CN115845816A - Magnetic microsphere, preparation thereof and application thereof in mass spectrum sample desalting - Google Patents
Magnetic microsphere, preparation thereof and application thereof in mass spectrum sample desalting Download PDFInfo
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- CN115845816A CN115845816A CN202211566961.XA CN202211566961A CN115845816A CN 115845816 A CN115845816 A CN 115845816A CN 202211566961 A CN202211566961 A CN 202211566961A CN 115845816 A CN115845816 A CN 115845816A
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- magnetic
- microspheres
- ion exchange
- microsphere
- polymer
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- Hard Magnetic Materials (AREA)
Abstract
The invention discloses a magnetic microsphere, a preparation method thereof and application thereof in mass spectrum sample desalination, wherein the magnetic microsphere comprises magnetic nanoparticles, high molecular polymers and chemical groups with ion exchange/adsorption functions, and is a magnetic composite material with a core-shell structure or a pore structure; the material has a specific adsorption effect on salt ions, is suitable for desalting mass spectrum samples, is suitable for manual operation and automation and high-throughput platforms, quickly realizes operations such as sample adding, mixing and magnetic separation, and efficiently adsorbs the salt ions, improves the sensitivity and accuracy of mass spectrum analysis, and effectively improves the spectrogram quality and detection result of mass spectrum; meanwhile, the material has simple preparation process and low cost, and can be generated on a large scale.
Description
Technical Field
The invention relates to the technical field of composite materials and mass spectrum sample processing, in particular to a magnetic microsphere, a preparation method thereof and application thereof in mass spectrum sample desalting.
Background
The development of mass spectrometry technology from 20 th century to 20 th century now over a century has become one of the main technical means of substance molecular analysis. The mass spectrometry is an analysis method for qualitatively and quantitatively analyzing a sample by analyzing the mass-to-charge ratio (M/Z) of sample molecular ions. Based on the principle of mass spectrometry, the mass spectrometry detection of sample molecular ion particles (ion mass-to-charge ratio) has obvious advantages in the aspects of sensitivity, specificity, precision, simultaneous detection of multiple indexes and the like, and is especially mature in the analysis application of small molecular substances. In clinical quantitative detection and analysis, the triple quadrupole rod LC-MS/MS is most applied, and can be used for qualitative and quantitative analysis of neonatal hereditary metabolic disease screening, drug concentration monitoring, vitamin detection, hormone detection and tumor marker detection.
In the mass spectrometry, salt ions greatly affect the quality of a spectrogram and an analysis result, and directly affect the accuracy of the analysis result. Based on the principle and the structure of a mass spectrometer, a sample firstly reaches an ion source through a sample introduction system, is ionized and gasified at the ion source and then enters a mass analyzer, and the sample enters a detector after being separated by the mass analyzer. If salt ions exist in a sample, the salt ions are easy to form a salt ion complex with sample molecules, particularly sample molecules containing groups (such as carboxyl groups or phosphate groups) with strong binding capacity with the salt ions, so that a salt ion addition peak of the sample molecules is obtained, and when the concentration of the salt ions exceeds a certain concentration, the sample molecule ion peak is completely inhibited, so that a serious interference phenomenon is generated on a detection result. Therefore, the interference problem of salt ions also becomes one of the most interesting problems for the clinical application of mass spectrometry.
In the field of mass spectrometry application, a common method for desalting is to add a small molecular substance as a competitive binding agent or a complexing agent, namely, the small molecular substance is added into a sample solution to be competitively bound with salt ions and sample molecules so as to inhibit the formation of a complex of the salt ions and the sample molecules, wherein the small molecular substance is various ammonium salts or organic ammonium salts, can effectively inhibit an addition peak of the salt ions, has good volatility and gas activity, and can improve the interference of the salt ions, but sometimes interference peaks such as an ammonium/ammonia addition peak can be generated due to the increase of the addition amount. Crown ether substances can effectively complex salt ions, and are often used for removing the salt ions, but the molecular weight of crown ether is larger than that of the salt ions, the addition amount is far larger than that of the salt ions to achieve a good desalting effect, and the desalting effect of the crown ether substances has dependence on the pH value, the solvent type and the like of a sample solution. In addition, small molecular substances directly added to a sample as a desalting agent are always present in the sample, thereby affecting the performance of mass spectrometry, such as baseline noise, analysis sensitivity and accuracy.
Mao-Feng Weng et al reported that the sol-gel/crown ether hybrid composite material is used as a desalting substrate for matrix-assisted laser desorption ionization mass spectrometry analysis of nucleic acid, namely, 2-hydroxymethyl [15] -crown-5 and 2-hydroxymethyl [18] -crown-6 of crown ether with hydroxyl groups are connected to silica gel through covalent bonds, and benzoic acid compounds with o-diamino structures are connected to the silica gel through covalent bonds, and then the gel is firstly dripped on the substrate to form a layer of thin film, and then the mixture of the matrix and the sample is dripped; however, the method is complex to manufacture and high in cost, only academic research reports are found at present.
The ion exchange resin is a commonly used desalting substance, such as AG-50W-X8 type cation exchange resin is directly added into a mass spectrum sample, and the resin is fully contacted with the mass spectrum sample solution through sealing and low-speed vertical rotation, and the resin is precipitated into the bottom through centrifugation; however, this method has many steps and is not suitable for automation.
Tips for reversed phase C18 purification are also applied to desalting of mass spectrum samples, and the technology is characterized in that a C8 film with a certain thickness is fixed at a Tip, the Tips are used for repeatedly absorbing/blowing the samples to adsorb target molecules, then, an eluent is used for cleaning and removing salt ions, and finally, the target molecules are eluted; however, most Tips of this type are currently imported brands and are expensive.
In addition, the desalting column method is also one of the common desalting methods, but the method is not suitable for desalting samples with high flux and trace amount and is expensive.
Based on this, in view of the defects of various existing desalting methods, the development of a quick, convenient, effective and low-cost desalting method which can be applied to mass spectrum samples has important significance.
Disclosure of Invention
In view of the above-mentioned shortcomings of the prior art, the present invention aims to provide a magnetic microsphere, its preparation and application in desalting mass spectrum samples, and to provide a new rapid, convenient, effective, low-cost technical means suitable for automation and high throughput for desalting mass spectrum samples.
