CN101130606A - Water dispersible magnetic polymer microsphere, preparing method and application of the same - Google Patents
Water dispersible magnetic polymer microsphere, preparing method and application of the same Download PDFInfo
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Abstract
The invention discloses a water-dispersible magnetic macromolecular microball and making method and application, which is the compound of superparamagnetism center and macromolecular polymer through mould method and two-step active polymeric method, wherein the grain size of the magnetic macromolecular microball is 70-5000nm with magnetic content at 5-40% and saturated magnetified strength at 1. 0-15. 0emu/g; the magnetic macromolecular microball is nuclear shell structure with nuclear made of the composition of superparamagnetism material in the center and high molecular polymer to be ultraviolet crosslinking; the case is made of a layer of hydrophilic polymer with superparamagnetism particle distributed in the macromolecular microball, which dispersed evenly without baring and has strong response of magnetic field; the monodispersity of the macromolecular microball is good, which can be dispersed in the water; the water-dispersible magnetic macromolecular microball can be applied in the additive of compound plastic and targeting drug carrier.
Description
Technical field
The invention belongs to technical field of polymer materials, particularly a kind of water dispersible magnetic high polymer microsphere and its production and application.
Background technology
Magnetic macromolecular microsphere has the magnetic responsiveness of high molecular numerous characteristic and magnetic substance concurrently, can pass through biologically active substance and magneticsubstance outer wrap biopolymers such as Intermolecular Forces desmoenzyme, cell and antibody on the one hand, thereby strengthened biocompatibility, can show the intensive magnetic responsiveness to externally-applied magnetic field on the other hand, therefore, its carrier of being used as enzyme, cell, medicine etc. has been widely applied to fields such as biomedical, cytology and biotechnology.In commercial run such as separation and purification, also have been widely used in addition.
Cellular segregation, magnetic microsphere is as insoluble carrier, connect sorbent material or other part (as antibody, fluorescent substance, external source coagulin etc.) active substance of biologically active on its surface, utilize them to combine with the specificity of designated cell, with cellular segregation, classification and to its kind, distributed number is studied under the effect of externally-applied magnetic field.It is good that they have specificity, highly sensitive, the advantage that accuracy is good, and this cell separation technology has the application of wide model in medical clinical diagnosis.Immobilized enzyme, fixation support as enzyme, magnetic macromolecular microsphere helps immobilized enzyme and separates from reaction system and reclaim, can also utilize the motion and the direction of external magnetic field control magneticsubstance immobilized enzyme, thereby replace traditional mechanical stirring mode, improve the catalytic efficiency of immobilized enzyme.Magnetic macromolecular microsphere also has the following advantages as the fixation support of enzyme: immobilized enzyme is reusable, reduces cost; Can improve the stability of enzyme, improve biocompatibility, immunocompetence, the hydrophilic and hydrophobic of enzyme; Separate and reclaim the simple to operate of enzyme, be fit to large-scale continuous operation.Targeted drug by surface-functionalized to magnetic microsphere, as pharmaceutical carrier, under the effect of externally-applied magnetic field, is loaded onto prospective region with medicine, realizes the target administration technology, improves the effectiveness of medicine, reduces its toxic side effect.
Magnetic macromolecular microsphere also can be used for affinity chromatography except that being used for above field, and as the fields such as solid phase carrier of organic synthesis.In addition, it also can be used as an organic inorganic compounding filler, is applied to magnetic plastics and magnetic rubber field.
From the situation of present research, magnetic macromolecular microsphere is generally the core-shell type structure: form nuclear by metal oxide (as oxide compounds such as iron, cobalt, nickel), macromolecular material is formed shell; Perhaps with macromolecular material as nuclear, magneticsubstance is as shell; In addition, also can make sandwich structure, promptly outer, internal layer is a macromolecular material, and the middle layer is a magneticsubstance.With regard to its preparation method, mainly contain entrapping method and monomer polymerization method.
