CN108192007A - A kind of carboxy-functionalized polyurethane coated magnetic microballoon and preparation method thereof - Google Patents
A kind of carboxy-functionalized polyurethane coated magnetic microballoon and preparation method thereof Download PDFInfo
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- CN108192007A CN108192007A CN201711458372.9A CN201711458372A CN108192007A CN 108192007 A CN108192007 A CN 108192007A CN 201711458372 A CN201711458372 A CN 201711458372A CN 108192007 A CN108192007 A CN 108192007A
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F212/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
- C08F212/02—Monomers containing only one unsaturated aliphatic radical
- C08F212/04—Monomers containing only one unsaturated aliphatic radical containing one ring
- C08F212/06—Hydrocarbons
- C08F212/08—Styrene
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/20—After-treatment of capsule walls, e.g. hardening
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/20—After-treatment of capsule walls, e.g. hardening
- B01J13/22—Coating
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F257/00—Macromolecular compounds obtained by polymerising monomers on to polymers of aromatic monomers as defined in group C08F12/00
- C08F257/02—Macromolecular compounds obtained by polymerising monomers on to polymers of aromatic monomers as defined in group C08F12/00 on to polymers of styrene or alkyl-substituted styrenes
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/30—Low-molecular-weight compounds
- C08G18/32—Polyhydroxy compounds; Polyamines; Hydroxyamines
- C08G18/3203—Polyhydroxy compounds
- C08G18/3206—Polyhydroxy compounds aliphatic
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- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
- C08G18/72—Polyisocyanates or polyisothiocyanates
- C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
- C08G18/76—Polyisocyanates or polyisothiocyanates cyclic aromatic
- C08G18/7657—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings
- C08G18/7664—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings containing alkylene polyphenyl groups
- C08G18/7671—Polyisocyanates or polyisothiocyanates cyclic aromatic containing two or more aromatic rings containing alkylene polyphenyl groups containing only one alkylene bisphenyl group
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- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
- C08J7/04—Coating
- C08J7/0427—Coating with only one layer of a composition containing a polymer binder
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- C08J7/12—Chemical modification
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- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
- C08J7/12—Chemical modification
- C08J7/14—Chemical modification with acids, their salts or anhydrides
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- C08J2325/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring; Derivatives of such polymers
- C08J2325/02—Homopolymers or copolymers of hydrocarbons
- C08J2325/04—Homopolymers or copolymers of styrene
- C08J2325/06—Polystyrene
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- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2351/00—Characterised by the use of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives of such polymers
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- C08J2475/00—Characterised by the use of polyureas or polyurethanes; Derivatives of such polymers
- C08J2475/04—Polyurethanes
- C08J2475/08—Polyurethanes from polyethers
Abstract
This case is related to a kind of carboxy-functionalized polyurethane coated magnetic microballoon and preparation method thereof; the preparation method first prepares crosslinked polystyrene microsphere; surface functionalization then is carried out to crosslinked polystyrene microsphere, modifies one kind in amino, carboxyl, sulfonyl, methoxyl group or chloromethyl；Then microballoon is magnetized, and to coating polyurethane coating through magnetized crosslinked polystyrene microsphere；Finally microballoon is carried out carboxy-functionalized.There is monodisperse using polyurethane coated magnetic microballoon carboxy-functionalized made from the method for the present invention, uphang buoyancy, high-biocompatibility and can be responded compared with ferromagnetism, there is good practical value and application prospect in fields such as enzyme immobilizatio, immunoassays, cell separation, the analyses of environment heavy metal analysis.
Description
Technical field
The present invention relates to nano-micrometre Material Fields, and in particular to a kind of carboxy-functionalized polyurethane coated magnetic microballoon
And preparation method thereof.
Background technology
Magnetic microsphere has in multiple medical treatment and biochemical field and has been widely used, for example, should to patient's treatment
In, desired body part can be targeted by the magnetic microsphere for carrying drug by applying magnetic field.For another example, in diagnostic assay application
In, magnetic field is applied to containing the analyte sample combined with magnetic microsphere so that i.e. separable without using centrifuging or filtering
The analyte, magnetic separation technique is namely utilized in this.This technology is using magnetic particle as carrier, and envelope antigen resists
The biomolecule such as body, enzyme either rhetorical function group, under outer plus magnetic oriented control, by adsorbing, cleaning, eluting
Deng operation, can from complicated biosystem, soil, water equal samples isolated target molecule, there is Magnetic Isolation letter
The advantages of folk prescription is just, absorption specificity is high, detection limit is low numerous.Magnetic particle has as biomolecule carrier：Monodisperse,
High specific surface area, good dispersibility, the response of faster magnetic property, preferable water solubility and more active function groups etc.