In order to attain the above and other related objects,
the invention provides a magnetic microsphere, which comprises a high molecular polymer and magnetic nanoparticles, wherein the magnetic nanoparticles are positioned in the high molecular polymer, or positioned in a pore structure of the high molecular polymer, or coated outside the high molecular polymer, the surface of the microsphere is modified by functional groups, and the functional groups are any one or combination of more of sulfonic acid groups, phosphate groups, carboxyl groups, ester groups, hydroxyl groups, ethers, amino groups and crown ethers.
Further, the polymer is selected from a high molecular compound synthesized from vinyl, styryl, acryl or acryl;
or, the polymer is selected from a channel-type ion exchange resin or porous polymer microspheres;
the magnetic nano-particles are selected from any one or combination of a plurality of magnetic ferroferric oxide, magnetic ferric oxide, modified magnetic ferroferric oxide, modified magnetic ferric oxide and carboxylated magnetic microspheres; preferably, the modified magnetic ferroferric oxide or modified magnetic ferric oxide is magnetic ferroferric oxide or magnetic ferric oxide modified by oleic acid/sodium oleate or modified by surface activity.
Further, when the magnetic microsphere has a core-shell structure, the magnetic nanoparticles and the polymer are of a core-shell structure, and the polymer is selected from a high molecular compound synthesized by vinyl, styryl, propenyl or acryloyl;
when the magnetic microspheres have a pore channel structure, the polymer is selected from a pore channel type ion exchange resin or porous polymer microspheres, and the porous polymer microspheres are selected from high molecular compounds which have a porous structure and are synthesized by vinyl, styryl, propenyl or acryloyl.
Further, the polymer is selected from any one or more of polystyrene and analogues thereof, polystyrene divinyl and analogues thereof;
or the polymer is formed by polymerization reaction of monomer compound with polymerization reaction functional group, wherein the monomer compound with polymerization reaction functional group is selected from any one or more of ethylene, styrene, acrylamide dimethylacrylamide and compound which has vinyl/styrene/acryloyl and can be polymerized.
Further, the porous ion exchange resin is selected from macroporous strong base anion exchange resin, macroporous weak base anion exchange resin, macroporous strong acid cation exchange resin and macroporous weak acid cation exchange resin. Dowex 509HCRW20; amberlite IR120; lewatit S100, KY2; diaion SK1B; duolite C2; tehua IRC007; ionresin 001.
Further, the crosslinking agent used when the magnetic nanoparticles are crosslinked with the polymer is selected from any one or more of silane crosslinking agents, divinylbenzene, and N, N-methylenebisacrylamide.
Further, the particle size of the magnetic microsphere is 10 nm-200 um, preferably 300 nm-1 μm.
Further, the particle shape of the magnetic microsphere is spherical, elliptical, rod-like or irregular.
Further, the magnetic ion exchange/adsorption material is used for adsorbing salt ions including but not limited to NH 4 + 、K + 、Na + 、Mg 2+ 、Pb 2+ 、Ni 2+ 、Cr 3+ 、Au 3+ 、Cu 2+ 、Cd 2+ 、Hg 2+ 、Ca 2+ 、Fe 3+ 、Ag + 、Zn 2+ 、Al 3+ And so on.
The invention also provides a preparation method of the magnetic microsphere, which is selected from any one of the following methods:
A. adding a chemical group with an ion exchange/adsorption function on a material with a core-shell structure formed by the magnetic nano-particles and the polymer to prepare the magnetic microsphere;
B. carrying out polymerization reaction on the magnetic nanoparticles, a monomer compound with a polymerization reaction functional group and a chemical group with an ion exchange/adsorption function and a cross-linking agent to prepare the magnetic microspheres;
C. loading the magnetic nanoparticles on pore channel type ion exchange resin to obtain magnetic ion exchange resin, namely the magnetic microspheres;
D. after the magnetic nano particles and the porous polymer microspheres are self-assembled, chemical groups with ion exchange/adsorption functions are added to prepare the magnetic microspheres;
E. performing chemical covalent bond coupling on the magnetic nanoparticles and a crown ether compound containing hydroxyl/amino to prepare the magnetic microspheres;
F. and carrying out polymerization reaction on the monomer compound with the polymerization reaction functional group, the compound containing the crown ether group and the magnetic nano-particles to obtain the magnetic microsphere.
Further, in the method a, the chemical group is a sulfonic acid group, and the material is provided with the sulfonic acid group through sulfonation reaction, so as to prepare the magnetic microsphere.
Further, the material is subjected to sulfonation reaction under the action of concentrated sulfuric acid or chlorosulfonic acid.
Further, in the method B, the monomer compound having a polymerization functional group and a chemical group having an ion exchange/adsorption function is selected from any one or a combination of plural kinds of vinylbenzenesulfonic acid and salts thereof, 2-acrylamido-2-methylpropanesulfonic acid and salts thereof, and a compound having a vinyl group/styryl group/acryloyl group and a sulfonic acid group and capable of undergoing polymerization.
Further, in the method C, the manner of loading the magnetic nanoparticles on the porous ion exchange resin to obtain the magnetic ion exchange resin includes: soaking the porous ion exchange resin in Fe 3+ And/or Fe 2+ In solution ofFiltering, adding an alkaline precipitator, and carrying out magnetic separation to obtain the magnetic ion exchange resin.
Further, the porous ion exchange resin contains Fe 3+ And/or Fe 2+ The soaking time in the solution of (1) is 0.5 to 15 hours, preferably 2 to 5 hours.
Further, the alkaline precipitant is selected from ammonia water.
Further, in the method E, the magnetic nanoparticles are selected from carboxylated magnetic microspheres.
Further, in the method R, the crown ether group-containing compound contains oxygen and or other heteroatoms including, but not limited to, nitrogen, sulfur, and the like.
The invention also provides the application of the magnetic microspheres and/or the magnetic microspheres prepared by the method in the desalination of mass spectrum samples.
The invention also provides a desalting method of the mass spectrum sample, which comprises the following steps: the magnetic microspheres and/or the magnetic microspheres prepared by the method are prepared into a magnetic solution, the magnetic solution is mixed with a mass spectrum sample solution to be desalted, and the magnetic solution is subjected to magnetic separation to obtain a desalted mass spectrum sample.
