CN101521067A - Core/shell type magnetic particle product and preparing method thereof - Google Patents
Core/shell type magnetic particle product and preparing method thereof Download PDFInfo
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- CN101521067A CN101521067A CN200810034073A CN200810034073A CN101521067A CN 101521067 A CN101521067 A CN 101521067A CN 200810034073 A CN200810034073 A CN 200810034073A CN 200810034073 A CN200810034073 A CN 200810034073A CN 101521067 A CN101521067 A CN 101521067A
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Abstract
The invention provides a core/shell type magnetic particle product and a preparing method thereof. The method comprises five steps of: preparation of magnetic oxide nanoparticles, wrapping of organic silicon source, chemical reduction, wrapping of inorganic silicon source, modification of silanized reagent with various functional groups and the like. The prepared core/shell type magnetic particle has good dispersity in water, strong magnetism of inner core matters, compact shell structure of silicon oxide, high chemical stability, strong oxidation resistance, no naked magnetic particles and good leak resistance. The product is applicable to separate and purify biological materials and medical products and can be used as carriers of biological molecules and medical molecules.
Description
Technical field
The invention belongs to magnetic and nano material preparation, relate to a kind of preparation method of core/shell type magnetic particle and the application in bio-separation thereof.
Technical background
Magnetic particle has wide application in biomedicine, cytology and the biotechnology field such as fixing of the separation of nucleic acid, protein and purifying, targeted drug, cell marking and sorting, biomolecular labeling and detection, immunoassay, enzyme.It is to have utilized the controlled feature of magnetic particle magnetic, and magnetic is controlled to be meant under the effect of magnetic particle outside magnetic field, moves and enrichment to the direction of appointment.Compare with separation method such as centrifugal process, the precipitation method, ion-exchange and chromatography commonly used, the magnetic of solid-liquid phase separates under the outside magnetic field effect, have simple and quickly, the separative efficiency height, equipment needed thereby is simple, energy consumption is low, cost is few, plurality of advantages such as pollution-free.Magnetic particle is as target medicine carrier, can be implemented in the enrichment of moving, fix a point of body interior orientation, thereby reach the purpose that improves result of treatment, reduces toxic and side effect, and having widely at aspects such as treatment tumour, cancers to have prospect.In animal, clinical testing, succeed in separating cancer cell and normal cell with magnetic particle, represented the application prospect that attracts people's attention.In the existing goods, mostly magnetic particle is the polymer microsphere that makes by investment, monomer copolymerization method or polymer microsphere swelling-take off swelling method etc., or the magnetic microsphere that is coated by polysaccharide molecule.Polymer microsphere is composited by magnetic grain and surface aggregate macromolecular material, the general more complicated of its synthesis technique, regular meeting uses some poisonous organic solvent or polymerization single polymerization monomers in the synthesis technique, molded microsphere surface is difficult to modify again, and this microballoon biocompatibility is relatively poor, only is adapted at external application; Though the microballoon biocompatibility that polysaccharide coats is better, the medicine that can be applied in the body is carried, the coating layer instability, and the shortcoming that exists magnetic particle to come off easily, these have all limited its range of application.
