基于液相色谱-多级多反应监测模式（LC-MRM<sup>3</sup>）的高灵敏定量分析新策略

李婷; 张珂; 李军; 王胜鹏; 宋月林

doi:10.11665/j.issn.1000-5048.2023062801

基于液相色谱-多级多反应监测模式（LC-MRM³）的高灵敏定量分析新策略

李婷^1,2,
张珂^1,2,
李军^1,2,
王胜鹏³,
宋月林¹

1.
北京中医药大学北京中医药研究院，北京 102488
2.
北京中医药大学中药学院，北京 102488
3.
澳门大学中药质量研究国家重点实验室，澳门 999078

基金项目: 国家自然科学基金资助项目（No.81973444）；中药质量研究国家重点实验室（澳门大学）开放课题资助项目（No.SKL-QRCM-OP21011）

计量
- 文章访问数: 565
- HTML全文浏览量: 18
- PDF下载量: 239
出版历程
- 收稿日期: 2023-06-27
- 修回日期: 2023-12-06
- 刊出日期: 2023-12-24

An emerging analytical tool for highly sensitive quantitative analysis based on liquid chromatography-multiple-reaction monitoring cubed (MRM³)

1.
Beijing Research Institute of Chinese Medicine,Beijing University of Chinese Medicine,Beijing 102488
2.
School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 102488
3.
State Key Laboratory of Quality Research in Chinese Medicine,University of Macau,Macao 999078, China

Funds: This study was supported by the National Natural Science Foundation of China (No.81973444) and the Open Research Project Programme of the State Key Laboratory of Quality Research in Chinese Medicine (University of Macau) (No.SKL-QRCM-OP21011)

摘要

摘要: 液相色谱多级质谱联用（LC-MS/MS）的多反应监测模式（multiple-reaction monitoring，MRM）已经成为复杂体系中多成分同步定量分析的金标准，广泛应用于药品、中药、食品等各个领域。然而，由于选择性的限制，在对复杂基质中痕量化学成分定量时，MRM无法有效降低噪音或基质干扰，灵敏度不足。多级多反应监测模式（multiple-reaction monitoring cubed，MRM³）是对碰撞诱导解离（collision induced dissociation，CID）产生的子离子碎片进行富集并再次裂解，检测其孙离子碎片信号。通过多次离子筛选，显著提升了选择性和灵敏度，因此LC-MRM³得到了广泛关注。本文针对该方法的原理、参数设置及在生物标志物分析、药物分析、法医和毒物分析、食品分析和环境分析等领域中的应用进行介绍和系统综述，为利用LC-MRM³实现复杂基质中痕量化学成分的定量分析提供参考。
- MRM³ /
- 定量分析 /
- 复杂基质 /
- 灵敏度 /
- LC-MS/MS
Abstract: Liquid chromatography-multiple-reaction monitoring (LC-MRM) has been widely recognized as the golden standard for multiple components-targeted quantitative analysis of complicated matrices,with extensive applications for analysis in such fields as chemical drugs, traditional Chinese medicines and foods.Unfortunately, when facing the task of quantitatively analyzing trace chemical components in complex matrices, MRM suffers dramatically from the background noise or matrix interference, leading to undesirable sensitivity and selectivity in terms of the lower limits of quantification (LOQ) and detection (LOD).In recent years, MRM cubed (MRM³), also known as MS³ scan, has received much attention because of its unique ability to significantly improve detection selectivity and sensitivity attributing to the successive ion filtering function, enabling LC-MRM³as an emerging analytical tool.In this review,our attention is devoted to: 1) the illustration of the principle for MRM³; 2) parameter settings; and 3) the application progress of LC-MRM³ in such fields as the pursuit of biomarkers, pharmaceutical analysis, forensic analysis, toxicological analysis, food chemistry, and environmental analysis, aiming to provide a promising analytical tool of LC-MRM³ advantageous in the quantification analysis of trace chemical components in complex matrices.
- MRM³ /
- quantitative analysis /
- complex matrices /
- sensitivity /
- LC-MS/MS

HTML全文

参考文献(77)