Further, the solvent used in preparing the magnetic solution and the mass spectrometry sample solution is selected from water, or a mixture of water and a water-soluble solvent, including but not limited to ethanol, acetonitrile, DMSO, DMF, tetrahydrofuran, and the like.
As described above, the magnetic microsphere of the present invention, the preparation thereof and the application thereof in the desalination of mass spectrum samples have the following beneficial effects:
the magnetic microspheres provided by the invention have a specific adsorption effect on salt ions, have almost no adsorption effect on other molecules, are suitable for desalting treatment of a mass spectrum sample to be desalted, are suitable for manual operation and an automatic and high-throughput platform, quickly realize operations such as sample adding, mixing, magnetic separation and the like, and simultaneously adsorb the salt ions efficiently, improve the sensitivity and accuracy of mass spectrum analysis, and effectively improve the mass spectrum quality and detection results of mass spectra.
Compared with the existing desalting reagent for mass spectrum samples, the magnetic microsphere provided by the invention has the advantages of simple preparation process, large-scale generation, no harsh reaction conditions, no expensive chemical reagent, no need of special instruments and equipment and lower cost.
Drawings
FIG. 1 is a schematic diagram showing the particle structure of the magnetic microspheres in the examples of the present application.
Fig. 2 is a schematic flow chart illustrating a desalting process performed on a sample solution of a mass spectrometry to be desalted using magnetic microspheres in example 9 of the present application.
FIG. 3 shows the mass spectrum of the mass spectrum sample after desalting treatment using M1 magnetic microspheres in example 9 of the present application.
FIG. 4 shows the mass spectrum of a mass spectrum sample after desalting treatment with a control group in example 9 of the present application.
Detailed Description
The following description of the embodiments of the present application is provided by way of specific examples, and other advantages and effects of the present application will be readily apparent to those skilled in the art from the disclosure herein. The present application is capable of other and different embodiments and its several details are capable of modifications and/or changes in various respects, all without departing from the spirit of the present application.
The terms "first," "second," and the like in the description and in the claims of the embodiments disclosed in the present application and in the drawings described above are used for distinguishing between similar elements and not necessarily for describing a particular sequential or chronological order. It should be understood that the data so used may be interchanged under appropriate circumstances such that embodiments of the present disclosure described herein may be made. Furthermore, the terms "comprising" and "having" and any variations thereof, is intended to cover non-exclusive inclusions.
The terms "plurality", "plurality" and "a plurality" mean two or more, unless otherwise specified.
In the embodiments disclosed in the present application, the character "/" indicates that the preceding and following objects are in an or relationship. For example, A/B represents: a or B.
The term "and/or" is an associative relationship that describes objects, meaning that three relationships may exist. For example, a and/or B, represents: a or B, or A and B.
Referring to fig. 1, an embodiment of the present application provides a magnetic microsphere, which includes magnetic nanoparticles, a polymer, and a chemical group with an ion exchange/adsorption function, and is a magnetic composite material with a core-shell structure or a pore structure;
the magnetic nanoparticles and the polymer are coupled together through crosslinking, encapsulation or chemical covalence;
the polymer is selected from macromolecular compounds synthesized by vinyl, styryl, propenyl or acryloyl, or the polymer is selected from porous channel type ion exchange resin or porous polymer microspheres;
the chemical group is selected from any one or more of sulfonic acid group, phosphoric acid group, carboxyl group, ester group, hydroxyl group, ether, amino group, amine group and crown ether.
In a disclosed embodiment of the present application, the magnetic nanoparticles are selected from any one or a combination of a plurality of magnetic ferroferric oxide, magnetic ferric oxide, modified magnetic ferroferric oxide, modified magnetic ferric oxide, and carboxylated magnetic microspheres; preferably, the modified magnetic ferroferric oxide or modified magnetic ferric oxide is magnetic ferroferric oxide or magnetic ferric oxide modified by oleic acid/sodium oleate or modified by surface activity.
Wherein, the magnetic ferroferric oxide and the magnetic ferric oxide can adopt a coprecipitation method, a solvothermal method, a precipitation oxidation method, a microemulsion method, a hydrothermal method, a mechanical grinding method, a coacervation method, a sol method and the like. The magnetic ferroferric oxide and the magnetic ferric oxide in the embodiment of the application are preferably prepared by adopting a coprecipitation method; the solvothermal method is also recommended.
The superparamagnetic property of the magnetic ferroferric oxide or the magnetic ferric oxide can be improved by modifying the magnetic ferroferric oxide or the magnetic ferric oxide with oleic acid or sodium oleate, so that the magnetic ferroferric oxide or the magnetic ferric oxide modified by oleic acid or sodium oleate is preferably adopted as the magnetic nanoparticles in the embodiment of the application; the surface activity modification of the magnetic ferroferric oxide or the magnetic ferric oxide is preferably modified by 2-bromoisobutyryl bromide.
The carboxylated magnetic microspheres are preferably formed by self-assembling a carboxylated polymer and magnetic ferroferric oxide/magnetic ferric oxide, and the carboxylated polymer is preferably any one or combination of carboxylated polystyrene and analogues thereof, and carboxylated polystyrene divinyl and analogues thereof. Further, in order to improve the ion exchange/adsorption capacity, the carboxylated magnetic microspheres may be further subjected to surface activity modification, such as modification with 2-bromoisobutyryl bromide.
In a disclosed embodiment of the present application, when the magnetic microsphere has a core-shell structure, the magnetic nanoparticles and a polymer are each in a core-shell structure, and the polymer is selected from a high molecular compound synthesized from vinyl, styryl, acryl or acryl;
when the magnetic microspheres have a pore channel structure, the polymer is selected from a pore channel type ion exchange resin or porous polymer microspheres, and the porous polymer microspheres are selected from high molecular compounds which have a porous structure and are synthesized by vinyl, styryl, propenyl or acryloyl.
In a disclosed embodiment of the present application, the polymer is selected from any one or a combination of polystyrene and its analogs, polystyrene divinyl and its analogs;
or the polymer is formed by polymerization reaction of monomer compound with polymerization reaction functional group, wherein the monomer compound with polymerization reaction functional group is selected from any one or more of ethylene, styrene, acrylamide dimethylacrylamide and compound which has vinyl/styrene/acryloyl and can be polymerized.
