EP2499655A1 - Détection et/ou quantification d'un composé dans un échantillon - Google Patents

Détection et/ou quantification d'un composé dans un échantillon

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Publication number
EP2499655A1
EP2499655A1 EP10798370A EP10798370A EP2499655A1 EP 2499655 A1 EP2499655 A1 EP 2499655A1 EP 10798370 A EP10798370 A EP 10798370A EP 10798370 A EP10798370 A EP 10798370A EP 2499655 A1 EP2499655 A1 EP 2499655A1
Authority
EP
European Patent Office
Prior art keywords
interest
ions
mass
candidate
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10798370A
Other languages
German (de)
English (en)
Inventor
Timothy Riley
James Landridge
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Micromass UK Ltd
Original Assignee
Micromass UK Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Micromass UK Ltd filed Critical Micromass UK Ltd
Publication of EP2499655A1 publication Critical patent/EP2499655A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/0027—Methods for using particle spectrometers
    • H01J49/0031—Step by step routines describing the use of the apparatus
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/0027—Methods for using particle spectrometers
    • H01J49/0036—Step by step routines describing the handling of the data generated during a measurement
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/004—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn
    • H01J49/0045—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn characterised by the fragmentation or other specific reaction

Definitions

  • This invention relates generally to a method of detecting and/or quantifying the amount of a compound in a sample using mass spectrometry (MS). More specifically, although not exclusively, this invention relates to a method of screening a sample in order to detect the presence and/or to quantify the amount of one or more compounds of interest.
  • MS mass spectrometry
  • tandem quadrupole MS liquid chromatography in combination with tandem quadrupole MS has been used very successfully to quantify targeted small molecules, peptides, and proteins contained in complex sample mixtures.
  • the tandem quadrupole MS system is typically operated in a multiple reaction monitoring (MRM) mode of data acquisition such that, at an appropriate time in the chromatographic separation of the mixture when a component of interest elutes into the mass spectrometer, the parent ion of that component is selected with nominal mass accuracy using the first mass filter of the tandem quadrupole instrument.
  • MRM multiple reaction monitoring
  • This precursor ion is subsequently dissociated in the tandem quadrupole collision cell and one or more of the product ions produced in this collisional induced dissociation process is selected with nominal mass accuracy for detection using the second quadrupole mass filter.
  • the intensity of these detected MRM product ion signal(s) is used as a quantitative measure of the amount of the component present in the mixture.
  • This MRM selection process can be repeated at high data acquisition rates thus allowing many targeted analytes to be quantified in a single chromatographic separation of a mixture.
  • the present invention seeks to provide improved selectivity and/or substantially improved detection limits and dynamic range compared to conventional low resolution, nominal mass accuracy tandem quadrupole MRM analysis for targeted quantitative analysis of complex mixtures.
  • the invention builds on LC-MSE alternating scan high and low energy acquisition methodology developed by the present applicants, which can be used to qualitatively and quantitatively characterize small molecules and proteins contained in complex mixtures. This methodology is explained in detail in US6717130 and US71 12784, the entire contents are incorporated herein by reference.
  • a more enabling implementation of the LC-MSE data acquisition strategy may be accomplished by acquiring the alternating high and low energy LC-MS full scan data at elevated resolution (> 5,000 RP FWHM) and high mass accuracy ( ⁇ 30 ppm).
  • this data When appropriately processed, this data provides accurate mass and intensity information on all detectable precursor and chromatographically aligned product ions and can be used to identify and quantify the level of components in the analyzed mixture.
  • this LC-MSE methodology may provide selectivity, limits of detection and dynamic range that are superior to that provided by LC-tandem quadrupole MRM analysis.
  • the present invention provides a method and apparatus for the detection and profiling of organic species, (in the preferred embodiment biomolecules), with the approach easily applied for a wide range of organic compounds, such as proteins, peptides, glycopeptides, endogenous small molecules such as lipids and sugars, small molecule metabolites or environmental contaminants.
  • One aspect of the present invention provides a method of detecting and/or quantifying the amount of one or more compounds of interest in a sample, the method comprising the steps of:
  • a second aspect of the invention provides a method of screening a sample for the presence of one or more compounds of interest, the method comprising the steps of: i) identifying one or more parent and/or daughter ion masses of interest;