[1]	Ferreirós N, Dresen S, Alonso RM, et al.Validated quantitation of angiotensin II receptor antagonists (ARA-II) in human plasma by liquid-chromatography-tandem mass spectrometry using minimum sample clean-up and investigation of ion suppression[J]. Ther Drug Monit, 2007, 29(6): 824-834.
[2]	Richards KH, Monk R, Renko K, et al. A combined LC-MS/MS and LC-MS³ multi-method for the quantification of iodothyronines in human blood serum[J]. Anal Bioanal Chem, 2019, 411(21): 5605-5616.
[3]	Aydin E, Drotleff B, Noack H, et al. Fast accurate quantification of salivary cortisol and cortisone in a large-scale clinical stress study by micro-UHPLC-ESI-MS/MS using a surrogate calibrant approach[J].J Chromatogr B Analyt Technol Biomed Life Sci, 2021, 1182: 122939.
[4]	Guironnet A, Wiest L, Vulliet E.Advantages of MS/MS/MS (MRM³) vs classic MRM quantification for complex environmental matrices: Analysis of beta-lactams in WWTP sludge[J]. Anal Chim Acta, 2022, 1205: 339773.
[5]	Duan X, Lu D, Zheng X, et al. Development and validation of an LC-MS/MS assay with multiple stage fragmentation for the quantification of alachlor in McF-7 cells[J].J Chromatogr B Analyt Technol Biomed Life Sci, 2023, 1214: 123550.
[6]	Berna M, Schmalz C, Duffin K, et al. Online immunoaffinity liquid chromatography/tandem mass spectrometry determination of a type II collagen peptide biomarker in rat urine: Investigation of the impact of collision-induced dissociation fluctuation on peptide quantitation[J]. Anal Biochem, 2006, 356(2): 235-243.
[7]	Manjunath Swamy J, Kamath N, Radha Shekar AK, et al. Sensitivity enhancement and matrix effect evaluation during summation of multiple transition pairs-case studies of clopidogrel and ramiprilat[J]. Biomed Chromatogr, 2010, 24(5): 528-534.
[8]	Campbell JL, Collings BA, Yves Le Blanc JC, et al. A novel MS³ experiment for quantifying ions with a linear ion trap[J]. Can J Chem, 2018, 96(7): 653-663.
[9]	Mayya V, Rezaul K, Cong YS, et al. Systematic comparison of a two-dimensional ion trap and a three-dimensional ion trap mass spectrometer in proteomics[J]. Mol Cell Proteomics, 2005, 4(2): 214-223.
[10]	Douglas DJ, Frank AJ, Mao D. Linear ion traps in mass spectrometry[J]. Mass Spectrom Rev, 2005, 24(1): 1-29.
[11]	Botitsi HV, Garbis SD, Economou A, et al. Current mass spectrometry strategies for the analysis of pesticides and their metabolites in food and water matrices[J]. Mass Spectrom Rev, 2011, 30(5): 907-939.
[12]	Hager JW. A new linear ion trap mass spectrometer[J]. Rapid Commun Mass Spectrom, 2002, 16(6): 512-526.
[13]	Cha B, Blades M, Douglas DJ. An interface with a linear quadrupole ion guide for an electrospray-ion trap mass spectrometer system[J]. Anal Chem, 2000, 72(22): 5647-5654.
[14]	Miyachi A, Murase T, Yamada Y, et al. Quantitative analytical method for determining the levels of gastric inhibitory polypeptides GIP1-42 and GIP3-42 in human plasma using LC-MS/MS/MS[J]. J Proteome Res, 2013, 12(6): 2690-2699.
[15]	Quinete N, Bertram J, Reska M, et al. Highly selective and automated online SPE LC-MS³ method for determination of cortisol and cortisone in human hair as biomarker for stress related diseases[J]. Talanta, 2015, 134: 310-316.
[16]	Hager JW, Yves Le Blanc JC. Product ion scanning using a Q-q-Q linear ion trap (Q TRAP) mass spectrometer[J]. Rapid Commun Mass Spectrom, 2003, 17(10): 1056-1064.
[17]	Sandra K, Devreese B, Van Beeumen J, et al. The Q-Trap mass spectrometer, a novel tool in the study of protein glycosylation[J]. J Am Soc Mass Spectrom, 2004, 15(3): 413-423.
