核壳型CdSe/ZnS量子点在生物分析中的应用
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摘要
核壳型量子点是一种新型的无机半导体纳米晶体材料。作为一种荧光标记探针,它展现出传统荧光染料所没有的许多光化学优点。首先,量子点具有宽的激发波长,可以方便地实现不同量子点的单波长同时激发,非常容易地实现多色应用;其次,量子点的荧光发射峰窄而对称,能有效减少多色应用中光谱交叠问题,不需要对光谱交叠问题进行严格的补偿;再次,量子点具有很好的光化学稳定性,经历长时间光源照射并不损失荧光特性,而且比有机荧光染料更不容易被降解;最后,虽然不同尺寸量子点具有不同的荧光发射波长(颜色),但是它们都具有良好方便的表面化学可修饰性,以及表面上生物分子偶联的灵活可兼容特性(即能与生物活性分子进行有效的偶联,如抗原抗体、蛋白、DNA序列等)。近年来,量子点在微球光学编码、基于编码微球的阵列分析(包括编码微球表面的DNA杂交分析、抗原/抗体免疫分析等)、分子细胞成像、FRET研究、毛细管电泳分析等众多方面都得到了广泛的应用。本论文主要工作是研究了不同粒径量子点的有效控制合成,同时也研究了其光学、表面化学、生物偶联等特性,并重点研究了合成的量子点作为荧光探针在生物和分析领域的具体应用。论文完成的工作如下:
1.采用油相合成法,通过对成核时间的控制,批量合成得到了多种不同发射波长的量子点(500~700 nm)。对其光学性质进行了表征,发现发射波长在590 nm附近时,量子点具有较好的荧光量子产率(43.5%),而发射波长蓝移或红移时,相应的量子点量子产率都有所降低。
2.通过对聚苯乙烯微球进行溶涨处理、量子点的吸附装载,完成了对微球的多色编码。我们利用量子点对微球进行了荧光编码及光谱检测,结果表明需要通过光谱分辨才能有效鉴别不同波长与强度的编码微球。对于确定的两种量子点,通过控制掺杂液中不同量子点浓度比率的梯度变化,可以得到信号强度比率也梯度变化的编码微球。而且,通过微球信号强度比率和装载液中两种QDs摩尔浓度比率的标准曲线,可以初步评估这两种量子点的有效编码库容量,并可用于指导微球的光谱编码。之后,在编码微球上固定human IgG抗原,对溶液中相应的抗体进行了检测,结果表明,该编码微球可以很好地检测到溶液中抗体的信号,抗体有效检测范围为2~15μM。这一结果表明,该方法编码得到的微球可以被有效的用于生物学研究。
3.介绍了一种基于量子点编码微球的流式分析技术,利用该技术对各种量子点编码微球的荧光光谱进行了很好的区分,并实现了对溶液中特定的靶分子的有效检测。这一检测系统是基于两个长波长的荧光信号(如黄色和红色量子点信号)来辨别确定微球的编码,用第三个短波长的荧光信号(如绿色,染料FITC的信号)作为报告信号来确定反应的发生与否,这样就可以利用量子点的荧光特性,只需一种光源就可对编码信号和报告信号进行同时检测。实验的结果表明,该方法具有良好的准确性和重现性。由于该系统在单光源激发下,具有快速、准确、简单、可批量实时检测等优点,相信在得到进一步的完善后,将具有较好的应用前景。
4.系统地介绍了脂溶性量子点水溶性修饰、量子点与生物分子偶联及其柱层析分离纯化,以及量子点/转铁蛋白偶联物(Tf-QD)对人肝癌细胞HepG2进行标记成像等量子点荧光探针从制备到应用的全部过程研究。具体为,用巯基乙酸钠(sodium thioglycolate HSCH2COONa)取代CdSe/ZnS量子点表面的TOPO,对实验室合成的脂溶性量子点进行了有效的水溶性修饰。利用紫外、荧光和层析柱对水溶性的量子点与转铁蛋白Tf偶联进行了表征,结果证实两者有效地偶联在了一起。之后,在对偶联物进行分离纯化后,利用它对人肝癌HepG2细胞进行了标记。结果表明,量子点探针首先标记在了细胞膜上,之后在转铁蛋白(Tf)/转铁蛋白受体(TfR)介导作用下转入到细胞内,并主要分布在细胞质部分,未能进入到细胞核内。进一步的观察发现,细胞内的量子点荧光随时间增长在减弱,经历大约十天后再也观察不到量子点荧光。而且,量子点并未由于本身具有的“生物毒性”而影响细胞的正常生长,10天后细胞仍然存活。这一工作为促进QD在生物中的应用提供了很好的借鉴作用。
5.采用发射波长为593 nm量子点,具体研究了luinol-H2 O2体系作为供体,脂溶性、水溶性(巯基羧酸修饰)以及偶联了HRP等三种情况下量子点作为受体时能量传递的情况。结果发现,三种情况下均能观察到量子点的发射峰,表明体系中发生了能量共振转移(Chemiluminescence resonance energy transfer, CRET)。脂溶性量子点情况下得到了最高的CRET效率,为10.7%,偶联物的CRET效率最低,为2.7%。这一结果与其量子产率是对应的(18.3%和0.4%)。而在利用两亲性聚合物修饰的量子点研究CRET时也得到同样的规律。我们推断量子点在不同情况下不同的量子产率对实验中CRET效率起着决定性的影响作用。此外,我们还观察到了luminol作为供体与多色量子点(三种)受体同时实现多元CRET的现象。这一工作为促进基于量子点的CRET研究提供了有效的支持。
Core-shell quantum dot (QD) is a new inorganic semiconductor nanocrystal material. As a fluorescent probe, it has many unique excellent optical characteristics compared with traditional organic dyes. Firstly, as QDs have broad effective excitation spectra, simultaneous excitation of multiple QDs can be accomplished easily with a single excitation light, which can promote multiple applications of QDs. Secondly, it is not necessary to strictly compensate for the measurements owing to the narrow and symmetrical emission of QDs. Thirdly, the fluorescence strength of QDs do not decrease when exposed to light for long periods of time (that is, QDs are photostable), and QDs are less susceptible to