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Deferential Mobility Spectrometry Coupled with Multiple Ion Monitoring in Regulated LC-MS/MS Bioanalysis of a Therapeutic Cyclic Peptide in Human Plasma

Fu, Yunlin and Xia, Yuan-qing and Flarakos, Jimmy and Tse, Francis and Miller, Jeffrey and Jones, Elliott and Li, Wenkui (2016) Deferential Mobility Spectrometry Coupled with Multiple Ion Monitoring in Regulated LC-MS/MS Bioanalysis of a Therapeutic Cyclic Peptide in Human Plasma. Analytical Chemistry.

Abstract

A differential mobility spectrometry (DMS) in combination with multiple ion monitoring (MIM) method was developed and validated for quantitative LC-MS/MS bioanalysis of SOM230 in human plasma. SOM230, a therapeutic cyclic peptide, exhibits poor collision-induced dissociation (CID) fragmentation for multiple reaction monitoring (MRM) detection. Therefore, a MIM approach was explored in an effort to increase the overall sensitivity of the assay. By selecting the most abundant doubly charged precursor ion in both Q1 and Q3 mass analyzer in MIM and combining the DMS capability to significantly reduce the high matrix/chemical baseline, this new LC-DMS-MIM method overcomes the poor CID fragmentation issue observed in the typical MRM method. Human plasma was spiked with SOM230 at a concentration range of 0.01 to 50 ng/mL. WCX SPE was employed for sample preparation. The sample extracts were analyzed with an SCIEX QTRAP® 6500 equipped with IonDrive™ source and SelexION™ DMS technology. The separation voltage (SV), compensation voltage (COV) of DMS and other parameters of the system were optimized to maximize signal response. The performance of the LC-DMS-MIM assay for quantitative analysis of SOM230 in human plasma was evaluated and compared to LC-MRM and LC-MIM without DMS. Assay sensitivity with DMS-MIM was at least 5-fold better than that observed in MRM mode or MIM without DMS. The assay was validated with accuracy (%) and precision (CV%) of the QC results at eight levels (0.01, 0.02, 0.05, 0.15, 0.3, 1.5, 15, 37.5 ng/mL) ranging from 95.2 to 105% and 0.7 to 8.6%, respectively, from the intra-day and inter-day runs. The current LC-DMS-MIM workflow can be expanded to quantitative analysis of any other molecules that have poor efficiency in CID.

Item Type: Article
Keywords: Differential mobility spectrometry (DMS), multiple ion monitoring (MIM), collision-induced dissociation (CID), CID deficiency, multiple reaction monitoring (MRM), LC-MS/MS, SOM230
Date Deposited: 27 Apr 2016 23:45
Last Modified: 27 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/27691

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