Feature.Reunion, sedimentation and leakage field phenomenon are generated between the magnetic particle being synthesized in order to prevent, it usually needs on its surface
High density protective layer is introduced, such as inorganic material, polysaccharide or polymer.
Polyurethane material is due to the incompatibility of soft and hard segments, and there are apparent micro phase separation structure, wherein soft segment provides bullet
Property, hard section, which plays, enhances filling and crosslinked action, and this multiphase macromolecule has high mechanical strength, and blood compatibility is good, tissue
The performances such as excellent in compatibility.So polyurethane material is widely used in biomedicine field, such as man-made organ, medical
Many therapeutic treatment necks such as conduit, birth control necessities, controllable sustained-release drug, medical adhesive, medical instrument, medical auxiliary material
Domain.A kind of super-hydrophobic polyurethane/oxide nano particle hybrid coating material and its preparation are proposed in CN201010145642.2
It is 1~5 μm, but due to the hydrophobicity of its coating that method, which using polyurethane is the grain size that wall material is prepared into Nd-Fe-B powder microcapsules,
Limit the application in biomedicine.CN201510069423.3 discloses a kind of silicon polished hydrolytic sol of nanometer titanium dioxide and coagulates
Glue method production method prepares the coating that hydrophilic silicon dioxide microsphere surface coats a strata urethane first, unfortunately,
It does not also carry out the modification of functional group so as to be difficult to be applied to biomedicine field again.Patent CN201310352022.X then exists
It is changed in synthetic method, first synthesis of polyurethane micella, then carries out coated magnetic particle, however this mode is easily made
Into coating uneven, the characteristics of product monodispersity is poor.
The main preparation method of magnetic polymer microsphere has at present：Coprecipitation, heteropolymerization method, electroless plating method, successively
Construction from part, hydrothermal synthesis method, emulsion method, sol-gal process etc. need one layer of coating for being easy to modification, such as inorganic material in outer layer
Silica, glucan, chitosan, cellulose and high molecular polymer etc., these coatings need satisfaction 1, are easy to surface modification,
2nd, there is certain antipollution function of albumen, i.e. surface can prevent certain non-specific adsorption, as albumen, nucleic acid, cell,
The non-specific adsorption of organic molecule etc., and coating also needs to modify corresponding functional group in outermost layer with rich after having modified
Its rich application.The active function groups of common function have the magnetic particle of amino, carboxyl, epoxy group etc., wherein carboxylated modification
It can be incited somebody to action under the action of specific coupling reagent (such as EDC (1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides))
The bio-ligands such as polypeptide, albumen, oligonucleotide covalent coupling can also carry out NHS (N- hydroxyls easily to magnetic particle surface
Base succinimide) etc. it is modified, be one of medicine and the mostly important carrier of molecular biology research.At present in progress,
Research in relation to carboxy-functionalized polyurethane coated magnetic microballoon is less, and develop the magnetic microsphere of this type not only can be to prevent
The only magnetic leakage phenomenon of microballoon can also obtain the preferable carboxy-functionalized magnetic microsphere of non-specific adsorption and be carried for nucleic acid
Take, protein purification, immunodiagnosis etc., there is very high business development to be worth.
Invention content
For shortcoming of the prior art, the present invention provides a kind of carboxy-functionalized polyurethane coated magnetic microballoons
And preparation method thereof, which not only has monodisperse, higher suspension, the characteristic that can be responded compared with ferromagnetism, but also the magnetic polymeric
Leakage field, surface do not have the function of certain non-specific adsorption that prevents, and the carboxyl functional group on its surface of utilization to object microballoon
It can be conducive to carry out various biological research with coupling protein.