[18]	Snyder DT, Peng WP, Cooks RG. Resonance methods in quadrupole ion traps[J]. Chem Phys Lett, 2017, 668: 69-89.
[19]	Collings BA, Stott WR, Londry FA. Resonant excitation in a low-pressure linear ion trap[J]. J Am Soc Mass Spectrom, 2003, 14(6): 622-634.
[20]	Li C. Research on high sensitivity quadrupole-inear ion trap tandem mass spectrometry(高灵敏度四极杆-线形离子阱串联质谱技术研究)[D]. Changchun: Jilin University, 2022.
[21]	Sordet M, Berlioz-Barbier A, Buleté A, et al. Quantification of emerging micropollutants in an amphipod crustacean by nanoliquid chromatography coupled to mass spectrometry using multiple reaction monitoring cubed mode[J]. J Chromatogr A, 2016, 1456: 217-225.
[22]	McCaffery P, Evans J, Koul O, et al. Retinoid quantification by HPLC/MSⁿ[J]. J Lipid Res, 2002, 43(7): 1143-1149.
[23]	Leuthold LA, Grivet C, Allen M, et al. Simultaneous selected reaction monitoring, MS/MS and MS³ quantitation for the analysis of pharmaceutical compounds in human plasma using chip-based infusion[J]. Rapid Commun Mass Spectrom, 2004, 18(17): 1995-2000.
[24]	Ma W, Xu Y, Wang SY, et al. Research on accurate quantitation technique using liquid chromatography coupled with triple quadrupole mass spectrometry and experiment optimization—take a novel diuretic as an example[J]. J Chin Pharm Sci, 2022, 31(3): 184.
[25]	Song Q, Li J, Huo H, et al. Retention time and optimal collision energy advance structural annotation relied on LC-MS/MS: an application in metabolite identification of an antidementia agent namely echinacoside[J]. Anal Chem, 2019, 91(23): 15040-15048.
[26]	Liu W, Li W, Zhang P, et al. Quality structural annotation for the metabolites of chlorogenic acid in rat[J]. Food Chem, 2022, 379: 132134.
[27]	Cao Y, Chai C, Chang A, et al. Optimal collision energy is an eligible molecular descriptor to boost structural annotation: an application for chlorogenic acid derivatives-focused chemical profiling[J]. J Chromatogr A, 2020, 1609: 460515.
[28]	Cao Y, Li W, Chen W, et al. Squared energy-resolved mass spectrometry advances quantitative bile acid submetabolome characterization[J]. Anal Chem, 2022, 94(44): 15395-15404.
[29]	Zeng W, Bateman KP.Quantitative LC-MS/MS.1.Impact of points across a peak on the accuracy and precision of peak area measurements[J]. J Am Soc Mass Spectrom, 2023, 34(6): 1136-1144.
[30]	Sordet M, Buleté A, Vulliet E. A rapid and easy method based on hydrophilic interaction chromatography coupled with tandem mass spectrometry (HILIC-MS/MS/MS) to quantify iodinated X-ray contrast in wastewaters[J]. Talanta, 2018, 190: 480-486.
[31]	Lopukhov LV, Balandina AV, Nigmatullina LS, et al. Evaluation of multiple reaction monitoring cubed performed by a quadrupole-linear ion trap mass spectrometer for quantitative determination of 6-sulfatoxymelatonin in urine[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2022, 1190: 123094.
[32]	Vonk RJ, Vaast A, Eeltink S, et al. Titanium-scaffolded organic-monolithic stationary phases for ultra-high-pressure liquid chromatography[J]. J Chromatogr A, 2014, 1359: 162-169.
[33]	Muscat Galea C, Didion D, Clicq D, et al. Method optimization for drug impurity profiling in supercritical fluid chromatography: Application to a pharmaceutical mixture[J]. J Chromatogr A, 2017, 1526: 128-136.
[34]	Korte R, Brockmeyer J. MRM³-based LC-MS multi-method for the detection and quantification of nut allergens[J]. Anal Bioanal Chem, 2016, 408(27): 7845-7855.
