疾病诊断用功能化量子点荧光探针的研究
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摘要
量子点(quantum dots,缩写为QDs),又叫做半导体纳米晶,由于其独特的光学和电学性质在生物医学领域具有广泛的应用前景。本文通过对所制备的亲油性量子点的表面改性,将其亲水性化,并在此基础上通过耦联生物大分子,制备特异性量子点荧光探针,用于疾病的诊断。具体研究内容如下:
1.通过高温油相法制备出尺寸均一、单分散性好且有较高结晶度的CdSe量子点。各种不同的CdSe量子点的荧光发射波长范围为535nm-580nm,粒径范围为2.8nm-4.37nm,荧光发射半峰宽范围为23-29nm,量子产率最高可达73%。分别研究了反应时间,配体种类及用量等对量子点光学性能的影响。紫外-可见分光光度计(UV-Vis),荧光分光光度计(PL)表征结果表明:随着反应时间的延长,CdSe量子点的吸收和发射光谱发生红移,粒径逐渐增大。继而又采用连续离子层吸附反应(SILAR)对亲油性CdSe量子点进行表面包覆改性,制备出多种不同的核壳结构量子点,并通过UV-Vis,PL,场发射透射电子显微镜(HRTEM),X射线粉末衍射仪(XRD)研究包覆前后量子点的光学性能,型貌,粒径及内部结构。结果表明,包覆后各种不同的核壳结构量子点的吸收和发射光谱出现明显红移,最大的荧光发射波长为640nm,荧光发射半峰宽范围为30nm-40nm,量子产率从改性前的0.1左右可提高到0.688。在此基础上,制备了含CdS和ZnS合金壳层的量子点,既最大限度的提高量子产率(0.5-0.7左右),又有效的控制荧光发射峰半峰宽(30nm-36nm)。
2.通过表面配体交换,双亲性高分子自组装,超声乳化改性以及二氧化硅包裹对亲油性量子点进行亲水性改性。结果表明:配体交换改性简单易行,但产品的胶体稳定性差,荧光效率较低;双亲性高分子自组装改性工艺简单,但纯化较难且繁琐;超声乳化方法改性简单易行,且产品纯化简单,离心即可,但所制备的颗粒较大且不均匀;二氧化硅包裹改性工艺成熟,制备的产品呈单分散,粒径较小,但制备周期较长。实验中还对不同结构和组成的量子点经过二氧化硅改性后的荧光性能做了系列研究,结果表明,具有多层壳的亲油性量子点二氧化硅改性后更具稳定性和较高的荧光效率。不同的改性方法各有优缺点,对于不同的生物医学应用可以采取相应的亲水性改性方法。
3.利用自制的量子点制备了两种拟用于生物检测的量子点荧光微球:(1)采用溶胀法成功制备出多种量子点聚苯乙烯(PS)荧光编码微球;荧光显微镜及荧光分光光度计检测结果说明:核壳结构量子点对PS微球染色效果要优于CdSe核量子点;通过调节溶胀时间可以获得不同强度编码的荧光微球。
4.采用超声乳化和二氧化硅包裹的方法制备荧光磁性多功能纳米颗粒。TEM表征结果表明,超声乳化方法制备的荧光磁性纳米颗粒粒径在200nm左右,粒径分布较宽;二氧化硅包裹的荧光磁性纳米颗粒粒径较小,40nm左右,且呈单分散。二者均借助光电子能谱(EDX)证明量子点和磁性纳米颗粒均被成功包载。实验中还研究了荧光效率和磁响应性之间的平衡,以保证在较高荧光效率的同时具有较好的磁响应性。
5.将亲水性量子点与生物大分子(如抗体)耦联,制备特异性荧光纳米探针,用于液相生物芯片检测。在羧基化聚苯乙烯微球表面通过耦联抗原分子致敏,再与所制备的特异性荧光量子点纳米探针发生抗原抗体反应,以检测特定抗原。
6.制备多色亲水性量子点用于高通量生物检测。将两种颜色的亲水性量子点耦联相应的抗体,加入到预先包被相应抗原的聚苯乙烯96孔板,发生免疫反应。结果表明,混合抗原样品的孔内能观察到两种颜色的荧光信号,说明多色量子点荧光探针能够用于高通量生物检测领域。
7.量子点荧光纳米探针用于禽流感病毒的检测。将亲水性量子点与禽流感多克隆抗体耦联,制备出对禽流感病毒具有特异性识别的荧光探针。结果表明,量子点荧光探针能有效检测禽流感病毒,检测快速且灵敏,适合在出入境口岸的快速检测。
综上所述,本文将纳米技术与疾病诊断技术相结合,采用具有特异性识别能力的量子点作为生物检测的荧光纳米探针用于疾病诊断的前期研究,充分利用量子点本身优越的荧光特性和所耦联生物分子的特异性研制出具有灵敏性高、特异性强、光稳定性好的高通量荧光诊断试剂,为疾病的早期诊断提供了重要的科学依据。
Quantum dots (QDs), also known as semiconductor nanocrystals, because of their unique optical and electrical properties,have attracted great interest and attention from physicists, chemists and biologists, and have become a most frequently studied matter in the nanotechnology field. In this paper, the hydrophobic high quality QDs were first prepared and surface modification was followed to prepare water-soluble QDs. Then through the coupling of biological macromolecules with QDs, the QDs bioconjugates were used in the preliminary study of diagnosis of disease.