The preparation method of shell/caryogram magnetic particle reports a lot, but its kernel is the more weak Fe of magnetic
3O
4On ferrite.For example, patent ZL02109817.4 discloses a kind of preparation method of composite magnetic particle, and its kernel is that particle diameter is the superparamagnetism Fe of 5～8nm
3O
4Nano particle; Patent ZL03111351.6 also discloses magnetic core-shell particle with high-intensity magnetic field responding ability and preparation method thereof, and its kernel is the magnetic ferrites nano particles, and shell is a silicon dioxide.Its magnetic ferrites nano particle is to refer to Fe
3O
4Nano particle, γ-Fe
2O
3Nano particle or mix transition metal and the magnetic ferrites nano particle of compound (particle diameter is 3～12nm).The method for preparing this magnetic ferrites～silicon dixoide nucleocapsid structure particulate is: preparation magnetic ferrites nano particle～coating～organosilicon source, inorganic silicon source coats.Its magnetic ferrites nano particle adopts known coprecipitation preparation.It is with Na that above-mentioned inorganic silicon source coats
2SiO
3As the inorganic silicon source, washed magnetic ferrites nano particle directly is distributed to without any surface treatment contains SiO
2The aqueous solution in, stir and to carry out coated with silica first time, be coated on the thick silicon dioxide layer of magnetic ferrites nanoparticle surface formation 1～2nm through current inorganic silicon source.The organosilicon source is to be the silicon source with the tetraethoxysilane, with the alcohol and water mixture is solvent, under the catalysis of alkali, carry out the coated with silica second time by the teos hydrolysis reaction, the particle diameter of the multilayer core/shell type magnetic particle that obtains is at 0.2～10 μ m, nuclear/shell magnetic particle contains 20～1000 magnetic ferrites nano particles, and the quality percentage composition of magnetic ferrites nano particle is 10～60% in the particulate.Utilizing tilt-pour process to carry out pure water under the permanent magnetic field that permanent magnet by 0.05～0.15T in the preparation process provides cleans and removes impurity.The magnetic responsiveness ability of particulate is: the hydrosol of this core-shell particle of 10ml, under the externally-applied magnetic field of 0.05T, the particle enrichment time is in 1 minute.
The Fe of existing patent (ZL03111351.6)
3O
4The coating layer of-silicon dioxide core/shell type magnetic particle is a silicon dioxide, thereby the existing excellent biological compatibility of particulate, better chemical stability, can also carry out various finishinges by different silylating reagents, the microparticle surfaces after modified can carry wears the various active groups that easily are connected with biomaterial.But the nuclear of this based fine particles more weak ferrite that is magnetic causes the responding ability in this external magnetic field of based fine particles on the weak side, need apply the enrichment that high-intensity external magnetic field could realize this particulate.In addition, also can reach enhancing particulate magnetic response ability, but the specific surface decline that the mean particle dia increase causes can cause surface-active reduction, thereby can directly reduce separative efficiency by the number (causing particulate to increase) that increases nanoparticle in the nuclear.Therefore, need under the condition that keeps particle size appropriateness (preferably being in the nanoscale category), further increase particulate is only the best to the magnetic response ability of externally-applied magnetic field selection.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and research can improve the magnetosensitive sensitivity of particulate, improves the responding ability of particulate to external magnetic field, makes kernel magnetic nano-particle safety and stable.
The invention provides a kind of goods of core/shell type magnetic particle.
Of the present invention is the core/shell type magnetic particle of nuclear with the metallic nano crystal, and its kernel is the mixture of nano metallic nickel granular material or nano metallic nickel granular material and magnetic oxide nano particle, and shell is a silica.The mixture of said nano metallic nickel granular material or nano metallic nickel granular material and magnetic oxide nano particle refers to Fe, Co, Ni or its alloy, Fe
3O
4, γ-Fe
2O
3, Co
3O
4, Co
2O
3Or Fe
(1-x)M
xFe
2O
4The nano particle of (M=Fe, Co, Ni, Zn, two valency transition metal ionss such as Mn), their particle diameters have superparamagnetism below 10nm.Said reducing agent is meant hydrogen (H
2), hydrazine hydrate (H
4N
2H
2O), potassium borohydride (KBH
4), sodium borohydride (NaBH
4) or its mixture in any one.Described particulate has coenocytism, and particle diameter sees that by transmission electron microscope the number of the magnetic nanometer particles of kernel in the silica core/shell type magnetic particle is 5～500 at 0.05～5 μ m.
Another object of the present invention provides a kind of preparation method of core/shell type magnetic particle product.
The inventive method is at first coating skim eyed structure silica (shell) outside magnetic metal oxide nano particle (nuclear), to examine whole or in part with reducing agent that in-situ reducing becomes nano metallic nickel granular material then, finally obtain that silica coats, be the core/shell type magnetic particle of kernel with the mixture of nano metallic nickel granular material or nano metallic nickel granular material and small part magnetic oxide nano particle.The result of in-situ reducing not only makes the high-load of magnetisable material in the nuclear be kept, and because the interior more weak metal oxide of magnetic of nuclear has become the stronger metal of magnetic whole or most ofly, has stronger responding ability thereby make magnetic check external magnetic field.Thicken coating through further silica, the compactness and the chemical stability of silica shell are further enhanced, and have strengthened the protection of internal nuclear magnetism metal greatly, and the kernel magnetic metal is avoided the influence of extraneous air and is in the state of safety and stability.Through the individual layer for the third time of microparticle surfaces being coated (modification), make the surface possess the required functional group of various application, thereby can adapt to various application demands widely again with the silylating reagent of various functional groups.
