CN116203119B - MALDI-MS matrix for detecting small molecular compounds and detection method - Google Patents
MALDI-MS matrix for detecting small molecular compounds and detection method Download PDFInfo
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- G—PHYSICS
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- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
- G01N27/64—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode using wave or particle radiation to ionise a gas, e.g. in an ionisation chamber
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
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Abstract
The invention belongs to the technical field of analysis and detection, and particularly discloses a MALDI-MS matrix for detecting small molecular compounds, and a method for detecting samples containing the small molecular compounds by adopting the matrix. The MALDI-MS detection method based on the DDDa as a matrix is used for qualitative and quantitative detection of small organic molecules with molecular weight below 300Da for the first time, and has the advantages of high specificity, accurate method, simple and convenient operation and high sensitivity.
Description
Technical Field
The invention relates to the technical field of analysis and detection, in particular to a MALDI-MS matrix for detecting small molecular compounds, and also relates to a method for detecting samples containing the small molecular compounds by adopting the matrix.
Background
In the mass spectrum detection field, particularly in the clinical mass spectrum field, the matrix assisted laser desorption ionization mass spectrometry (MALDI-MS) is a high-flux and automatic mass spectrometry method, has the advantages of high sensitivity, good stability, short experimental period, simplicity in operation and low sample and manpower consumption, and has extremely high potential value for detecting clinical indexes.
When the MALDI-MS is used for analysis, high-concentration matrix molecules are required to be mixed with a detection sample, so that the detected molecules are wrapped in crystals of the matrix molecules, and the detected molecules with complete structures fly out and generate stable ionization under the bombardment of laser energy, so that the detection is completed in a mass analyzer of a mass spectrometer. The matrix molecules are used as a medium for transmitting laser energy in the ionization process, so that the energy of the detected molecules can be mildly lifted and desorbed, and a certain charge is combined at the same time, so as to assist in completing the ionization of the detected molecules and the subsequent mass spectrometry. Currently, most of commonly used MALDI-MS positive ion matrixes are small molecular organic acid substances containing a conjugated large pi bond structure, most commonly include 2, 5-dihydroxybenzoic acid (DHB), sinapic Acid (SA), alpha-cyano-4-hydroxycinnamic acid (CHCA) and the like, and the molecules can be effectively used as mediums to complete energy transfer and ion transfer to a detected substance, so that the ionization efficiency of a plurality of different types of detected substances is greatly improved, and the MALDI-MS positive ion matrixes are ideal and are commercialized and widely applied in practical work.
However, under the excitation of laser, the small organic molecular matrixes commonly used at present are extremely easy to ionize, conjugated organic acids are easy to form a series of molecular cluster ions, and the molecular weights of the matrix ions and the matrix molecular cluster ions are mostly below 500Da, so that a large number of matrix-related signals are generated in the range of mass spectrum m/z < 500; meanwhile, since the concentration of the matrix adopted in the detection is generally far greater than the concentration of the detected target object (often hundreds to tens of thousands times higher than the concentration of the detected molecule), the matrix-related signal with high intensity is often only detected in a small molecular weight range of a mass spectrum (m/z <500, especially m/z < 300), and the signal of the detected target molecule is severely suppressed, so that normal detection cannot be realized or even the detection can be performed, and the sensitivity is extremely poor.
For the above reasons, MALDI-MS is currently mainly used for analysis and detection of macromolecular substances with molecular weights above 600Da, such as proteins, polypeptides, nucleic acids and macromolecular lipids, and is not basically used for detection of small molecular substances, in particular small molecular metabolites with molecular weights below 300 Da.