metabolic degradation than organic fluorophores. Finally, although QDs with different sizes have different emission wavelengths (different colors), they have similar physical properties (such as dimension and polarity) and biological conjugation ability (namely, that can effectively conjugate to biomolecules and proteins). In recent years, quantum dots have been widely used in optical encoding of microbeads, encoded bead based array technology (including DNA hybridization assay and antibody/antigen immunoassay), molecular and cellular imaging, fluorescence resonance energy transfer (FRET) and capillary electrophoresis. This thesis mainly focuses on the synthesis and control of different size QDs, optical properties, surface chemistry and bioconjugation, and especially its practical application in biological and analytical filed as fluorescent probe. The main contents and results are summarized as follows:
1. Different diameter CdSe/ZnS semiconductor nanocrystals (average diameter: from ~3.5 to ~20 nm), quantum dots (QDs) were synthesized by changing the nucleation time, using organometallic reagents. These quantum dots possess narrow and symmetrical fluorescent emissions. The emission wavelengths of these composite dots span most of the visible spectrum from 500 nm through 700 nm. Furthermore, it is found that the quantum dots with an emission at ~590 nm, tend to have a good quantum yield (such asΦ590= 43.5%). While the emission wavelength of prepared CdSe/ZnS QDs shifts toward blue or red from 590 nm, the quantum yield tends to decrease.
2. Multiple-color encoded beads were achieved by incorporating two color core-shell quantum dots (CdSe/ZnS) to commercial polystyrene beads. By controlling the molar ratio of the QDs in doping solution, various encoded beads with different discriminable codes could be obtained. For two certain QDs, the relation curve about the intensity ratio of single encoded bead and the molar ratio of the two QDs in doping solution could be achieved firstly. Then the curve could be used to estimate the capacity of encoding based on these two QDs, and guide the quantitative encoding in the coming experiment. The results of antibody conjugation suggest that the encoded beads obtained in this method could be effectively used in biological applications. After that, optical encoding of microbeads with these quantum dots was carried out, and the spectra of encoded beads were identified. The result indicates that, to identify the encoded beads with different emission wavelengths and emission intensities, it is needed to acquire and differentiate the spectra of beads. After immobilized with human IgG, the encoded beads were used to detect the corresponding antibody in solution. The result indicates that the encoded beads can detect the antibody signal effectively. And the effective detection range of the antibody is about 2~15μM.
