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WO2011073740A1 - Matrices pour imagerie par spectrométrie de masse - Google Patents

Matrices pour imagerie par spectrométrie de masse Download PDF

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Publication number
WO2011073740A1
WO2011073740A1 PCT/IB2009/056037 IB2009056037W WO2011073740A1 WO 2011073740 A1 WO2011073740 A1 WO 2011073740A1 IB 2009056037 W IB2009056037 W IB 2009056037W WO 2011073740 A1 WO2011073740 A1 WO 2011073740A1
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Prior art keywords
dhb
analyte
matrix
biological tissue
tissue section
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PCT/IB2009/056037
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English (en)
Inventor
Isabelle Fournier
Michel Salzet
Céline MERIAUX
Julien Franck
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Centre National de la Recherche Scientifique CNRS
Universite Lille 1 Sciences et Technologies
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Centre National de la Recherche Scientifique CNRS
Universite Lille 1 Sciences et Technologies
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6848—Methods of protein analysis involving mass spectrometry
    • G01N33/6851—Methods of protein analysis involving laser desorption ionisation mass spectrometry

Definitions

  • the present invention concerns new ionic liquid matrices and their use in mass spectrometry imaging.
  • MALDI-MSI uses the detection capability of mass spectrometry with the positional information of molecular histology, generating mass spectra correlated to known locations within a tissue.
  • MALDI mass spectrometry imaging is able to reveal the distribution of a large range of analytes. This information can be used to determine the distribution of an analyte throughout a tissue or organism. Since its introduction by the team of Caprioli Mass Spectrometry Imaging (MSI) has become a powerful and versatile tool for analyzing different classes of endogenous and exogenous molecules including drugs imaging 2"4 , peptides and polypeptides 5"9 . Lipids were widely studied by MSI 10"14 due to the fact that this class of biomolecules is extremely important and is involved in different pathology including Alzheimer disease 15 and down syndrome 16 .
  • Lipid analysis by MALDI-MS is generally performed using 2,5-Dihydroxybenzoic
  • 2,6-dihydroxyacetophenone (2,6-DHAP) as matrix was employed for analysis of lipids in both positive and negative mode 19"21 .
  • 2,6-DHAP was shown to be unstable under vacuum leading to the sublimation of the matrix 30 or 45 min after introduction of the sample into the mass spectrometer 22 .
  • Others substances were tested as matrices for lipid analysis including p-nitroaniline (PNA).
  • PNA p-nitroaniline
  • ATT 6-aza-2-thiothymine
  • ATT 6-aza-2-thiothymine
  • 2- Mercaptobenzothiazole (MBT) 25 was shown to be very efficient for lipid detection after spray deposition providing very homogenous crystallization, a high stability under vacuum and allowing the detection of a wide variety of lipids.
  • the incorporation into matrix crystals is not necessary for their detection in gas phase.
  • Different procedures to apply matrix on tissue including solvent-free matrix coating 26 for phospholipid detection and matrix sublimation 27 were developed to enhance crystal formation on the tissue avoiding delocalisation of analytes.
  • Ionic matrix Another alternative, is the use of Ionic matrices (IM) as we have already described for peptides 28 .
  • IMs were presented as a good alternative to conventional matrices for MSI for their very good stability under vacuum and the better sensitivity often observed 29 .
  • ILM Liquid Ionic Matrix
  • ILM Liquid Ionic Matrix
  • a good compromise between extraction of analytes from the tissue and derealization may be achieved by using microspotting of matrices. Due to the amount of solution deposited on the surface of the tissue, good extraction efficiency is achieved leading to the delocalization of analytes only on the surface of the spots.
  • Sample preparation is a very important parameter in Mass Spectrometry Imaging experiments.
  • the choice of the matrix and the procedure is critical to obtain high quality spectra and molecular images.
  • lipids and of other analytes in MSI the conventional 2,5-DHB matrix is commonly used but heterogeneous crystallization is caused by the microspotting of the matrix. It was shown that surface properties of tissues could be modified by various treatments and thus crystallization of 2,5-DHB could be greatly improved.
  • lipids and other analytes are known to be very soluble in a wide variety of solvents including alcohol, acetone, chloroform or xylem. It is thus very difficult to submit tissue sections to specific washing/treatment steps without losing some molecules of interest.
  • the present application describes new liquid ionic matrices (IML) and their use for MALDI mass spectrometry imaging. These matrices are obtained by adding a base to 2,5- DHB. These matrices enable a very stable deposition of the matrix leading to the formation of very homogeneous spots of matrix. Moreover, the matrices of the present invention are very stable under vacuum and the spectra obtained were similar to those obtained using conventional 2,5-DHB or 2,6-DHAP as matrix in terms of the species which are detected. Further, the matrices of the present invention are efficient in both positive and negative mode. Another advantage is that a low amount of matrix is required to obtain spectra with intense peaks.