In a disclosed embodiment of the present application, the channel-type ion exchange resin is selected from any one or more of a macroporous strong base anion exchange resin, a macroporous weak base anion exchange resin, a macroporous strong acid cation exchange resin, and a macroporous weak acid cation exchange resin, for example: dowex 509HCRW20, amberlite IR120, lewatit S100, KY2, diaion SK1B, duolite C2, tehua IRC007, ionresin 001, and the like. The above-mentioned pore type ion exchange resins are commercially available.
In a disclosed embodiment of the present application, the porous polymer microspheres are selected from any one or more of porous polystyrene microspheres and their analogs, porous polystyrene divinyl and their analogs.
In a disclosed embodiment of the present application, the crosslinking agent used when the magnetic nanoparticles are crosslinked with the polymer is selected from any one or a combination of more of silane-based crosslinking agents, divinylbenzene, and N, N-methylenebisacrylamide.
In a disclosed embodiment of the present application, the particle size of the magnetic microsphere is 10nm to 200um, preferably 300nm to 1 μm.
In a disclosed embodiment of the present application, the magnetic microspheres have a spherical, elliptical, rod-like or irregular particle shape.
In a disclosed embodiment of the present application, the magnetic ion exchange/adsorption material is used for adsorbing salt ions including but not limited to NH 4 + 、K + 、Na + 、Mg 2+ 、Pb 2+ 、Ni 2+ 、Cr 3+ 、Au 3+ 、Cu 2+ 、Cd 2+ 、Hg 2+ 、Ca 2+ 、Fe 3+ 、Ag + 、Zn 2+ 、Al 3+ And so on.
The invention also provides a preparation method of the magnetic microsphere, which is selected from any one of the following methods:
A. adding a chemical group with an ion exchange/adsorption function on a material with a core-shell structure formed by the magnetic nano particles and the polymer to prepare the magnetic microsphere;
B. carrying out polymerization reaction on the magnetic nanoparticles, a monomer compound with a polymerization reaction functional group and a chemical group with an ion exchange/adsorption function and a cross-linking agent to prepare the magnetic microspheres;
C. loading the magnetic nanoparticles on pore channel type ion exchange resin to obtain magnetic ion exchange resin, namely the magnetic microspheres;
D. after the magnetic nano particles and the porous polymer microspheres are self-assembled, chemical groups with ion exchange/adsorption functions are added to prepare the magnetic microspheres;
E. performing chemical covalent bond coupling on the magnetic nanoparticles and a crown ether compound containing hydroxyl/amino to prepare the magnetic microspheres;
F. and carrying out polymerization reaction on the monomer compound with the polymerization reaction functional group, the compound containing the crown ether group and the magnetic nano-particles to obtain the magnetic microsphere.
In a disclosed embodiment of the present application, in the method a, the chemical group is a sulfonic acid group, and the magnetic microsphere is prepared by a sulfonation reaction to make the material have the sulfonic acid group.
In a disclosed embodiment of the present application, the material is sulfonated with concentrated sulfuric acid or chlorosulfonic acid. The dosage of the reactant, the temperature and time of the sulfonation reaction and other conditions can be controlled and adjusted according to the actually selected material and the mechanism and the requirement of the sulfonation reaction.
One disclosed embodiment of the present application provides a method for preparing magnetic microspheres, comprising the steps of:
taking styrene, sodium styrene sulfonate/acrylic acid/crown ether compound containing hydroxyl/amino, an initiator and Divinylbenzene (DVB) as dispersion liquid, and carrying out ultrasonic emulsification to prepare mixed liquid; adding the magnetic nanoparticles into an organic solvent, adding the mixture into the mixed solution after ultrasonic dispersion, and completely performing ultrasonic dispersion again; then heating and stirring under the condition of protective gas to carry out polymerization reaction; and after the polymerization reaction is finished, carrying out magnetic separation, washing and drying to obtain the magnetic microspheres.
Wherein, the mass ratio of styrene, sodium styrene sulfonate/acrylic acid/crown ether compound containing hydroxyl/amino, initiator, divinyl benzene (DVB) and magnetic nano particles is (1-10): (1-10): (0.05-0.3): (0.05 to 3): (1-3);
the crown ether compound containing hydroxyl/amino groups is selected from one or more of 2-aminomethyl-18-crown-6, 2-aminomethyl-15-crown-5, and 2-acrylamidomethyl-18-crown-6, but is not limited thereto;
the initiator is preferably Azobisisobutyronitrile (AIBN);
the organic solvent is preferably ethanol, methanol or isopropanol, and more preferably 70% ethanol solution;
during the polymerization reaction, the heating temperature is 60-80 ℃, and the preferable temperature is 70 ℃; the reaction time is 20 to 30 hours, preferably 24 hours;
the washing mode comprises the following steps: washing with ethanol, 5% sulfuric acid solution and deionized water in sequence, and repeating for 3-6 times, preferably 5 times;
the drying is carried out in a vacuum oven at a temperature of 35 to 45 deg.C, preferably 40 deg.C.
In a disclosed embodiment of the present application, in the method B, the monomer compound having a polymerization functional group and a chemical group having an ion exchange/adsorption function is selected from any one or more of vinylbenzenesulfonic acid and salts thereof, 2-acrylamido-2-methylpropanesulfonic acid and salts thereof, and a compound having a vinyl/styryl/acryloyl group and a sulfonic acid group and capable of undergoing polymerization. The conditions of the dosage of reactants, the reaction temperature, the reaction time and the like in the polymerization reaction process can be controlled and adjusted according to the actually selected compound and the mechanism and the requirement of the polymerization reaction.
In a disclosed embodiment of the present application, in the method C, the manner of loading the magnetic nanoparticles onto the porous ion exchange resin to obtain the magnetic microspheres includes: soaking the porous ion exchange resin in Fe 3+ And/or Fe 2+ Filtering, adding an alkaline precipitator, and carrying out magnetic separation to obtain the magnetic ion exchange resin, namely the magnetic microspheres.
Wherein the porous ion exchange resin contains Fe 3+ And/or Fe 2+ The soaking time in the solution of (1) is 0.5 to 15 hours, preferably 2 to 5 hours; the alkalinity isThe precipitant is selected from ammonia water. In a disclosed embodiment of the present application, in the method E, the magnetic nanoparticles are selected from carboxylated magnetic microspheres.
