生物活性物质的分离分析新方法研究
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摘要
生物活性物质的分离分析在现代分析科学中已显出越来越重要的作用,并广泛用于食品安全、环境监测、临床检验、药物分析、医药卫生和质量控制等诸多领域。在这些领域中通常需要对复杂体系中的一种或多种组分进行分离分析,如中药分析中的某些有效成分的浓度测定、临床诊断中对疾病相关标志物的检测、食品分析中对牛奶中三聚氰胺的检出等。这就使得简便、快速、灵敏、低成本的分离分析方法显得尤为重要。本研究就建立生物活性物质的分离分析方法开展了以下几方面的工作:
1.高效液相色谱-程序波长设计紫外检测法用于同时测定血浆色氨酸和犬尿氨酸及其应用研究
本研究通过高效液相色谱-程序波长设置紫外检测建立了血浆色氨酸和犬尿氨酸的同时测定方法,该方法具有简单,快速,灵敏,特异等优点。在Agilent Hypersil ODS(125mm×4.0mm,5μm)柱上6分钟内即可完成血浆色氨酸和犬尿氨酸两种组分的同时分离测定。流出液通过紫外检测器程序波长设计检测,0到4分钟波长设置为360nm以检测犬尿氨酸,4到6分钟波长设置为278nm以检测色氨酸,这样可实现这两种组分在一次流动过程中的同时检测。该方法测定犬尿氨酸的线性范围是0.269到21.20μmol/L,色氨酸的线性范围是3.35到678.0μmol/L。犬尿氨酸和色氨酸的检出限分别是0.028μmol/L和0.053μmol/L。精密度和回收率都符合临床检验要求。该方法被用于分析川崎病、过敏性紫癜、肾病综合征、急性肾炎儿童患者的血浆色氨酸和犬尿氨酸浓度。结果显示川崎病组各指标和对照组间有显著性差异,其它组疾病与对照组无显著性差异。
2.功能化超顺磁性磁珠用于肿瘤标志物检测
利用超顺磁性磁珠,结合以丝网印刷电极(SPCE)为工作电极的电化学检测技术,提出一种新型的利用磁场固定生物组分的免疫传感器,用于肿瘤标志物CA199的分离检测。该传感器是通过在环氧基末端修饰的超顺磁性纳米磁珠表面结合上链酶亲和素,利用链酶亲和素和生物素反应,将生物素标记的抗体连接在磁珠表面,再加入经离线温育的样品和辣根过氧化物酶标记的抗体(HRP-anti-CA199),这样酶标抗体被成功连接在超顺磁性磁珠表面,通过磁场将其固定在SPCE表面,加入邻苯二胺.过氧化氢体系进行电化学检测。电化学响应信号与CA199抗原浓度成正比,线性范围为5.0～120U/mL。该方法无需固定化试剂,具有简单、灵敏、低成本等特点。
3.微流控芯片电化学检测在免疫分析中的应用
随着分析化学、生物学、电子学、计算机技术和微加工技术的迅速发展,新的分析仪器和方法不断被应用于检验医学,使检验医学也相应地得到了快速发展。检验医学已逐步提出向即时检验(point-of-caretesting,POCT)、家庭检测或野外检测方向发展,以实现标本的快速方便的检测。近年来发展起来的微流控免疫分析在仪器的微型化和便携化方面具有较好的应用前景,使实现POCT的目标成为可能。微流控免疫分析是通过微加工技术在芯片材料上构建出微米级的通道用于免疫分析。微流控免疫分析因其独特的性质,能大大改善常规免疫分析性能:(1)由于微通道结构较大的比表面积,能使免疫反应大大缩短,提高分析效率。微流控芯片分析多在几秒或几十秒时间内就能完成组分的分离检测。(2)由于通道的尺寸小,能大大节约贵重的免疫试剂消耗量,降低检测成本。微流控分析的进样量已降低至纳升级甚至更低的水平。(3)易于实现仪器便携化,微型化和操作自动化,有望用于POCT。本研究通过微流控通道中的免疫反应,将印刷电极整合在芯片上实现微流控芯片免疫分析电化学检测一体化装置用于肿瘤标志物含量测定。研究将微流控芯片电进样技术、免疫分析和微流控通道柱端电化学检测结合起来,试图构建一种集进样、分离、检测于一体的简便易携的微流控免疫分析芯片,实现血清肿瘤标志物检测。
The separation and determination of biological active substances have become more and more important in modern analytical chemistry,which has widely been used in food safety,environmental monitoring,clinical diagnosis,pharmaceutical analysis,medicine sanitation,quality control and other fields.One or several components in a complex system should be separated and analyzed in these fields,such as the quantity determination of some effect components in Chinese medicine or detection of biomarks for some diseases in clinical diagnosis or the determination of melamine in milk in food analysis.Thus,a simple,fast,sensitive and low cost method for separation and determination shows great importance.Based on separation and determination of active substances in biological samples, this work focuses on development of new methods showed as follows.