  • the matrices of the present invention are therefore very suitable for the detection of various analytes including lipids in MSI experiments after microspotting.
  • 2,5 DHB /3AP is a matrix of choice for the detection of lipids for MSI experiments after microspotting.
  • liquid ionic matrices of the present invention are especially useful for the quantification of small molecules and lipids in tissue sections. Upon microspotting of the matrix onto the tissue section, most of the analyte is locally extracted from the tissue section and accumulates in the microspot of matrix where it the analyte can be quantified efficiently by MALDI-MSI.
  • the present invention relates to methods for detection and/or quantification of an analyte in a biological tissue section comprising the following steps: a) Depositing a liquid ionic matrix onto the biological tissue section wherein the liquid ionic matrix comprises 2,5-DHB and an organic base, b) Analysing the biological tissue by Matrix Assisted Laser Desorption Mass spectrometry Imaging.
  • the liquid ionic matrix is selected from, 2,5-DHB/ ANI,
  • the liquid ionic matrix is deposited onto the biological tissue section by micro-spotting.
  • At least one micro-spot of between 5 and 15 nL of ionic liquid matrix is deposited onto the biological tissue section.
  • a defined pattern of micro-spots of ionic liquid matrix is deposited onto the biological tissue section.
  • the analyte is a lipid.
  • the analyte is selected from phospoethanolamines (PE), phosphocho lines (PC), phosphoserines (PS), sphingomyelins, phospho inositols (PI), sulfatides (ST), hydroxylated sulfatides (ST-OH).
  • PE phospoethanolamines
  • PC phosphocho lines
  • PS phosphoserines
  • PI phospho inositols
  • ST hydroxylated sulfatides
  • ST-OH hydroxylated sulfatides
  • the biological tissue section is analysed by Matrix Assisted Laser Desorption Mass spectrometry Imaging in both positive and negative reflector mode.
  • the analyte is both detected and quantified in the biological tissue section.
  • Another object of the present invention is a composition comprising between 5 and 30 mg/mL 2,5-DHB in a solvent and an organic base selected from 3AP, ANI, Pyr, DANI and/or DEANI.
  • the ratio organic base/2,5-DHB is comprised between 0,5 and 2.
  • the solvent comprises methanol, ethanol and TFA.
  • the present invention is also related to the use of such a composition for the detection and/or quantification of an analyte in a biological tissue section by Matrix Assisted Laser Desorption Mass spectrometry Imaging.
  • the present invention is related to the use of a composition for detection and/or quantification of an analyte in a biological tissue section by Matrix Assisted Laser Desorption Mass spectrometry Imaging wherein the analyte is a lipid.
  • Mass spectrometry is an analytical tool used for measuring the molecular mass of an analyte. Mass spectrometers can be divided into three fundamental parts, namely the ionization source, the analyzer and the detector.
  • MALDI matrix assisted laser desorption ionization
  • Time-of- flight mass spectrometry is a common technique largely described in the litterature.
  • TOF-MS is a method of mass spectrometry in which ions are accelerated by an electric field. The velocity of the ion depends on the mass-to-charge ratio. The time that it subsequently takes for the particle to reach a detector at a known distance is measured. This time will depend on the mass-to-charge ratio of the ion. From this time and the known experimental parameters one can find the mass-to-charge ratio of the ion.
  • the type of mass spectrometer advantageously used with MALDI is the TOF (time-of- flight) mass spectrometer.
  • TOF time-of- flight
  • any suitable mass spectrometer may be used in the methods of the present invention.
  • the present invention relates to MALDI mass spectrometry imaging (MALDI-
  • MALDI-MSI links the universal detection capability of mass spectrometry with the positional information of molecular histology, generating mass spectra correlated to known locations within a biological tissue.
  • tissue sections are mounted onto a support and a suitable MALDI matrix is applied to the tissue.
  • the support is inserted into a MALDI mass spectrometer which records the spatial distribution of different analytes.
  • Suitable image processing software is used to import data from the mass spectrometer to allow visualization of analytes on the optical image of the tissue section.
  • a MALDI-MSI process comprises two steps: preparation of the sample including deposition of the matrix followed by ionization and desorption of the analyte by intense short pulses of laser light.
  • the matrix provides for absorption of energy from the laser light to desorb the analyte and promotes ionization.
  • matrix refers to a material which generates matrix-embedded analyte molecules (i.e. proteins) that are successfully desorbed by laser irradiation and ionized from the solid phase.
  • the matrix usually consists of molecules of low molecular weight to provide for vaporization but large enough not to evaporate during sample preparation or while standing in the spectrometer. Matrices also have a strong optical absorption in the UV range, so that they rapidly and efficiently absorb the laser irradiation.
  • MALDI matrix solution is mixed with the sample or applied onto the sample.