In a disclosed embodiment of the present application, in the method F, the crown ether group-containing compound contains oxygen and or other heteroatoms, including but not limited to nitrogen, sulfur, and the like.
The invention also provides the application of the magnetic microspheres and/or the magnetic microspheres prepared by the method in the desalting of mass spectrum samples.
The embodiment of the application also provides a desalination method of a mass spectrum sample, which comprises the following steps: the magnetic microspheres and/or the magnetic microspheres prepared by the method described in the above embodiment are prepared into a magnetic solution, the magnetic solution is mixed with a mass spectrum sample solution to be desalted, and the mixture is subjected to magnetic separation to obtain a desalted mass spectrum sample.
Wherein, the solvent used for preparing the magnetic solution and the mass spectrum sample solution is selected from water or a mixed solution of water and a water-soluble solvent, and the water-soluble solvent includes but is not limited to ethanol, acetonitrile, DMSO, DMF, tetrahydrofuran, and the like; preferably, the magnetic solution is an aqueous solution, and the mass spectrometry sample solution is an aqueous solution.
Wherein, the magnetic solution is preferably a solution with solid content of 0.5-10%.
In a disclosed embodiment of the present application, a method for desalting a mass spectrometry sample comprises the steps of:
the magnetic microspheres as described in the above examples and/or the magnetic microspheres prepared by the method as described in the above examples are prepared into magnetic solutions with corresponding concentrations according to actual needs. As shown in fig. 2, a pipetting device (a pipettor, an automatic pipetting platform, etc.) is used to dispense the magnetic solution into a small reaction vessel in a quantitative manner or directly add the magnetic solution into the mass spectrum sample solution to be desalted, and after the magnetic solution is mixed sufficiently by means of inversion shaking or oscillation, the mass spectrum sample solution is subjected to magnetic separation to obtain the desalted mass spectrum sample solution. The mass spectrum sample solution after the desalting treatment can be used for further detection and analysis, for example, a proper amount of the mass spectrum sample solution after the desalting treatment is dripped onto a target plate (including but not limited to a stainless steel target plate, a silicon-based target plate, and the like) pre-embedded with a matrix film, and after drying, the mass spectrum sample solution can be placed into a mass spectrometer for mass spectrum detection and analysis.
The present invention will be described in detail with reference to the following specific examples. It should also be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention, and that numerous insubstantial modifications and adaptations of the invention described above will occur to those skilled in the art. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below.
Example 1
Preparing magnetic ferroferric oxide particles:
adding 400mL of deionized water into a 1000mL three-neck flask provided with a mechanical stirring device, introducing nitrogen, adding 80mmol of FeCl 3 ·6H 2 O and 48mmol FeSO 4 ·7H 2 And O, continuously stirring for 20 minutes, keeping the stirring speed at 1000r/min, heating the solution to be orange red in a water bath, slowly dropwise adding 50mL of concentrated ammonia water for about 15 minutes until the pH value of the solution is 9-10, quickly changing the orange red color of the solution into black color, continuously stirring for reaction for 30 minutes, raising the temperature to 80 ℃, adding 20g of oleic acid, continuously stirring for 1 hour, carrying out magnetic separation on the obtained reaction solution, washing with ethanol and deionized water, and repeatedly washing for 5 times. And (3) drying the obtained magnetic ferroferric oxide particles in a vacuum drying oven at 40 ℃.
Preparing sulfonated magnetic microspheres:
15g of styrene, 5g of sodium styrenesulfonate, 0.5g of Azobisisobutyronitrile (AIBN), 0.5g of Divinylbenzene (DVB) and 300mL of a 70% ethanol solution are added to a 1000mL three-neck flask as a dispersion, and ultrasonic emulsification is carried out; dispersing 5g of the obtained magnetic ferroferric oxide particle solid in 50mL of 70% ethanol solution, adding the mixture into the prepared mixed solution after ultrasonic dispersion, completely dispersing the mixture again by ultrasonic dispersion, introducing nitrogen for 30 minutes in the stirring process, keeping the stirring speed at about 300rpm, heating the mixture to 70 ℃, and reacting the mixture for 24 hours. And after the polymerization reaction is finished, performing magnetic separation, sequentially washing with ethanol, 5% sulfuric acid solution and deionized water for 5 times, and drying the obtained product in a vacuum oven at 40 ℃ to obtain sulfonated magnetic microspheres marked as M1 magnetic microspheres.
Example 2
Preparing polystyrene microspheres:
5.0g of polyvinylpyrrolidone is added into 250mL of ethanol, stirred and dissolved, nitrogen is introduced, 10mL of styrene which is washed by 2% sodium hydroxide aqueous solution, dried and distilled under reduced pressure and 0.1g of Azobisisobutyronitrile (AIBN) are sequentially added, and the reaction is carried out for 24 hours at 70 ℃ with the stirring speed of 650 r/min. After the reaction is finished, centrifuging for many times, washing with a mixed solution of ethanol and water of 1/1, and drying the obtained polystyrene microspheres in a vacuum drying oven for 10 hours.
Preparing porous polystyrene microspheres:
and (2) adding 1g of the polystyrene microsphere into 20mL of a pore-foaming agent with a dibutyl phthalate/toluene ratio of 1.
Preparing sulfonated porous polystyrene microspheres:
adding 500mg of the porous polystyrene microsphere synthesized in the previous step into 40mL of concentrated sulfuric acid, performing ultrasonic dispersion for 5 minutes, stirring and reacting for a certain time at 65 ℃, slowly adding 300mL of deionized water after the reaction is finished, centrifuging and washing, repeating the operation for 3 times, and drying the obtained solid in a vacuum drying oven for 10 hours to obtain the sulfonated porous polystyrene microsphere.
Preparing sulfonated porous polystyrene magnetic microspheres:
adding 1.4g of ferrous chloride tetrahydrate and 2.4g of ferric chloride hexahydrate into 20mL of deionized water, introducing nitrogen, stirring for dissolving, adding 200mg of sulfonated porous polystyrene microspheres synthesized in the previous step, ultrasonically dispersing for 15 minutes, filtering, dispersing solids into 20mL of deionized water, adding 2mL of ammonia water, heating to 90 ℃, stirring for reacting for 8 hours, cooling to room temperature, and washing with magnetic separation water to be neutral. Washing with ethanol, 5% sulfuric acid solution, washing with deionized water, repeating for 5 times, and oven drying the magnetic material in a vacuum oven at 40 deg.C to obtain sulfonated porous polystyrene magnetic microsphere labeled as M2 magnetic microsphere.