To achieve the above object, technical scheme is as follows：
A kind of preparation method of carboxy-functionalized polyurethane coated magnetic microballoon, includes the following steps：
1) crosslinked polystyrene microsphere is prepared：By azodiisobutyronitrile, styrene, polyvinylpyrrolidone, absolute ethyl alcohol
Cause 10-30min in advance at 45-55 DEG C with water, after being warming up to 60-65 DEG C of reaction 2-4h, add divinylbenzene and benzene second
Alkene, and 70-90 DEG C is warming up to, react 16~20h；After reaction, eccentric cleaning is dried to obtain crosslinked polystyrene microsphere；
2) surface functionalization：By the crosslinked polystyrene microsphere that step 1) obtains by surface modified into amino, carboxylic
One kind in base, sulfonyl, methoxyl group or chloromethyl；
3) magnetize：Step 2) is taken to be dispersed in iron salt solutions by the crosslinked polystyrene microsphere of surface functionalization, is added in
Stabilizer reacts at room temperature 10-200min, adds in ammonium hydroxide, is warming up to 60-80 DEG C of reaction 1-2h；Cooling, Magnetic Isolation are obtained through magnetic
The crosslinked polystyrene microsphere of change；
4) polyurethane coating coats：Step 3) is scattered in through magnetized crosslinked polystyrene microsphere in organic solvent, is added
Enter polyisocyanates and react 2-4h in 80 DEG C；Polyisocyanates and at least one non-monohydric alcohol are then added in again at 70-90 DEG C
React 16-20h；
5) it is carboxy-functionalized：Add in carboxyl modified agent and polyisocyanates into the reaction system of step 4) the reaction was continued 4-
Carboxy-functionalized polyurethane coated magnetic microballoon is made after washing and drying by 8h.
Preferably, the preparation method, wherein, in step 1), the dosage of azodiisobutyronitrile accounts for the 0.1- of total amount
0.5%, the dosage of divinylbenzene accounts for the 10~70% of total amount.
Preferably, the preparation method, wherein, in step 3), the iron salt solutions are divalent iron salt and ferric iron
The molar ratio of the mixed liquor of salt, divalent iron salt and trivalent iron salt is 1: 1-3, and divalent iron salt is selected from FeSO47H2O, sulphur
Sour ferrous ammonium hexahydrate, frerrous chloride tetrahydrate, anhydrous frerrous chloride or combination；Trivalent iron salt is selected from six water of iron chloride
Close object, ferric sulfate, ferric nitrate nonahydrate or combination；The stabilizer is in PVP K12, PVP K15, PVP K17
One or two kinds of mixing.
Preferably, the preparation method, wherein, the organic solvent in step 4) is does not react with isocyanates
Organic solvent.
Preferably, the preparation method, wherein, step 4) and 5) in polyisocyanates be selected from two isocyanide of methylene
Acid esters, 2,4 toluene diisocyanate or its isomers, 4,4 '-oxygen bis- (phenyl isocyanates), 4,4 '-diphenyl methane two are different
Cyanate, isoflurane chalcone diisocyanate, phenylene vulcabond, 2,4- diphenyl diisocyanates, di-2-ethylhexylphosphine oxide hexamethylene
Group diisocyanate, hexamethylene diisocyanate, the own ester of 1,6- diisocyanates, 1,5 naphthalene diisocyanate ester, to tetramethyl two
One kind in toluene di-isocyanate(TDI), trans-cyclohexane -1,4- diisocyanate and tetramethylxylene diisocyanate
It is or a variety of.
Preferably, the preparation method, wherein, in step 4), the non-monohydric alcohol is selected from ethylene glycol, a contracting dipropyl
It is glycol, triethylene glycol, 1,2- propylene glycol, ten glycol, 1,2- hexylene glycols, 2- methyl-1,3-propanediols, 1,4- butanediols, two sweet
Alcohol, seven glycol, tetraethylene glycol, polypropylene glycol 200,1,6-HD, polypropylene glycol 400, polyethylene glycol, glycerine, butantriol, three
One kind in (methylol) aminomethane, oxyhydroquinone, glycerine, 2- amino-2-methyl -1,3- propylene glycol, pentaerythrite
It is or a variety of.
Preferably, the preparation method, wherein, in step 5), the carboxyl modified agent is selected from glycolic, bright ammonia
Acid, tryptophan, serine, 6- Amino-n-hexanoic acids, arginine, glutamic acid, lysine, glycine, asparatate, the poly- second of amino
It is one or more in bis- (methylol) propionic acid of glycol carboxyl, 2,2-.
It is a kind of to use polyurethane coated magnetic microballoon carboxy-functionalized made from as above any one of them preparation method.
The beneficial effects of the invention are as follows：
1st, the present invention provides a kind of carboxy-functionalized polyurethane coated magnetic microballoon, has monodisperse, uphangs buoyancy, biology
It compatibility and can be responded compared with ferromagnetism, in enzyme immobilizatio, immunoassays, cell separation, the analysis of environment heavy metal analysis etc.
Field has good practical value and application prospect.