Entrapping method is that magnetic particle is scattered in the macromolecular solution, obtains magnetic macromolecular microsphere by means such as atomizing, flocculation, deposition, evaporations; As described in Josephson.USP 4672040.Generally speaking, its magnetic particle of magnetic microsphere (magnetic nuclear) of obtaining of entrapping method and outer shell combines mainly by Van der Waals force (comprising hydrogen bond); The covalent linkage that the metal ion on magnetic grain surface and the sequestering action of macromolecular chain and magnetic particle surface functional group and polymer shell layer function base form.Utilize entrapping method to prepare magnetic microsphere, method is simple, but the distribution of the particle diameter of gained is wide, out-of-shape, particle diameter is wayward, mixes some impurity such as emulsifying agent in the shell unavoidably, be used for immunoassay, fields such as cellular segregation can be very restricted.Monomer polymerization method is in the presence of magnetic particle and monomer, adds the core-shell type magnetic macromolecular microsphere that initiator, stablizer etc. are polymerized.Up to now, the method for monomer polymerization method synthesizing magnetic microballoon mainly contains: suspension polymerization, dispersion polymerization, letex polymerization (comprising emulsifier-free emulsion polymerization, seeding polymerization) etc.People such as Tricot are in USP 4339337, and under the condition of oil-soluble initiator, suspension stabilizer and magnetic coexistence, having made particle size range is the magnetic macromolecular microsphere of 0.05mm～3mm.Margel etc. utilize suspension polymerization in USP 4783336, having made particle size range is the magnetic polypropylene aldehydes microballoon of 0.03 μ m～80 μ m.Tsuruta has at first made the suspension of magnetic fluid, monomer, initiator, dispersion agent in JP62204501, applying low-frequency ultrasonic waves when stirring disperses, to obtain particle size range be 0.1 magnetic macromolecular microsphere to the dozens of micron in polymerization then, and its size changes with frequency of ultrasonic.It is the hydrophobic magnetic macromolecular microsphere of 0.03 μ m～5 μ m that Daniel etc. adopt microsuspension to obtain particle size range in USP4358388, but the magnetic inorganic particulate in the gained magnetic microsphere tend to migrate to microballoon around.It is the crosslinked composite magnetic microballoon of hydrophobic of 0.05 μ m～10 μ m that same employing microsuspension in USP 5356713 such as Charmot has synthesized particle size range.In this invention, magnetic particle concentrates on the inside of composite magnetic microballoon, and housing contains magnetic particle hardly.But still have " blank " microballoon that does not contain magnetic in the thus obtained microsphere, need under magnetic field, be separated greater than 10%.Its advantage is the microballoon that method simply can prepare big particle diameter, and its shortcoming is that the monodispersity of microspheres prepared is poor, and magnetic is inhomogeneous, and the exposed phenomenon of magneticmedium might be arranged.
Letex polymerization is the more a kind of method for preparing magnetic macromolecular microsphere of using at present, and it also comprises methods such as emulsifier-free emulsion polymerization, seeded emulsion polymerization.Among the USP 4421660 in being dispersed with the aqueous phase system of magnetic particle emulsified monomer, obtain stable emulsification system, use the hydrophobic magnetic polymer microsphere that letex polymerization has obtained the colloid size then.Magnetic macromolecular microsphere is wider in the application of biomedical sector, and as diagnostic reagent etc., but this field not only requires its monodispersity good to the having relatively high expectations of magnetic macromolecular microsphere, and should not have non-specific cohesion factor (as emulsifying agent etc.).And the magnetic macromolecular microsphere of emulsion polymerization prepared can't satisfy these requirements, therefore people have developed the emulsifier-free emulsion polymerization technology again, he has solved the residual problem of emulsifying agent, but the microspherulite diameter that obtains is less, microballoon magnetic content difference to each other is big, particle size dispersion is bigger, and magneticmedium tends to the edge near microballoon.
Reported with in-situ method among the USP 4774265 to prepare magnetic macromolecular microsphere, and developed serial commercial prod Dynabeads with this method.This method at first makes monodispersed densification or porous polymer microsphere, and this microballoon contains and can form the group of coordinate bond or ionic linkage (as the various N of containing groups, epoxy group(ing), an OH, a COOH, a SO with molysite according to different needs
3H etc.).Can prepare magnetic macromolecular microsphere with diverse ways according to the difference in functionality base that polymer microballoon had subsequently, have following advantage: (1) is because of in magnetic history, the particle diameter and the size distribution of monodisperse polymer micro-sphere are constant, and the magnetic macromolecular microsphere of therefore final gained has good monodispersity; (2) inorganic particles with superparamagnetism is evenly dispersed in the whole polymer microballoon, and each microballoon contains the magnetic particle of same concentrations, thereby guarantees that all magnetic microspheres have consistent magnetic responsiveness under magnetic field; (3) can prepare the densification of various particle diameters or porous magnetic polymer microsphere (bestly is 0.5um～20.0um), and can prepares magnetic content greater than 30% high magnetic content microballoon.
Atom transfer radical polymerization (ATRP) is a kind of of living polymerization, flowcollector aggregation scheme FlowCollector is to be based upon on the halogen atom transferred free radical addition reaction basis transition metal-catalyzed in the organic chemistry, introduce a quick reversible balance of free radical, the rate constant of the passivation reaction in active centre (growth free radical) is much higher than the priming reaction rate constant of dormancy kind, the concentration of free radical is very low in the system, the double-basis termination reaction of free radical has obtained effective inhibition, thereby has realized that polymeric is controlled.Its advantage is the polymkeric substance that can obtain relative molecular mass controlled and relative molecular mass narrowly distributing and compound with regular structure under relatively gentleer simple condition.
The method for preparing magnetic microsphere, method is simple, but the particle diameter of gained or distribute wide, out-of-shape, particle diameter is wayward, and perhaps magnetic content is high or mix some impurity such as emulsifying agent, be used for immunoassay, fields such as cellular segregation can be very restricted.
Summary of the invention
In order to overcome above-mentioned the deficiencies in the prior art part, primary and foremost purpose of the present invention is to provide a kind of water dispersible magnetic high polymer microsphere.The mixture that this magnetic macromolecular microsphere is made of jointly superparamagnetism center and high molecular polymer, the method that is adopted is template and living polymerization method.The particle diameter of this magnetic macromolecular microsphere is 70～5000nm, and magnetic content is 5～40%, and saturation magnetization is 1.0～15.0emu/g, and superparamagnetism center (being magnetic particle) be uniformly dispersed in polymer microsphere inside, strong to magnetic responsiveness; The polymer microsphere monodispersity well also can well be dispersed in the water.