Example 3
The method comprises the following steps of preparing magnetic ferroferric oxide by a solvothermal method, taking the magnetic ferroferric oxide as a core, modifying the core, and grafting/polymerizing the modified core on the surface of the core to obtain the magnetic sulfonated polystyrene microspheres, wherein the specific process comprises the following steps:
preparing magnetic ferroferric oxide:
300mL of ethylene glycol and 20.0g of ferric chloride hexahydrate are weighed and added into a beaker, stirred and dissolved, and 24.0g of sodium acetate is added and stirred and dissolved. 6.0g of polyethylene glycol (PEG 400) was slowly added under stirring, followed by high-speed stirring for 30 minutes, and the resulting solution was transferred into an autoclave having a polytetrafluoroethylene inner liner, sealed, and then placed in a high-temperature oven to react at 200 ℃ for 11 hours. And naturally cooling to room temperature. And (3) carrying out magnetic separation on reactants, removing reaction liquid, dispersing solid in ethanol, carrying out magnetic separation after carrying out ultrasonic treatment for 10 minutes, and repeating the operation for 3 times. The washed solid was dried in a vacuum oven at 60 ℃ for 10 hours.
Surface activity modification of magnetic ferroferric oxide:
5g of the ferroferric oxide particles in the previous step are dispersed in 200mL of methanol, ultrasonic dispersion is carried out for 10 minutes, 0.5g of tetraethyl silicate (TEOS), 0.4g of 3-Aminopropyltriethoxysilane (APTES) and 0.3mL of ammonia water are sequentially added, and stirring reaction is carried out for 11 hours under the protection of nitrogen. After the reaction is finished, carrying out magnetic separation, washing by using a mixed solution of ethanol and water in a ratio of 1/1, and repeating for three times. Drying the mixture in a vacuum oven at 60 ℃ for 10 hours.
And (2) placing 1g of the reaction product in the previous step into a reaction bottle, adding 30mL of acetonitrile for dispersion, cooling to 5 ℃, introducing nitrogen, sequentially adding 0.1g of triethylamine and 0.1g of 2-bromoisobutyryl bromide under stirring, reacting for 4 hours, carrying out magnetic separation, cleaning with a mixed solution of ethanol and water in a ratio of 1/1, and repeating for three times to obtain the 2-bromoisobutyryl bromide modified magnetic trimodal particle tetraoxide.
Preparing sulfonated polystyrene magnetic microspheres:
1g of magnetic trisomy tetraoxide particle solid modified by 2-bromoisobutyryl bromide is added into a 100mL three-neck flask, and then 0.3g of styrene, 0.3g of sodium styrene sulfonate, 0.01g of Azobisisobutyronitrile (AIBN), 0.01g of Divinylbenzene (DVB) and 20mL of 70% ethanol solution are added as dispersion liquid for ultrasonic emulsification; and introducing nitrogen for 30 minutes during stirring, keeping the stirring speed at about 300rpm, heating to 70 ℃, and reacting for 24 hours. After the polymerization reaction is finished, performing magnetic separation, washing with ethanol, washing with 5% sulfuric acid solution and washing with deionized water in sequence, repeating for 5 times, putting the obtained magnetic material into a vacuum oven at 40 ℃ to dry the sulfonated polystyrene magnetic microspheres, and marking as M3 magnetic microspheres.
Example 4
The magnetic ferroferric oxide is prepared by a solvothermal method, is used as a core, and is grafted and polymerized on the surface of the core after being modified to obtain the carboxylated magnetic microsphere, and the specific process is as follows:
the preparation of magnetic ferroferric oxide and the surface activity modification operation are the same as those in embodiment 3.
Taking 1g of magnetic trimodal tetroxide particles modified by 2-bromoisobutyryl bromide, putting the particles into a 100mL three-neck flask, adding 0.3g of styrene, 0.3g of acrylic acid, 0.05g of Azobisisobutyronitrile (AIBN), 0.05g of Divinylbenzene (DVB) and 20mL of 70% ethanol solution as a dispersion liquid, and carrying out ultrasonic emulsification; and introducing nitrogen for 30 minutes during stirring, keeping the stirring speed at about 300rpm, heating to 70 ℃, and reacting for 24 hours. And after the polymerization reaction is finished, performing magnetic separation, sequentially washing with ethanol and deionized water for 5 times, and drying the obtained product in a vacuum oven at 40 ℃ to obtain the carboxylated magnetic microspheres, wherein the carboxylated magnetic microspheres are marked as M3 magnetic microspheres.
Example 5
The method comprises the following steps of using carboxylated polystyrene microspheres as cores, carrying out self-assembly with nano ferroferric oxide particles, modifying, grafting on the surfaces of the modified nano ferroferric oxide particles, and polymerizing to obtain the sulfonated magnetic microspheres, wherein the specific process comprises the following steps:
self-assembly of carboxylated polystyrene microspheres and nano ferroferric oxide particles:
10g of carboxylated polystyrene microspheres with the particle size of 500nm are dispersed in 200mL of 80% ethanol aqueous solution, 1.3g of magnetic ferroferric oxide particles (prepared by the method of example 3) with the particle size of 20nm prepared by a solvothermal method are added, stirred for 30 minutes at room temperature, kept stand, and the upper solution is poured out and repeated for 3 times.
5g of the above-obtained product was dispersed in 150mL of methanol, and 0.6g of tetraethyl silicate (TEOS), 0.4g of 3-Aminopropyltriethoxysilane (APTES) and 0.3mL of ammonia water were sequentially added thereto, and the mixture was stirred and reacted for 12 hours under nitrogen protection. After the reaction is finished, carrying out magnetic separation, washing by using a mixed solution of ethanol and water with the proportion of 1/1, and repeating for three times. Drying in a vacuum oven at 60 ℃ for 10 hours to obtain carboxylated polystyrene/Fe 3 O 4 A microsphere solid.