To solve the problem of MALDI-MS detection of small molecular substances, many researchers have attempted to develop MALDI-MS matrix materials suitable for detection of small molecular substances. For example, a large molecular weight substance capable of transmitting laser energy and transferring ions is used as a matrix, and theoretically, the large molecular weight substance assists in desorption and ionization of the detected molecules, and a signal generated by the matrix is located in a high molecular weight range, so that detection of target molecules in a small molecular weight range is not affected. There are also materials that do not generate ion signals of small molecular weight, such as various carbon-based nanomaterials, porous silicon materials, metal nanoparticles, and the like, as a matrix. Although the data show that these different types of matrix materials can be used for MALDI-MS detection of small molecules, in practice, in most cases, many molecular fragment signals remain in the small molecular range of m/z <300, and interference with small molecule analyte detection remains to some extent. Analysis has shown that these molecular fragments generally result from the laser bombardment of the macromolecular matrix material and from the presence of polymer monomers that are inherently present in the insufficiently pure material. At the same time, these new matrix materials tend to be less efficient at assisting in analyte desorption and ionization than conventional small molecule organic acid matrices such as DHB, CHCA, etc.
Therefore, MALDI-MS detection of small molecular substances is still a current research difficulty, and development of a matrix material suitable for efficient MALDI-MS detection of small molecular substances is an important research topic.
Disclosure of Invention
The invention mainly solves the technical problem of providing a MALDI-MS matrix for detecting small molecular compounds, and the MALDI-MS detection method adopting the matrix can be used for qualitative and quantitative detection of organic small molecules with molecular weight below 300Da, and has the advantages of high specificity, accurate method, simple and convenient operation and high sensitivity.
The invention also provides a MALDI-MS matrix composition for detecting the small molecule compounds.
The invention also provides a detection method of the small molecular compound.
In order to solve the above technical problems, in a first aspect, the present invention provides a MALDI-MS matrix for detecting small molecular compounds, wherein the matrix is 2, 7-di-tert-butyl-9, 9-dimethylxanthene-4, 5-dicarboxylic acid (abbreviated as DDDa), and the structural formula is:
it was found that DDDa has a conjugated large pi-bond structure with multiple benzene rings and carboxyl groups on the aromatic ring, which has the potential to deliver laser energy and ionize analytes as a MALDI-MS matrix. DDDa has larger molecular weight, the molecular weight is more than 400Da, and under the condition of not generating molecular fragments, the generation of mass spectrum signals and interference below m/z300 can be effectively avoided in mass spectrum detection, so that the inhibition of the peak of an analyte is effectively avoided. Therefore, DDDa can be used as a matrix for MALDI-MS analysis of small molecular substances below 300 Da.
In a second aspect, the invention provides a MALDI-MS matrix composition for detection of small molecule compounds, comprising 2, 7-di-tert-butyl-9, 9-dimethylxanthene-4, 5-dicarboxylic acid.
As a preferred embodiment of the present invention, the content of 2, 7-di-t-butyl-9, 9-dimethylxanthene-4, 5-dicarboxylic acid in the matrix composition is 1.0 to 20.0mg/mL.
Preferably, the content of 2, 7-di-tert-butyl-9, 9-dimethylxanthene-4, 5-dicarboxylic acid in the matrix composition is 1.0 to 15.0mg/mL.
More preferably, the content of 2, 7-di-tert-butyl-9, 9-dimethylxanthene-4, 5-dicarboxylic acid in the matrix composition is 2.0 to 10.0mg/mL.
As a preferred embodiment of the present invention, an organic solvent is included in the matrix composition, preferably the organic solvent is methanol.
As a preferred embodiment of the present invention, trifluoroacetic acid, preferably in a volume ratio of trifluoroacetic acid to the organic solvent of (1 to 50) is included in the matrix composition: 1000, more preferably (1 to 25): 1000, more preferably (1 to 15): 1000. the ionization efficiency can be improved by adding an appropriate amount of trifluoroacetic acid to the matrix composition.
As a preferred embodiment of the present invention, the matrix composition further comprises isopropyl alcohol, preferably in a volume ratio of isopropyl alcohol to the organic solvent of (300 to 1000): 1000, more preferably (400 to 600): 1000, more preferably (450 to 550): 1000. the addition of an appropriate amount of isopropanol to the matrix composition can promote the solubility of the matrix composition and has good intersolubility with the detected small molecular compound.
In a third aspect, the invention provides the use of a MALDI-MS matrix as described or a matrix composition as described in the detection of small molecule compounds.
Preferably, the MALDI-MS matrix or the matrix composition is used for MALDI-MS analysis and detection of small molecule compounds with molecular weight below 300 Da.