Another object of the present invention is to provide the preparation method of above-mentioned water dispersible magnetic high polymer microsphere.
A further object of the present invention is to provide the application of above-mentioned water dispersible magnetic high polymer microsphere.
Purpose of the present invention realizes by following technical proposals: a kind of water dispersible magnetic high polymer microsphere, it is characterized in that the outer hydrophilic polymer that is, but internal layer be can be UV-crosslinked polymkeric substance and original position produce the polymkeric substance at magnetic center, between two kinds of polymkeric substance of internal layer is random copolymerization, above-mentioned two kinds of polymkeric substance and outer field polymkeric substance are block copolymerizations, are the superparamagnetism center but produce the inorganic superparamagnetic material that the polymer in situ at magnetic center forms with original position; Make with template and living polymerization (living polymerization is an atom transfer radical polymerization) method, described diameter of micro ball scope is 70～5000nm, magnetic content is 5～40% (mass percents), and saturation magnetization is 1.0～15.0emu/g, and has good water dispersible.
The monomer of described hydrophilic polymer has water-soluble or wetting ability, as the polyoxyethylene esters of acrylic acid, as poly glycol monomethyl ether acrylate etc.
The monomer of described polymkeric substance that can be UV-crosslinked is the material of side chain just like reactive groups such as protection hydroxyl, protection amidos, as: 2-methacrylic acid trimethylsilyl ethers ethyl ester or vinylformic acid trimethylsilyl ethers ethyl ester etc.
It is tert-butyl acrylate that but described original position produces the monomer of the polymkeric substance at magnetic center.
Described inorganic superparamagnetic material is for having paramagnetic inorganic metal and oxide compound thereof, as iron (Fe) simple substance, Z 250 (Fe
3O
4) or γ-ferric oxide (γ-Fe
2O
3) etc.
The preparation method of above-mentioned water dispersible magnetic high polymer microsphere comprises the steps:
(1) preparation of template initiator (activation of template)
Add in the nano-form powder and contain 0.1～1.0Wt%N, in the anhydrous tetrahydrofuran solution of dinethylformamide (DMF), drip activating reagent, stirring is spent the night; Solid is taken out in centrifugal or filtration back, and with the anhydrous tetrahydro furan washing, vacuum-drying obtains the template initiator;
(2) with template initiator grafting bi-block copolymer
But template initiator, the monomer+original position of polymkeric substance that can be UV-crosslinked produce deoxygenation after monomer, solvent and the catalyst mix of polymkeric substance at magnetic center; The aglucon that adds deoxygenation again was in 60～110 ℃ of stirring reactions 12～48 hours; With the mixed solvent dialysis of reaction solution with methyl alcohol and tetrahydrofuran (THF), be deposited in the anhydrous diethyl ether, vacuum-drying obtains product A; Described template initiator: but the monomer of polymkeric substance that can be UV-crosslinked+original position produces the monomer of the polymkeric substance at magnetic center: solvent: catalyzer: aglucon (mass ratio)=1: 30: 30: 0.12: 0.288～1: 400: 400: 1.6: 3.84; But described original position produces the monomer of the polymkeric substance at magnetic center: the monomeric mass ratio of polymkeric substance that can be UV-crosslinked is 4: 1～3: 1.
Get deoxygenation after monomer, solvent and the catalyst mix of above-mentioned product A, hydrophilic polymer, add the aglucon of deoxygenation again, in 60～110 ℃ of reactions 12～48 hours down, the dialysis of reaction solution water obtains dialyzate; Described product A: the monomer of hydrophilic polymer: solvent: catalyzer: aglucon (mass ratio)=1: 2.5: 2.5: 0.025: 0.06～1: 80: 80: 0.8: 1.92.
(3) micro-sphere structure is fixing
The dialyzate that step (2) is obtained stirs hydrolysis 2～6 hours with the hydrochloric acid soln of 1～10Wt%, volatilizes solvent, and vacuum-drying obtains product B, with being dissolved in the product B in the pyridine, obtains solution C; Other gets cinnamyl chloride and is dissolved in the pyridine, obtains the cinnamyl chloride pyridine solution, and the cinnamyl chloride pyridine solution is added drop-wise in the solution C, and sealing was stirred 8～14 hours, and with reacting liquid filtering, filtrate is added drop-wise in the ether, filters, and will precipitate vacuum-drying, obtains product D; Product D is scattered in the water, under ultraviolet lamp, shone 3～12 hours, make it crosslinking curing, obtain the aqueous solution of cross-linking products.
(4) preparation of magnetic microsphere
With the aqueous solution of the cross-linking products that obtains in the step (3) and hydrofluoric acid solution reaction 3～8 hours, remove the template material with etching, the aqueous solution of described cross-linking products: the hydrofluoric acid solution volume ratio was 1: 0.2～0.5; Then with the reaction solution dialysis, volatilize solvent seasoning after; The gained solid disperses with the solution of trifluoroacetic acid and methylene dichloride, removes the tertiary butyl in the cross-linking products with hydrolysis; Described trifluoroacetic acid: the volume ratio of methylene dichloride is 1: 3; Product earlier with the methyl alcohol dialysis again with the water dialysis, then with dialyzate and ferrous ion (Fe
2+) solution mix with volume ratio 1: 1, sealing is stirred, and makes the abundant combination of carboxyl and ferrous ion, regulating pH value with alkali is 7～9, makes and carboxyl bonded ferrous iron precipitates, and adds hydrogen peroxide (H then
2O
2) be ferric iron to generate the superparamagnetism center with oxidation of divalent, separate with strong magnet, obtain water dispersible magnetic high polymer microsphere.
