WO2006046697A1 - Maldi-tof ms用基板及びそれを用いた質量分析方法 - Google Patents
Maldi-tof ms用基板及びそれを用いた質量分析方法 Download PDFInfo
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- WO2006046697A1 WO2006046697A1 PCT/JP2005/019900 JP2005019900W WO2006046697A1 WO 2006046697 A1 WO2006046697 A1 WO 2006046697A1 JP 2005019900 W JP2005019900 W JP 2005019900W WO 2006046697 A1 WO2006046697 A1 WO 2006046697A1
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Classifications
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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
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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
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J49/00—Particle spectrometers or separator tubes
- H01J49/02—Details
- H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
- H01J49/0409—Sample holders or containers
- H01J49/0418—Sample holders or containers for laser desorption, e.g. matrix-assisted laser desorption/ionisation [MALDI] plates or surface enhanced laser desorption/ionisation [SELDI] plates
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/02—Devices for withdrawing samples
- G01N1/22—Devices for withdrawing samples in the gaseous state
Definitions
- the present invention relates to a substrate for MALDI-TOF MS and a mass spectrometry method using the same.
- MALDI-TOF MS (Matrix Assisted Laser Desorption Ionization—Time Of Flight Mass Spectrometry) is a method widely used for mass spectrometry of biopolymers. is there.
- MALDI is a technique in which a test sample is mixed with a matrix (a compound that absorbs laser light) and irradiated with a laser beam of a few nanoseconds for a short time. In addition, it has a wide range of fats, fats, and the like, and it does not decompose biological substances, and has the characteristics of ionizing under mild conditions.
- TOF MS accelerates an ionized sample between high-voltage electrodes, introduces it into a tube called a flight tube in a high-vacuum non-electric field region, makes it fly at a constant speed, and measures the time required to fly a certain distance. This is a method for calculating the mass. In principle, even when the mass is large, the measurement conditions only require a long time and there are no theoretical measurement limits, so this is a mass spectrometry method suitable for polymers.
- Patent Document 1 Japanese Patent Application Laid-Open No. 2001-13110
- Patent Document 2 JP 2004-266100 A
- Patent Document 3 US Patent 6,743,607B2
- Patent Document 4 US Patent 6,693,187B 1
- Patent Document 5 US Patent Publication 2003 / 0220254A1
- Non-patent literature l Koomen, J. et al., Anal. Chem., 72: 3860 (2000)
- Non-Patent Document 2 Vorm, O. et al., Anal. Chem., 66: 3287 (1994)
- Non-Patent Document 3 Berggren, W. Tsuji, et al "Anal. Chem., 74: 1745 (2002)
- Non-Patent Document 4 Papac, D. I. et al., Anal. Chem., 68: 3215 (1996)
- Non-Patent Document 5 Hung, K. C. et al., Anal. Chem., 70: 3088 (1998)
- An object of the present invention is to provide a substrate for MALDI-TOF MS, which can perform mass analysis with high reproducibility and can easily obtain a mass spectrum even for a high-molecular substance such as protein or nucleic acid. And a mass spectrometry method using MALDI-TOF MS using the same. Means for solving the problem
- test substance adhesion region a nanodot region on which a test substance is adhered, the surface of which is made of a substance easily adsorbed to nucleic acids or proteins.
- test substance adhesion region On a substrate for MALDI-TOF MS, and by performing MALDI-TOF MS with the test substance attached to the nanodot region, mass spectrometry can be performed with high reproducibility even for polymer substances such as proteins and nucleic acids. And the present invention has been completed by finding that mass spectra can be easily obtained.
- the present invention provides a MALDI-TOF MS substrate having a nanodot region to which a test substance is attached, the surface of which is easily adsorbed to nucleic acids or proteins.
- the present invention also provides a method for mass spectrometry of nucleic acid or protein, wherein the substrate of the present invention is used and mass spectrometry is performed by MALDI-TOF MS using nucleic acid or protein as a test sample.
- a MALDI-TOF MS substrate capable of performing mass spectrometry with high reproducibility and easily obtaining a mass spectrum, even for a polymer substance such as protein and nucleic acid, and the same A mass spectrometric method using MALDI-TOF MS was provided.