1.Simultaneous determination of tryptophan and kynurenine in plasma samples by high-performance liquid chromatography with programmed wavelength ultraviolet detection
A simple,fast,sensitive and specific high-performance liquid chromatography(HPLC) method is developed for simultaneous determination of kynurenine(Kyn) and tryptophan(Trp) with ultraviolet (UV) detection setting programmed wavelength.The separation was carried out on an Agilent Hypersil ODS column(125 mm×4.0 mm,5μm) in less than 6 min and the eluate was monitored by the programmed wavelength detection setting at 360 nm from 0 to 4 min for Kyn,and at 278 nm from 4 min to 6 min for Trp in a single run with UV detector.The linearities of the method were from 0.269 to 21.20μmol/L for Kyn and 3.35 to 678.0μmol/L for Trp,and the detection limits were 0.028μmol/L for Kyn and 0.053μmol/L for Trp,respectively.Satisfactory precisions and recoveries were obtained by this method.The assay was employed to analyze plasma samples of children patients with Kawasaki disease(KD), allergic purpura(AP),nephrotic syndrome(NS) and nephritis.Compared with the control group,KD group showed great difference while other groups showed little difference.
2.Functional paramagnetic beads applied to the detection of tumor marker
An electrochemical immunoassay method using a novel magnetic field fixation of biological substance by paramagnetic beads combined with sreen-printed carbon electrode was proposed for the separation and detection of tumor marker using CA199 as a model analyte.The immunosensor was prepared with streptavidin immobilized epoxysilane modified paramagnetic beads,and the biotinlated antibody was connected to the surface of the paramagnetic beads though the reaction of streptavidin and biotin,and then after the off-line incubation the sample and HRP-anti-CA199 were added.Thus,the HRP-anti-CA199 was connected to the surface of the paramagnetic beads successfully,which was then added to the surface of the work electrode of the screen-printed carbon electrode.The electrochemical detection was performed after adding the mixture of o-phenylenediamine(OPD) and H_2O_2 as substrate under the magnetic field.The electrochemical response signal was proportional to the concentration of CA199 in the range of 5.0～120 U/mL.No reagent for immobilization was needed in this method,and it also has the characteristic of simple,sensitive and low cost.
3.Microfluidics applied to immunoassay by electrochemical detection
In this research,a microfluidic immunoassay method was developed by performing an immunoreaction in a microchannel and integrating the screen-printed electrodes in a chip for electrochemical determination of tumor markers.The convenient carry-home microchip congregates the functions of sampling,separation and detection for immunoassay in detection of tumor markers.
1.高效液相色谱-程序波长设计紫外检测法用于同时测定血浆色氨酸和犬尿氨酸及其应用研究
本研究通过高效液相色谱-程序波长设置紫外检测建立了血浆色氨酸和犬尿氨酸的同时测定方法,该方法具有简单,快速,灵敏,特异等优点。在Agilent Hypersil ODS(125mm×4.0mm,5μm)柱上6分钟内即可完成血浆色氨酸和犬尿氨酸两种组分的同时分离测定。流出液通过紫外检测器程序波长设计检测,0到4分钟波长设置为360nm以检测犬尿氨酸,4到6分钟波长设置为278nm以检测色氨酸,这样可实现这两种组分在一次流动过程中的同时检测。该方法测定犬尿氨酸的线性范围是0.269到21.20μmol/L,色氨酸的线性范围是3.35到678.0μmol/L。犬尿氨酸和色氨酸的检出限分别是0.028μmol/L和0.053μmol/L。精密度和回收率都符合临床检验要求。该方法被用于分析川崎病、过敏性紫癜、肾病综合征、急性肾炎儿童患者的血浆色氨酸和犬尿氨酸浓度。结果显示川崎病组各指标和对照组间有显著性差异,其它组疾病与对照组无显著性差异。
2.功能化超顺磁性磁珠用于肿瘤标志物检测
利用超顺磁性磁珠,结合以丝网印刷电极(SPCE)为工作电极的电化学检测技术,提出一种新型的利用磁场固定生物组分的免疫传感器,用于肿瘤标志物CA199的分离检测。该传感器是通过在环氧基末端修饰的超顺磁性纳米磁珠表面结合上链酶亲和素,利用链酶亲和素和生物素反应,将生物素标记的抗体连接在磁珠表面,再加入经离线温育的样品和辣根过氧化物酶标记的抗体(HRP-anti-CA199),这样酶标抗体被成功连接在超顺磁性磁珠表面,通过磁场将其固定在SPCE表面,加入邻苯二胺.过氧化氢体系进行电化学检测。电化学响应信号与CA199抗原浓度成正比,线性范围为5.0～120U/mL。该方法无需固定化试剂,具有简单、灵敏、低成本等特点。
3.微流控芯片电化学检测在免疫分析中的应用
随着分析化学、生物学、电子学、计算机技术和微加工技术的迅速发展,新的分析仪器和方法不断被应用于检验医学,使检验医学也相应地得到了快速发展。检验医学已逐步提出向即时检验(point-of-caretesting,POCT)、家庭检测或野外检测方向发展,以实现标本的快速方便的检测。近年来发展起来的微流控免疫分析在仪器的微型化和便携化方面具有较好的应用前景,使实现POCT的目标成为可能。微流控免疫分析是通过微加工技术在芯片材料上构建出微米级的通道用于免疫分析。微流控免疫分析因其独特的性质,能大大改善常规免疫分析性能:(1)由于微通道结构较大的比表面积,能使免疫反应大大缩短,提高分析效率。微流控芯片分析多在几秒或几十秒时间内就能完成组分的分离检测。(2)由于通道的尺寸小,能大大节约贵重的免疫试剂消耗量,降低检测成本。微流控分析的进样量已降低至纳升级甚至更低的水平。(3)易于实现仪器便携化,微型化和操作自动化,有望用于POCT。本研究通过微流控通道中的免疫反应,将印刷电极整合在芯片上实现微流控芯片免疫分析电化学检测一体化装置用于肿瘤标志物含量测定。研究将微流控芯片电进样技术、免疫分析和微流控通道柱端电化学检测结合起来,试图构建一种集进样、分离、检测于一体的简便易携的微流控免疫分析芯片,实现血清肿瘤标志物检测。