In the step (1), described nano-form powder is for the surperficial inorganic nanoparticles that contains reactive groups such as hydroxyl or amido, as nano silicon (SiO
2) or nano titanium oxide (TiO
2) etc., its particle size range is 20～500nm.Described activating reagent is thionyl chloride (SOCl
2) or contain etheride such as 2 bromo propionyl bromide or the 2-bromine isobutyl acylbromide etc. that replace halogen element.
In the step (2), described solvent is DMF (N, dinethylformamide), toluene or methyl-phenoxide etc.Described catalyzer is that the halogen of IB family or VIIIB family is as cuprous chloride, cuprous bromide, cuprous acetate, protobromide nickel, iron protochloride or palladium diacetate etc.Described aglucon is the polyamines class, as: PMDETA (PMDETA), Me
6TREN (three-(N, N dimethylamine base ethyl) amine) or dNbpy (second bipyridine) etc.
In order to realize the present invention better, particularly preferred nano-form powder is the nano silicon of particle diameter 20nm.
The method of deoxygenation is the method that vacuumizes with frozen liq or the method for logical rare gas element such as nitrogen or argon gas in the described step (2).
Methyl alcohol in the mixed solvent of methyl alcohol and tetrahydrofuran (THF) in the described step (2): the volume ratio of tetrahydrofuran (THF) is preferably 1: 1.
Preferable reaction temperature is 60～110 ℃ in the described step (2), and the reaction times is 12～24 hours.
In the described step (4), described alkali is alkali such as 2Wt% sodium hydroxide or ammoniacal liquor.
Above-mentioned water dispersible magnetic high polymer microsphere can be used for fields such as the additive of composite plastic, various separation and purification process (fixed enzyme vector, biologically active substance enrichment), target medicine carrier, and purposes is very extensive.
The present invention compared with prior art has following advantage and beneficial effect:
1, the present invention adopts template, and template can be removed to improve the capacity of magneticmedium in etching, improves the magnetic responsiveness of microballoon, and realizes that according to template the height of particle diameter is controlled.2, the present invention adopts the living polymerization method, improves the controllability of microspherulite diameter, reduces the size distribution of microballoon.3, the microballoon of the present invention's preparation is pure, does not have non-specific cohesion impurity, can be applied to fields such as medical treatment, bio-science.4, owing to aqueous systems in the reality is widely used, use poly glycol monomethyl ether esters of acrylic acid (polyoxyethylene glycol (400) monomethyl ether acrylate) hydrophilic monomer, microballoon of the present invention has good water dispersible and biocompatibility.5, the microballoon of the present invention's preparation has well dispersing characteristic again in water, after the microballoon drying, can at an easy rate it be scattered in again in the water and stable existence, is very easy to store and transportation.
Embodiment
The present invention is described in further detail below in conjunction with embodiment, but embodiments of the present invention are not limited thereto.
Embodiment 1
(1) preparation of template initiator (activation of template)
Get 5g SiO
2(particle diameter 20nm) powder adds 200mL with it and contains 0.1Wt%N, in anhydrous tetrahydro furan (THF) solution of dinethylformamide (DMF), drips 10mL thionyl chloride (SOCl
2), stirring is spent the night; Filter and take out lower floor's solid, with anhydrous tetrahydro furan washing 5 times, normal temperature vacuum-drying obtains SiO
2The template initiator.
(2) the template initiator grafting bi-block copolymer for preparing with step (1)
A, get 1mLME
6The logical nitrogen of TREN half an hour is with deoxygenation; Get the 0.1g SiO of step (1) preparation
2Template initiator, 20mgCuBr, 4g tert-butyl acrylate (t-BA), 1g 2-methacrylic acid trimethylsilyl ethers ethyl ester (HEMA-tms), 7mLDMF mix, and vacuumize deoxygenation with liquid nitrogen freezing; The ME that adds 48mg deoxygenation in advance then
6TREN was in 110 ℃ of stirring reactions 12 hours, and after reaction finished, reaction solution was deposited in the anhydrous diethyl ether with methyl alcohol and tetrahydrofuran (THF) mixed solvent (volume ratio 1: 1) dialysis, and vacuum-drying obtains product A 2.2g.Wherein, SiO
2Template initiator: HEMA-tms+t-BA: DMF: CuBr: ME
6TREN (mass ratio)=1: 50: 50: 0.2: 0.48; The mass ratio of t-BA: HEMA-tms is 4: 1.
B, get above-mentioned product A 0.5g, 12.5mgCuBr, 1.25g polyoxyethylene glycol (400) monomethyl ether acrylate, 3mL DMF mixing deoxygenation after, add the 30mg ME of deoxygenation in advance
6TREN reacted 12 hours down in 80 ℃, and the dialysis of reaction solution water obtains dialyzate.Wherein, product A: polyoxyethylene glycol (400) monomethyl ether acrylate: DMF: CuBr: ME
6TREN (mass ratio)=1: 2.5: 2.5: 0.025: 0.06.