[35]	Jaffuel A, Lemoine J, Aubert C, et al. Optimization of liquid chromatography-multiple reaction monitoring cubed mass spectrometry assay for protein quantification: application to aquaporin-2 water channel in human urine[J]. J Chromatogr A, 2013, 1301: 122-130.
[36]	Guo JJ, Zhou W, Su WQ. Application strategy of mass spectrometry in protein biomarker discovery[J]. Chin J Mod Appl Pharm(中国现代应用药学), 2022, 39(23): 3183-3188.
[37]	van Faassen M, van der Veen A, van Ockenburg S, et al. Mass spectrometric quantification of urinary 6-sulfatoxymelatonin: age-dependent excretion and biological variation[J]. Clin Chem Lab Med, 2020, 59(1): 187-195.
[38]	Gaudl A, Kratzsch J, Bae YJ, et al. Liquid chromatography quadrupole linear ion trap mass spectrometry for quantitative steroid hormone analysis in plasma, urine, saliva and hair[J]. J Chromatogr A, 2016, 1464: 64-71.
[39]	Jones JW, Pierzchalski K, Yu J, et al. Use of fast HPLC multiple reaction monitoring cubed for endogenous retinoic acid quantification in complex matrices[J]. Anal Chem, 2015, 87(6): 3222-3230.
[40]	Szeitz A, Nguyen TA, Riggs KW, et al. A validated assay to quantitate serotonin in lamb plasma using ultrahigh-performance liquid chromatography-tandem mass spectrometry: applications with LC/MS³[J]. Anal Bioanal Chem, 2014, 406(20): 5055-5059.
[41]	Wright MJ, Thomas RL, Stanford PE, et al. Multiple reaction monitoring with multistage fragmentation (MRM³) detection enhances selectivity for LC-MS/MS analysis of plasma free metanephrines[J]. Clin Chem, 2015, 61(3): 505-513.
[42]	Kumar A, Gangadharan B, Zitzmann N. Multiple reaction monitoring and multiple reaction monitoring cubed based assays for the quantitation of apolipoprotein F[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2016, 1033/1034: 278-286.
[43]	Simon R, Lemoine J, Fonbonne C, et al. Absolute quantification of podocin, a potential biomarker of glomerular injury in human urine, by liquid chromatography-multiple reaction monitoring cubed mass spectrometry[J]. J Pharm Biomed Anal, 2014, 94: 84-91.
[44]	Pailleux F, Beaudry F. Evaluation of multiple reaction monitoring cubed for the analysis of tachykinin related peptides in rat spinal cord using a hybrid triple quadrupole-linear ion trap mass spectrometer[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2014, 947/948: 164-167.
[45]	Vaclavik L, Krynitsky AJ, Rader JI. Quantification of aristolochic acids I and II in herbal dietary supplements by ultra-high-performance liquid chromatography-multistage fragmentation mass spectrometry[J]. Food Addit Contam Part A Chem Anal Control Expo Risk Assess, 2014, 31(5): 784-791.
[46]	Ren T, Zhang Z, Fawcett JP, et al. Micro-solid phase extraction and LC-MS³ for the determination of triptorelin in rat plasma and application to a pharmacokinetic study[J]. J Pharm Biomed Anal, 2019, 166: 13-19.
[47]	Cesari N, Fontana S, Montanari D, et al. Development and validation of a high-throughput method for the quantitative analysis of D-amphetamine in rat blood using liquid chromatography/MS³ on a hybrid triple quadrupole-linear ion trap mass spectrometer and its application to a pharmacokinetic study[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2010, 878(1): 21-28.
[48]	Yin L, Ji Z, Cao H, et al. Comparison of LC-MS³ and LC-MRM strategy for quantification of methotrexate in human plasma and its application in therapeutic drug monitoring[J]. J Pharm Biomed Anal, 2021, 205: 114345.