  • the organic solvent allows hydrophobic molecules to dissolve into the solution, while the water allows for water-soluble (hydrophilic) molecules to do the same. Then, the solvents vaporize, leaving only the re-crystallized matrix, but now with analyte spread throughout the crystals.
  • the matrix and the analyte are said to be co-crystallized in a MALDI spot.
  • a major problem in MALDI-MSI is the derealization of analytes, especially of lipids and small molecules such as drugs, upon application of the MALDI matrix onto the tissue section.
  • the present invention is related to new MALDI-MS matrices and to their use for the detection of analytes. These MALDI-MSI matrices provide for less derealization of analytes and crystallize homogeneously onto the tissue sample.
  • the present invention relates to methods for detection and/or quantification of an analyte in a biological tissue section comprising the following steps:
  • the methods of the present invention are preferably in vitro methods.
  • the methods of the present invention provide for detection of an analyte in a biological tissue section.
  • detection refers both to localization and identification of the analyte in the tissue section.
  • the methods of the present invention may provide for quantification of the analyte in the biological tissue section.
  • the analyte is a lipid.
  • Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, monoglycerides, diglycerides, phospholipids, etc. Lipids may be broadly defined as hydrophobic or amphiphilic small molecules.
  • the analyte is selected from phospoethanolamines (PE), phosphocho lines (PC), phosphoserines (PS), sphingomyelins, phosphoinositols (PI), sulfatides (ST), hydroxylated sulfatides (ST-OH).
  • PE phospoethanolamines
  • PC phosphocho lines
  • PS phosphoserines
  • PI phosphoinositols
  • ST hydroxylated sulfatides
  • the analyte is a small molecule having a size comprised between 23 and 2000 M/z, preferably between 23 and 500, 1000 or 1500 M/z.
  • M/z refers to mass-to-charge ratio obtained by dividing the mass of an ion by the unified atomic mass unit and by its charge number.
  • Such small molecules may be subject to derealization in biological tissue sections when a MALDI matrix is applied.
  • the matrices of the present invention provide for detection of such molecules without derealization within the biological tissue section.
  • Small molecules of interest may for example include various therapeutic molecules i.e. drugs.
  • the analyte may be detected, localized and/or identified in any biological tissue section of interest.
  • the biological tissue section preferably has a thickness comprised between 5 and 20 ⁇ . Any tissue or organism may be analyzed in the methods of the present invention.
  • the tissue section is prepared according to known methods. Thin sections/slices are typically obtained from frozen tissues and applied onto solid supports. The tissue sections are then usually dried in a dessicator. The tissue sections immobilized onto a solid support may also be washed prior to further preparation of the sample for MALDI-MS. Solid supports or plates suitable for MALDI-MS are largely described in the literature. Any suitable support may be used in the methods of the present invention.
  • the liquid ionic matrix is deposited onto the biological tissue section using any suitable method.
  • the matrix may for example be dispensed by pipetting, by spraying or by printing small amounts of matrix by a chemical injet printer.
  • Printers and spotters which deposit a small amount of MALDI matrix in a user-defined pattern directly onto the tissue by so called "microspotting" have been described. Deposition of the matrix in small amounts on a defined spot by micro-spotting is preferred in the methods of the present invention to further avoid any derealization of the analyte to be detected in the biological tissue section.
  • the liquid ionic matrix is deposited onto the biological tissue section by micro-spotting.
  • At least one micro-spot of between 5, 10 and 15 nL of ionic liquid matrix is deposited onto the biological tissue section.
  • a defined pattern of micro-spots of ionic liquid matrix is deposited onto the biological tissue section.
  • Mass spectrometer records, detects and identifies each analyte in each microspot. Suitable software is used to allow visualization and comparison with the optical image of the biological tissue section.
  • the liquid ionic matrices of the present invention comprise an acid (2,5-DHB 2,5- Dihydroxybenzoic Acid) and an organic base.
  • the organic base is preferably selected in the group consisting of 3-Acetylpyridine (3AP), Pyridine (Pyr), Aniline (ANI), N,N- dimethylaniline (DANI) and ⁇ , ⁇ -diethylaniline (DEANI).
  • the liquid ionic matrix is selected from, 2,5-DHB/ ANI, 2,5-DHB/3AP, 2,5-DHB/Pyr, 2,5-DHB/DANI and/or 2,5-DHB/DEANI.
  • the biological tissue section may be analysed by Matrix Assisted Laser Desorption
  • Mass spectrometry Imaging in positive ion and/or negative ion reflector mode Mass spectrometry Imaging in positive ion and/or negative ion reflector mode.
  • the type of mass spectrometer advantageously used with MALDI is the TOF (time-of- flight) mass spectrometer.
  • TOF time-of- flight
  • any suitable mass spectrometer may be used in the methods of the present invention.
  • Another object of the present invention is a composition comprising between 5 and 30 mg/mL 2,5-DHB in a solvent and an organic base selected from 3AP, ANI, Pyr, DANI and/or DEANI.