Further preferably, the small molecule compound having a molecular weight of 300Da or less is carnitine, arginine, dopamine, leucine or the like.
In a fourth aspect, the invention provides a method for detecting a small molecular compound, which adopts 2, 7-di-tert-butyl-9, 9-dimethyl xanthene-4, 5-dicarboxylic acid as a MALDI-MS matrix, and the detection method comprises the following steps:
(1) Preparing the MALDI-MS matrix into a MALDI-MS matrix composition;
(2) The detection sample containing the small molecule compound is spotted on a MALDI-MS target plate, and the MALDI-MS matrix composition is mixed on the sample spot, and then detection is performed using MALDI-MS.
Preferably, in step (1), formulating the MALDI-MS matrix into a MALDI-MS matrix composition comprises: the MALDI-MS matrix was mixed with methanol and trifluoroacetic acid to prepare a MALDI-MS matrix composition.
Further preferably, the content of the MALDI-MS matrix in the MALDI-MS matrix composition is 1.0 to 20.0mg/mL; the volume ratio of trifluoroacetic acid to methanol is (1-50): 1000.
still more preferably, isopropyl alcohol is also added to the MALDI-MS matrix composition, preferably in a volume ratio of isopropyl alcohol to methanol of (300-1000): 1000.
preferably, an acidifying reagent is added to the detection sample containing the small molecule compound to keep the detection sample acidic.
Still more preferably, the acidifying agent is trifluoroacetic acid.
Preferably, the sample application amount of the detection sample containing the small molecule compound is the same as the sample application amount volume of the MALDI-MS matrix composition.
Further preferably, the solution to be analyzed, i.e. the detection sample, is spotted on the MALDI-MS target plate, and then the same volume of DDDa solution, i.e. the MALDI-MS matrix composition, is mixed on the spot, thoroughly mixed and dried in air, and then mass spectrometry is performed.
According to the detection method of the small molecular compound, the high-concentration DDDa solution and the sample solution are mixed and spotted on the MALDI-MS target plate, so that the detection method is used for mass spectrum analysis of small molecular substances in a sample, particularly for analyzing the small molecular substances with the molecular weight smaller than 300Da, and is mainly used for detecting signals in a mass spectrum range of m/z < 300.
When the MALDI-MS is used for analysis and detection, a target plate is loaded into a MALDI-MS mass spectrometer for mass spectrometry. Authentication can be performed in reflectance mode using a SHIMADZU AXIMA RESONANCE MALDI-IT-TOF mass spectrometer. MALDI mass spectra were obtained by accumulating and averaging 400 shots (shots) in a cationic mode with a laser intensity of 100-120. Spectrogram acquisition and processing was performed using Shimadzu Biotech Launchpad software (version 2.9), other commercially available MALDI-MS mass spectrometers could also be used, and this disclosure is not limited in this regard.
In the detection process, a standard curve is drawn according to the mass spectrum signal intensity of the detected standard substance and the concentration of the added standard substance, and then the concentration of the detected substance in the detection sample is calculated according to the detection result of the detection sample.
In some embodiments, the assays of the invention are qualitative assays for identifying the molecular weight and type of an analyte, i.e., a small molecule compound.
In some embodiments, the assay of the invention is a quantitative assay for detecting the content of small molecule compounds.
Experiments show that the DDDa is used as a matrix of the MALDI-MS, different kinds of small molecular weight analytes can be effectively detected, the sensitive detection of the target object under lower concentration is realized, and meanwhile, a strong interference signal from the matrix of the DDDa is hardly generated in the molecular weight range.
The beneficial effects of the invention are as follows:
(1) The invention provides a brand-new matrix molecule which can be used for micro-molecular MALDI mass spectrometry, almost does not generate strong molecular ion peak or fragment peak from the matrix in the m/z <300 range, is beneficial to improving the sensitivity of micro-molecular MALDI analysis and avoids the inhibition or interference of matrix signals on analyte signals;
(2) Compared to conventional MALDI matrices, the DDDa matrices of the invention show a stronger signal-to-noise ratio and sensitivity due to the avoidance of interference of matrix signals and suppression of analyte signals.