2nd, the present invention can be by the ratio of ethyl alcohol and water, the dosage of initiator, the dosage and monomer of PVP and crosslinking agent
The grain size of proportion adjustment magnetic microsphere, the polystyrene microsphere that can prepare different-grain diameter are used for different fields；It is poly- by disperseing
A legal step prepares the crosslinked polystyrene microsphere of different-grain diameter.
3rd, the present invention takes substep to add in synthesis of polyurethane coating procedure, the mode successively reacted, effective to improve
The shortcomings that cladding that polymer magnetic bead is brought due to bad dispersibility during the reaction is inhomogenous.
4th, the hydrophobic of polyurethane magnetic bead can effectively be improved by the use of dihydric alcohol, trihydroxylic alcohol, tetrahydroxylic alcohol etc. as chain extender
Property, has adjusted the electrophilicity of entire microballoon by the proportional arrangement of hard section and soft segment, and the surface of ethylene glycol or polyethylene glycol
Effectively reduce the characteristic of non-specific adsorption albumen, nucleic acid, cell.
5th, not only its surface coating is thicker for carboxy-functionalized polyurethane coated magnetic microballoon, and a fixed length can freely be configured
The indirect arm of degree, when coupling protein, reduce the space steric effect of albumen, reduce albumen dosage, and utilize carboxyl-functional
Group can be coupled many widely used protein antibodies, have practical significance in diagnosis industry.
Description of the drawings
Fig. 1 is the synthesis schematic diagram of carboxy-functionalized polyurethane coated magnetic microballoon.
Fig. 2 is the Sample Scan electricity obtained in involved reaction process in carboxy-functionalized polyurethane coated magnetic microballoon
Sub- microscope figure, wherein, (a) crosslinked polystyrene microsphere (5 μm)；(b) crosslinked polystyrene magnetic microsphere (5 μm)；(c) it is crosslinked
Magnetic Polystyrene Microsphere (5 μm)；(d) carboxy-functionalized polyurethane coated magnetic microballoon (5 μm).
Specific embodiment
The present invention is described in further detail below in conjunction with the accompanying drawings, to enable those skilled in the art with reference to specification text
Word can be implemented according to this.
A kind of carboxy-functionalized polyurethane coated magnetic microballoon, includes the following steps：
1), prepared by 0.5~5 μm of crosslinked polystyrene microsphere：Measure 200~320mL absolute ethyl alcohols and 20~40mL deoxidations
Pure water is poured into beaker and is uniformly mixed.5~20g of precise PVP (polyvinylpyrrolidone) are added in beaker, will be upper
It states mixed solution to pour into flask, opens nitrogen deoxygenation, mechanical agitation.Precise 0.5~2.4g initiator As IBN (azos two
Isobutyronitrile) it adds in beaker, it then measures 58~72mL of monomer styrene and pours into beaker, the two is uniformly mixed and pours into flask
In, 50 DEG C are warming up to after mechanical agitation 1h, causes 30min in advance, after then heating to 65 DEG C of mechanical agitation 4h, 20~75mL is handed over
Connection agent divinylbenzene and 12~58mL styrene are dissolved in 20~100mL ethyl alcohol and being added dropwise in flask, then heat to 70~
90 DEG C, react 16~20h.After reaction, eccentric cleaning, respectively with ethyl alcohol, water eccentric cleaning respectively three times, then will crosslinking it is poly-
Phenylethylene micro ball drying preserves；
2), crosslinked polystyrene microsphere surface functionalization：By above-mentioned microballoon by it is surface modified into amino, carboxyl,
This electronegative functional group of sulfonyl, methoxyl group or chloromethyl etc., preferably carboxyl and sulfonyl be more advantageous to it is subsequent
Experiment；
3), crosslinked polystyrene microsphere magnetizes：Take above-mentioned functionalized crosslinked polystyrene microsphere 1-10g be dispersed in 10~
In 500mL iron salt solutions, 0.1~2g stabilizers are added in, react at room temperature 10~200min, add in the ammonium hydroxide of 10~50g 25%,
Temperature is risen to 60~80 DEG C and continues 1~2h.Suspension is cooled down, the magnetized crosslinked polystyrene microsphere of Magnetic Isolation, used
0.01M HCl, deionized water, ethyl alcohol clean above-mentioned material repeatedly, and finally drying preserves；
4), polyurethane coating coats：0.5~5g the magnetic microspheres cleaned are scattered in 50~90mL organic solvents,
Flask sealing 10~30min of logical nitrogen, 200~500mg of polyisocyanates is dissolved in 5~10mL organic solvents, adds in flask
In, 80 DEG C of 2~4h of reaction.Finally 200~1000mg of polyisocyanates is dissolved in 5~10mL organic solvents, adds in flask, so
It adds in afterwards in 100~2000 μ L to flask of at least one non-monohydric alcohol (alcohols containing two or two or more hydroxyls).React item
70~90 DEG C of part leads to nitrogen, 16~20h of mechanic whirl-nett reaction；
5) it is, carboxy-functionalized：150~1000mg of carboxyl modified agent and 100~500mg of polyisocyanates were dissolved in second day
In 5~10mL organic solvents, flask is added in, the reaction was continued 4~8h is finally cleaned repeatedly with second alcohol and water, and drying preserves.
