CE-MS of Biological Substances Using Chiral Polymers

使用手性聚合物对生物物质进行 CE-MS

基本信息

批准号：
8075447
负责人：
SHAHAB AHMED SHAMSI
金额：
$ 19.12万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8075447
关键词：
Affect Amines Amino Acids Antibiotics Belief Biological Biological Assay Biological Sciences Biotechnology Buffers CYP2D6 gene Capillary Electrophoresis Charge Chromatography Clinical Coughing Coupling Crosslinker Cyclodextrins Data Detection Development Dextromethorphan Dextrorphan Dipeptides Diphenhydramine Drug Kinetics Experimental Designs Gases Gene Mutation Goals Health Human Hydroxylation In Vitro Inorganic Sulfates Ions Laboratories Levomethorphan Levorphanol Libraries Ligands Link Liquid substance Mass Spectrum Analysis Measures Medicine Metabolic Diseases Metabolism Metals Methodology Methods Micelles Modification Molecular Molecular Weight Nebulizer Oils Patient Care Patients Peptides Permeability Pharmaceutical Preparations Pharmacologic Substance Phase Pilot Projects Polychlorinated Biphenyls Polymers Progress Reports Reaction Research Resolution Role Sampling Series Surface Tail Techniques Technology Temperature Testing Time Unspecified or Sulfate Ion Sulfates Urine Volatile Oils Warfarin base chiral molecule combinatorial chemistry design drug metabolism enantiomer imprint improved in vivo ionization meetings metabolic abnormality assessment monomer nanoparticle novel organic acid pressure stem sugar surfactant tool voltage

项目摘要

DESCRIPTION (provided by applicant): The overall hypothesis of this research stems from our belief that polymers of chiral surfactants (aka. molecular micelles) provide better separation and detection in capillary electrophoresis-mass spectrometry (CE-MS) than conventional (unpolymerized) micelles. In addition, it also provides sensitive MS detection compared to any existing low molecular weight chiral selectors (cyclodextrins, macrocyclic antibiotics, unpolymerized surfactants). This hypothesis is based upon previous CE-MS strategies developed in our laboratory for enhanced separation and MS detection of chiral molecules. Furthermore, we have progress report and preliminary data provided in this proposal, which clearly support this hypothesis. Thus, the overall goal of this R01 application is to expand the scope of polymers of chiral surfactant to develop better, faster, rugged and in particular even more sensitive as well quantitative method for chiral analysis to meet the needs in life sciences, medicine and biotechnology. Three different aims are suggested for this research. The first aim involves synthesis and development of several novel classes of anionic and cationic molecular micelles that have zero CMC, low surface activity, function as pseudophases over a wide range of concentrations and pH as well as provide stable electrospray for micellar electrokinetic chromatography-mass spectrometry (MEKC-MS). Two additional significant advantages of molecular micelles are that they form very stable microemulsions and very homogenous molecularly imprinted nanoparticles (resulting in no peak tailing of the second eluting enantiomer). Utilizing the former advantage, we propose to develop microemulsion polymers (polymerized with volatile co-surfactant and oil) or micelle polymers dissolved in volatile microemulsion buffers, which could be very beneficial to the analysis of very hydrophobic chiral molecules. In addition, the latter advantage could effectively be utilized for ultrafast analysis of enantiomers in CE-MS. The second component of the proposed research involves the development of novel surfactant-based monolithic columns for CEC-MS. This second aim builds upon expertise that we have developed under first aim on the synthesis of chiral surfactant monomers. In particular, CEC-MS will be used for the separation of several classes of short chain or polar anionic, cationic and neutral chiral compounds that are difficult to separate by MEKC-MS. The third aim involves developing novel applications of chiral MEKCMS/ MS for trace level detection and quantitation of warfarin metabolites in patients undergoing warfarin therapy. In addition, MEKC-MS/MS will also be applied to study dextromethorphan metabolism in urine to distinguish between the users and abusers of this enantiomeric drug. PUBLIC HEALTH RELEVANCE Chiral separations are very important for developing pure, safe and affordable pharmaceutical drug, which affect human health. We proposed to develop novel molecular micelles and monolithic phases, which can measure these enantiomeric drugs in biological samples based on powerful separation techniques of capillary electrophoresis and very sensitive mass spectrometry methods. We propose to test these methodologies by analyzing the metabolism of drugs in patient samples with various metabolic diseases.