  • the first data set may comprise a set of fragmented data, e.g. a set of data derived or measured from fragmented ions, and/or a set of unfragmented data, e.g. a set of data derived or measured from unfragmented ions.
  • the acquisition of the first set of data may comprise the use of an alternating scan, high and low energy acquisition method, e.g. as described above.
  • the method is preferably carried out using a mass spectrometer, for example which comprises a filtering device that may be used in the selection step, e.g. to select the candidate parent ions of interest, and/or a fragmentation device that may be used in the fragmentation step, e.g. to fragment the selected candidate parent ions of interest, and/or one or more mass analysers that may be used in the acquisition and/or mass spectrum creation step or steps, e.g. to acquire the first data set and/or to create the mass spectrum, e.g. of at least some of the candidate daughter ions of interest.
  • a mass spectrometer for example which comprises a filtering device that may be used in the selection step, e.g. to select the candidate parent ions of interest, and/or a fragmentation device that may be used in the fragmentation step, e.g. to fragment the selected candidate parent ions of interest, and/or one or more mass analysers that may be used in the acquisition and/or mass spectrum creation step or steps, e.g.
  • the filtering device and/or mass analyser may comprise a quadrupole, for example the selection step and/or acquisition step and/or mass spectrum creation step or steps may involve the use of a resolving quadrupole. Additionally or alternatively, the filtering device may comprise a two dimensional or three dimensional ion trap or time-of-flight (ToF) mass analyser.
  • the mass analyser or mass analysers may comprise or further comprise one or more of a time-of-flight mass analyser and/or an ion cyclotron resonance mass analyser and/or an orbitrap mass analyser and/or a two dimensional or three dimensional ion trap.
  • Filtering by means of selection based upon mass-to-charge ratio (m/z) can be achieved by means of a first mass analyser.
  • This mass analyser can be used to serially select ions based upon m/z, for example a quadrupole; or to transmit a wide m/z range, separate ions according to their m/z, and then select the ions of interest by means of their m/z value.
  • An example of the latter would be a time-of-flight mass analyser combined with a timed ion selector(s).
  • one embodiment of the invention provides a filtering window set to allow the parent ion of interest and isotopically labelled analogues to be selected, e.g. during the selection step.
  • the method may further comprise isolating and/or separating the one or more compounds of interest, for example from two or more of a plurality of compounds, e.g. using a chromatographic technique such as liquid chromatography, which may be carried out using a liquid chromatograph.
  • the method may further comprise measuring an elution time for the compound of interest and/or comparing the measured elution time with an expected elution time.
  • the method of the first aspect of the invention further comprises determining or calculating the quantity of a second compound of interest from the / or a further mass spectrum.
  • the method of the second aspect of the invention may further comprise confirming the presence or absence of a second compound of interest in the or a further mass spectrum.
  • the first and second compounds of interest may be separated using a chromatographic technique such as liquid chromatography, which may be carried out using a liquid chromatograph. Additionally, the first and second compounds of interest may be selected by order or time of elution, e.g. from a liquid chromatograph. It will be appreciated that the aforementioned methods may be used to determine or calculate the quantity or confirm the presence of multiple or a plurality of compounds of interest. The method may further comprise measuring an elution time for the first and/or second compounds of interest and/or comparing the measured elution time with an expected elution time.
  • the first and second compounds of interest may be separated using an ion mobility technique, which may be carried out using an ion mobility cell. Additionally, the first and second compounds of interest may be selected by order or time of ion mobility drift. It will be appreciated that the aforementioned methods may be used to determine or calculate the quantity or confirm the presence of multiple or a plurality of compounds of interest. The method may further comprise measuring a drift time for the first and/or second compounds of interest and/or comparing the measured drift time with an expected drift time.
  • An optional feature of the invention provides the use of one or more collisional cross section calculation techniques, for example to enable a user to predict the order of elution of the candidate parent ions of interest, e.g. to facilitate the selection of the first and second compounds of interest.
  • the method may involve the use of an ion mobility technique after the selection step and/or before the fragmentation step, for example to separate between two parent ions of the same or similar mass and/or with the same or similar elution time. Additionally or alternatively, the method may involve the use of an ion mobility technique for the selection step, e.g. the step of selecting the candidate parent ions of interest. The ion mobility technique may be carried out using an ion mobility cell.
