纳米传感与传输技术研究及其生物医学应用
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摘要
生物纳米技术是一门前沿的新兴交叉学科,它的发展为生物医学及其相关学科的研究与发展提供了新的思路和手段。但是,许多工作都还处于初步发展阶段,远未达到广泛实际应用的水平,因此纳米技术在生物医学领域中的应用还需要进一步的开发与发展。近年来,本研究小组在结合纳米技术、分析技术、生物技术以及材料制备技术的基础上,开展了以核壳生物纳米颗粒为核心的系统研究工作。本论文在相关工作的基础上,继续深入开展纳米颗粒在生物医学领域中的应用,着重围绕基于纳米颗粒的纳米传感器件与基因传输器件开展工作,取得了以下几个方面的成果:
1.首次利用反相微乳液技术发展了一种同时包埋pH敏感染料(FITC)和参比染料(RuBPY)的硅壳荧光纳米颗粒,构建了一种适合细胞内pH测量的比例型纳米pH传感器。该传感器大小在42nm左右,大小均匀,水溶液中分散性好,抗光漂白能力强,响应重现性好,线性范围为pH4-7,检测灵敏度为0.05pH。利用它尺寸小的优势,纳米pH传感器通过细胞的胞吞作用可以无损伤地进入细胞,实现细胞内pH的高灵敏、准确、实时、原位、非侵入式的无创快速监测,而且比例型纳米pH传感器可以改善染料浓度、细胞数量及环境变化等因素的影响,实现细胞内pH的定量化研究。细胞内的应用表明,本文制备的纳米pH传感器可以实时测定药物刺激细胞后胞内pH的动态变化,并且发现了地塞米松诱导HeLa细胞的凋亡首先经历了一个细胞内酸化过程,为揭示细胞凋亡机制提供了一种新的研究手段,也为抗癌策略——诱导癌细胞酸化的用药提供了一种新的筛选模式。该传感器的制备方法简单,改变功能化的内核材料可以推广到多种敏感染料的包埋,发展成为一种集成化的纳米传感器,实现多组分的同步分析,而且二氧化硅壳纳米颗粒具有稳定的理化性能、良好的生物相容性,因此基于硅壳纳米颗粒发展的纳米传感器有望用于细胞内多种生理生化变化的实时监测。
2.利用微乳液法合成了包埋联钌吡啶的硅壳荧光纳米颗粒,通过温和的EDC交联法将生物配体修饰到纳米颗粒上,构建了一种新型的生物功能化的荧光标记探针。EDC交联法反应条件温和,并能有效地保留修饰的生物配体的活性,同时通过基因工程的方法将阴性细胞进行荧光标记,在大量阴性细胞存在的情况下,实现了在同一个显微镜视野下根据荧光分布来判断新型荧光标记探针特异性识别的准确性,为体外细胞的特异识别提供了直观的证据。在此基础上,成功地将这种生物功能化的荧光探针用于外周血中肝癌细胞的识别。硅壳荧光纳米颗粒具有良好的生物相容性、荧光信号强、光稳定性好以及低毒性等优点,这些都为癌细胞的超灵敏检测提供了可能。这种基于荧光纳米颗粒探针的标记方法有望用于
The development of bionanotechnology has provided many new opportunities for the research of biology and medicine. However, many efforts are needed to further develop their applications. Recently, our group has developed a biocompatible core-shell nanoparticle and has carried out systemic researches with the combination of nanotechnology, analytical chemistry, biotechnology and material science. On the basis of our correlative researches, this dissertation focuses on the studies of the nanosensors and gene carriers based on nanoparticles and their applications in the biomedicine.
1. We synthesized a nanoparticle and utilized it as a pH nanosensor for noninvasive monitoring intracellular pH change induced by drug stimulation. The pH sensor was a two dye doped silica nanoparticle (2DFNS) that contained a pH sensitive indicator (FITC) and a reference dye (RuBPY). The 2DFNS had an average diameter of 42±3nm and could be well dispersed in aqueous solution. This allowed it to be easily taken up by cells for noninvasive intracellular pH measurement. The 2DFNS had excellent pH sensing capability and reproducibility. The dynamic range of the nanosensor was between pH 4 and 7 with a sensitivity of 0.05 pH units. The 2DFNS could act as sensitive ratometric nanosensors for monitoring pH change and the calculation of pH was independent on cell number and dye concentration. This new 2DFNS was used for intracellular pH measurement in a variety of biological samples. Lysosomal pH change in murine macrophages stimulated by chloroquine and intracellular acidification in apoptotic cancer cells were monitored. The 2DFNS was stable and reproducible. There was no dye leakage and the photosatbility was excellent. The biological applications of nanosensors have demonstrated their excellent utility in intracellular measurements. It is possible to develop multiple-analyte sensors by the encapsulation of multiple sensitive dyes, given their high sensitivity and extremely simple fabrication.