(3) micro-sphere structure is fixing
Get above-mentioned dialyzate and stirred 6 hours with the 3Wt% hydrochloric acid soln, volatilize solvent, vacuum-drying gets 0.95g solid B.
Get the reaction flask adding 10mL exsiccant pyridine dissolving that exsiccant product B 0.95g places lucifuge, obtain solution C; Other gets the 0.2g cinnamyl chloride and is dissolved in the 10mL exsiccant pyridine, obtain the cinnamyl chloride pyridine solution, the cinnamyl chloride pyridine solution is added drop-wise in the solution C, and sealing was stirred 12 hours, reacting liquid filtering, filtrate is added drop-wise in the ether, obtain white solid, filter, precipitation vacuum-drying, product keeps in Dark Place, and gets product D 1.1g.
The 0.7g product D is scattered in the water, made it crosslinking curing in 3 hours, obtain the aqueous solution of structure fixed cross-linking products with the long ultra violet lamp of 500w all-wave.
(4) preparation of magnetic microsphere
The hydrofluoric acid aqueous solution of getting 38%Wt is added drop-wise in the aqueous solution of said structure fixed cross-linking products reaction and removed silicon-dioxide with etching, the aqueous solution of cross-linking products in 6 hours: the hydrofluoric acid solution volume ratio is 1: 0.4; The methyl alcohol dialysis is extremely anhydrous then with the water dialysis of reaction solution elder generation, after volatilizing solvent seasoning fully, methylene dichloride and trifluoroacetic acid solution (methylene dichloride: trifluoroacetic acid volume ratio 3: 1) disperse the gained solid with 10ml, stirring is spent the night and is removed the tertiary butyl in the cross-linking products with hydrolysis, product with the methyl alcohol dialysis then with the abundant dialysis of water, then with the FeCl of dialyzate and 5Wt%
2The solution of solution mixes sealing, stirs 12 hours, and solution is removed unnecessary FeCl with the water dialysis
2, it is 9 to make and carboxyl bonded ferrous iron precipitates that the sodium hydroxide that adds 2Wt% is regulated pH value, adds 3mL hydrogen peroxide (H then
2O
2) be ferric iron with oxidation of divalent, form Z 250 or γ-ferric oxide generating the superparamagnetism center, and make magnetic center growth 4 hours, separate with strong magnet, wash 5 times, obtain water dispersible magnetic high polymer microsphere 1.2g.The diameter of gained magnetic macromolecular microsphere is 75nm, and magnetic content is 37.8%, and saturation magnetization is 14.2emu/g.
Embodiment 2
(1) preparation of template initiator (activation of template)
Get 5g SiO
2(particle diameter 20nm) powder adds 200mL with it and contains 1.0Wt%N, in anhydrous tetrahydro furan (THF) solution of dinethylformamide (DMF), drips 10mL thionyl chloride (SOCl
2), stirring is spent the night; 2000～4000 commentaries on classics/min are centrifugal, take out solid, and with anhydrous tetrahydro furan washing 4 times, normal temperature vacuum-drying obtains SiO
2The template initiator.
(2) the template initiator grafting bi-block copolymer for preparing with step (1)
A, get 1mLME
6The logical nitrogen of TREN half an hour is with deoxygenation; Get the 0.15g SiO of step (1) preparation
2Template initiator, 3.4g tert-butyl acrylate (t-BA), 1.1g 2-methacrylic acid trimethylsilyl ethers ethyl ester (HEMA-tms), 6mL toluene, 18mgCuCl mix, and vacuumize deoxygenation with liquid nitrogen freezing; The 43mgME that in reaction flask, adds deoxygenation then
6TREN was in 110 ℃ of stirring reactions 12 hours.After reaction finishes with reaction solution with methyl alcohol and tetrahydrofuran (THF) (volume ratio is 1: 1) mixed solvent dialysis, be deposited in the anhydrous diethyl ether vacuum-drying.Obtain product A 1.9g.Wherein, SiO
2Template initiator: HEMA-tms+t-BA: toluene: CuCl: ME
6TREN (mass ratio)=1: 30: 30: 0.12: 0.288～1: 400: 400: 1.6: 3.84; The mass ratio of t-BA: HEMA-tms is 3: 1.
B, get above-mentioned product A 0.2g, 4.0g polyoxyethylene glycol (400) monomethyl ether acrylate, 5mL toluene, 40mgCuCl mixing deoxygenation after, add the 96mg ME of deoxygenation in advance
6Among the TREN, reacted 12 hours down in 100 ℃, the dialysis of reaction solution water obtains dialyzate.Wherein, product A: polyoxyethylene glycol (400) monomethyl ether acrylate: toluene: CuCl: ME
6TREN (mass ratio)=1: 20: 20: 0.2: 0.48.
(3) micro-sphere structure is fixing
Get above-mentioned whole dialyzate and stirred 2 hours with the 10Wt% hydrochloric acid soln, volatilize solvent, vacuum-drying gets product B 1.8g.
Get the reaction flask that exsiccant product B 1g places lucifuge, add the dissolving of 10mL exsiccant pyridine, obtain solution C, other gets the 0.2g cinnamyl chloride and is dissolved in the 10mL exsiccant pyridine, obtains the cinnamyl chloride pyridine solution, and the cinnamyl chloride pyridine solution is added drop-wise in the above-mentioned solution C, sealing was stirred 8 hours, reacting liquid filtering is used ether sedimentation, filters, obtain white solid, precipitation vacuum-drying gets product D 0.9g, and product keeps in Dark Place.