3. A flow cytometric detecting technology based on quantum dots (QDs)-encoded beads has been described. Using this technology, several QD encoded beads with different code were identified effectively, and the target molecule (DNA sequence) in solution was also detected accurately by coupling to its complementary sequence probed on QDs-encoded beads through DNA hybridization assay. The resolution of this technology for encoded beads is resulted from two longer wavelength fluorescence identification signals (yellow and red fluorescent signals of QDs), and the third shorter wavelength fluorescence signal (green reporting signal of fluorescein isothiocyanate (FITC)) for the determination of reaction between probe and target. In experiment, because of QDs’unique optical character, only one excitation light source was needed to excite the QDs and probe dye FITC synchronously comparing with other flow cytometric assay technology. The results show that this technology has present excellent repeatability and good accuracy. It will become a promising multiple assay platform in various application fields after further improvement.
4. Quantum dot (QD) solubilization, conjugation with biomolecules, column purification and labeling of human HepG2 cells with transferrin-QD (Tf-QD) conjugates are reported in detail in this paper. Water-soluble QDs (WQDs) were obtained using sodium thiolycolate to replace the surface ligand tri-n-octylphosphine oxide (TOPO) on the surface of oil-soluble QDs, and Tf-QD conjugates were produced by coupling Tf to WQD. The resulting Tf-QDs were characterized by UV and luminescence spectrophotometry, and purified by Sephadex column. The results indicate that Tf has been conjugated to QD successfully. Based on transferrin/transferrin-receptor-mediated delivery system, the Tf-QD conjugates were used to label human HepG2 cells. After a short incubation, the QDs were mainly localized to the membrane of cells. After 12-hour incubation, QDs appear mainly in the cytoplasm portion. However, QDs were not found in the nucleus of the cells. Furthermore, the fluorescence intensity of QDs in the cells reduces gradually over time, and fluorescence cannot be observed after 10 days. However, the growth of the labeled cells was not markedly affected by the toxicity of QDs, and they are alive for 10 days. These results can be used for further application of QDs in bioscience.
5. The resonance energy transfer between chemiluminescence donor (luminol-H2 O2 system) and Quantum dots (QDs, emission at 593 nm) acceptors (CRET) was investigated. Concretely, the resonance energy transfer efficiencies were compared while the oil soluble QDs, water soluble QDs (modified with thioglycolate) and QD-HRP conjugates were used as acceptor respectively. The fluorescence of QD acceptor can be observed in the three cases, which suggests that the CRET occurs while the different QD acceptor was used. The highest CRET efficiency (10.7%) was observed in the case of oil soluble QDs. And the lowest CRET efficiency (2.7%) was observed in the QD-HRP conjugates case. This result is coincident with the quantum yields of the acceptors (18.3% and 0.4%). The same result was observed in another similar set of experiment, in which the amphiphilic-polymer modified QDs (emission at 675 nm) were used. It suggests that the quantum yield of the QD in different status is the crucial factor to the CRET efficency. Furthermore, the multiplexed CRET also be observed between luminol donor and three different size QD acceptors simultaneously. This work will offer useful support for improving the study of CRET based on QDs.
1.采用油相合成法,通过对成核时间的控制,批量合成得到了多种不同发射波长的量子点(500~700 nm)。对其光学性质进行了表征,发现发射波长在590 nm附近时,量子点具有较好的荧光量子产率(43.5%),而发射波长蓝移或红移时,相应的量子点量子产率都有所降低。