The MALDI-MS detection method based on the DDDa as a matrix is used for qualitative and quantitative detection of small organic molecules with molecular weight below 300Da for the first time, and has the advantages of high specificity, accurate method, simple and convenient operation and high sensitivity.
Drawings
FIG. 1 is a MALDI mass spectrum of DDDa obtained in example 1 of the present invention;
FIG. 2 is a MALDI mass spectrum of an arginine sample analyzed by using DDDa solutions of three different compositions as a matrix in example 2 of the present invention;
FIG. 3 is a MALDI mass spectrum of an arginine sample analyzed by using four DDDa solutions of different concentrations as a matrix in example 3 of the present invention;
FIG. 4 is a spectrum of MALDI mass spectrometry performed on different types of small molecule compound standard solutions in example 4 of the present invention;
FIG. 5 is a mass spectrum of MALDI MS analysis of arginine, carnitine and dopamine respectively using DDDa, DHB, CHCA as matrix in example 5 of the present invention;
FIG. 6 is a graph showing the standard concentration of arginine and carnitine obtained in example 6 of the present invention.
Detailed Description
Reference now will be made in detail to embodiments of the invention, one or more examples of which are described below. Each example is provided by way of explanation, not limitation, of the invention. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment can be used on another embodiment to yield still a further embodiment.
Accordingly, it is intended that the present invention cover such modifications and variations as fall within the scope of the appended claims and their equivalents. Other objects, features and aspects of the present invention will be disclosed in or be apparent from the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only, and is not intended as limiting the broader aspects of the present invention.
In the following examples, samples containing small molecule compounds were examined using 2, 7-di-t-butyl-9, 9-dimethylxanthene-4, 5-dicarboxylic acid (DDDa) as a matrix for MALDI-MS.
The detection step comprises the following steps:
firstly, preparing a DDDa solution, dissolving the DDDa into a methanol/isopropanol mixed solution, adding a certain amount of trifluoroacetic acid into the solution, and uniformly mixing the solution by vortex vibration to obtain the DDDa solution, wherein the concentration of the DDDa is 1.0-20.0 mg/mL;
adding trifluoroacetic acid into the prepared sample solution to be analyzed to acidify the sample solution;
spotting 1uL of the sample to be analyzed on a MALDI-MS target plate;
mixing 1uL of DDDa solution, adding the mixed solution on a sample point of a MALDI-MS target plate to be analyzed, repeatedly sucking the mixed solution for several times by a liquid-transferring gun to uniformly mix the sample and the matrix solution, and then naturally drying the target plate in air;
after the sample is completely dried, the target plate is loaded into a MALDI-MS mass spectrometer for mass spectrometry.
Preferably, when preparing the DDDa solution, in the mixed solution of methanol and isopropanol, the volume ratio of isopropanol to methanol is (300-1000): 1000; the volume ratio of the added trifluoroacetic acid to the methanol is (1-50): 1000.
the technical scheme of the invention is described in detail through specific examples.
Example 1
In this example, MALDI-MS mass spectrometry of DDDa molecules was performed as follows:
1) Preparing a DDDa solution, dissolving the DDDa into a mixed solution of methanol/isopropanol (volume ratio is 1:1), wherein the concentration is 2.5mg/mL, adding 0.5% trifluoroacetic acid (0.5% is relative to the volume percentage of the mixed solution), and uniformly mixing by vortex vibration;
2) Adding 1uL of DDDa solution to a sample point of a MALDI-MS target plate to be analyzed, repeatedly sucking the mixed solution for several times by using a pipette, and then naturally drying the target plate in air;
3) After the sample is completely dried, loading the target plate into a MALDI-MS mass spectrometer for mass spectrometry; authentication was performed in reflectance mode using a SHIMADZU AXIMA RESONANCE MALDI-IT-TOF mass spectrometer; MALDI mass spectra were obtained by accumulating and averaging 400 shots in a cationic mode with a laser intensity of 100-120, and were collected and processed using Shimadzu Biotech Launchpad software (version 2.9).