Above-mentioned 0.7g product D is scattered in the water made it crosslinking curing in 12 hours, obtain the aqueous solution of structure fixed cross-linking products with the long ultra violet lamp of 500w all-wave.
(4) preparation of magnetic microsphere
The hydrofluoric acid aqueous solution of 38Wt% is added drop-wise in the aqueous solution of said structure fixed cross-linking products reaction and removed silicon-dioxide with etching, the aqueous solution of cross-linking products in 6 hours: the hydrofluoric acid solution volume ratio is 1: 0.2; The methyl alcohol dialysis is extremely anhydrous then with the water dialysis of reaction solution elder generation, after volatilizing solvent seasoning fully, with the methylene dichloride of 10ml and the solution of trifluoroacetic acid (methylene dichloride: trifluoroacetic acid volume ratio 3: 1) disperse the gained solid, stirring is spent the night and is removed the tertiary butyl in the cross-linking products with hydrolysis, product with the methyl alcohol dialysis after again with the abundant dialysis of water, then with the FeCl of dialyzate and 5Wt%
2The solution of solution mixes sealing, stirs 12 hours, and solution is removed unnecessary FeCl with the water dialysis
2, adding ammoniacal liquor adjusting pH value is 7, makes the ferrous iron precipitation, adds 3mL hydrogen peroxide (H then
2O
2) oxidation, be that ferric iron forms Z 250 or γ-ferric oxide generating the superparamagnetism center with oxidation of divalent, and make magnetic center growth 4 hours, separate with strong magnet, wash 6 times, get water dispersible magnetic high polymer microsphere 1.0g.The diameter of gained magnetic macromolecular microsphere is 80nm, and magnetic content is 8.2%, and saturation magnetization is 2.7emu/g.
Embodiment 3
(1) preparation of template initiator (activation of template)
Get 5g nano titanium oxide (TiO
2) (particle diameter 100nm) powder, it is added 200mL contain 0.5Wt%N, in anhydrous tetrahydro furan (THF) solution of dinethylformamide (DMF), drip 10mL2-bromine isobutyl acylbromide, stirring is spent the night; Filter and take out lower floor's solid, with anhydrous tetrahydro furan washing 5 times, normal temperature vacuum-drying obtains TiO
2The template initiator.
(2) the template initiator grafting bi-block copolymer for preparing with step (1)
A, get the logical argon gas of 1mL PMDETA half an hour with deoxygenation; Get the 0.1g TiO of step (1) preparation
2Template initiator, 24mgCuCl, 4.5g tert-butyl acrylate (t-BA), 1.5g vinylformic acid trimethylsilyl ethers ethyl ester, 8mL methyl-phenoxide mix, logical argon gas deoxygenation; The PMDETA that adds 57.6mg deoxygenation in advance then was in 85 ℃ of stirring reactions 24 hours, and after reaction finished, reaction solution was deposited in the anhydrous diethyl ether with methyl alcohol and tetrahydrofuran (THF) mixed solvent (volume ratio 1: 1) dialysis, and vacuum-drying obtains product A 2.4g.Wherein, TiO
2Template initiator: vinylformic acid trimethylsilyl ethers ethyl ester+t-BA: methyl-phenoxide: CuCl: PMDETA (mass ratio)=1: 60: 60: 0.24: 0.576; T-BA: the mass ratio of vinylformic acid trimethylsilyl ethers ethyl ester is 3: 1.
B, get above-mentioned product A 0.1g, 40mgCuCl, 4.0g polyoxyethylene glycol (400) monomethyl ether acrylate, 5mL methyl-phenoxide mixing deoxygenation after, add the 96mg PMDETA of deoxygenation in advance, reacted 24 hours down in 85 ℃, the dialysis of reaction solution water obtains dialyzate.Wherein, product A: polyoxyethylene glycol (400) monomethyl ether acrylate: methyl-phenoxide: CuCl: PMDETA (mass ratio)=1: 40: 40: 0.4: 0.96.
(3) micro-sphere structure is fixing
Get above-mentioned dialyzate and stirred 4 hours with the 1Wt% hydrochloric acid soln, volatilize solvent, vacuum-drying gets 1.65g solid B.
Get the reaction flask adding 10mL exsiccant pyridine dissolving that exsiccant product B 0.85g places lucifuge, obtain solution C; Other gets the 0.2g cinnamyl chloride and is dissolved in the 10mL exsiccant pyridine, obtain the cinnamyl chloride pyridine solution, the cinnamyl chloride pyridine solution is added drop-wise in the solution C, and sealing was stirred 12 hours, reacting liquid filtering, filtrate is added drop-wise in the ether, obtain white solid, filter, precipitation vacuum-drying, product keeps in Dark Place, and gets product D 0.9g.
The 0.7g product D is scattered in the water, made it crosslinking curing in 8 hours, obtain the aqueous solution of structure fixed cross-linking products with the long ultra violet lamp of 500w all-wave.