1. In this paper, we successfully prepared CdSe quantum dots (QDs) by colloid chemistry method, which were high crystallization and monodisperse. About the different types of CdSe QDs, the emission wavelength region were between 535nm and 580nm, the region of the full width at half maximum (fwhm) of the photoluminescence (PL) peak were between 23nm and 29nm, the quantum yield (QY) was as high as 0.73. And then, the influences of reaction time and ligand on optical property of QDs had been discussed. From ultraviolet visible spectra (UV-Vis) and photoluminescence (PL), we could get the results: with the increase of reaction time and the concentration of ODA and TOPO, the size of QDs was increased, as well as the absorption and emission spectra were clearly red shifted; using TOP to prepare Se precursors benefited to prepare different QDs with various colors. We used successive ion layer adsorption and reaction (SILAR) method to modify CdSe QDs, which could lead us to gain different core/shell QDs with several different structures. And we compared optical properties, size, and inner structures of pure CdSe QDs and modified CdSe QDs with UV, PL, HRTEM and XRD, and so on. After surface passivation, the QY of all the core shell QDs had improved from about 0.1 to about 0.4~0.7, and the fwhm region was between 30nm and 40nm. The introduction of the CdxZn1-xS shell could benefit the growth of core/shell QDs and prefect the crystal properties, which could more efficiently protect the core QDs.
2. There were four methods in this paper for the water-solublization of hydrophobic QDs. Namely, ligand exchange, amphiphilic polymer self-assembly, ultrasound emulsification and silica coating. The results showed that: a simple modification of ligand exchange modification is easy, but the colloid stability of products is poor and low QY; Amphiphilic polymer self-assembly modification of QDs is simple, but have difficult and cumbersome purification; ultrasound emulsification modified method is simple, and purification procedure is easy with centrifugation, but with big size and uneven size distribution; silica coating is a mature technology, good at preparation of ultrafine particles and with narrow size distribution, but a longer preparation period. In this paper, effect of varying types of QDs on the QY after silica-encapsulation is systematically studied. The results showed that QDs with appropriate structure and composition of shells can much better retain the initial QY after silanization. Different methods have their own shortcomings, thus we could choose proper modification method for different biomedical applications.
3. We also prepared two different QDs fluorescence microspheres, which could be applied as biochips. The results gained from fluorescence microscopy and PL indicated that several PS-QDs fluorescence encoding microspheres could be successfully gained by swelling; stained effect used with core-shell QDs was obviously better than that used with core QDs; fluorescence microspheres with different intensities could be easily gained through the change of reaction time, which could not gained through the change of sweller.