The separation and determination of biological active substances have become more and more important in modern analytical chemistry,which has widely been used in food safety,environmental monitoring,clinical diagnosis,pharmaceutical analysis,medicine sanitation,quality control and other fields.One or several components in a complex system should be separated and analyzed in these fields,such as the quantity determination of some effect components in Chinese medicine or detection of biomarks for some diseases in clinical diagnosis or the determination of melamine in milk in food analysis.Thus,a simple,fast,sensitive and low cost method for separation and determination shows great importance.Based on separation and determination of active substances in biological samples, this work focuses on development of new methods showed as follows.
1.Simultaneous determination of tryptophan and kynurenine in plasma samples by high-performance liquid chromatography with programmed wavelength ultraviolet detection
A simple,fast,sensitive and specific high-performance liquid chromatography(HPLC) method is developed for simultaneous determination of kynurenine(Kyn) and tryptophan(Trp) with ultraviolet (UV) detection setting programmed wavelength.The separation was carried out on an Agilent Hypersil ODS column(125 mm×4.0 mm,5μm) in less than 6 min and the eluate was monitored by the programmed wavelength detection setting at 360 nm from 0 to 4 min for Kyn,and at 278 nm from 4 min to 6 min for Trp in a single run with UV detector.The linearities of the method were from 0.269 to 21.20μmol/L for Kyn and 3.35 to 678.0μmol/L for Trp,and the detection limits were 0.028μmol/L for Kyn and 0.053μmol/L for Trp,respectively.Satisfactory precisions and recoveries were obtained by this method.The assay was employed to analyze plasma samples of children patients with Kawasaki disease(KD), allergic purpura(AP),nephrotic syndrome(NS) and nephritis.Compared with the control group,KD group showed great difference while other groups showed little difference.
2.Functional paramagnetic beads applied to the detection of tumor marker
An electrochemical immunoassay method using a novel magnetic field fixation of biological substance by paramagnetic beads combined with sreen-printed carbon electrode was proposed for the separation and detection of tumor marker using CA199 as a model analyte.The immunosensor was prepared with streptavidin immobilized epoxysilane modified paramagnetic beads,and the biotinlated antibody was connected to the surface of the paramagnetic beads though the reaction of streptavidin and biotin,and then after the off-line incubation the sample and HRP-anti-CA199 were added.Thus,the HRP-anti-CA199 was connected to the surface of the paramagnetic beads successfully,which was then added to the surface of the work electrode of the screen-printed carbon electrode.The electrochemical detection was performed after adding the mixture of o-phenylenediamine(OPD) and H_2O_2 as substrate under the magnetic field.The electrochemical response signal was proportional to the concentration of CA199 in the range of 5.0～120 U/mL.No reagent for immobilization was needed in this method,and it also has the characteristic of simple,sensitive and low cost.
3.Microfluidics applied to immunoassay by electrochemical detection
In this research,a microfluidic immunoassay method was developed by performing an immunoreaction in a microchannel and integrating the screen-printed electrodes in a chip for electrochemical determination of tumor markers.The convenient carry-home microchip congregates the functions of sampling,separation and detection for immunoassay in detection of tumor markers.
引文
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