(4) preparation of magnetic microsphere
The hydrofluoric acid aqueous solution of getting 38%Wt is added drop-wise in the aqueous solution of said structure fixed cross-linking products reaction and removed silicon-dioxide with etching, the aqueous solution of cross-linking products in 6 hours: the hydrofluoric acid solution volume ratio is 1: 0.5; The methyl alcohol dialysis is extremely anhydrous then with the water dialysis of reaction solution elder generation, after volatilizing solvent seasoning fully, with the methylene dichloride of 10ml and the solution of trifluoroacetic acid (methylene dichloride: trifluoroacetic acid volume ratio 3: 1) disperse the gained solid, stirring is spent the night and is removed the tertiary butyl in the cross-linking products with hydrolysis, product with the methyl alcohol dialysis then with the abundant dialysis of water, then with the FeCl of dialyzate and 5Wt%
2The solution of solution mixes sealing, stirs 14 hours, and solution is removed unnecessary FeCl with the water dialysis
2, the sodium hydroxide adjusting pH value that adds 2Wt% is 8, makes and carboxyl bonded ferrous iron precipitation, adds 3mL hydrogen peroxide (H then
2O
2) be that ferric iron forms Z 250 or γ-ferric oxide generating the superparamagnetism center with oxidation of divalent, and make magnetic center growth 4 hours, separate with strong magnet, wash 5 times, obtain water dispersible magnetic high polymer microsphere 1.2g.The diameter of gained magnetic macromolecular microsphere is 500nm, and magnetic content is 11.3%, and saturation magnetization is 5.2emu/g.
Embodiment 4～7 related conditional parameters see Table 1, and other steps are with embodiment 1.
Each specific embodiment of table 1
| Embodiment | Nano-form powder diameter (n m) | Catalyzer | Aglucon | Temperature in the step (2) (℃), the time (h) | The template initiator: but the monomer of polymkeric substance that can be UV-crosslinked+original position produces the monomer of the polymkeric substance at magnetic center: solvent: catalyzer: aglucon (mass ratio) | But original position produces the monomer of the polymkeric substance at magnetic center: the monomeric mass ratio of polymkeric substance that can be UV-crosslinked | Product A: the monomer of outer hydrophilic polymer: solvent: catalyzer: aglucon (mass ratio) | Diameter of micro ball (nm) | Magnetic content (%) | Saturation magnetization (em u/g) |
| 1 | 20 | CuBr | Me 6TREN | 110，12 | 1∶50∶50∶0.2∶0.48 | 4∶1 | 1∶2.5∶2.5∶0.025∶0.06 | 75 | 37.8 | 14.2 |
| 2 | 20 | CuCl | Me 6TREN | 110，12 | 1∶30∶30∶0.12∶0.288 | 3∶1 | 1∶20∶20∶0.2∶0.48 | 80 | 8.2 | 2.7 |
| 3 | 100 | CuCl | PMDETA | 85，24 | 1∶60∶60∶0.24∶0.576 | 3∶1 | 1∶40∶40∶0.4∶0.96 | 500 | 11.3 | 5.2 |
| 4 | 100 | CuCl | Me 6TREN | 60，48 | 1∶100∶100∶0.4∶0.96 | 4∶1 | 1∶5∶5∶0.05∶0.12 | 500 | 35 | 13 |
| 5 | 200 | CuBr | PMDETA | 110，12 | 1∶120∶120∶0.4∶0.96 | 3∶1 | 1∶80∶80∶0.8∶1.92 | 1000 | 7.5 | 1.9 |
| 6 | 200 | CuCl | dNbpy | 60，48 | 1∶200∶200∶0.8∶1.92 | 4∶1 | 1∶8∶8∶0.08∶0.192 | 1000 | 36.5 | 13.8 |
| 7 | 500 | CuBr | dNbpy | 85，24 | 1∶400∶400∶1.6∶3.84 | 4∶1 | 1∶16∶16∶0.16∶0.384 | 5000 | 30 | 11.3 |
The foregoing description is a preferred implementation of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. water dispersible magnetic high polymer microsphere, it is characterized in that: described water dispersible magnetic high polymer microsphere is outer to be hydrophilic polymer, but internal layer be can be UV-crosslinked polymkeric substance and original position produce the polymkeric substance at magnetic center, between two kinds of polymkeric substance of internal layer is random copolymerization, above-mentioned two kinds of polymkeric substance and outer field polymkeric substance are block copolymerizations, are the superparamagnetism center but produce the inorganic superparamagnetic material that the polymer in situ at magnetic center forms with original position; Described diameter of micro ball scope is 70～5000nm, and magnetic content is 5～40%, and saturation magnetization is 1.0～15.0emu/g.
2. a kind of water dispersible magnetic high polymer microsphere according to claim 1 is characterized in that: the monomer of described hydrophilic polymer is the poly glycol monomethyl ether acrylate; The monomer of described polymkeric substance that can be UV-crosslinked is 2-methacrylic acid trimethylsilyl ethers ethyl ester or vinylformic acid trimethylsilyl ethers ethyl ester; It is tert-butyl acrylate that but described original position produces the monomer of the polymkeric substance at magnetic center; Described inorganic superparamagnetic material is iron simple substance, Z 250 or γ-ferric oxide.