  • the method may further comprise selecting the candidate parent ions of interest based on the first set of candidate daughter ions of interest.
  • One embodiment of the invention relates to determining the presence or quantity of ions of a particular class or species.
  • This method could comprise identifying a daughter ion indicative of the particular class or species of interest and may subsequently comprise selecting candidate parent ions to determine the presence and/or identity of the ions of the class or species.
  • the compounds of interest may be identified after quantification, e.g. using the mass spectrum and/or data relating to the selected parent ions of interest.
  • Quantification can be divided into label-free and isotope labelling methods.
  • quantification can be achieved by comparison of the peak intensity, or area under the mass spectral peak for the precursor or fragment m/z values of interest between injections and across samples.
  • the use of an internal standard normalisation factor to account for any associated analytical error is known.
  • Another label-free method of quantification, spectral counting involves summing the number of fragment ion spectra, or scans, that are acquired for each given peptide, in a non-redundant or redundant fashion. The associated peptide mass spectra for each protein are then summed, providing a measure of the number of scans per protein with this being proportional to a proteins abundance. Comparison can then be made between samples.
  • analogue peptides are typically produced by incorporating stable isotopes into the peptide or protein sequences, making the peptide either different in mass (isotope labelling), or having a different reporter ion mass in the MS/MS spectrum (isobaric labelling). Quantification can subsequently be performed through comparison of the mass spectral peak intensity, or area, of the light and heavy labelled peptides.
  • the ion source is selected from the group comprising or consisting of: (i) an Electrospray lonisation (“ESI”) ion source; (ii) an Atmospheric Pressure Photo lonisation (“APPI”) ion source; (iii) an Atmospheric Pressure Chemical lonisation (“APCI”) ion source; (iv) a Matrix Assisted Laser Desorption lonisation (“MALDI”) ion source; (v) a Laser Desorption lonisation (“LDI”) ion source; (vi) an Atmospheric Pressure lonisation (“API”) ion source; (vii) a Desorption lonisation On Silicon (“DIOS”) ion source; (viii) an Electron Impact ("El”) ion source; (ix) a Chemical lonisatjon (“CI”) ion source; (x) a Field lonisation (“Fl”) ion source; (xi) a Field Desorption (“FD”)
  • aspects of the invention provide an apparatus and/or control system configured or adapted or operative or programmed to execute the method, a computer program element comprising computer readable program code means for causing a processor to execute a procedure to implement the method and/or a computer readable medium embodying such a computer program element.
  • a yet further aspect of the invention provides a computer readable medium having a program stored thereon, where the program is to make a computer execute a procedure to implement the method.
  • LC-MSE alternating low and elevated energy
  • a target list of molecules is supplied that contains information such as, but is not limited to, m/z of precursor and fragment ions, retention time, ion mobility drift time and rate of change of mobility (e.g. FAIMS).
  • the first mass analyzer MS1 selects a narrow m/z range (of a variable and changeable width) to pass ions through to the gas cell.
  • the ions are subsequently fragmented (or not) and product ions are recorded with the second mass analyzer.
  • the instrument then switches back to the LC-MSE mode of operation after the ion finishes eluting or the retention time window ends.
  • This approach builds upon the methodology described in US6717130 and US71 12784 and numerous combinations or analytical derivations of this technique can be applied.
  • This invention provides a method to qualitatively profile mixtures via LC-MSE, with the target mode providing specific fragment ion information with enhanced signal to noise and increased specificity for target compound quantification.
  • the distinguishing features of this approach are the ability to profile samples with a variety of prior knowledge in a highly specific manner. Compared to MRM it has wider profiling or open platform capabilities.
  • variable band width nature of the first mass analyzer allows for multiple species to be selected simultaneously for fragmentation and quantification (such as isotope labelled peptide or modified peptides).
  • the method and apparatus of the present invention improves on the LC-MSE strategy through the addition of another stage of mass filtering.
  • the invention can be illustrated on a quadrupole time-of-flight type mass spectrometer system although other geometry mass spectrometry systems may also be employed.
  • sample ions created in the ion source of a quadrupole time-of-flight type instrument are transmitted through the quadrupole analyzer which is operated continuously in broad band pass mode. These ions are then transmitted into a collision cell which alternately and repeatedly switches between a first mode where the sample precursor ions are substantially fragmented to product ions and a second mode wherein the sample precursor ions are not substantially fragmented.