描述（由申请人提供）：这项研究的总体假设源于我们相信手性表面活性剂的聚合物（又称分子胶束）比常规（未透明）胶束在毛细血管电泳 - 质谱（CE-MS）中提供更好的分离和检测。此外，与任何现有的低分子量手性选择器（环糊精，大环抗生素，未散色表面活性剂）相比，它还提供了敏感的MS检测。该假设基于我们实验室中先前开发的CE-MS策略，以增强手性分子的分离和MS检测。此外，我们还提供了本提案中提供的进度报告和初步数据，这显然支持了这一假设。因此，该R01应用的总体目标是扩大手性表面活性剂聚合物的范围，以发展更好，更快，坚固，尤其是更敏感的手性分析方法，以满足生命科学，医学和生物技术的需求。为这项研究提出了三种不同的目标。第一个目的是合成和开发几种新型的阴离子和阳离子分子胶束，这些胶束的CMC为零，表面活性低，在广泛的浓度和pH值中充当伪酶，并为胶束电动色谱和胶束电动物质涂抹提供稳定的电喷雾。分子胶束的另外两个显着优势是它们形成非常稳定的微乳液和非常同质的分子印迹纳米颗粒（导致第二个洗脱映体的峰值尾巴没有峰值）。利用前者的优势，我们建议开发微乳液聚合物（用挥发性共抗活性剂和油聚合）或溶解在挥发性微乳液缓冲液中的胶束聚合物，这可能非常有益于对非常疏水性手性手性分子的分析。此外，后一种优势可以有效地用于对CE-MS中对映异构体的超快分析。拟议的研究的第二个组成部分涉及开发用于CEC-MS的新型基于表面活性剂的整体柱。这第二个目标是基于我们首先建立手性表面活性剂单体的首次旨在发展的专业知识。特别是，CEC-MS将用于分离几类短链或极性阴离子，阳离子和中性手性化合物，这些化合物很难通过MEKC-MS分离。第三个目的是开发手性MEKCMS/ MS的新型应用，用于在接受华法林治疗的患者中对华法林代谢产物的微量水平检测和定量。此外，MEKC-MS/MS还将应用于研究尿液中的右美甲苯代谢，以区分这种对映体药物的使用者和施虐者。公共卫生相关性手性分离对于开发影响人类健康的纯，安全和负担得起的药物非常重要。我们提出了开发新型的分子胶束和整体层相，可以根据毛细管电泳的强大分离技术和非常敏感的质谱法测量生物样品中的这些对映体药物。我们建议通过分析患有各种代谢疾病的患者样本中药物的代谢来测试这些方法。

项目成果

期刊论文数量（51）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Amino acid bound surfactants: a new synthetic family of polymeric monoliths opening up possibilities for chiral separations in capillary electrochromatography.

DOI：
10.1021/ac300944z
发表时间：
2012-06-19
期刊：
ANALYTICAL CHEMISTRY
影响因子：
7.4
作者：
He, Jun;Wang, Xiaochun;Morill, Mike;Shamsi, Shahab A.
通讯作者：
Shamsi, Shahab A.

Combination of chiral capillary electrochromatography with electrospray ionization mass spectrometry: method development and assay of warfarin enantiomers in human plasma.

手性毛细管电色谱与电喷雾电离质谱的组合：人血浆中华法林对映体的方法开发和测定。

DOI：
10.1021/ac030193j
发表时间：
2003
期刊：
Analytical chemistry.
影响因子：
0
作者：
Zheng,Jack;Shamsi,ShahabA
通讯作者：
Shamsi,ShahabA

Optimized separation of beta-blockers with multiple chiral centers using capillary electrochromatography-mass spectrometry.

DOI：
10.1016/j.jchromb.2008.06.028
发表时间：
2008-11-01
期刊：
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
影响因子：
0
作者：
Bragg W;Norton D;Shamsi SA
通讯作者：
Shamsi SA

Development of a CZE-ESI-MS assay with a sulfonated capillary for profiling picolinic acid and quinolinic acid formation in multienzyme system.