[49]	Ma D, Ji Z, Cao H, et al. LC-MS³ strategy for quantification of carbamazepine in human plasma and its application in therapeutic drug monitoring[J]. Molecules, 2022, 27(4): 1224.
[50]	Sun Q, Cao H, Liu Y, et al. Comparison of LC-MS³ and LC-MRM methods for quantifying amantadine and its application in therapeutic amantadine monitoring in human plasma[J]. Molecules, 2022, 27(21): 7619.
[51]	Dziadosz M, Klintschar M, Teske J. Imatinib quantification in human serum with LC-MS³ as an effective way of protein kinase inhibitor analysis in biological matrices[J]. Drug Metab Pers Ther, 2017, 32(3): 147-150.
[52]	Dziadosz M. The application of multiple analyte adduct formation in the LC-MS³ analysis of valproic acid in human serum[J].J Chromatogr B Analyt Technol Biomed Life Sci, 2017, 1040: 159-161.
[53]	Dziadosz M. γ-Hydroxybutyrate analysis in human serum with liquid chromatography-tandem mass spectrometry on the basis of MS³ mass transition[J].J Chromatogr B Analyt Technol Biomed Life Sci, 2015, 986/987: 8-11.
[54]	Shi X, Liu M, Sun M, et al.Development of a LC-ESI-MS³ method for determination of nitrendipine in human plasma[J]. J Pharm Biomed Anal, 2011, 56(5): 1101-1105.
[55]	Stone NL, Murphy AJ, England TJ, et al. A systematic review of minor phytocannabinoids with promising neuroprotective potential[J]. Br J Pharmacol, 2020, 177(19): 4330-4352.
[56]	Dulaurent S, Gaulier JM, Imbert L, et al. Simultaneous determination of Δ9-tetrahydrocannabinol, cannabidiol, cannabinol and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid in hair using liquid chromatography-tandem mass spectrometry[J].Forensic Sci Int, 2014, 236: 151-156.
[57]	Cho HS, Cho B, Sim J, et al. Detection of 11-nor-9-carboxy-tetrahydrocannabinol in the hair of drug abusers by LC-MS/MS analysis[J]. Forensic Sci Int, 2019, 295: 219-225.
[58]	Park M, Kim J, Park Y, et al. Quantitative determination of 11-nor-9-carboxy-tetrahydrocannabinol in hair by column switching LC-ESI-MS(3)[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2014, 947/948: 179-185.
[59]	Thieme D, Sachs U, Sachs H, et al. Significant enhancement of 11-hydroxy-THC detection by formation of picolinic acid esters and application of liquid chromatography/multi stage mass spectrometry (LC-MS(3)): application to hair and oral fluid analysis[J]. Drug Test Anal, 2015, 7(7): 577-585.
[60]	Thieme D, Sachs H, Uhl M. Proof of cannabis administration by sensitive detection of 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid in hair using selective methylation and application of liquid chromatography- tandem and multistage mass spectrometry[J]. Drug Test Anal, 2014, 6(1/2): 112-118.
[61]	Hehet P, Franz T, Kunert N, et al. Fast and highly sensitive determination of tetrahydrocannabinol (THC) metabolites in hair using liquid chromatography-multistage mass spectrometry (LC-MS³)[J]. Drug Test Anal, 2022, 14(9): 1614-1622.
[62]	Zubaidi FA, Choo YM, Tan GH, et al. A novel liquid chromatography tandem mass spectrometry technique using multi-period-multi-experiment of MRM-EPI-MRM³ with library matching for simultaneous determination of amphetamine type stimulants related drugs in whole blood, urine and dried blood stain (DBS)-application to forensic toxicology cases in Malaysia[J]. J Anal Toxicol, 2019, 43(7): 528-535.
[63]	Jung HN, Park DH, Choi YJ, et al. Simultaneous quantification of chloramphenicol, thiamphenicol, florfenicol, and florfenicol amine in animal and aquaculture products using liquid chromatography-tandem mass spectrometry[J].Front Nutr, 2022, 8: 812803.