Carboxylated polystyrene/Fe 3 O 4 Surface active modification of microsphere solid:
500mg of carboxylated polystyrene/Fe reaction product obtained in the previous step 3 O 4 Placing the microsphere solid in a reaction bottle, adding 10mL of acetonitrile for dispersion, cooling to 5 ℃, introducing nitrogen, adding 0.1g of triethylamine and 0.1g of 2-bromoisobutyryl bromide in sequence under stirring, reacting for 4 hours, carrying out magnetic separation, cleaning by using a mixed solution of ethanol and water with the proportion of 1/1, and repeating for three times.
Preparing sulfonated magnetic microspheres:
adding the magnetic nanoparticle microspheres obtained in the previous step into a 50mL three-neck flask, sequentially adding 0.2g of styrene, 0.5g of acrylic acid, 0.05g of Azobisisobutyronitrile (AIBN), 0.05g of Divinylbenzene (DVB) and 20mL of 70% ethanol solution as dispersion liquid, and carrying out ultrasonic emulsification; and introducing nitrogen for 30 minutes during stirring, keeping the stirring speed at about 300rpm, heating to 70 ℃, and reacting for 24 hours. After the polymerization reaction is finished, performing magnetic separation, washing with ethanol, washing with 5% sulfuric acid solution and washing with deionized water in sequence, repeating for 5 times, putting the obtained product into a vacuum oven at 40 ℃ to dry the sulfonated magnetic microspheres, and marking the sulfonated magnetic microspheres as M5 magnetic microspheres.
Example 6
The carboxylated polystyrene microsphere is used as a core, is grafted and polymerized on the surface of the nano ferroferric oxide particle after being self-assembled with the nano ferroferric oxide particle to obtain the carboxylated magnetic microsphere, and the specific process is as follows:
self-assembly of carboxylated polystyrene microspheres and nano ferroferric oxide particles:
10g of carboxylated polystyrene microspheres with the particle size of 500nm are dispersed in 200mL of ethanol, 1.3g of magnetic ferroferric oxide particles (prepared by the method of example 3) with the particle size of 20nm prepared by a solvothermal method are added, stirred for 30 minutes at room temperature, kept stand, and the upper solution is poured out and repeated for 3 times.
5g of the solid obtained in the previous step is dispersed in 150mL of methanol, ultrasonic dispersion is carried out for 10 minutes, 0.6g of tetraethyl silicate (TEOS), 0.4g of aminopropyltriethyl silicate (APTES) and 0.3mL of ammonia water are sequentially added, and the mixture is stirred and reacted for 12 hours under the protection of nitrogen. After the reaction is finished, carrying out magnetic separation, washing by using a mixed solution of ethanol and water in a ratio of 1/1, and repeating for three times. Drying the mixture in a vacuum oven at 60 ℃ for 10 hours to obtain carboxylated polystyrene/Fe 3 O 4 A microsphere solid.
Preparing sulfonated carboxyl magnetic microspheres:
500mg of the carboxylated polystyrene/Fe synthesized in the previous step is taken 3 O 4 Adding microspheres into a 50mL three-neck flask, sequentially adding 0.2g of styrene, 0.5g of acrylic acid, 0.05g of Azobisisobutyronitrile (AIBN), 0.05g of Divinylbenzene (DVB) and 20mL of 70% ethanol solution as a dispersion, and ultrasonically emulsifying; and introducing nitrogen for 30 minutes during stirring, keeping the stirring speed at about 300rpm, heating to 70 ℃, and reacting for 24 hours. After the polymerization reaction is finished, performing magnetic separation, washing with ethanol and deionized water in sequence, repeating for 5 times, putting the obtained magnetic material into a vacuum oven at 40 ℃ to dry the sulfonated carboxyl magnetic microspheres, and marking as M6 magnetic microspheres.
Example 7
Derivatization is carried out by utilizing carboxylated polystyrene microspheres, crown ether groups are modified and connected on the surfaces of the microspheres, and the magnetic microspheres with crown ether structures are obtained, wherein the specific process is as follows:
dispersing 500mg of the sulfonated carboxyl magnetic microsphere prepared in example 6 in 10mL of acetonitrile, cooling to 15 ℃, sequentially adding 100mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC), 90mg of N-hydroxysuccinimide (NHS), 10mg of 2-aminomethyl-18-crown-6 and 10mg of 2-aminomethyl-15-crown-5, placing the reaction tube on a rotary mixer, mixing overnight, after the reaction is finished, carrying out magnetic separation, sequentially washing with ethanol and deionized water, repeating for 5 times, placing the obtained magnetic material in a vacuum oven at 40 ℃ and drying to obtain the crown etherified carboxyl magnetic microsphere, wherein the label is M7 magnetic microsphere.
Example 8
10g of styrene and 3g of 2-acrylamido methyl-18-crown-6 g were added to a 1000mL three-necked flask, 0.3g of Azobisisobutyronitrile (AIBN), 0.3g of Divinylbenzene (DVB) and 200mL of 70% ethanol solution are taken as dispersion liquid and are ultrasonically emulsified; 3g of the magnetic ferroferric oxide particle solid obtained in the example 1 is dispersed in 35mL of 70% ethanol solution, the mixture is added into the prepared mixed solution after ultrasonic dispersion, the mixture is completely dispersed again by ultrasonic dispersion, nitrogen is introduced for 30 minutes during stirring, the stirring speed is kept at about 300rpm, the temperature is raised to 70 ℃, and the reaction is carried out for 24 hours. And after the polymerization reaction is finished, performing magnetic separation, sequentially washing with ethanol, 5% sulfuric acid solution and deionized water for 5 times, and drying the obtained magnetic microspheres in a vacuum oven at 40 ℃ to obtain crown etherified magnetic microspheres, wherein the crown etherified magnetic microspheres are marked as M8 magnetic microspheres.
Example 9
Preparing a magnetic microsphere solution:
respectively taking 200mg of the M1-M8 magnetic microspheres, dispersing in 3mL of deionized water, adding water to a constant volume of 5mL, and obtaining M1-M8 magnetic solution with the solid content of 4%. The control cation exchange resin was Dowex 50wx8-200.
Mass spectrum sample to be desalted:
the sample solution contains three nucleic acid reference molecule substances (with molecular weights of 5528, 7740 and 8068Da respectively), and aqueous solutions of potassium ions, sodium ions and magnesium ions with certain concentrations.