  • the ratio organic base/2,5-DHB is comprised between 0,5 and 2.
  • the solvent comprises methanol, ethanol and TFA.
  • the present invention is also related to the use of such a composition as matrix for the detection and/or quantification of an analyte in a biological tissue section by Matrix Assisted Laser Desorption Mass spectrometry Imaging.
  • the present invention is related to the use of such a composition as matrix for detection and/or quantification of an analyte in a biological tissue section by Matrix Assisted Laser Desorption Mass spectrometry Imaging wherein the analyte is a lipid.
  • Another object of the present invention is a method for the in vitro clinical diagnosis on a biological tissue section using a matrix or the methods according to the present invention.
  • Figure 1 Optical images of spots saved after deposition of (a) 2,5-DHB, (b) DHAP and (c) 2,5-DHB/3AP on a rat brain tissue section.
  • Figure 2 MS spectra acquired in positive reflector mode after deposition of DHAP and saved after (a) introduction of the target in the mass spectrometer and (b) after lh in the vacuum. MS spectra acquired positive reflector mode after deposition of 2,5-DHB/3AP and saved after (c) introduction of the target in the mass spectrometer and (d) after 2 days in the vacuum.
  • FIG 3 Structure of ILM including (a) 2,5-DHB/ANI (Aniline), (b) 2,5-DHB/DANI ( ⁇ , ⁇ -dimethylaniline), (c) 2,5-DHB/DEANI ( ⁇ , ⁇ -diethylaniline), (d) 2,5-DHB/Pyr (Pyridine) and (e) 2,5-DHB/3AP (3-acetylpyridine).
  • Figure 4 MS spectra acquired in positive reflector mode after deposition of (a) 2,5- DHB/ANI, (b) 2,5-DHB/DANI, (c) 2,5-DHB/DEANI, (d) 2,5-DHB/Pyr and (e) 2,5- DHB/3AP.
  • Figure 5 MS spectra acquired in negative reflector mode after deposition of (a) 2,5- DHB/ANI, (b) 2,5-DHB/DANI, (c) 2,5-DHB/DEANI, (d) 2,5-DHB/Pyr and (e) 2,5- DHB/3AP.
  • Figure 6 MS spectra acquired in positive reflector mode after deposition of (a) 2,5-DHB and (b) 2,5-DHB/3AP. MS spectra acquired in negative reflector mode after deposition of (c) 2,5-DHB and (d) 2,5-DHB/3AP.
  • 2,5-Dihydroxybenzoic Acid (2,5-DHB), 2,6-dihydroxyacetophenone (2,6-DHAP), 3- Acetylpyridine (3AP), Pyridine (Pyr), Aniline (ANI), ⁇ , ⁇ -dimethylaniline (DANI), N,N- diethylaniline (DEANI), Trifluoracetic acid (TFA), Ethanol (EtOH), Water Chromasolv plus for HPLC (H 2 0) were purchased from Sigma-Aldrich (Saint Quentin Fallavier, France). Samples
  • Frozen rat brains were cut into 10 tissue sections using a cryostat Leica CM1510S (Leica Microsystems, Nanterre, France). The sections were applied onto ITO- coated conductive glass slides (Bruker Daltonics, Bremen, Germany) and dried in a desiccator for 10 minutes.
  • Liquid ionic matrices 2,5-DHB/ANI, 2,5-DHB/DANI, 2,5-DHB/DEANI, 2,5-
  • DHB/Pyr and 2,5-DHB/3AP were used as matrix and were prepared just prior to use by adding 1.2 equivalent of organic base to a solution containing 20 mg/mL of 2,5-DHB (1 equivalent) in EtOH/aqueous TFA 0.1%> (7:3, v:v). Solutions were then vortexed/agitated for several minutes before use. Matrices solutions must be used within one day of preparation. The total volume of ILM was set to 5 nL and was deposited directly on tissue using the CHIP- 1000.
  • 2,5-DHB was deposited on a discrete location of a rat brain tissue section using a microspotter in order to improve the crystallisation.
  • microspotter leads to the formation of very homogeneous spots of matrices as presented with 3-hydroxypicolinic acid (3HPA) 31 known for the formation of heterogeneous crystals and "hot spots".
  • 3HPA 3-hydroxypicolinic acid
  • Crystallization of 2,5- DHB with the shape of a circle was observed leading to a lack of information in the center of the spots. It could be a strong drawback by considering that position teaching for MALDI-MSI experiment after microspotting, is generally done using the center of spots. Laser will thus shot in the center where no crystals are observed and therefore no analytes will be detected. The formation of such crystals could be explained by physical properties of tissue section without any chemical treatments.
  • matrix solutions for lipid analysis consist generally to the use of polar solvents such as alcohol including EtOH. By using these solvents, droplets of matrix solution spread on the surface of the tissue leading to the formation of 2,5-DHB crystals from the outer rim of the deposited solution.
  • ILM including 2,5-DHB/ANI, 2,5-DHB/DANI, 2,5-DHB/DEANI, 2,5-DHB/Pyr and 2,5-DHB/3AP as matrix ( Figure 3) were then studied and were deposited on a discrete location of a rat brain tissue section using the microspotter.
  • ILM is a very good matrix suitable for MSI of lipids and other analytes.
  • Table 1 Example of lipids detected in positive reflector mode after deposition of 2,5-DHB/3AP as matrix on a rat brain tissue section.
  • PE phosphoethanolamine
  • PC phosphocholine
  • PS phosphoserine
  • SM sphingomyelin
  • ILM such as 2,5-DHB/3AP
  • ILM such as 2,5-DHB/3AP
  • phospholipids such as phosphoinositols (PI)
  • sphingolipides such as sulfatides (ST) and gangliosides.
  • ST sulfatides
  • gangliosides An example of lipids detected using 2,5-DHB/3AP in negative reflector mode is presented in Table 2.
  • Table 2 Example of lipids detected in negative reflector mode after deposition of 2,5- DHB/3AP as matrix on a rat brain tissue section. Abbreviations: phosphoinositol (PI), sulfatide (ST), hydroxylated sulfatide (ST-OH).
  • PI phosphoinositol
  • ST sulfatide
  • ST-OH hydroxylated sulfatide