4. Multi-functional fluorescent magnetic nanoparticles were prepared in two ways: ultrasound emulsification and silica-coating. TEM characterization showed that ultrasound emulsification is opt for preparation of big size nanoparticles with ca.200nm, a wide size distribution; while ultrafine nanoparticles with ca.40nm, monodisperse distribution were obtained with silica-coating. With the help of EDX analysis, it proved that the samples obtained with the above two methods contain both quantum dots and magnetic nanoparticles in a single nanoparticle. The effects of both QY and magnetic response of the multi-functional fluorescent magnetic nanoparticles were taken into account; we designed experiments for the balance of QY and response to the magnetic effect.
5. Specific fluorescent nano probes used for the suspending detection were prepared by using the as-prepared water-soluble QDs and biological macromolecules (such as antibodies). Combination of the carboxyl polystyrene (PS) microspheres prepared in our lab, the as-prepared specific QDs-probes were designed and used for the suspending fluorescent detection in liquid phase. Antigen-antibody reaction can be occurred on the surface of antigen-coated PS microspheres.
6. Preparation of hydrophilic multi-color quantum dots for high-throughput biological detection. In this paper, two colors of QDs were used to link two antibodies, and then added into the antigen pre-coated polystyrene plates. The results showed that the mixed antigen sample hole can be observed in two colors of fluorescent signal. That means multi-color fluorescent QDs can be used to the high-throughput biodetection.
7. The preparation of fluorescent QDs nano-probe for the detection of avian influenza virus. Hydrophilic QDs were bioconjugated with the avian influenza virus antibodies, and such bioconjugates have specific targeting ability to the avian influenza virus. The results showed that the as-prepared QDs nano-probes have excellent detection ablility to the avian influenza virus. The detection is rapid and sensitive, suitable for rapid detection in the import and export port.
To sum up, in this study, the newly nanotechnology and disease diagnosis technology were combined to develop a novel kind of fluorescent detection system. Making full use of the advantages of QDs and the coupling of specific biological molecules to construct a specific, sensitive and strong stable fluorescent diagosis reagent for the diagnosis of diseases. The research results in this paper provide foundation for the real-use of QDs in the diagonis area.
1.通过高温油相法制备出尺寸均一、单分散性好且有较高结晶度的CdSe量子点。各种不同的CdSe量子点的荧光发射波长范围为535nm-580nm,粒径范围为2.8nm-4.37nm,荧光发射半峰宽范围为23-29nm,量子产率最高可达73%。分别研究了反应时间,配体种类及用量等对量子点光学性能的影响。紫外-可见分光光度计(UV-Vis),荧光分光光度计(PL)表征结果表明:随着反应时间的延长,CdSe量子点的吸收和发射光谱发生红移,粒径逐渐增大。继而又采用连续离子层吸附反应(SILAR)对亲油性CdSe量子点进行表面包覆改性,制备出多种不同的核壳结构量子点,并通过UV-Vis,PL,场发射透射电子显微镜(HRTEM),X射线粉末衍射仪(XRD)研究包覆前后量子点的光学性能,型貌,粒径及内部结构。结果表明,包覆后各种不同的核壳结构量子点的吸收和发射光谱出现明显红移,最大的荧光发射波长为640nm,荧光发射半峰宽范围为30nm-40nm,量子产率从改性前的0.1左右可提高到0.688。在此基础上,制备了含CdS和ZnS合金壳层的量子点,既最大限度的提高量子产率(0.5-0.7左右),又有效的控制荧光发射峰半峰宽(30nm-36nm)。