3. the preparation method of the described water dispersible magnetic high polymer microsphere of claim 1 is characterized in that comprising the steps:
(1) preparation of template initiator
Add in the nano-form powder and contain 0.1～1.0Wt%N, in the anhydrous tetrahydrofuran solution of dinethylformamide, drip activating reagent, stirring is spent the night; Solid is taken out in centrifugal or filtration back, and with the anhydrous tetrahydro furan washing, vacuum-drying obtains the template initiator;
(2) with template initiator grafting bi-block copolymer
But template initiator, the monomer+original position of polymkeric substance that can be UV-crosslinked produce deoxygenation after monomer, solvent and the catalyst mix of polymkeric substance at magnetic center; The aglucon that adds deoxygenation again was in 60～110 ℃ of stirring reactions 12～48 hours; With the mixed solvent dialysis of reaction solution with methyl alcohol and tetrahydrofuran (THF), be deposited in the anhydrous diethyl ether, vacuum-drying obtains product A; Described template initiator: but the monomer of polymkeric substance that can be UV-crosslinked+original position produces the monomer of the polymkeric substance at magnetic center: and solvent: catalyzer: the mass ratio of aglucon is 1: 30: 30: 0.12: 0.288～1: 400: 400: 1.6: 3.84; But described original position produces the monomer of the polymkeric substance at magnetic center: the monomeric mass ratio of polymkeric substance that can be UV-crosslinked is 4: 1～3: 1;
Get deoxygenation after monomer, solvent and the catalyst mix of above-mentioned product A, hydrophilic polymer, add the aglucon of deoxygenation again, in 60～110 ℃ of reactions 12～48 hours down, the dialysis of reaction solution water obtains dialyzate; Described product A: the monomer of hydrophilic polymer: solvent: catalyzer: the mass ratio of aglucon is 1: 2.5: 2.5: 0.0255: 0.06～1: 80: 80: 0.8: 1.92;
(3) micro-sphere structure is fixing
The dialyzate that step (2) is obtained stirs hydrolysis 2～6 hours with the hydrochloric acid soln of 1～10Wt%, volatilizes solvent, and vacuum-drying obtains product B, with being dissolved in the product B in the pyridine, obtains solution C; Other gets cinnamyl chloride and is dissolved in the pyridine, obtains the cinnamyl chloride pyridine solution, and the cinnamyl chloride pyridine solution is added drop-wise in the solution C, and sealing was stirred 8～14 hours, and with reacting liquid filtering, filtrate is added drop-wise in the ether, filters, and will precipitate vacuum-drying, obtains product D; Product D is scattered in the water, under ultraviolet lamp, shone 3～12 hours, make it crosslinking curing, obtain the aqueous solution of cross-linking products;
(4) preparation of magnetic microsphere
With the aqueous solution of the cross-linking products that obtains in the step (3) and hydrofluoric acid solution reaction 3～8 hours, the aqueous solution of described cross-linking products: the hydrofluoric acid solution volume ratio was 1: 0.2～0.5; Then with the reaction solution dialysis, volatilize solvent seasoning after; The gained solid disperses with the solution of trifluoroacetic acid and methylene dichloride; Described trifluoroacetic acid: the volume ratio of methylene dichloride is 1: 3; Product earlier with the methyl alcohol dialysis again with the water dialysis, then dialyzate was mixed with the solution of ferrous ion in 1: 1 by volume, sealing is stirred, regulating the pH value with alkali is 7～9, adding hydrogen peroxide then is that ferric iron is to generate the superparamagnetism center with oxidation of divalent, separate with strong magnet, obtain water dispersible magnetic high polymer microsphere;
The nano-form powder is nano silicon or nano titanium oxide in the described step (1), and its particle size range is 20～500nm; Described activating reagent is thionyl chloride, 2 bromo propionyl bromide or 2-bromine isobutyl acylbromide;
Solvent is N in the described step (2), dinethylformamide, toluene or methyl-phenoxide; Described catalyzer is the halogen of IB family or VIIIB family; Described aglucon is PMDETA, three-(N, N dimethylamine base ethyl) amine or second bipyridine.
4. the preparation method of water dispersible magnetic high polymer microsphere according to claim 3, it is characterized in that: the catalyzer in the described step (2) is cuprous chloride, cuprous bromide, cuprous acetate, protobromide nickel, iron protochloride or palladium diacetate.
5. the preparation method of water dispersible magnetic high polymer microsphere according to claim 3, it is characterized in that: described nano-form powder is the nano silicon of particle diameter 20nm.
6. the preparation method of water dispersible magnetic high polymer microsphere according to claim 3 is characterized in that: the method for deoxygenation is the method that vacuumizes with frozen liq or the method for logical rare gas element in the described step (2).
7. the preparation method of water dispersible magnetic high polymer microsphere according to claim 3 is characterized in that: methyl alcohol in the mixed solvent of methyl alcohol and tetrahydrofuran (THF) in the described step (2): the volume ratio of tetrahydrofuran (THF) is 1: 1.
8. the preparation method of water dispersible magnetic high polymer microsphere according to claim 3 is characterized in that: temperature of reaction is 60～110 ℃ in the described step (2), and the reaction times is 12～24 hours.
9. the preparation method of water dispersible magnetic high polymer microsphere according to claim 3 is characterized in that: alkali is 2Wt% sodium hydroxide or ammoniacal liquor in the described step (4).
10. the described water dispersible magnetic high polymer microsphere of claim 1 is in additive, fixed enzyme vector or the target medicine carrier Application for Field of composite plastic.
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