩目。目前除CdTe外,其它量子点如CdS、CdSe、ZnS等在水相中均不能得到高质量的荧光性能。基于上述研究现状,本项研究立足于利用廉价环保的绿色有机相法制备高质量荧光量子点,并考查它们在生物大分子标记以及肿瘤细胞的免疫成像等领域中的应用。
首先,采用绿色无污染、价格低廉易得的石蜡作为反应溶剂和还原剂,在无需除氧的条件下,选用长链不饱和酸—油酸作为反应配体和稳定剂,常见无机试剂为反应原料,合成出CdS、CdSe/CdS以及Se掺杂的CdS等三种纳米量子点。经光学性能表征,所制备的三种量子点均具有荧光产率较高、半峰宽窄、峰形对称等优良的光谱性能；结构性能表征表明合成的量子点尺寸分布均匀,为近似球形颗粒。最后,将制得的量子点经巯基乙酸修饰后转移至水相,从而使其在生命科学领域中具有很好的应用前景。
其次,为了验证和考察采用油酸/石蜡体系制备的量子点在生命领域中的应用情况,经过实验实现了CdSe量子点与生物大分子的链接,总结了量子点与酶、蛋白质等生物大分子结合的作用规律。实验中选取四种具有代表性的生物大分子进行研究,分别为：简单蛋白—牛血清白蛋白、胰凝乳蛋白酶,结合蛋白—牛血红蛋白以及Cu/Zn-超氧化物歧化酶。研究结果表明,量子点与简单蛋白结合后,蛋白质会以共价键形式结合在量子点的表面,使其表面钝化,从而导致量子点荧光强度明显提高。然而,在量子点与结合蛋白的作用中,由于金属离子的影响,使其与蛋白质的作用复杂化,荧光光谱表现为蛋白质与金属离子的双重作用结果,即简单蛋白使量子点荧光增强,而部分金属离子使荧光减弱。
再者,基于与上述生物大分子的作用规律,利用量子点表面的羧基基团与抗体中氨基基团之间的相互作用,分别实现了CdSe量子点与兔抗人CEA8抗体以及羊抗兔免疫球蛋白的结合,通过抗原—抗体之间的特异性反应,采用直接和间接方法分别完成了CdSe量子点对宫颈癌上皮细胞—HeLa细胞的免疫标记与成像。间接方法可以消除量子点在细胞表面的非特异性吸附,表现出比直接方法更好的标记效果。标记完成24 h后,量子点标记的HeLa细胞表面仍然呈现出了明亮的荧光,具有很好的荧光稳定性。
分别考查了巯基丙酸和半胱胺稳定的CdTe量子点与纳米金纳米颗粒之间的相互作用。利用金纳米粒子能够稳定而迅速地吸附蛋白质以及量子点能与蛋白质结合的特性,以胰凝乳蛋白酶为桥梁,实现了纳米金与巯基丙酸修饰的CdTe量子点之间的荧光共振能量转移,为纳米颗粒与生物大分子之间的相互作用提供了新的研究思路。
简言之,本项工作以寻求简单、环保的制备高质量量子点的方法为出发点,建立了制备一系列量子点的新方法。同时,讨论了量子点与生物大分子之间结合的作用规律,并以此为基础,将量子点与抗体结合,实现了对肿瘤细胞的免疫标记和成像。此外,还对纳米金与量子点之间的相互作用做了系统考查。研究还表明,在量子点的多功能化、特异性检测等方面仍然存在很大的发展空间,是今后该领域很有前景的研究方向之一。
The key skill for developing fluorescent probes is to explore fine fluorescence materials and reagents with high sensitivity, good stability and diversification. Although with characteristics of high fluorescence yields, conventional organic dyes show some shortcomings such as narrower excitation, broader emission spectra, lower sensitivity and poor stability, which lead to much difficulty to distinguish them from self fluorescence of bio-molecules in applications. Quantum dots (QDs) just come to overcome these limitations of organic dyes and attract much attention of researchers in analytical and biological fields.