- the substrate of the present invention the measurement results can be reproduced even if the test substance is protein or nucleic acid. It is possible to obtain accurate measurements, mass spectra can be obtained quickly, and the peaks become clear, so accurate measurement is possible. Therefore, the present invention is expected to greatly contribute to mass spectrometry of biologically related substances such as proteins and nucleic acids.
- FIG. 1 is a schematic cross-sectional view of a substrate for MALDI-TOF MS having a nanodot region produced in an example of the present invention.
- FIG. 2 is a schematic plan view illustrating a method for identifying each spot on a MALDI-TOF MS substrate having a nanodot region, which was produced in an example of the present invention.
- FIG. 3 Mass spectrum (upper) obtained by mass spectrometry of a DNA mixture by MALDI-TOF MS using the substrate of the present invention performed in the example of the present invention, and obtained using a commercially available substrate. It is a figure which shows the obtained mass spectrum (lower stage).
- FIG. 4 Probability (mass spots A1 to E4) of mass spectra obtained by mass spectrometry of a DNA mixture by MALDI-TOF MS using the substrate of the present invention conducted in the examples of the present invention and commercially available products. It is a figure which shows the probability (left end) that the mass spectrum was obtained using the board
- FIG. 5 Mass spectrum (upper) obtained by mass spectrometry of DNA comprising 40-mer poly C using the substrate of the present invention, and a commercially available substrate. It is a figure which shows the obtained mass spectrum (lower stage).
- FIG. 6 MALDI-TOF MS was performed using the substrate of the present invention or a commercially available substrate, using 24-mer DNA as an internal standard, varying the concentration of 23-mer DNA, and carried out in the examples of the present invention.
- the calibration curve drawn by taking the ratio of the peak areas of the obtained mass spectrum is shown.
- FIG. 7 Mass spectrum of the DNA mixture by MALDI-TOF MS using the substrate of the present invention in which the nanodot region is formed of platinum, gold, or titanium in the embodiment of the present invention.
- FIG. 5 is a diagram showing the probability (%) obtained when a nanodot region as a comparative reference is formed, and the probability when a SiO substrate and a commercially available substrate are used.
- the MALDI-TOF MS substrate of the present invention includes a nanodot region to which a test substance is attached, the surface of which has a substance force that is easily adsorbed to nucleic acids or proteins.
- the nanodot region is a substance (at least the surface of which is easily adsorbed to nucleic acids or proteins ( Hereinafter, it simply consists of an “adsorbable substance”).
- the easily adsorbing substances include metals other than alkali metals and alkaline earth metals (such as alloys thereof) such as gold, platinum, silver, copper, and iron, and polystyrene, polyethylene, and polypropylene.
- One example is a hydrophobic polymer.
- the lower layer may be made of a different substance.
- an adhesive layer or the like that enhances adhesion to the substrate may be interposed.
- platinum or gold is used as an easily adsorbing substance, but a platinum layer or a gold layer is formed on the surface of the silicon oxide film via a titanium layer.
- a region to which a test substance is attached is a nanodot region having the above-described easily adsorbable substance force.
- the “nanodot region” means a minute region having a diameter of less than l z m, preferably about 10 nm to 150 nm, and more preferably about 20 nm to 40 nm.
- the shape of the nanodot region is not limited to a circle, and may be other shapes such as a triangle, a square, a rectangle, a pentagon, a hexagon, an octagon, or another polygon.
- the major axis or the longest side is the above size, it is included in the “nanodot region” in the present invention.
- the minor axis or the shortest side is included in the above range.
- a circular shape is particularly preferred because of its ease of manufacture.
- the test substance adhesion region is a nanodot region.
- a MALDI-TOF MS substrate having a gold surface is already known and is also commercially available.
- gold is an easily adsorbable substance that is preferably used in the present invention.
- the inventors of the present application have made the region to which the test substance is attached a nanodot region, thereby comparing with a MALDI-TO FMS substrate formed from the same easily adsorbable substance and not having a nanodot region.
- the material of the substrate on which the test substance adhesion region is formed on the surface thereof is not particularly limited. Masle. That is, in a preferred embodiment of the present invention, a nanodot region having a surface with an easily adsorbing material force is formed on a hardly adsorbing substrate.
- the hardly adsorbing material include silicon and silicon oxide.
- a silicon substrate or a substrate on which a silicon oxide film is formed on the surface of a silicon substrate has a fine processing technique established, and can easily form grooves and the like described later. .