2.通过对聚苯乙烯微球进行溶涨处理、量子点的吸附装载,完成了对微球的多色编码。我们利用量子点对微球进行了荧光编码及光谱检测,结果表明需要通过光谱分辨才能有效鉴别不同波长与强度的编码微球。对于确定的两种量子点,通过控制掺杂液中不同量子点浓度比率的梯度变化,可以得到信号强度比率也梯度变化的编码微球。而且,通过微球信号强度比率和装载液中两种QDs摩尔浓度比率的标准曲线,可以初步评估这两种量子点的有效编码库容量,并可用于指导微球的光谱编码。之后,在编码微球上固定human IgG抗原,对溶液中相应的抗体进行了检测,结果表明,该编码微球可以很好地检测到溶液中抗体的信号,抗体有效检测范围为2~15μM。这一结果表明,该方法编码得到的微球可以被有效的用于生物学研究。
3.介绍了一种基于量子点编码微球的流式分析技术,利用该技术对各种量子点编码微球的荧光光谱进行了很好的区分,并实现了对溶液中特定的靶分子的有效检测。这一检测系统是基于两个长波长的荧光信号(如黄色和红色量子点信号)来辨别确定微球的编码,用第三个短波长的荧光信号(如绿色,染料FITC的信号)作为报告信号来确定反应的发生与否,这样就可以利用量子点的荧光特性,只需一种光源就可对编码信号和报告信号进行同时检测。实验的结果表明,该方法具有良好的准确性和重现性。由于该系统在单光源激发下,具有快速、准确、简单、可批量实时检测等优点,相信在得到进一步的完善后,将具有较好的应用前景。
4.系统地介绍了脂溶性量子点水溶性修饰、量子点与生物分子偶联及其柱层析分离纯化,以及量子点/转铁蛋白偶联物(Tf-QD)对人肝癌细胞HepG2进行标记成像等量子点荧光探针从制备到应用的全部过程研究。具体为,用巯基乙酸钠(sodium thioglycolate HSCH2COONa)取代CdSe/ZnS量子点表面的TOPO,对实验室合成的脂溶性量子点进行了有效的水溶性修饰。利用紫外、荧光和层析柱对水溶性的量子点与转铁蛋白Tf偶联进行了表征,结果证实两者有效地偶联在了一起。之后,在对偶联物进行分离纯化后,利用它对人肝癌HepG2细胞进行了标记。结果表明,量子点探针首先标记在了细胞膜上,之后在转铁蛋白(Tf)/转铁蛋白受体(TfR)介导作用下转入到细胞内,并主要分布在细胞质部分,未能进入到细胞核内。进一步的观察发现,细胞内的量子点荧光随时间增长在减弱,经历大约十天后再也观察不到量子点荧光。而且,量子点并未由于本身具有的“生物毒性”而影响细胞的正常生长,10天后细胞仍然存活。这一工作为促进QD在生物中的应用提供了很好的借鉴作用。
5.采用发射波长为593 nm量子点,具体研究了luinol-H2 O2体系作为供体,脂溶性、水溶性(巯基羧酸修饰)以及偶联了HRP等三种情况下量子点作为受体时能量传递的情况。结果发现,三种情况下均能观察到量子点的发射峰,表明体系中发生了能量共振转移(Chemiluminescence resonance energy transfer, CRET)。脂溶性量子点情况下得到了最高的CRET效率,为10.7%,偶联物的CRET效率最低,为2.7%。这一结果与其量子产率是对应的(18.3%和0.4%)。而在利用两亲性聚合物修饰的量子点研究CRET时也得到同样的规律。我们推断量子点在不同情况下不同的量子产率对实验中CRET效率起着决定性的影响作用。此外,我们还观察到了luminol作为供体与多色量子点(三种)受体同时实现多元CRET的现象。这一工作为促进基于量子点的CRET研究提供了有效的支持。
Core-shell quantum dot (QD) is a new inorganic semiconductor nanocrystal material. As a fluorescent probe, it has many unique excellent optical characteristics compared with traditional organic dyes. Firstly, as QDs have broad effective excitation spectra, simultaneous excitation of multiple QDs can be accomplished easily with a single excitation light, which can promote multiple applications of QDs. Secondly, it is not necessary to strictly compensate for the measurements owing to the narrow and symmetrical emission of QDs. Thirdly, the fluorescence strength of QDs do not decrease when exposed to light for long periods of time (that is, QDs are photostable), and QDs are less susceptible to metabolic degradation than organic fluorophores. Finally, although QDs with different sizes have different emission wavelengths (different colors), they have similar physical properties (such as dimension and polarity) and biological conjugation ability (namely, that can effectively conjugate to biomolecules and proteins). In recent years, quantum dots have been widely used in optical encoding of microbeads, encoded bead based array technology (including DNA hybridization assay and antibody/antigen immunoassay), molecular and cellular imaging, fluorescence resonance energy transfer (FRET) and capillary electrophoresis. This thesis mainly focuses on the synthesis and control of different size QDs, optical properties, surface chemistry and bioconjugation, and especially its practical application in biological and analytical filed as fluorescent probe. The main contents and results are summarized as follows:
1. Different diameter CdSe/ZnS semiconductor nanocrystals (average diameter: from ~3.5 to ~20 nm), quantum dots (QDs) were synthesized by changing the nucleation time, using organometallic reagents. These quantum dots possess narrow and symmetrical fluorescent emissions. The emission wavelengths of these composite dots span most of the visible spectrum from 500 nm through 700 nm. Furthermore, it is found that the quantum dots with an emission at ~590 nm, tend to have a good quantum yield (such asΦ590= 43.5%). While the emission wavelength of prepared CdSe/ZnS QDs shifts toward blue or red from 590 nm, the quantum yield tends to decrease.