2.通过表面配体交换,双亲性高分子自组装,超声乳化改性以及二氧化硅包裹对亲油性量子点进行亲水性改性。结果表明:配体交换改性简单易行,但产品的胶体稳定性差,荧光效率较低;双亲性高分子自组装改性工艺简单,但纯化较难且繁琐;超声乳化方法改性简单易行,且产品纯化简单,离心即可,但所制备的颗粒较大且不均匀;二氧化硅包裹改性工艺成熟,制备的产品呈单分散,粒径较小,但制备周期较长。实验中还对不同结构和组成的量子点经过二氧化硅改性后的荧光性能做了系列研究,结果表明,具有多层壳的亲油性量子点二氧化硅改性后更具稳定性和较高的荧光效率。不同的改性方法各有优缺点,对于不同的生物医学应用可以采取相应的亲水性改性方法。
3.利用自制的量子点制备了两种拟用于生物检测的量子点荧光微球:(1)采用溶胀法成功制备出多种量子点聚苯乙烯(PS)荧光编码微球;荧光显微镜及荧光分光光度计检测结果说明:核壳结构量子点对PS微球染色效果要优于CdSe核量子点;通过调节溶胀时间可以获得不同强度编码的荧光微球。
4.采用超声乳化和二氧化硅包裹的方法制备荧光磁性多功能纳米颗粒。TEM表征结果表明,超声乳化方法制备的荧光磁性纳米颗粒粒径在200nm左右,粒径分布较宽;二氧化硅包裹的荧光磁性纳米颗粒粒径较小,40nm左右,且呈单分散。二者均借助光电子能谱(EDX)证明量子点和磁性纳米颗粒均被成功包载。实验中还研究了荧光效率和磁响应性之间的平衡,以保证在较高荧光效率的同时具有较好的磁响应性。
5.将亲水性量子点与生物大分子(如抗体)耦联,制备特异性荧光纳米探针,用于液相生物芯片检测。在羧基化聚苯乙烯微球表面通过耦联抗原分子致敏,再与所制备的特异性荧光量子点纳米探针发生抗原抗体反应,以检测特定抗原。
6.制备多色亲水性量子点用于高通量生物检测。将两种颜色的亲水性量子点耦联相应的抗体,加入到预先包被相应抗原的聚苯乙烯96孔板,发生免疫反应。结果表明,混合抗原样品的孔内能观察到两种颜色的荧光信号,说明多色量子点荧光探针能够用于高通量生物检测领域。
7.量子点荧光纳米探针用于禽流感病毒的检测。将亲水性量子点与禽流感多克隆抗体耦联,制备出对禽流感病毒具有特异性识别的荧光探针。结果表明,量子点荧光探针能有效检测禽流感病毒,检测快速且灵敏,适合在出入境口岸的快速检测。
综上所述,本文将纳米技术与疾病诊断技术相结合,采用具有特异性识别能力的量子点作为生物检测的荧光纳米探针用于疾病诊断的前期研究,充分利用量子点本身优越的荧光特性和所耦联生物分子的特异性研制出具有灵敏性高、特异性强、光稳定性好的高通量荧光诊断试剂,为疾病的早期诊断提供了重要的科学依据。
Quantum dots (QDs), also known as semiconductor nanocrystals, because of their unique optical and electrical properties,have attracted great interest and attention from physicists, chemists and biologists, and have become a most frequently studied matter in the nanotechnology field. In this paper, the hydrophobic high quality QDs were first prepared and surface modification was followed to prepare water-soluble QDs. Then through the coupling of biological macromolecules with QDs, the QDs bioconjugates were used in the preliminary study of diagnosis of disease.
1. In this paper, we successfully prepared CdSe quantum dots (QDs) by colloid chemistry method, which were high crystallization and monodisperse. About the different types of CdSe QDs, the emission wavelength region were between 535nm and 580nm, the region of the full width at half maximum (fwhm) of the photoluminescence (PL) peak were between 23nm and 29nm, the quantum yield (QY) was as high as 0.73. And then, the influences of reaction time and ligand on optical property of QDs had been discussed. From ultraviolet visible spectra (UV-Vis) and photoluminescence (PL), we could get the results: with the increase of reaction time and the concentration of ODA and TOPO, the size of QDs was increased, as well as the absorption and emission spectra were clearly red shifted; using TOP to prepare Se precursors benefited to prepare different QDs with various colors. We used successive ion layer adsorption and reaction (SILAR) method to modify CdSe QDs, which could lead us to gain different core/shell QDs with several different structures. And we compared optical properties, size, and inner structures of pure CdSe QDs and modified CdSe QDs with UV, PL, HRTEM and XRD, and so on. After surface passivation, the QY of all the core shell QDs had improved from about 0.1 to about 0.4~0.7, and the fwhm region was between 30nm and 40nm. The introduction of the CdxZn1-xS shell could benefit the growth of core/shell QDs and prefect the crystal properties, which could more efficiently protect the core QDs.