Of the present invention is that the technology of preparing of core/shell type magnetic particle of nuclear comprises with the metallic nano crystal: preparation magnetic oxide nano particle, the coating of organosilicon source, electronation, inorganic silicon source coat, with 5 technical processs such as silylating reagent modification of various functional groups.Concrete steps are as follows:
(1) utilizes the preparation method of patent (200410073680.6) to prepare the magnetic oxide nano particle, be i.e. after the mixed reaction of molysite and aqueous slkali, add entry and stir, finish the crystallization reaction of particle; Again crystalline particle is passed through external magnetic field or centrifugation, clean impurity with distilled water, the particle diameter of the magnetic oxide nano particle that makes is at 3～10nm;
(2) the magnetic oxide nano particle after will washing directly is dispersed in the mixed solvent of alcohol and water, under alkali condition, carry out the silica coating first time by esters of silicon acis (methyl silicate, tetraethoxysilane, butyl silicate etc.) hydrolysis, the surface of the magnetic oxide nano particle that process organosilicon source coats has the silica of meso-hole structure to coat thin layer, the thickness of coating layer can be regulated by regulating and control organosilyl amount, by external magnetic field or centrifugation, clean impurity with distilled water;
(3) will finish the magnetic oxide Nanoparticles Hydrosol hydrogen (H that the first time, silica coated
2), hydrazine hydrate (H
4N
2H
20), potassium borohydride (KBH
4), sodium borohydride (NaBH
4) or its mixture in any one reducing agent reduce, because the silicon oxide layer on surface has meso-hole structure, reducing agent sees through the silica mesh and enters kernel, the magnetic oxide nano particle is under the effect of reducing agent, the all or part of magnetic metal simple substance nano particle that is reduced into, obtain coating for the first time with silica, metallic nano crystal is the core/shell type magnetic compound particles of nuclear, by external magnetic field or centrifugation, cleans impurity with distilled water;
(4) will finish the magnetic compound particles that silica coats for the first time with reduction reaction and be dispersed in SiO
2Water-soluble glue in stir, with 0.5mol/L acetic acid, hydrochloric acid, sulfuric acid, regulator solution pH value to 6～10, mixed solution 2～20 hours, the silica once more of finishing magnetic compound particles coats, the silica shell that makes the core/shell type magnetic particle is enough fine and close abundant, can secluding air and the outer medium of nuclear, avoid metal nanoparticle by the oxidation of the institute of the oxidizing substance in air or the solution; By external magnetic field or centrifugation, clean impurity with distilled water; Obtaining particle diameter is the core/shell type magnetic particle that the silica of nuclear coats with the metallic nano crystal at 0.05～5 mu m range.
(5) step (4) core/shell type magnetic particle carries out finishing with the silylating reagent that has groups such as amino, sulfydryl, epoxy radicals, ester group, alkylene, obtains the silica that the surface has different functional groups and coats, is the core/shell type magnetic particle of nuclear with the metallic nano crystal.
Wherein said nano metallic nickel granular material is meant nanometer Fe particle, nano Co particle, nanometer Ni particle or Nanoalloy particle, and the magnetic oxide nano particle is meant nanometer Fe
3O
4Particle, nanometer γ-Fe
2O
3Particle, nano Co
3O
4Particle, nano Co
2O
3Or Fe
(1-x)M
xFe
2O
4Particle etc.