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Abstract

La présente invention concerne des matrices ioniques liquides pour l'imagerie par spectrométrie de masse MALDI (MALDI-MSI) de sections tissulaires et leur utilisation pour la détection et la localisation de substances à analyser comme des lipides. Les matrices comprennent de l'acide 2,5- dihydroxy benzoïque et une base organique afin de réduire la délocalisation des substances à analyser.
PCT/IB2009/056037 2009-12-15 2009-12-15 Matrices pour imagerie par spectrométrie de masse Ceased WO2011073740A1 (fr)

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Cited By (7)

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WO2012126873A1 (fr) * 2011-03-21 2012-09-27 Imabiotech Procédé de détection et de quantification d'une molécule cible dans un échantillon
JP2016099304A (ja) * 2014-11-26 2016-05-30 株式会社島津製作所 質量分析を用いた糖タンパク質の分析方法
US9645138B2 (en) 2013-02-25 2017-05-09 Imabiotech Method to evaluate the tissue targeting of a molecule of interest
US10132796B2 (en) 2011-05-31 2018-11-20 Imabiotech Method for detecting and quantifying a target molecule in a tissue
CN109187717A (zh) * 2018-09-27 2019-01-11 中国科学技术大学 一种植物中外源有机污染物的检测方法
CN115060786A (zh) * 2022-06-24 2022-09-16 山东博德医药研究院有限公司 一种分析牛蒡根中功能成分的空间分布的方法
CN116660360A (zh) * 2023-05-31 2023-08-29 中国科学院化学研究所 1-氯-4-肼基酞嗪反应性基质在单糖maldi msi原位分析中的应用

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