The MALDI mass spectrum of the obtained DDDa is shown in FIG. 1, and the result of FIG. 1 shows that: MALDI-MS mass spectrum signals of DDDa mainly appear in the range of m/z 350-420; there is substantially no strong mass spectrum signal present in the range below m/z 300. The results demonstrate that DDDa produces very limited interfering signals within the small molecular weight range, facilitating signal detection of small molecule analytes.
Example 2
In this example, MALDI-MS analysis and effect comparison were performed on arginine samples using DDDa solutions of different compositions, and the steps were as follows:
1) Three DDDa solutions of different compositions were prepared, as follows:
solution (a): a methanol/trifluoroacetic acid solution of DDDa, wherein the volume ratio of methanol/trifluoroacetic acid is 1000:1;
solution (b): a methanol/isopropanol/trifluoroacetic acid solution of DDDa, wherein the volume ratio of methanol/isopropanol/trifluoroacetic acid is 1000:500:1.5;
solution (c): a methanol/isopropanol/trifluoroacetic acid solution of DDDa, wherein the volume ratio of methanol/isopropanol/trifluoroacetic acid is 1000:500:15;
in the three solutions, the concentration of DDDa is 2.5mg/mL; vortex vibration and uniform mixing are carried out;
2) Preparing 20uM of arginine water solution, and adding 0.1% (volume percentage relative to the arginine water solution) of trifluoroacetic acid to acidify the arginine water solution; wherein arginine is an arginine standard;
3) 1uL of arginine sample was spotted on MALDI MS target plate;
4) Respectively taking 1uL of DDDa solutions with different compositions, respectively mixing and adding the DDDa solutions on sample points of arginine to be analyzed, repeatedly sucking the mixed solution for several times by a pipette gun to uniformly mix the sample and the matrix solution, and then naturally drying the target plate in the air;
5) After the sample is completely dried, loading the target plate into a MALDI-MS mass spectrometer for mass spectrometry; authentication was performed in reflectance mode using a SHIMADZU AXIMA RESONANCE MALDI-IT-TOF mass spectrometer; MALDI mass spectra were obtained by accumulating and averaging 400 shots in a cationic mode with a laser intensity of 100-120, and were collected and processed using Shimadzu Biotech Launchpad software (version 2.9).
MALDI mass spectra of arginine samples analyzed using the above three DDDa solutions of different compositions as matrices are shown in FIG. 2, wherein (a), (b), and (c) correspond to solution (a), solution (b), and solution (c), respectively.
The results in fig. 2 show that: (a) Compared to (b), the arginine signal in (b) has a higher signal-to-noise ratio and better detection sensitivity, indicating that the addition of isopropanol to the DDDa solvent system helps to promote and optimize the signal of the analyte detected, and that isopropanol helps to better crystallize the assay mixture, thereby allowing better ionization of the analyte under laser bombardment. (b) The significantly enhanced signal of arginine in (c) as compared to (c) further increases the detection sensitivity, indicating that increasing the concentration of trifluoroacetic acid in the matrix system helps to increase the signal intensity of the analyte. As described above, the signal to noise ratio of the analyte can be optimized by adding a certain amount of isopropanol, and a higher concentration of trifluoroacetic acid, to the solvent of DDDa.
Example 3
In the embodiment, MALDI-MS analysis and effect comparison are carried out on arginine samples by adopting DDDa solutions with different concentrations, and the steps are as follows:
1) Four DDDa solutions with different concentrations are prepared, wherein the solvent composition is methanol/isopropanol/trifluoroacetic acid, and the volume ratio of the methanol/isopropanol/trifluoroacetic acid is 1000:500:15; the concentrations of the DDDa in the four DDDa solutions are respectively 1mg/mL (a), 2.5mg/mL (b), 10mg/mL (c), 20mg/mL (d), and vortex vibration and uniform mixing are carried out;
2) Preparing 20uM of arginine water solution, and adding 0.1% (volume percentage relative to the arginine water solution) of trifluoroacetic acid to acidify the arginine water solution; wherein arginine is an arginine standard;
3) 1uL of arginine sample was spotted on MALDI-MS target plate;
4) Respectively taking 1uL of DDDa solutions with different concentrations, respectively mixing and adding the DDDa solutions on sample points of arginine to be analyzed, repeatedly sucking the mixed solution for several times by a pipette gun to uniformly mix the sample and the matrix solution, and then naturally drying the target plate in the air;
5) After the sample is completely dried, loading the target plate into a MALDI-MS mass spectrometer for mass spectrometry; authentication was performed in reflectance mode using a SHIMADZU AXIMA RESONANCE MALDI-IT-TOF mass spectrometer; MALDI mass spectra were obtained by accumulating and averaging 400 shots in a cationic mode with a laser intensity of 100-120, and were collected and processed using Shimadzu Biotech Launchpad software (version 2.9).