In the above-mentioned cladding process, when the described organosilicon of step (2) source coats, the concentration that is dispersed in magnetic oxide nano particle in the mixed solvent of alcohol and water is 0.01～0.15mol/L, organosilyl concentration is 0.01～1.0mol/L, and organosilicon can be methyl silicate, tetraethoxysilane or butyl silicate; Alcohol in the mixed solvent of alcohol and water can be methyl alcohol, ethanol, ethylene glycol, propyl alcohol, propylene glycol, glycerol, isopropyl alcohol or butanols, the pure volumn concentration 40%～98% in the mixed solvent, the volumn concentration 2%～60% of water; Add mass percent concentration and be 25%～28% concentrated ammonia liquor in above-mentioned solution, the concentration of ammoniacal liquor in reaction system is 0.2～1.5mol/L, then stirring reaction 2～20 hours under the speed of 100～2000rpm.In the organosilicon source coated, organosilyl adding can be dropwise to add, and also can disposablely add, and can also add in batches, and the time interval of adjacent twice adding is 1～5 hour in batches, after organosilicon all adds, was continuing reaction 3～20 hours.By controlling organosilyl addition, can regulate the thickness of the silicon oxide layer that coats for the first time.
Step (3) is described when carrying out electronation, and the mol ratio of the consumption of reducing agent and magnetic oxide nano particle is 0.1～5, and the reduction reaction time is 0.5～10 hour.When the inorganic silicon source coats, SiO
2Concentration be 0.05～3mol/L, be adjusted between 6～10 with the pH value of 0.5mol/L hydrochloric acid reaction solution, mixing speed is to react 2～20 hours under the condition of 100～2000rpm.The modification of silylating reagent can also can be carried out in above-mentioned alcohol in the aqueous solution, and the volume percent content of silylating reagent is 0.1%～10%.
The good dispersion of core-shell type magnetic particulate in water of silica double-coated described in the invention, inner core materials magnetic is strong; The densification of silica shell structurre, so chemical stability height, oxidation resistance is strong; Do not have exposed magnetic particle, good leak integrity is arranged.
Another purpose of the present invention provides the application of a kind of core/shell type magnetic particle product in bio-separation.
The core/shell type magnetic particle of the present invention preparation joined in the solution that contains nucleic acid mix, by adding in conjunction with liquid, under the outside magnetic field, isolate nucleic acid-magnetic particle compound, be that 70% ethanol cleans nucleic acid-magnetic particle compound with volume fraction again, last is that 7～9 TE buffer solution or aqua sterilisa elute nucleic acid with pH value again, realizes purpose quick, high efficiency separation nucleic acid.
Utilization has the silane coupler of groups such as amino, sulfydryl, epoxy radicals silicon oxide surface is modified, obtain having the surface of functional groups such as amino, sulfydryl, epoxy radicals, easily be connected with drug molecule with various bioactivators such as protein, antigen, antibody, enzymes.Be specially adapted to separating and purifying of biomaterial and pharmaceutical products, and can be used as the carrier of biomolecule and drug molecule.
Embodiment
Embodiment 1: the preparation of core-shell type magnetic particulate kernel
With 0.1mol/L FeCl
2With 0.2mol/L FeCl
3Mixed with concentrated ammonia liquor, react after 10 minutes, add 100 times of amounts, 10 ℃ water, stirring is 3 hours under 5000rpm, and the crystallization reaction of particle is finished; Under 10000rpm,, promptly obtain the Fe that particle diameter is 2～12nm after cleaning with the crystalline particle centrifugation
3O
4Nano particle.Get 2.3 gram Fe
3O
4It is in the mixed solvent of 25%～28% concentrated ammonia liquor that nano particle is dispersed in by 500ml ethanol, 10ml water, 15ml mass percent concentration, at room temperature, drip the methyl silicate of 0.1mol/L with the 500rpm mixing speed, reacted 12 hours, permanent magnet with 0.1T is isolated black solid, solid matter is finished silica coating for the first time with distilled water washing 3～5 times.The magnetic composite that the first time, silica coated is dispersed in the water, at room temperature adds 4 gram NaBH
4Carry out reduction reaction, separate with the permanent magnet of 0.1T, the gained solid fully washs with distilled water, promptly gets magnetic Fe nano particle and Fe
3O
4Nano particle is mixed into the composite material of the silica coating of kernel.