- the nanodot region with an easily adsorbable substance and forming the substrate (that is, the periphery of the nanodot area) with a hardly adsorbable material. Further, the effect S of the present invention that the mass spectrum can be easily obtained is further improved.
- the analyte in the test sample added to the substrate is more or less collected on the nanodot region (the nanodot region is so small that it cannot be seen with an optical microscope.
- test sample is applied to a region with a somewhat large area including the nanodot region that is not spotted only on the nanodot region, the test sample is also applied to a region other than the nanodot region). It is presumed to affect the crystallization of the above analyte.
- a plurality of nanodot regions are usually formed on a single substrate in order to increase measurement sensitivity.
- the period of the arrangement (the distance between the centers of the plurality of nanodot regions) is not particularly limited, but the density can be increased by reducing the period. For this reason, the period is preferably lOOOnm or less, and more preferably 600 nm or less.
- the lower limit of the period is necessarily larger than the diameter of the nanodot region, and is preferably at least twice the diameter of the nanodot region.
- the easily adsorbable material constituting each nanodot region when multiple nanodot regions are formed, the easily adsorbable material constituting each nanodot region Although it is convenient and preferable to manufacture the same material, it is also possible to use a combination of nanodot regions formed from different easily adsorbing materials.
- a group of nanodot regions may be made into one group, and one group of nanodot regions may be formed in a region surrounded by a groove formed in the substrate, and a plurality of such gnorapes (spots) may be formed. ,.
- a plurality of such gnorapes spots
- the nanodot regions are grouped, for example, the same test sample is measured in each group, and the test sample is different in different groups. Can do. Since the test sample dropped on the spot does not flow outside the groove defining the spot, mixing of the test sample between the spots is prevented.
- the size of such a spot is not limited at all, but is usually about a diameter force of S0.5 mm to 5 mm.
- the nanodot region can be formed on the substrate by a known method.
- the easily adsorbing substance is a metal
- it can be easily formed by vacuum deposition using a photoresist or an electron beam resist.
- vacuum deposition electron beam (EB) deposition that facilitates the production of a uniform film is preferable.
- EB electron beam
- the mass spectrometric method by MALDI-TOF MS of the present invention uses the above-mentioned substrate of the present invention, and attaches the mixture of the test sample and the matrix to the test substance adhesion region and provides for the measurement. Except for the above, it can be performed in the same manner as conventional MALD TOF MS, and an example of a specific method is described in the following examples.
- the test substance adhesion region is a nanodot region, but the nanodot region is a small one that cannot be seen with an optical microscope, so that the test sample is selectively spotted only on the nanodot region. This is difficult, and the test sample is applied to a wider area including the nanodot area.
- test sample is also applied to regions other than the nanodot region.
- the amount of the test sample applied to the substrate is not particularly limited, but is usually about 0.5 to 5 ⁇ L, particularly about 1 to 2 ⁇ L.
- concentration of the test substance (nucleic acid, protein, etc. to be subjected to mass spectrometry) in the test sample is not particularly limited, but is usually about ⁇ . ⁇ ⁇ ⁇ to about ⁇ ⁇ ⁇ , preferably 1 ⁇ ⁇ to 50 It is about ⁇ .
- Example 1
- a nanodot region schematically shown in FIG. 1 was formed by EB evaporation using an electron beam resist on a substrate on which a 1 ⁇ m thick thermal oxide film was formed on the surface of a 2 inch diameter silicon substrate.
- the lower titanium layer had a thickness of 2 nm and a diameter of 30 nm
- the upper platinum layer had a thickness of 50 nm and a diameter of 30 ⁇ m.
- the period of each nanodot region (both vertical and horizontal) is 60 nm, 90 nm, or 120 nm, and each nanodot region is formed in the silicon oxide film with a diameter of 2.4 to 2.5 mm, a width of 100 / im, and a depth. It was formed in a region (spot) surrounded by a 190-nm or 250-nm ring-shaped groove and gnoleped.
- EB lithography system JBX9300FS (manufactured by JEOL Ltd.) 100 kV, 7 nA (beam diameter: about 20 wakes), EB was irradiated on the part where the nanodot region was formed. Development was performed by immersing in developer ZED-N50 (manufactured by Nippon Zeon) for 60 seconds. Next, a titanium layer having a thickness of 2 mm and a platinum layer having a thickness of 50 mm were deposited thereon by EB vapor deposition using a commercially available EB vapor deposition apparatus.
