毛细管电泳—激光诱导荧光检测应用于单细胞分析和多药耐药性研究
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摘要
本论文在自行搭建的毛细管电泳-激光诱导荧光检测(CE-LIF)装置上实现了单细胞水平分析,并应用到多药耐药性研究领域。选取白血病细胞系(K562)作为研究对象,开展了多药耐药性相关机理研究,考察了碳纳米管作为载体在药物运输中的可能性,并探讨了以多药耐药性研究为核心的单细胞分析在方法学和实际临床中的意义和应用前景。主要研究内容如下:
第一,采用CE-LIF联合流式细胞仪高通量地对单个白血病细胞系母细胞系(K562S)细胞中的荧光物质罗丹明123进行了定量检测,并将CE-LIF与流式细胞仪的测定结果进行了关联。定量计算了罗丹明123对K562S细胞的转运速度以及表观渗透系数。
第二,建立了CE-LIF表征单个K562细胞上渗透性糖蛋白(Pgp)的方法,同时引入多药耐药性参数来评价细胞系之间的多药耐药性差异。单细胞分析、多细胞分析和流式细胞仪得到的结果一致。
第三,考察了氧化多壁碳纳米管作为药物转运载体的可能性,将氧化多壁碳纳米管与异硫氰酸荧光素反应生成荧光探针(CNTP)后,分别用CE-LIF和流式细胞仪检测CNTP在多药耐药性细胞K562A和K562S中的分布,结果表明CNTP可以被动透过细胞膜并停留在细胞中而不会被Pgp所泵出,说明氧化多壁碳纳米管有可能成为药物转运载体。
第四,采用CE-LIF定量检测了CNTP在酵母细胞中的分布,定量获取了CNTP在酵母中流入时间和温度依赖曲线,定量计算了CNTP流入酵母的表观渗透系数,结果表明CNTP可以通过内吞的方式进入酵母细胞内,这将有助于评价氧化多壁碳纳米管对于细胞膜的渗透性。
In this thesis, a home made capillary electrophoresis-laser-induced fluorescence (CE-LIF) system has been established for application in single cell analysis and multidrug resistance research to elucidate the relative mechanisms of multidrug resistance. Leukemia cell lines (K562) were selected as the target cell line of investigation and carbon nanotubes were investigated as drug transporter for anti-cancer research. The main research contents are as following:
Firstly, a method of combination CE-LIF with flow cytometry was established for high throughput determination and quantitation of fluorophores Rhodamine 123 in single intact K562 parental cell line (K562S) cells. The results of CE-LIF and flow cytometry were correlated. The membrane properties of K562S cell including fluophor transport rate and apparent permeability coefficient were further quantitatively characterized.
Secondly, a method was established to characterize P-glycoprotein on single K562 cells by CE-LIF. A resistance factor so called multidrug resistance multiple was introduced to evaluate the multidrug resistance difference between cell lines. The results of single cell analysis, multi-cell analysis and flow cytometry were consistent.
Thirdly, the possibility of oxidized multi-walled carbon nanotubes as drug transporter was evaluated. They were derivatised with fluorescein isothiocyanate to form carbon nanotube probe (CNTP). Analyses of CNTP in K562 multidrug resistance cell (K562A) and K562S cell using both CE-LIF and flow cytometryshowed that CNTP could transverse the cellular membrane without being pumped out by P-glycoprotein.
Fourthly, the distribution of CNTP in yeast was quantitatively determined by CE-LIF. The time and temperature dependent influx patterns of CNTP in yeast were obtained. The apparent permeability coefficient for influx of CNTP into yeast was calculated, which suggested that CNTP might permeate into yeast through endocytosis.
第一,采用CE-LIF联合流式细胞仪高通量地对单个白血病细胞系母细胞系(K562S)细胞中的荧光物质罗丹明123进行了定量检测,并将CE-LIF与流式细胞仪的测定结果进行了关联。定量计算了罗丹明123对K562S细胞的转运速度以及表观渗透系数。
第二,建立了CE-LIF表征单个K562细胞上渗透性糖蛋白(Pgp)的方法,同时引入多药耐药性参数来评价细胞系之间的多药耐药性差异。单细胞分析、多细胞分析和流式细胞仪得到的结果一致。
第三,考察了氧化多壁碳纳米管作为药物转运载体的可能性,将氧化多壁碳纳米管与异硫氰酸荧光素反应生成荧光探针(CNTP)后,分别用CE-LIF和流式细胞仪检测CNTP在多药耐药性细胞K562A和K562S中的分布,结果表明CNTP可以被动透过细胞膜并停留在细胞中而不会被Pgp所泵出,说明氧化多壁碳纳米管有可能成为药物转运载体。
第四,采用CE-LIF定量检测了CNTP在酵母细胞中的分布,定量获取了CNTP在酵母中流入时间和温度依赖曲线,定量计算了CNTP流入酵母的表观渗透系数,结果表明CNTP可以通过内吞的方式进入酵母细胞内,这将有助于评价氧化多壁碳纳米管对于细胞膜的渗透性。
In this thesis, a home made capillary electrophoresis-laser-induced fluorescence (CE-LIF) system has been established for application in single cell analysis and multidrug resistance research to elucidate the relative mechanisms of multidrug resistance. Leukemia cell lines (K562) were selected as the target cell line of investigation and carbon nanotubes were investigated as drug transporter for anti-cancer research. The main research contents are as following:
Firstly, a method of combination CE-LIF with flow cytometry was established for high throughput determination and quantitation of fluorophores Rhodamine 123 in single intact K562 parental cell line (K562S) cells. The results of CE-LIF and flow cytometry were correlated. The membrane properties of K562S cell including fluophor transport rate and apparent permeability coefficient were further quantitatively characterized.
Secondly, a method was established to characterize P-glycoprotein on single K562 cells by CE-LIF. A resistance factor so called multidrug resistance multiple was introduced to evaluate the multidrug resistance difference between cell lines. The results of single cell analysis, multi-cell analysis and flow cytometry were consistent.
Thirdly, the possibility of oxidized multi-walled carbon nanotubes as drug transporter was evaluated. They were derivatised with fluorescein isothiocyanate to form carbon nanotube probe (CNTP). Analyses of CNTP in K562 multidrug resistance cell (K562A) and K562S cell using both CE-LIF and flow cytometryshowed that CNTP could transverse the cellular membrane without being pumped out by P-glycoprotein.
Fourthly, the distribution of CNTP in yeast was quantitatively determined by CE-LIF. The time and temperature dependent influx patterns of CNTP in yeast were obtained. The apparent permeability coefficient for influx of CNTP into yeast was calculated, which suggested that CNTP might permeate into yeast through endocytosis.
引文
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