Embodiment 2: the preparation of core-shell type magnetic particulate kernel
With 0.2mol/L FeCl
2With 0.4mol/L FeCl
3Mixed with 2mol/L NaOH, react after 25 minutes, add 100 times of amounts, 15 ℃ water, stirring is 1 hour under 10000rpm, and the crystallization reaction of particle is finished; By applying magnetic field crystalline particle is separated, promptly obtain the Fe that particle diameter is 2～12nm after cleaning with distilled water
3O
4Nano particle.Get 3.5 gram Fe
3O
4It is in the mixed solvent of 25%～28% concentrated ammonia liquor that nano particle is dispersed in by 1000ml isopropyl alcohol, 20ml water, 40ml mass percent concentration, at room temperature, drip the tetraethoxysilane of 0.6mol/L with the 800rpm mixing speed, reacted 20 hours, permanent magnet with 0.1T is isolated black solid, solid matter is finished silica coating for the first time with distilled water washing 3～5 times.The magnetic composite that the first time, silica coated is dispersed in the water, at room temperature adds 8 gram KBH
4Carry out reduction reaction, separate with the permanent magnet of 0.05T, the gained solid fully washs with distilled water, promptly gets magnetic Fe nano particle and Fe
3O
4Nano particle is mixed into the composite material of the silica coating of kernel.
Embodiment 3: the preparation of core-shell type magnetic particulate kernel
With 0.3mol/L FeCl
2With 0.6mol/L CoCl
3Mixed with concentrated ammonia liquor, react after 10 minutes, add 100 times of amounts, 8 ℃ water, stirring is 4.5 hours under 20000rpm, and the crystallization reaction of particle is finished; Under 0.1T magnetic field, crystalline particle is separated, promptly obtain the FeCo that particle diameter is 2～12nm after cleaning
2O
4Nano particle.Get 4.6 gram FeCo
2O
4It is in the mixed solvent of 25%～28% concentrated ammonia liquor that nano particle is dispersed in by 500ml propylene glycol, 10ml water, 15ml mass percent concentration, at room temperature, drip the butyl silicate of 0.1mol/L with the 500rpm mixing speed, reacted 12 hours, permanent magnet with 0.1T is isolated black solid, solid matter is finished silica coating for the first time with distilled water washing 3～5 times.The magnetic composite that the first time, silica coated is dispersed in the water, at room temperature adds 9 gram hydrazine hydrates and carry out reduction reaction, separate with the permanent magnet of 0.05T, the gained solid fully washs with distilled water, promptly gets magnetic Co nano particle and FeCo
2O
4Nano particle is a kernel.
Embodiment 4: the core-shell type magnetic microparticle shell coats
Claim composite material 1 gram of the silica coating of embodiment 1, embodiment 2 or embodiment 3, be dispersed in 5.0 gram Na
2SiO
3(SiO
2Content is 27%) dissolving the 450ml aqueous solution in, pH value with the acetic acid regulator solution is 8.5, at room temperature, reacted 12 hours in the flask of 1000ml with the 300rpm mixing speed, after reaction finishes, permanent magnet with 0.08T separates, with distilled water washing 3～5 times, obtaining particle diameter is the silica core/shell type magnetic particle of average grain diameter 0.5 μ m, 0.5g silica core/shell type magnetic particle joined in 0.3% the aminopropyl triethoxysilane coupling agent ethanolic solution, under 75 ℃ of temperature, stir, obtain amidized core/shell type magnetic particle.
Embodiment 5: the core-shell type magnetic microparticle shell coats
Claim composite material 2.5 grams of the silica coating of embodiment 1, embodiment 2 or embodiment 3, be dispersed in 7.5 gram Na
2SiO
3(SiO
2Content is 27%) dissolving the 850ml aqueous solution in, pH value with hydrochloric acid conditioning solution is 6.5, at room temperature, reacted 18 hours in the flask of 1000ml with the 500rpm mixing speed, after reaction finishes, permanent magnet with 0.08T separates, with distilled water washing 3～5 times, obtaining particle diameter is the silica core-shell type magnetic particulate of average grain diameter 1.5 μ m, 1.5g silica core/shell type magnetic particle joined in 1.0% the mercaptopropyltriethoxysilane coupling agent aqueous solution, under 85 ℃ of temperature, stir, obtain the core/shell type magnetic particle of sulfhydrylation.