[64]	Faulkner DV, Cantley ML, Kennedy DG, et al.MRM³-based UHPLC-MS/MS method for quantitation of total florfenicol residue content in milk and withdrawal study profile of milk from treated cows[J]. Food Chem, 2022, 379: 132070.
[65]	Sun L, Ye N, Wang YL, et al. Determination of β-agonists residues in complex animal derived food by LC-MS/MS/MS in high selectivity MRM³[J]. Chin J Vet Drug(中国兽药杂志), 2021, 55(7): 22-29.
[66]	Ye L, Liu JC, Wang YL, et al.Development of a three-compartment toxicokinetic model for T-2 toxin in shrimp by blindfold particle swarm optimization algorithm[J]. Ecotoxicol Environ Saf, 2021, 208: 111698.
[67]	Lim CW, Tai SH, Lee LM, et al. Analytical method for the accurate determination of tricothecenes in grains using LC-MS/MS: a comparison between MRM transition and MS³ quantitation[J].Anal Bioanal Chem, 2012, 403(10): 2801-2806.
[68]	Chung SWC, Lam CH. Development of an analytical method for analyzing pyrrolizidine alkaloids in different groups of food by UPLC-MS/MS[J]. J Agric Food Chem, 2018, 66(11): 3009-3018.
[69]	He JZ, Huang LZ. Determination of aconitine in medicated wine by LC-MS³[J]. Occup Health(职业与健康), 2021, 37(10): 1323-1326, 1332.
[70]	Korte R, Monneuse JM, Gemrot E, et al. New high-performance liquid chromatography coupled mass spectrometry method for the detection of lobster and shrimp allergens in food samples via multiple reaction monitoring and multiple reaction monitoring cubed[J]. J Agric Food Chem, 2016, 64(31): 6219-6227.
[71]	von Bargen C, Brockmeyer J, Humpf HU. Meat authentication: a new HPLC-MS/MS based method for the fast and sensitive detection of horse and pork in highly processed food[J]. J Agric Food Chem, 2014, 62(39): 9428-9435.
[72]	von Bargen C, Dojahn J, Waidelich D, et al. New sensitive high-performance liquid chromatography-tandem mass spectrometry method for the detection of horse and pork in halal beef[J]. J Agric Food Chem, 2013, 61(49): 11986-11994.
[73]	Hartung NM, Mainka M, Pfaff R, et al. Development of a quantitative proteomics approach for cyclooxygenases and lipoxygenases in parallel to quantitative oxylipin analysis allowing the comprehensive investigation of the arachidonic acid cascade[J].Anal Bioanal Chem, 2023, 415(5): 913-933.
[74]	Musile G, Mazzola M, Shestakova K, et al. A simple and robust method for broad range screening of hair samples for drugs of abuse using a high-throughput UHPLC-Ion Trap MS instrument[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2020, 1152: 122263.
[75]	Hoffner G, van der Rest G, Dansette PM, et al. The end product of transglutaminase crosslinking: simultaneous quantitation of [nepsilon-(gamma-glutamyl) lysine]and lysine by HPLC-MS³[J].Anal Biochem, 2009, 384(2): 296-304.
[76]	Arioli F, Gamberini MC, Pavlovic R, et al. Quantification of cortisol and its metabolites in human urine by LC-MSⁿ: applications in clinical diagnosis and anti-doping control[J]. Anal Bioanal Chem, 2022, 414(23): 6841-6853.
[77]	Park J, Yu F, Fulcher JM, et al. Evaluating linear ion trap for MS3-based multiplexed single-cell proteomics[J]. Anal Chem, 2023, 95 (3): 1888-1898.

施引文献(3)

期刊类型引用(3)

1.	丁艳，刘培培，闻武，陈捷，杭太俊. 环境中毒品检测技术研究进展与展望. 中国法医学杂志. 2024(01): 14-22 . 百度学术
2.	覃昆飞，黄丽珍，何建忠. LC-MRM~3法测定中草药和药酒中3种强心作用的生物碱. 职业与健康. 2024(17): 2337-2345 . 百度学术
3.	张小军，符慧慧. LC-MS/MS法对血栓通注射液中皂苷成分快速定量分析. 婚育与健康. 2024(22): 79-81 . 百度学术