  • this invention improves the specificity of the LC-MSE analysis for targeted quantitative analysis by using the quadrupole time-of-flight type instrument or a functionally equivalent mass spectrometer that provides an ion source, a first mass analyzer capable of low or high resolution m/z selection, a capability to dissociate the ions selected in the first mass analyzer and a second mass analyzer capable of mass measuring the ions produced in this dissociation process preferably at elevated resolution (>5000 FWHM and high mass accuracy ( ⁇ 30ppm).
  • a Trap-ToF mass spectrometer can be used in a similar way instead of a quadrupole time-of-flight type instrument.
  • Further embodiments of the invention could include the use of a Quadrupole followed by a linear trap and a ToF, a linear Trap followed by an orbitrap, a Quadrupole followed by a linear trap and an Orbitrap, or any other type of selective analyser (that may itself be a collisional device i.e. a trap) or filter followed by a collision cell and then a full scan analyser. In the instance that the selective analyser is also a collisional device the following collision cell may not be essential.
  • the ion source may comprise any suitable ion source.
  • the ion source is preferably one of: an Electrospray lonisation (“ESI”) ion source; an Atmospheric Pressure Photo lonisation (“APPI”) ion source; an Atmospheric Pressure Chemical lonisation (“APCI”) ion source; a Matrix Assisted Laser Desorption lonisation (“MALDI”) ion source; a Laser Desorption lonisation (“LDI”) ion source; an Atmospheric Pressure lonisation (“API”) ion source; a Desorption lonisation On Silicon (“DIOS”) ion source; an Electron Impact (“El”) ion source; a Chemical lonisatjon (“CI”) ion source; a Field lonisation (“Fl”) ion source; a Field Desorption (“FD”) ion source; an Inductively Coupled Plasma (“ICP”) ion source; a Fast Atom Bombardment
  • EI
  • the first mass analyzer of the mass spectrometer (MS1 ) is used to select a narrow m/z range (of a variable and changeable width) of sample precursor ions which includes the m/z of the targeted precursor ion. These selected ions are then transferred to an instrument stage capable of dissociating the ions by means of alternate and repeated switches between a first mode where the sample precursor ions are substantially fragmented to product ions and a second mode wherein the sample precursor ions are not substantially fragmented.
  • the invention improves the specificity of the first embodiment by complementing the targeted MS1 mass selection precursor selection and coupled high resolution accurate mass alternating scan parent and product ion data acquisition process with ion mobility selection.
  • a mass spectrometer that is functionally equivalent to a quadrupole time-of-flight type instrument geometry capable of ion mobility separation such as the Synapt G2 HDMS system is used for the analysis.
  • accurate mass and chromatographic retention time attributes characteristic of the target analyte would be used for its quantitative measurement.
  • information about at least some, preferably most, in some cases all, ions present may be extracted from the first data set, e.g. quantification of the quantities of ions or identification of the presence and identity of ions.
  • the unique aspect to this invention is the combination of an open-platform discovery approach (LC-MSE), with a simultaneous quantitative approach that provides greater specificity and sensitivity.
  • LC-MSE open-platform discovery approach
  • MS/MS elevated energy
  • the present invention relates to a method, utilizing a mass spectrometer that can be used to detect and quantitatively profile surrogate peptides, or metabolites in complex mixtures.
  • the method incorporates analysis of the sample, by liquid chromatography in combination with mass spectrometry using a combination of different scan modes. In brief these include: a) Inject the sample and start the LC-MSE acquisition
  • this first mass analyzer might be an ion mobility spectrometer.
  • Figure 1 is a schematic of one embodiment of the present invention
  • Figure 2 is a schematic of a second embodiment of the present invention.
  • Figure 3 is a schematic of a third embodiment of the present invention.
  • the method could be altered in several different ways and this may well provide additional utility.
  • isotope labelled compounds where a set mass difference indicates quantitative changes
  • the ability to broaden MS1 to pass both isotopes is beneficial.
  • the fragment ions can then be used to identify which component is which.
  • An alternative embodiment of the invention may involve having a collision cell that may be bypassed in such a way that only ions desired to be fragmented to produce product ions are passed through the collision cell.
  • chromatographic separation such as capillary electrophoresis and gas chromatography, may be used in an analogous manner to perform targeted quantification of analytes in complex mixtures. It will be appreciated by those skilled in the art that any number of combinations of the aforementioned features and/or those shown in the appended drawings provide clear advantages over the prior art and are therefore within the scope of the invention described herein.