MALDI mass spectra of arginine samples analyzed by using the four DDDa solutions with different concentrations as a matrix are shown in FIG. 3, wherein (a), (b), (c) and (d) respectively correspond to the concentrations of the DDDa solutions of 1mg/mL, 2.5mg/mL, 10mg/mL and 20mg/mL.
The results in fig. 3 show that: the DDDa solution substrates with different concentrations have obvious influence on the signal intensity of the analyte; under the condition that the DDDa concentration is 2.5mg/mL, better signal-to-noise ratio of the analyte signal can be obtained.
Example 4
In this embodiment, DDDa solution is used as a matrix, and MALDI mass spectrometry is performed on different types of small molecule compound standard solutions, where the detected small molecules include: leucine (a), carnitine (b), and dopamine (c), arginine (d), were subjected to MALDI-MS analysis as follows:
1) Preparing a DDDa solution, wherein the solvent composition is methanol/isopropanol/trifluoroacetic acid (volume ratio is 1000:500:15), and the concentration of the DDDa is 2.5mg/mL, and the solution is uniformly mixed by vortex vibration;
2) Preparing 5uM leucine and 20uM arginine, carnitine and dopamine water solutions respectively, and adding 0.1% (volume percent relative to the sample water solution) of trifluoroacetic acid respectively to acidify the solutions;
3) Respectively taking 1uL of the standard substance solution prepared in the step 2), and respectively spotting on MALDI-MS target plates;
4) Respectively taking 1uL of DDDa solution, respectively mixing and adding the solution on a sample point to be analyzed, repeatedly sucking and beating the mixed solution for several times by using a pipetting gun to uniformly mix the sample with the matrix solution, and then naturally drying the target plate in the air;
5) After the sample is completely dried, loading the target plate into a MALDI-MS mass spectrometer for mass spectrometry, and identifying in a reflection mode by using a SHIMADZU AXIMA RESONANCE MALDI-IT-TOF mass spectrometer; MALDI mass spectra were obtained by accumulating and averaging 400 shots in a cationic mode with a laser intensity of 100-120, and were collected and processed using Shimadzu Biotech Launchpad software (version 2.9).
The spectrum of MALDI mass spectrometry performed on different types of small molecule compound standard solutions using DDDa solution as a matrix is shown in FIG. 4. Wherein (a), (b), (c) and (d) correspond to the detection results of leucine, carnitine, dopamine and arginine respectively.
The results in fig. 4 show that: different types of small molecular weight substances (molecular weight below 200 Da) can obtain stable MALDI-MS signals by taking DDDa as a matrix. Wherein leucine can obtain molecular ion peaks (m/z 132 and 154) of +H and +Na, arginine can obtain molecular ion peak (m/z 175), carnitine can obtain molecular ion peak (m/z 162), and dopamine can obtain molecular ion peak (m/z 154). The results show that DDDa can be used as a matrix material which is widely applicable to detection of small molecule MALDI-MS. Meanwhile, in a small molecular weight range, DDDa does not generate other influencing interference signals from the matrix, and is beneficial to improving the detection sensitivity of the analyte.
