CE-MS of Biological Substances Using Chiral Polymers

使用手性聚合物对生物物质进行 CE-MS

• 批准号: 6700298
• 负责人: SHAHAB AHMED SHAMSI
• 金额: $ 17.88万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700298
• 关键词: capillary electrophoresis; chemical synthesis; chemotherapy; chromatography; drug /agent; drug interactions; drug metabolism; electrospray ionization mass spectrometry; high throughput technology; human subject; ionization; mass spectrometry; micelles; molecular polarity; patient oriented research; polymers; stereoisomer; stoichiometry; technology /technique development; thalidomide; warfarin

In many health related fields the resolution and structural identification of enantiomeric compounds are necessary steps for studying racemic drug interactions. The coupling of capillary electrophoresis (CE) to mass spectrometry (MS) using conventional micelles [above the critical micelle concentration (CMC)] is very difficult if not impossible. Preliminary data in our laboratory indicates that the uses of polymerized surfactant or micelle polymers provide one possible solution for this difficult coupling. This is because of many positive attributes of micelle polymers which includes zero CMC, lower surface activity, low volatility and function as suitable separation media even at lower concentrations of pseudophases. These are some benefits that produce a stable electrospray. This proposal is aimed at synthesis and development of new class of chiral anionic and cationic micelle polymers for use in chiral electrokinetic chromatography (EKC)-MS. Depending on the polarity of the chiral analytes two different approaches are proposed for the success of chiral EKC-MS. The first approach involves simply the use of chiral micelle polymers as additives in EKC-MS or partial-filling EKC-MS for the separation of very polar and charged compounds. For the chiral separation and MS detection of very hydrophobic and neutral chiral molecules that have large capacity factors and low ionization efficiency, a second approach is proposed. This involves the use metal complexes of anionic micelle polymers as reagents for the coupling of ligand exchange-EKC to coordination ion mass spectrometry. The combined use of metal with chiral micelle polymers will not only provide faster and efficient chiral separations of hydrophobic molecules but will also help in efficient transport of complexes to the gas phase for electrospray ionization. In addition, a dual chiral selector system, capillary electrochromatography (CEC)-EKC-MS is also proposed for analytes with multiple chiral centers. Following studies on the optimization of chiral EKC-MS of wide variety of chiral compounds, two different methods will be developed to improve the concentration sensitivity of CE-MS. The first methodology includes a new approach in developing an automated capillary isotachophoresis in conjunction with chiral EKC to improve the sample loadability of the chiral analytes which will benefit analysis of chiral metabolites at therapeutic levels without sample preparation. Besides this, a second methodology involves investigation on chiral EKC-MS-MS for trace level detection and understanding of the metabolic pathways of patients undergoing warfarin and thalidomide therapy for various diseases. We realize that the application of this valuable technology of chiral EKC-MS and chiral EKC-MS-MS will lead to the significant advances across several scientific disciplines. The strategies described in this proposal may signal a new beginning of a highly efficient and information rich hyphenated technology, which will enable our research group and others to acquire significant high throughput screening methods for analysis of chiral drugs than ever previously experienced.

在许多与健康相关的领域中，对映体化合物的分辨率和结构鉴定是研究外消毒药物相互作用的必要步骤。 使用常规胶束[高于临界胶束浓度（CMC）]的毛细管电泳（CE）与质谱（MS）的偶联非常困难，即使不是不可能。我们实验室中的初步数据表明，聚合表面活性剂或胶束聚合物的使用为这种困难耦合提供了一种可能的解决方案。 这是因为胶束聚合物的许多正属性，包括零CMC，较低的表面活性，低波动率和功能作为合适的分离培养基，即使在较低浓度的假偶像酶下也是如此。 这些是产生稳定电喷雾的一些好处。 该建议旨在综合和开发新的手性阴离子和阳离子胶束聚合物，用于手性电动色谱（EKC）-MS。 根据手性分析的极性，提出了两种不同的方法，以成功地进行手性EKC-MS。 第一种方法仅涉及将手性胶束聚合物用作EKC-MS中的添加剂或部分填充EKC-MS的分离非常极性和带电的化合物。 对于具有较大容量因子和低电离效率的非常疏水和中性手性分子的手性分离和MS检测，提出了第二种方法。 这涉及使用金属胶束聚合物的使用金属复合物作为配体交换-EKC与配位离子质谱法偶联的试剂。 金属与手性胶束聚合物的联合使用不仅将提供疏水分子的更快，有效的手性分离，而且还将有助于将复合物的有效运输到气相中进行电喷雾电离。 此外，还为具有多个手性中心的分析物提出了双手性选择器系统，毛细血管电印（CEC）-EKC-MS。 经过有关多种手性化合物的手性EKC-MS优化的研究，将开发两种不同的方法来提高CE-MS的浓度敏感性。 第一种方法包括一种与手性EKC结合开发自动毛细管等距离治疗的新方法，以提高手性分析物的样品负荷性，这将有助于在没有样品准备的情况下对治疗水平的手性代谢产物的分析。 除此之外，第二种方法还涉及对手性EKC-MS-MS进行调查，以痕量检测和理解各种疾病的华法林和沙利度胺治疗的患者的代谢途径。我们意识到，这种有价值的EKC-MS和手性EKC-MS-MS的宝贵技术的应用将导致几个科学学科的重大进步。 该提案中描述的策略可能标志着高效且信息丰富的连字符技术的新开始，这将使我们的研究小组和其他人能够获得比以前经历过的大量高通量筛查方法，用于分析手性药物。