- the resist was developed by immersion in Shifley Remover 1165 (trade name), and only the nanodot region in which the platinum layer was laminated on the titanium layer was left on the substrate.
- Shifley Remover 1165 trade name
- a ring-shaped groove was formed in the silicon oxide film, and each group of nanodot regions formed earlier was surrounded by each ring-shaped groove.
- ZEP resist manufactured by Nippon Zeon
- ZEP resist was spin-coated (film thickness: 250 nm) and pre-betated in an oven at 165 ° C for 30 minutes.
- the spots surrounded by each ring-shaped groove are 1, 2, 3, and 4 in the vertical direction (with the straight line portion of the substrate on the left), and eight in the horizontal direction. Identify with 8, 0 ⁇ (for example, specify a place like A1 or C3).
- This operation was specifically performed as follows.
- the DNA was made into a mixed solution of 5 pmol / ⁇ 1 using MilliQ water.
- 3HPA used was 10 mg / ml dissolved in 50% acetonitrile 50% water (0.1% TFA).
- 1 ⁇ l of sample solution and 1 ⁇ m of 3 ⁇ solution were dropped onto the substrate, mixed and air-dried.
- the substrate was attached to an adapter for loading the apparatus. This was loaded into a MALDI-TOF MS apparatus (manufactured by Bruker Dart Nitas Co., Ltd.), MALD and T OF MS were performed as described in the apparatus instructions, and a mass spectrum chart was drawn.
- the upper chart is a mass spectrum obtained using the substrate of the present invention prepared in Example 1, and the lower chart is obtained using a commercially available MALDI-TOF MS substrate. quality The quantity spectrum is shown. As can be seen from FIG. 3, when the substrate of the present invention was used, the peaks of each oligonucleotide appeared more clearly and the measured mass was more accurate than when a commercially available substrate was used. . When a silicon substrate having a ring-shaped groove that does not form a nanodot region was used, an effective spectrum could not be obtained at any spot.
- A1 to E1 are 60 nm periods
- A2 to E2 are 90 nm periods
- A3 to E4 are 120 nm periods.
- Different numbering in the same period is the difference in dot size resulting from the difference in exposure dose at the nanodot plate fabrication stage.
- the left side of the horizontal axis shows the results when a commercially available substrate is used, and the probability of obtaining a spectrum is only about 15%.
- the results for each spot of the substrate of the present invention are shown except for the leftmost side of the horizontal axis. It can be seen that any spot can be measured with high reproducibility by using the substrate of the present invention, which has a much higher probability than a commercially available substrate.
- FIG. 5 The upper part of FIG. 5 is a mass spectrum of 40-mer DN A obtained using the substrate of the present invention prepared in Example 1, and the lower part is obtained using a commercially available substrate.
- the mass spectrum for 40-mer DNA is shown.
- the S / N ratio and detection sensitivity were successfully increased.
- a substrate having a gold nanodot region was produced in the same manner as in Example 1 except that gold was used instead of platinum in Example 1. However, in addition to the 60 ⁇ m, 90 nm, and 120 nm periods, the nanodot region was also fabricated with 240 nm, 480 nm, and lOOOnm.
- Example 1 a substrate having a titanium nanodot region was prepared in the same manner as in Example 1 except that the thickness of the titanium layer was 50 mm, and platinum was not deposited on the titanium layer. Was made. However, in addition to the 60nm, 90nm, and 120nm periods of the nanodot region, 240nm, 480nm, and lOOOnm were also produced.
- a substrate having a platinum nanodot region was produced in the same manner as in Example 1. However, in addition to the 60 nm, 90 nm, and 120 nm periods of the nanodot region, 240 nm, 480 nm, and lOOOnm were also fabricated.
- the performance of the substrates manufactured in Examples 6 to 8 was measured in the same manner as in Example 3, and the probability of obtaining a mass spectrum (signal acquisition probability) was measured.
- the concentration of DNA is 20 ⁇
- the composition of the matrix solution is 50 mg / ml 3- ⁇ and 5 mg / m in 30% acetonitrile (containing 0.1% TFA).
- One containing 1 oxalic acid and 2 ammonium was used.
