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 i nvolves 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 i nvolves 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.
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.
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