Desalting:
as shown in FIG. 2, 2. Mu.L to 4. Mu.L of the magnetic solution prepared as described above was pipetted, added to 9. Mu.L of the sample solution, shaken or shaken for 1 to 5 minutes, and magnetically separated for 30 seconds to obtain a clear solution. Wherein, compared with the cation exchange resin, 16 mu L of deionized water is firstly added, then 2-6 mg of the cation exchange resin is added, after the membrane is sealed, the resin is vertically rotated at a low speed for 30 minutes, and then the resin is centrifugally precipitated at the bottom of the hole.
Mass spectrometry of desalted samples:
and (3) sucking the clear solution after desalting by using a pipette gun, dripping the clear solution onto a 96-hole silicon-based target plate with a pre-embedded 3-HPA/DHC matrix in a sample dropping hole, dripping 0.2 mu L of a desalting sample into each sample dropping hole, drying at room temperature, putting into MALDI-TOF (model: zhongyuan Huiji EXS 3000) for mass spectrometry, and collecting a mass spectrum. The spectrogram of the mass spectrum sample subjected to the M1 magnetic solution desalting treatment is shown in fig. 3, the mass spectrum signal is free of deletion, the signal peak intensity is high, the signal-to-noise ratio is high, no salt ion addition peak is generated, and the acquisition success rate is high; spectrograms of mass spectrum samples subjected to desalting treatment by the M2-M8 magnetic solution are similar to those in the graph shown in figure 3, mass spectrogram signals are free of deletion, signal peak intensity is high, signal-to-noise ratio is high, salt ion addition peaks are avoided, and acquisition success rate is high; the spectrum of the mass spectrum sample after the control group is subjected to the desalting treatment is shown in figure 4, and a salt ion addition peak exists. The specific analysis results are shown in table one.
TABLE I desalting analysis results
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Those skilled in the art can modify or change the above-described embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (9)
1. The magnetic microsphere comprises a high molecular polymer and magnetic nanoparticles, wherein the magnetic nanoparticles are positioned inside the high molecular polymer, or positioned in a pore structure of the high molecular polymer, or coated outside the high molecular polymer, the surface of the microsphere is modified by functional groups, and the functional groups are any one or combination of more of sulfonic acid groups, phosphoric acid groups, carboxyl groups, ester groups, hydroxyl groups, ethers, amino groups and crown ethers.
2. The magnetic microsphere of claim 1, wherein the polymer is selected from the group consisting of high molecular compounds synthesized from vinyl, styryl, acryl or acryl groups;
or, the polymer is selected from a porous ion exchange resin or a porous polymer microsphere;
the magnetic nano-particles are selected from any one or combination of a plurality of magnetic ferroferric oxide, magnetic ferric oxide, modified magnetic ferroferric oxide, modified magnetic ferric oxide and carboxylated magnetic microspheres.
3. The magnetic microsphere according to any one of claims 1 or 2, wherein: when the magnetic microsphere has a core-shell structure, the magnetic nanoparticles and the high molecular polymer are mutually in the core-shell structure, and the high molecular polymer is selected from a high molecular compound synthesized by vinyl, styryl allyl or acryloyl;
when the magnetic microspheres have a pore channel structure, the polymer is selected from a pore channel type ion exchange resin or porous polymer microspheres, and the porous polymer microspheres are selected from high molecular compounds which have a porous structure and are synthesized by vinyl, styryl propenyl or acryloyl.
4. The magnetic microsphere of claim 1 or 2, wherein: the particle size of the magnetic microsphere is 10 nm-200 um;
and/or the particle shape of the magnetic microsphere is spherical, elliptical, rod-like or irregular.
5. Use of magnetic microspheres according to claims 1-4 for the adsorption of salt ions.
6. The method for preparing magnetic microspheres according to claims 1 to 4, wherein the method is selected from any one of the following methods:
A. adding a chemical group with an ion exchange/adsorption function on a material with a core-shell structure formed by the magnetic nano-particles and the polymer to prepare the magnetic microsphere;
B. carrying out polymerization reaction on the magnetic nanoparticles, a monomer compound with a polymerization reaction functional group and a chemical group with an ion exchange/adsorption function and a cross-linking agent to prepare the magnetic microspheres;
C. loading the magnetic nanoparticles on pore channel type ion exchange resin to obtain magnetic ion exchange resin, namely the magnetic microspheres;
D. after the magnetic nano particles and the porous polymer microspheres are self-assembled, chemical groups with ion exchange/adsorption functions are added to prepare the magnetic microspheres;
E. performing chemical covalent bond coupling on the magnetic nanoparticles and crown ether compounds containing hydroxyl/amino to prepare the magnetic microspheres;
F. and carrying out polymerization reaction on the monomer compound with the polymerization reaction functional group, the compound containing the crown ether group and the magnetic nano-particles to obtain the magnetic microsphere.
7. The method of claim 6, wherein: in the method A, the chemical group is a sulfonic acid group, and the material is provided with the sulfonic acid group through sulfonation reaction to prepare the magnetic microsphere;
and/or, in the method B, the monomer compound with the polymerization reaction functional group and the chemical group with the ion exchange/adsorption function is selected from any one or more of vinyl benzene sulfonic acid and salt thereof, 2-acrylamide-2-methyl propane sulfonic acid and salt thereof, and a compound which has vinyl/styrene group/acryloyl group and sulfonic acid group and can be subjected to polymerization reaction;
and/or in the method C, the manner of loading the magnetic nanoparticles onto the porous ion exchange resin to obtain the magnetic ion exchange resin includes: soaking the porous ion exchange resin in a solution containing Fe 3+ And/or Fe 2+ Filtering, adding an alkaline precipitator, and carrying out magnetic separation to obtain the magnetic ion exchange resin, namely the magnetic microspheres.
8. Use of magnetic microspheres according to any one of claims 1 to 4 and/or magnetic microspheres produced according to the method of any one of claims 6 to 7 for desalting a mass spectrometric sample.
9. A method of desalting a mass spectrometry sample, the method comprising: preparing magnetic microspheres according to any one of claims 1 to 4 and/or magnetic microspheres prepared according to the method of any one of claims 6 to 7 into a magnetic solution, mixing the magnetic solution with a mass spectrometry sample solution to be desalted, and performing magnetic separation to obtain a desalted mass spectrometry sample.
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