Example 5
In this example, different small molecule compounds were analyzed by MALDI mass spectrometry using DDDa and conventional MALDI-MS matrix 2, 5-dihydroxybenzoic acid (DHB), α -cyano-4-hydroxycinnamic acid (CHCA), and the results of the analysis were compared as follows:
1) Three different matrix solutions were formulated:
DDDa solution, wherein the solvent composition is methanol/isopropanol/trifluoroacetic acid (volume ratio 1000:500:15), and the DDDa concentration is 2.5mg/mL;
preparing DHB and CHCA solutions, wherein the solvents are water/acetonitrile/trifluoroacetic acid (volume ratio of 500:500:0.1), and the concentrations are 10mg/mL;
2) Preparing 20uM of arginine, dopamine and carnitine water solutions respectively, and adding 0.1% (volume percentage relative to the sample water solution) of trifluoroacetic acid respectively to acidify the arginine, dopamine and carnitine water solutions;
3) Respectively taking 1uL of the sample solution prepared in the step 2), and respectively spotting on MALDI-MS target plates;
4) Respectively taking 1uL of different matrix solutions prepared in the step 1), respectively mixing and adding the different matrix solutions on a sample point to be analyzed, repeatedly sucking and beating the mixed solution for several times by using a liquid-transfering gun to uniformly mix the sample and the matrix solution, and then naturally drying a target plate in the air;
5) After the sample is completely dried, loading the target plate into a MALDI-MS mass spectrometer for mass spectrometry, and identifying in a reflection mode by using a SHIMADZU AXIMA RESONANCE MALDI-IT-TOF mass spectrometer; MALDI mass spectra were obtained by accumulating and averaging 400 shots in a cationic mode with a laser intensity of 100-120, and were collected and processed using Shimadzu Biotech Launchpad software (version 2.9).
The mass spectrum of MALDI MS analysis of arginine, carnitine and dopamine respectively using DDDa, DHB, CHCA as matrix is shown in FIG. 5. In the figures, (a), (b) and (c) are mass spectra of arginine, carnitine and dopamine respectively for three different matrices.
The results in fig. 5 show that: conventional matrices DHB and CHCA produce extremely strong matrix signals in the small molecular weight range (m/z < 200), suppressing the peak of the target analyte, and the analytes arginine, dopamine and carnitine are essentially free of peaks or only able to detect signals severely suppressed by matrix peaks. In contrast, with DDDa as the matrix, a stable MALDI-MS signal of the small molecule compound to be analyzed can be obtained. Meanwhile, in a small molecular weight range, DDDa does not generate strong interference signals from a matrix, and is beneficial to improving the detection sensitivity of the analyte. This suggests that DDDa is more suitable for MALDI MS analysis of small molecule compounds than conventional matrices.
Example 6
In the embodiment, DDDa solution is used as a matrix to quantitatively analyze arginine and carnitine with different concentrations, and a standard concentration curve is drawn, and the steps are as follows:
1) Preparing a DDDa solution, wherein the solvent composition is methanol/isopropanol/trifluoroacetic acid (volume ratio is 1000:500:15), the DDDa concentration is 2.5mg/mL, and vortex vibration and mixing are uniform;
2) Preparing 40, 20, 10, 5 and 2uM arginine and carnitine water solutions respectively, and adding 0.1% (volume percent relative to the sample water solution) of trifluoroacetic acid respectively to acidify the arginine and the carnitine water solutions;
3) Spot 1uL of standard sample on MALDI-MS target plate;
4) 1uL of DDDa solution was mixed and added to the sample site to be analyzed, and the mixed solution was repeatedly pipetted several times with a pipette, so that the sample and the matrix solution were uniformly mixed. Then the target plate is placed in the air for natural drying;
5) After the sample was completely dried, the target plate was loaded into a MALDI-MS mass spectrometer for mass spectrometry, identified in reflection mode using a SHIMADZU AXIMA RESONANCE MALDI-IT-TOF mass spectrometer, MALDI mass spectra were accumulated and averaged 400 times of shots in a cation mode with a laser intensity of 100-120, and spectrogram acquisition and processing was performed using Shimadzu Biotech Launchpad software (version 2.9). And then, drawing a standard concentration curve of arginine and carnitine by taking the concentrations of arginine and carnitine as the abscissa and taking the mass spectrum signal intensity of each concentration as the ordinate.