2. Bio-functioned fluorescent silica nanoparticles have been synthesized for cell labeling and cell differentiation and have shown great promise as novel fluorescent probes. The galactose-conjugated fluorescent nanoparticles (GCFNPs) were synthesized by the conjugation of amino-modified fluorescent nanoparticles with lactobionic acid (LA) through EDC linkage. This yielded GCFNPs retained excellent biological activity and could be used to label the hepatocyte as an
1.首次利用反相微乳液技术发展了一种同时包埋pH敏感染料(FITC)和参比染料(RuBPY)的硅壳荧光纳米颗粒,构建了一种适合细胞内pH测量的比例型纳米pH传感器。该传感器大小在42nm左右,大小均匀,水溶液中分散性好,抗光漂白能力强,响应重现性好,线性范围为pH4-7,检测灵敏度为0.05pH。利用它尺寸小的优势,纳米pH传感器通过细胞的胞吞作用可以无损伤地进入细胞,实现细胞内pH的高灵敏、准确、实时、原位、非侵入式的无创快速监测,而且比例型纳米pH传感器可以改善染料浓度、细胞数量及环境变化等因素的影响,实现细胞内pH的定量化研究。细胞内的应用表明,本文制备的纳米pH传感器可以实时测定药物刺激细胞后胞内pH的动态变化,并且发现了地塞米松诱导HeLa细胞的凋亡首先经历了一个细胞内酸化过程,为揭示细胞凋亡机制提供了一种新的研究手段,也为抗癌策略——诱导癌细胞酸化的用药提供了一种新的筛选模式。该传感器的制备方法简单,改变功能化的内核材料可以推广到多种敏感染料的包埋,发展成为一种集成化的纳米传感器,实现多组分的同步分析,而且二氧化硅壳纳米颗粒具有稳定的理化性能、良好的生物相容性,因此基于硅壳纳米颗粒发展的纳米传感器有望用于细胞内多种生理生化变化的实时监测。
2.利用微乳液法合成了包埋联钌吡啶的硅壳荧光纳米颗粒,通过温和的EDC交联法将生物配体修饰到纳米颗粒上,构建了一种新型的生物功能化的荧光标记探针。EDC交联法反应条件温和,并能有效地保留修饰的生物配体的活性,同时通过基因工程的方法将阴性细胞进行荧光标记,在大量阴性细胞存在的情况下,实现了在同一个显微镜视野下根据荧光分布来判断新型荧光标记探针特异性识别的准确性,为体外细胞的特异识别提供了直观的证据。在此基础上,成功地将这种生物功能化的荧光探针用于外周血中肝癌细胞的识别。硅壳荧光纳米颗粒具有良好的生物相容性、荧光信号强、光稳定性好以及低毒性等优点,这些都为癌细胞的超灵敏检测提供了可能。这种基于荧光纳米颗粒探针的标记方法有望用于
The development of bionanotechnology has provided many new opportunities for the research of biology and medicine. However, many efforts are needed to further develop their applications. Recently, our group has developed a biocompatible core-shell nanoparticle and has carried out systemic researches with the combination of nanotechnology, analytical chemistry, biotechnology and material science. On the basis of our correlative researches, this dissertation focuses on the studies of the nanosensors and gene carriers based on nanoparticles and their applications in the biomedicine.
1. We synthesized a nanoparticle and utilized it as a pH nanosensor for noninvasive monitoring intracellular pH change induced by drug stimulation. The pH sensor was a two dye doped silica nanoparticle (2DFNS) that contained a pH sensitive indicator (FITC) and a reference dye (RuBPY). The 2DFNS had an average diameter of 42±3nm and could be well dispersed in aqueous solution. This allowed it to be easily taken up by cells for noninvasive intracellular pH measurement. The 2DFNS had excellent pH sensing capability and reproducibility. The dynamic range of the nanosensor was between pH 4 and 7 with a sensitivity of 0.05 pH units. The 2DFNS could act as sensitive ratometric nanosensors for monitoring pH change and the calculation of pH was independent on cell number and dye concentration. This new 2DFNS was used for intracellular pH measurement in a variety of biological samples. Lysosomal pH change in murine macrophages stimulated by chloroquine and intracellular acidification in apoptotic cancer cells were monitored. The 2DFNS was stable and reproducible. There was no dye leakage and the photosatbility was excellent. The biological applications of nanosensors have demonstrated their excellent utility in intracellular measurements. It is possible to develop multiple-analyte sensors by the encapsulation of multiple sensitive dyes, given their high sensitivity and extremely simple fabrication.
2. Bio-functioned fluorescent silica nanoparticles have been synthesized for cell labeling and cell differentiation and have shown great promise as novel fluorescent probes. The galactose-conjugated fluorescent nanoparticles (GCFNPs) were synthesized by the conjugation of amino-modified fluorescent nanoparticles with lactobionic acid (LA) through EDC linkage. This yielded GCFNPs retained excellent biological activity and could be used to label the hepatocyte as an
引文
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