- the signal acquisition probability was clearly higher.
- the nanodot period is 60 ⁇ !
- the signal acquisition probability was clearly higher over the range of ⁇ lOOOnm than when the control substrate was used.
- the MALDI-TOF MS substrate of the present invention can perform mass spectrometry with high reproducibility even for a polymer substance such as protein and nucleic acid, and can easily obtain a mass spectrum. . Therefore, by using the substrate of the present invention, even if the test substance is a protein or nucleic acid, the measurement result can be obtained with good reproducibility, and a mass spectrum can be obtained immediately and the peak is clear. Therefore, accurate measurement is possible. Therefore, the present invention is useful for mass spectrometry of biological materials such as proteins and nucleic acids.
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT05805348T ATE491938T1 (de) | 2004-10-29 | 2005-10-28 | Substrat für maldi-tof-ms und massenspektrometrisches verfahren unter verwendung davon |
DE602005025401T DE602005025401D1 (de) | 2004-10-29 | 2005-10-28 | Hes verfahren unter verwendung davon |
US11/666,462 US8294090B1 (en) | 2004-10-29 | 2005-10-28 | Substrate for MALDI-TOF MS and mass spectrometry method using the same |
JP2006542343A JP4649416B2 (ja) | 2004-10-29 | 2005-10-28 | Maldi−tofms用基板及びそれを用いた質量分析方法 |
EP05805348A EP1830184B1 (en) | 2004-10-29 | 2005-10-28 | Substrate for maldi-tof ms and mass spectrometry method using the same |
Applications Claiming Priority (2)
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JP2004315699 | 2004-10-29 | ||
JP2004-315699 | 2004-10-29 |
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WO2006046697A1 true WO2006046697A1 (ja) | 2006-05-04 |
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PCT/JP2005/019900 WO2006046697A1 (ja) | 2004-10-29 | 2005-10-28 | Maldi-tof ms用基板及びそれを用いた質量分析方法 |
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US (1) | US8294090B1 (ja) |
EP (1) | EP1830184B1 (ja) |
JP (1) | JP4649416B2 (ja) |
AT (1) | ATE491938T1 (ja) |
DE (1) | DE602005025401D1 (ja) |
WO (1) | WO2006046697A1 (ja) |
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JP2006329977A (ja) * | 2005-04-28 | 2006-12-07 | National Institute Of Advanced Industrial & Technology | 質量分析用イオン化基板及び質量分析装置 |
JP2008041648A (ja) * | 2006-07-11 | 2008-02-21 | Canon Inc | 質量分析用基板及び質量分析用基板の製造方法 |
JP2008204654A (ja) * | 2007-02-16 | 2008-09-04 | Univ Of Tokyo | Ldiプレート、レーザー脱離イオン化質量分析装置、レーザー脱離イオン化質量分析方法及びldiプレート製造方法 |
WO2008136058A1 (ja) * | 2007-04-25 | 2008-11-13 | Shimadzu Corporation | レーザ脱離イオン化用サンプルプレート及び該サンプルプレートを用いた質量分析装置 |
JP2009244267A (ja) * | 2008-03-31 | 2009-10-22 | Sony Dadc Austria Ag | 基材及びターゲットプレート(substrateandtargetplate) |
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JP2015520382A (ja) * | 2012-06-08 | 2015-07-16 | ブルーカー ダルトニック ゲーエムベーハー | マイクロコロニーからの微生物のmaldi質量分析法による分析 |
CN105324831A (zh) * | 2013-03-13 | 2016-02-10 | 基纳生物技术有限公司 | 针对maldi质谱的制备强化和使用方法 |
US9873912B2 (en) | 2008-01-15 | 2018-01-23 | Agena Bioscience, Inc. | Compositions and processes for improved mass spectrometry analysis |
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Also Published As
Publication number | Publication date |
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JP4649416B2 (ja) | 2011-03-09 |
US8294090B1 (en) | 2012-10-23 |
EP1830184A1 (en) | 2007-09-05 |
JPWO2006046697A1 (ja) | 2008-08-07 |
DE602005025401D1 (de) | 2011-01-27 |
ATE491938T1 (de) | 2011-01-15 |
EP1830184A4 (en) | 2008-09-24 |
EP1830184B1 (en) | 2010-12-15 |
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