Embodiment 6: the core-shell type magnetic microparticle shell coats
Claim composite material 5.0 grams of the silica coating of embodiment 1, embodiment 2 or embodiment 3, be dispersed in 10.0 gram Na
2SiO
3(SiO
2Content is 27%) dissolving the 1100ml aqueous solution in, pH value with sulfuric acid regulation solution is 7.0, at room temperature, reacted 20 hours in the flask of 2000ml with the 800rpm mixing speed, after reaction finishes, permanent magnet with 0.08T separates, with distilled water washing 3～5 times, obtaining particle diameter is the silica core-shell type magnetic particulate of 3.0 μ m, 1g silica core/shell type magnetic particle joined in γ-epoxypropoxy three alcoxyl silane coupler glycerol solution of 0.8%, under 90 ℃ of temperature, stir, obtain the core/shell type magnetic particle of epoxy radicalsization.
Embodiment 7: core-shell type magnetic separation of particles purifying DNA plasmid
Pour 1.5ml Escherichia coli nutrient solution into microcentrifugal tube, the centrifugal supernatant of abandoning is collected thalline; Add the TE buffer solution that 100ul contains 20ug/ml RNA enzyme to thalline, 200ul contains the alkaline lysis liquid of 0.2M NaOH and 1% (m/v) SDS, and the pH value that adds 150ul again is 5 5M potassium acetate solution, mixes, centrifugal 5 minutes of 12000rpm transfers to supernatant in the new centrifuge tube; In centrifuge tube, add core-shell type magnetic particulate 1.5mg of the present invention, the concussion mixing, incubation 2-5min places centrifuge tube on the magnetic separator frame, inhales and abandons supernatant; Add 500ul 70% ethanol and clean DNA-magnetic particle compound twice, add 50ul TE buffer solution suspension magnetic particle, magnetic separated and collected eluent obtains the highly purified DNA of about 20ug.
Embodiment 8: core-shell type magnetic separation of particles purification bacillus coli gene group DNA
With the Escherichia coli 100 μ L of incubated overnight, centrifugal; Abandon supernatant, precipitation is resuspended in TSE1 buffer solution (50mM Tris-HCl, pH8.0,20% sucrose, 50mM EDTA, 100 μ g lysozymes), puts 37 ℃ of water-bath 20min; Add 10 μ L 10%SDS in reaction mixes, 5 μ L 20mg/ml Proteinase Ks are put 37 ℃ of water-bath 20min; Add 1mL cracking adsorption liquid (3M GuSCN, 2% Triton X-100) and 1mg core-shell type magnetic particulate, incubated at room 5min; Place on the magnetic separator frame, magnetic liquid separates the back and removes supernatant; 700 μ L, 70% ethanol washed twice; 100 μ L aqua sterilisa wash-outs obtain 1ug bacillus coli gene group DNA.
Claims (10)
1, a kind of core/shell type magnetic particle product, it is characterized in that this particle product is the core/shell type magnetic particle of nuclear with the metallic nano crystal, its kernel is the mixture of nano metallic nickel granular material or nano metallic nickel granular material and magnetic oxide nano particle, and shell is a silica; Described diameter of particle is at 0.05～5 μ m, and the number of the magnetic nanometer particles of kernel is 5～500 in the silica core/shell type magnetic particle.