2. Multiple-color encoded beads were achieved by incorporating two color core-shell quantum dots (CdSe/ZnS) to commercial polystyrene beads. By controlling the molar ratio of the QDs in doping solution, various encoded beads with different discriminable codes could be obtained. For two certain QDs, the relation curve about the intensity ratio of single encoded bead and the molar ratio of the two QDs in doping solution could be achieved firstly. Then the curve could be used to estimate the capacity of encoding based on these two QDs, and guide the quantitative encoding in the coming experiment. The results of antibody conjugation suggest that the encoded beads obtained in this method could be effectively used in biological applications. After that, optical encoding of microbeads with these quantum dots was carried out, and the spectra of encoded beads were identified. The result indicates that, to identify the encoded beads with different emission wavelengths and emission intensities, it is needed to acquire and differentiate the spectra of beads. After immobilized with human IgG, the encoded beads were used to detect the corresponding antibody in solution. The result indicates that the encoded beads can detect the antibody signal effectively. And the effective detection range of the antibody is about 2~15μM.
3. A flow cytometric detecting technology based on quantum dots (QDs)-encoded beads has been described. Using this technology, several QD encoded beads with different code were identified effectively, and the target molecule (DNA sequence) in solution was also detected accurately by coupling to its complementary sequence probed on QDs-encoded beads through DNA hybridization assay. The resolution of this technology for encoded beads is resulted from two longer wavelength fluorescence identification signals (yellow and red fluorescent signals of QDs), and the third shorter wavelength fluorescence signal (green reporting signal of fluorescein isothiocyanate (FITC)) for the determination of reaction between probe and target. In experiment, because of QDs’unique optical character, only one excitation light source was needed to excite the QDs and probe dye FITC synchronously comparing with other flow cytometric assay technology. The results show that this technology has present excellent repeatability and good accuracy. It will become a promising multiple assay platform in various application fields after further improvement.
4. Quantum dot (QD) solubilization, conjugation with biomolecules, column purification and labeling of human HepG2 cells with transferrin-QD (Tf-QD) conjugates are reported in detail in this paper. Water-soluble QDs (WQDs) were obtained using sodium thiolycolate to replace the surface ligand tri-n-octylphosphine oxide (TOPO) on the surface of oil-soluble QDs, and Tf-QD conjugates were produced by coupling Tf to WQD. The resulting Tf-QDs were characterized by UV and luminescence spectrophotometry, and purified by Sephadex column. The results indicate that Tf has been conjugated to QD successfully. Based on transferrin/transferrin-receptor-mediated delivery system, the Tf-QD conjugates were used to label human HepG2 cells. After a short incubation, the QDs were mainly localized to the membrane of cells. After 12-hour incubation, QDs appear mainly in the cytoplasm portion. However, QDs were not found in the nucleus of the cells. Furthermore, the fluorescence intensity of QDs in the cells reduces gradually over time, and fluorescence cannot be observed after 10 days. However, the growth of the labeled cells was not markedly affected by the toxicity of QDs, and they are alive for 10 days. These results can be used for further application of QDs in bioscience.
5. The resonance energy transfer between chemiluminescence donor (luminol-H2 O2 system) and Quantum dots (QDs, emission at 593 nm) acceptors (CRET) was investigated. Concretely, the resonance energy transfer efficiencies were compared while the oil soluble QDs, water soluble QDs (modified with thioglycolate) and QD-HRP conjugates were used as acceptor respectively. The fluorescence of QD acceptor can be observed in the three cases, which suggests that the CRET occurs while the different QD acceptor was used. The highest CRET efficiency (10.7%) was observed in the case of oil soluble QDs. And the lowest CRET efficiency (2.7%) was observed in the QD-HRP conjugates case. This result is coincident with the quantum yields of the acceptors (18.3% and 0.4%). The same result was observed in another similar set of experiment, in which the amphiphilic-polymer modified QDs (emission at 675 nm) were used. It suggests that the quantum yield of the QD in different status is the crucial factor to the CRET efficency. Furthermore, the multiplexed CRET also be observed between luminol donor and three different size QD acceptors simultaneously. This work will offer useful support for improving the study of CRET based on QDs.
引文
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