The resulting standard concentration profile of arginine and carnitine is shown in fig. 6, where (a) is the arginine standard profile and (b) is the carnitine standard profile.
The results in fig. 6 show that: the DDDa is taken as a MALDI-MS matrix, the mass spectrum signal intensity of the analyzed small molecules is in linear correlation with the concentration of the analyzed small molecules within a certain concentration range, and the linear correlation coefficients are all above 0.99, so that the MALDI-MS method for analyzing the small molecules by taking the DDDa as the matrix can be used for quantitative analysis of the small molecules in a sample; this is an analysis effect which is not available with most conventional MALDI-MS matrices, and fully demonstrates that DDDa can be used as a matrix for MALDI-MS detection of small molecule compounds.
As can be seen from the above examples, the DDDa provided by the invention can be used as a matrix for MALDI-MS detection, is used for qualitative and quantitative detection of small organic molecules with molecular weight below 300Da, and has the advantages of high specificity, accurate method, simple and convenient operation and high sensitivity.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (18)
1. The application of the MALDI-MS matrix in the MALDI-MS detection of a small molecular compound is characterized in that the matrix is 2, 7-di-tert-butyl-9, 9-dimethyl xanthene-4, 5-dicarboxylic acid, and the small molecular compound is a compound with a molecular weight of less than 300 Da.
2. MALDI-MS matrix composition for detecting small molecular compounds, which is characterized in that the matrix composition comprises 2, 7-di-tert-butyl-9, 9-dimethyl xanthene-4, 5-dicarboxylic acid, methanol and trifluoroacetic acid, and the small molecular compounds are compounds with molecular weight less than 300 Da.
3. The composition of claim 2, wherein the 2, 7-di-tert-butyl-9, 9-dimethylxanthene-4, 5-dicarboxylic acid is present in the matrix composition in an amount of 1.0 to 20.0mg/mL.
4. The composition of claim 2, wherein the 2, 7-di-tert-butyl-9, 9-dimethylxanthene-4, 5-dicarboxylic acid is present in the matrix composition in an amount of 1.0 to 15.0mg/mL.
5. The composition of claim 2, wherein the 2, 7-di-tert-butyl-9, 9-dimethylxanthene-4, 5-dicarboxylic acid is present in the matrix composition in an amount of 2.0 to 10.0mg/mL.
6. The composition according to claim 2, wherein the volume ratio of trifluoroacetic acid to methanol is (1-50): 1000.
7. the composition according to claim 2, wherein the volume ratio of trifluoroacetic acid to methanol is (1-25): 1000.
8. the composition according to claim 2, wherein the volume ratio of trifluoroacetic acid to methanol is (1-15): 1000.
9. the composition of claim 2, wherein isopropyl alcohol is further included in the matrix composition.
10. The composition according to claim 9, wherein the volume ratio of isopropyl alcohol to methanol is (300-1000): 1000.
11. the composition according to claim 9, wherein the volume ratio of isopropyl alcohol to methanol is (400-600): 1000.
12. the composition according to claim 9, wherein the volume ratio of isopropyl alcohol to methanol is (450-550): 1000.
13. use of a matrix composition according to any one of claims 2 to 12 for the detection of small molecule compounds.
14. The use according to claim 13, wherein the small molecule compound is carnitine, arginine, dopamine or leucine.
15. A detection method of a small molecular compound is characterized by adopting 2, 7-di-tert-butyl-9, 9-dimethyl xanthene-4, 5-dicarboxylic acid as a MALDI-MS matrix, and comprises the following steps:
(1) Formulating the MALDI-MS matrix into a MALDI-MS matrix composition according to any of claims 2 to 12;
(2) The detection sample containing the small molecule compound is spotted on a MALDI-MS target plate, and the MALDI-MS matrix composition is mixed on the sample spot, and then detection is performed using MALDI-MS.
16. The method according to claim 15, wherein an acidifying reagent is added to the sample containing the small molecule compound.
17. The method of claim 16, wherein the acidifying reagent is trifluoroacetic acid.
18. The method of any one of claims 15 to 17, wherein the detection comprises identifying the molecular weight and/or type of small molecule compound; alternatively, the content of the small molecule compound is detected.
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