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  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)

Abstract

Cette invention concerne un procédé de criblage et/ou de détection et/ou de quantification de la quantité d'un ou de plusieurs composés d'intérêt dans un échantillon. Elle concerne également un système de commande et un spectromètre de masse programmés pour mettre en œuvre le procédé selon l'invention. Le procédé implique l'identification d'une ou de plusieurs masses d'ions parents et/ou filles d'intérêt, l'acquisition d'un premier ensemble de données provenant de l'échantillon, l'établissement de la présence d'ions parents candidats d'intérêt et/ou d'une première série d'ions filles candidats d'intérêt dans le premier ensemble de données, la sélection des ions parents candidats d'intérêt, la fragmentation des ions parents candidats d'intérêt sélectionnés pour obtenir une seconde série d'ions filles candidats d'intérêt et la création d'un spectre de masse portant sur au moins une partie de la seconde série d'ions filles candidats d'intérêt. Un mode de réalisation selon l'invention implique la détermination ou le calcul de la quantité d'au moins un premier composé d'intérêt à partir du spectre de masse. Un autre mode de réalisation selon l'invention implique la confirmation de la présence ou de l'absence d'un premier composé d'intérêt dans le spectre de masse.
EP10798370A 2009-11-13 2010-11-15 Détection et/ou quantification d'un composé dans un échantillon Withdrawn EP2499655A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0919870A GB0919870D0 (en) 2009-11-13 2009-11-13 A method to detect and quantitatively profile organic species using a mass spectrometer
PCT/GB2010/051904 WO2011058381A1 (fr) 2009-11-13 2010-11-15 Détection et/ou quantification d'un composé dans un échantillon

Publications (1)

Publication Number Publication Date
EP2499655A1 true EP2499655A1 (fr) 2012-09-19

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EP10798370A Withdrawn EP2499655A1 (fr) 2009-11-13 2010-11-15 Détection et/ou quantification d'un composé dans un échantillon

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WO (1) WO2011058381A1 (fr)

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JP5947567B2 (ja) * 2012-03-02 2016-07-06 株式会社日立ハイテクノロジーズ 質量分析システム
WO2013138326A2 (fr) * 2012-03-12 2013-09-19 Leco Corporation Détection et quantification analytiques sélectives dans une spectrométrie de masse à l'aide de la multiplication de canaux de signaux haute résolution
GB2504572B (en) 2012-05-18 2017-01-11 Micromass Ltd Method of MS/MS mass spectrometry
US10325766B2 (en) 2014-04-01 2019-06-18 Micromass Uk Limited Method of optimising spectral data
US9881778B2 (en) 2014-04-17 2018-01-30 Micromass Uk Limited Hybrid acquisition method incorporating multiple dissociation techniques
WO2015191999A1 (fr) * 2014-06-13 2015-12-17 Waters Technologies Corporation Analyse de matrices biologiques complexes par ciblage et alignement avancé d'ions précurseurs et de produits

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US20010052569A1 (en) * 2000-06-09 2001-12-20 Bateman Robert Harold Methods and apparatus for mass spectrometry
US7112784B2 (en) * 2002-07-24 2006-09-26 Micromass Uk Limited Method of mass spectrometry and a mass spectrometer
WO2006133191A2 (fr) * 2005-06-03 2006-12-14 Waters Investments Limited Procedes et appareil de mise en correspondance de temps de retention

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CA2340150C (fr) * 2000-06-09 2005-11-22 Micromass Limited Methodes et appareil pour la spectrometrie de masse
CA2518568C (fr) * 2003-04-09 2012-09-25 Mds Inc., Doing Business Through Its Mds Sciex Division Exclusion du signal de fond dynamique de donnees de chromatographie/spectrometrie de masse, acquisition de donnees
US7498568B2 (en) * 2005-04-29 2009-03-03 Agilent Technologies, Inc. Real-time analysis of mass spectrometry data for identifying peptidic data of interest

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Publication number Priority date Publication date Assignee Title
US20010052569A1 (en) * 2000-06-09 2001-12-20 Bateman Robert Harold Methods and apparatus for mass spectrometry
US7112784B2 (en) * 2002-07-24 2006-09-26 Micromass Uk Limited Method of mass spectrometry and a mass spectrometer
WO2006133191A2 (fr) * 2005-06-03 2006-12-14 Waters Investments Limited Procedes et appareil de mise en correspondance de temps de retention

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Title
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Also Published As

Publication number Publication date
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WO2011058381A1 (fr) 2011-05-19

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