For any fluorescent materials, facile synthesis method should be developed before they are used widely. Now, quantum dots are mostly prepared using TOP/TOPO system in which reagents are injected into a hot coordinating solvent tri-n-octylphosphine oxide (TOPO) at high temperature (about 300℃). This method would not be popular because the synthesis and storage procedures need to be operated under rigorous conditions such as full of nitrogen, without water and oxygen etc, even though the as prepared QDs possess good optical properties and high quantum yields (QYs). Furthermore, overlooking the markets at home and abroad, QDs, as a type of fluorescence reagents, are very expensive. Therefore, it is very important to search greener and effective routes to fulfil the demands in different fields. Among them, synthesis methods in aqueous solution and green organic ligands attracted much more attention. Unfortunately, QDs such as CdS, CdSe, ZnS obtained in aqueous solution usually show low QYs, although they have good biological compatibility. Based on above states, the aim of the present work is to synthesize high-quality QDs in a new way and then use them in macro-molecules probes, as well as immuno-imagings of tumor cells.
For the preparation of QDs, as described in the second and third part of this thesis, a convenient and environment friendlier strategy, in which paraffin was used as solvent and reductant while oleic acid acted as stabilizer, was applied to prepare CdS, CdSe/CdS and Se doped CdS QDs. Optical and structure properties indicated that the as prepared QDs showed excellent fluorescence spectra with narrow FWHM (the full width at the half maximum), good dispersibility and desirable fluorescence yields. TEM images indicated that QDs dispersed well in aquous solution and the shape was approximately spherical. After modification with 2-mercaptoacetic acid, QDs were transferred into aqueous solution and got water-solublity for further applications in biological system.
For the applications of QDs in analytical and biological fields, a study about the conjugation between CdSe QDs and macromolecules was carried out, in which the interaction rules between QDs and biological macromolecules such as proteins and enzymes were obtained. In this work described in the fourth part of this thesis, four kinds of proteins were chosen, they were normal proteins-bovine serum albumin (BSA) and chymotrpsin, as well as metalloproteinase-Cu/Zn SOD and bovine hemoglobin. Experimental results indicated that normal proteins could be covalently linked to QDs and the fluorescence intensity of QDs enhanced markedly after conjugating with BSA and chymotrypsin due to their passivation on the defects of QDs. However, for the conjugation of QDs with metalloprotein, the presence of metal ions made the conjugation be complicated and lead to the fluorescence spectra showing two kinds of results:the normal proteins could enhance its intensity and the matal ions in metalloprotein could quench it.
With the similar linking method as described above, CdSe QDs were conjugated with rabbit anti-CEA8 antibody and goat anti-rabbit IgG through the interaction of carboxylic groups on the surface of QDs and amino groups on antibody. By the reaction between antibody and antigen, both QDs-antibody and QDs-IgG probes were successfully used to label HeLa cells, as described in the fifth part. Experimental results of fluorescence imaging indicated that the non-specific adsorption could be eliminated through the indirect labeling method. Tracking the signal of imaging for 24 h, QDs still exhibited high and stable fluorescence.
In the sixth part, the interaction between gold nanoparticles (NCs) and CdTe QDs capped with mercaptopropionic acid or cysteamine were studied. Proteins can be not only adsorbed on the surface of gold NCs, but also linked to QDs in appropriate solution atmosphere. Based on that, fluorescence resonance energy transfers (FRET) assemble between QDs and gold NCs with chymotrypsin as the binding bridge is developed. This work provided some valuable information for the further study on the interaction mechanism among nanoparticles.
In conclusion, this work began with seeking for a new environment friendly and simple route to synthesize high-quality QDs, then studied the conjugation ahout QDs with macromolecules. After linking with primary or second antibody, the QDs probes were used to label HeLa cells. At last, a deeper study on interaction between QDs and gold NCs was carried out. All experiments indicated that there are great potential in the multifunction and specific detection of QDs probes, which would turn to one of most promising research branches in this field.
引文
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