2. There were four methods in this paper for the water-solublization of hydrophobic QDs. Namely, ligand exchange, amphiphilic polymer self-assembly, ultrasound emulsification and silica coating. The results showed that: a simple modification of ligand exchange modification is easy, but the colloid stability of products is poor and low QY; Amphiphilic polymer self-assembly modification of QDs is simple, but have difficult and cumbersome purification; ultrasound emulsification modified method is simple, and purification procedure is easy with centrifugation, but with big size and uneven size distribution; silica coating is a mature technology, good at preparation of ultrafine particles and with narrow size distribution, but a longer preparation period. In this paper, effect of varying types of QDs on the QY after silica-encapsulation is systematically studied. The results showed that QDs with appropriate structure and composition of shells can much better retain the initial QY after silanization. Different methods have their own shortcomings, thus we could choose proper modification method for different biomedical applications.
3. We also prepared two different QDs fluorescence microspheres, which could be applied as biochips. The results gained from fluorescence microscopy and PL indicated that several PS-QDs fluorescence encoding microspheres could be successfully gained by swelling; stained effect used with core-shell QDs was obviously better than that used with core QDs; fluorescence microspheres with different intensities could be easily gained through the change of reaction time, which could not gained through the change of sweller.
4. Multi-functional fluorescent magnetic nanoparticles were prepared in two ways: ultrasound emulsification and silica-coating. TEM characterization showed that ultrasound emulsification is opt for preparation of big size nanoparticles with ca.200nm, a wide size distribution; while ultrafine nanoparticles with ca.40nm, monodisperse distribution were obtained with silica-coating. With the help of EDX analysis, it proved that the samples obtained with the above two methods contain both quantum dots and magnetic nanoparticles in a single nanoparticle. The effects of both QY and magnetic response of the multi-functional fluorescent magnetic nanoparticles were taken into account; we designed experiments for the balance of QY and response to the magnetic effect.
5. Specific fluorescent nano probes used for the suspending detection were prepared by using the as-prepared water-soluble QDs and biological macromolecules (such as antibodies). Combination of the carboxyl polystyrene (PS) microspheres prepared in our lab, the as-prepared specific QDs-probes were designed and used for the suspending fluorescent detection in liquid phase. Antigen-antibody reaction can be occurred on the surface of antigen-coated PS microspheres.
6. Preparation of hydrophilic multi-color quantum dots for high-throughput biological detection. In this paper, two colors of QDs were used to link two antibodies, and then added into the antigen pre-coated polystyrene plates. The results showed that the mixed antigen sample hole can be observed in two colors of fluorescent signal. That means multi-color fluorescent QDs can be used to the high-throughput biodetection.
7. The preparation of fluorescent QDs nano-probe for the detection of avian influenza virus. Hydrophilic QDs were bioconjugated with the avian influenza virus antibodies, and such bioconjugates have specific targeting ability to the avian influenza virus. The results showed that the as-prepared QDs nano-probes have excellent detection ablility to the avian influenza virus. The detection is rapid and sensitive, suitable for rapid detection in the import and export port.
To sum up, in this study, the newly nanotechnology and disease diagnosis technology were combined to develop a novel kind of fluorescent detection system. Making full use of the advantages of QDs and the coupling of specific biological molecules to construct a specific, sensitive and strong stable fluorescent diagosis reagent for the diagnosis of diseases. The research results in this paper provide foundation for the real-use of QDs in the diagonis area.
引文
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