2, a kind of preparation method of core/shell type magnetic particle product is characterized in that this method comprises the following steps:
(1) preparation magnetic oxide nano particle: after the mixed reaction of molysite and aqueous slkali, add entry and stir, finish the crystallization reaction of particle; Again crystalline particle is passed through external magnetic field or centrifugation, clean impurity with distilled water, the particle diameter of the magnetic oxide nano particle that makes is at 3～10nm;
(2) the magnetic oxide nano particle after will washing directly is dispersed in the mixed solvent of alcohol and water, under the alkali condition of ammoniacal liquor
PH 9～14, by methyl silicate, tetraethoxysilane or butyl silicate hydrolysis, carry out the silica coating first time, the surface of the magnetic oxide nano particle that process organosilicon source coats has the silica of meso-hole structure to coat thin layer, by external magnetic field or centrifugation, clean impurity with distilled water;
(3) the magnetic oxide Nanoparticles Hydrosol that will finish silica coating is for the first time reduced with any reducing agent in hydrogen, hydrazine hydrate, potassium borohydride or sodium borohydride or their mixtures, obtain coating for the first time with silica, metallic nano crystal is the core/shell type magnetic compound particles of nuclear, by external magnetic field or centrifugation, clean impurity with distilled water;
(4) will finish the magnetic compound particles that silica coats for the first time with reduction reaction and be dispersed in SiO
2Water-soluble glue in stir, with 0.5mol/L acetic acid, hydrochloric acid, sulfuric acid, regulator solution pH value to 6～10, mixed solution 2～20 hours, the silica once more of finishing magnetic compound particles coats, by external magnetic field or centrifugation, clean impurity with distilled water, obtaining particle diameter is the core/shell type magnetic particle that the silica of nuclear coats with the metallic nano crystal at 0.05～5 mu m range;
(5) step (4) core/shell type magnetic particle carries out finishing with the silylating reagent that has amino, sulfydryl, epoxy radicals, ester group and an alkylene group, obtains the silica that the surface has different functional groups and coats, is the core/shell type magnetic particle product of nuclear with the metallic nano crystal.
3, the preparation method of a kind of core/shell type magnetic particle product according to claim 2, the magnetic kernel that it is characterized in that making product is nanocrystalline or magnetic metal and the nanocrystalline mixture of magnetic metal oxide of magnetic metal, and non-magnetic shell is a silica; The particle diameter of core/shell type magnetic particle is 0.05～5.0 μ m, and each particulate is coated with 5～500 magnetic Nano crystalline substances.
4, the preparation method of a kind of core/shell type magnetic particle product according to claim 2 is characterized in that the described magnetic oxide nano particle of step (1) is Fe
(1-x)M
xFe
2O
4, wherein M is Fe, Co, Ni, any in Zn or Mn two valency transition metal ionss or their mixed oxides.
5, according to the preparation method of the described a kind of core/shell type magnetic particle product of claim 2, when it is characterized in that step (2) organosilicon source coats, the concentration of magnetic oxide nano particle is 0.01～0.15mol/L, organosilyl concentration is 0.01～1.0mol/L, and organosilicon is methyl silicate, tetraethoxysilane or butyl silicate; In the mixed solvent of alcohol and water, alcohol is methyl alcohol, ethanol, ethylene glycol, propyl alcohol, propylene glycol, glycerol, isopropyl alcohol or butanols, the volumn concentration 40%～98% of alcohol in the mixed solvent, the volumn concentration 2%～60% of water; The concentration of step (2) ammoniacal liquor in reaction system is 0.2～1.5mol/L, and consumption is a mixed solvent mass percent concentration 25%～28%; Stirring reaction is 2～20 hours under the speed of 100～2000rpm.
6, the preparation method of a kind of core/shell type magnetic particle product according to claim 2 is characterized in that magnetic metal in the described magnetic Nano nucleus of step (3) is nanocrystalline for by in a kind of or their hybrid alloys in Fe particle, Co particle or the Ni particle any.
7, the preparation method of a kind of core/shell type magnetic particle product according to claim 2 is characterized in that the consumption of step (3) reducing agent and the mol ratio of magnetic oxide nano particle are 0.1～5, and the reduction reaction time is 1～24 hour.
8, the preparation method of a kind of core/shell type magnetic particle product according to claim 2, when it is characterized in that the described inorganic silicon of step (4) source coats, SiO
2The concentration of the aqueous solution is 0.05～3mol/L, regulates pH value 0.5mol/L acetic acid, hydrochloric acid or sulfuric acid, and the pH value is 6～10, and mixing speed is 100～2000rpm, 2～20 hours reaction time.
9, the preparation method of a kind of core/shell type magnetic particle product according to claim 1, it is characterized in that the described silylating reagent modification of step (5), silylating reagent is the silylating reagent that has amino, sulfydryl, epoxy radicals, ester group or alkylene group.
10, the application of a kind of a kind of core/shell type magnetic particle product as claimed in claim 1 in bio-separation is characterized in that can be used for the separation and purification field of nucleic acid.
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