Preferably, in step 1), initiator amount be total amount (monomer+crosslinking agent) 0.1~0.5%, crosslinking agent diethyl
Alkenyl benzene accounts for the 10~70% of total amount, it is preferred that crosslinking agent accounts for the 20~50% of total amount, and more preferably, crosslinking agent accounts for total amount
25~35%, the ratio of ethyl alcohol and water must not be less than 8 times, and PVP molecular weight is 10000~80000, it is preferred that the molecule of PVP
Measure is 20000~50000.More preferably, the molecular weight of PVP is 40000, i.e. PVP K30 are the most suitable.
Preferably, in step 3), mixed liquor of the iron salt solutions for divalent iron salt and trivalent iron salt, ferrous iron and ferric
Molar ratio is 1: 1~3, and divalent iron salt can be FeSO47H2O, iron ammonium sulfate hexahydrate, four water of frerrous chloride
One or several kinds of mixing in object, anhydrous frerrous chloride are closed, trivalent iron salt can be ferric chloride hexahydrate, ferric sulfate, nitre
The mixing of one or more of sour iron nonahydrate.Stabilizer is the PVP of low molecular weight, can be PVP K12, PVP K15,
One or two kinds of mixing of PVP K17.
Preferably, the organic solvent in step 4) does not react with isocyanates as reaction medium, can be benzene class (first
Benzene, benzene), acetonitrile, acetone, chloroform, ethers (n-butyl ether, ether, methyl ether, n-amylether, isopropyl ether, butyl glycol ether, dipropyl
Glycol butyl ether, ethylene glycol monohexylether), it is more preferred to acetonitrile, dimethylformamide and ether), dimethylformamide
(DMF), dimethylacetylamide (DMAC) etc., most preferably acetonitrile, dimethylformamide, dimethylacetylamide, ethers.
Preferably, in step 4), the polyisocyanates that can be used is different including methylene diisocyanate, 2,4- toluene two
Cyanate (2,4-TDI) (and its isomers or its mixture), 4,4 '-oxygen bis- (phenyl isocyanates), 4,4 '-diphenyl methane
Diisocyanate (MDI), isoflurane chalcone diisocyanate (IPDI), phenylene vulcabond (p-PDI), 2,4- diphenyl two
Isocyanates, methylene-bis-cyclohexyl diisocyanate (H12MDI), hexamethylene diisocyanate (HDI), bis- isocyanides of 1,6-
The own ester (DICH) of acid, 1,5 naphthalene diisocyanate ester (NDI), to tetramethylxylene diisocyanate (p-TMXDI), trans--ring
Hexane -1,4- diisocyanate (CHDI) or tetramethylxylene diisocyanate (m-TMXDI).Particularly preferred polyisocyanate cyanogen
Acid esters is MDI.
Preferably, in step 4), preferably using two kinds of dihydric alcohols, preferred dihydric alcohol includes ethylene glycol, a contracting dipropyl
Glycol, triethylene glycol, 1,2-PD, ten glycol, 1,2- hexylene glycols, 2- methyl-1s, it is 3-propanediol, 1,4-butanediol, seven sweet
Alcohol, tetraethylene glycol, polypropylene glycol 200,1,6- hexylene glycols, polypropylene glycol 400, polyethylene glycol, polyethylene glycol such as PEG 200,
300th, 400,500,600,800,1000, preferred diol combination is diethylene glycol (DEG) and PEG300.Also glycerine, fourth three can be added in
Alcohol, three (methylol) aminomethanes, 1,2,4- benzenetriols, 2-Amino-2-methyl-1,3-propanediol, pentaerythrite, contribute to shape
Networking shaped polymer figure layer, being more conducive to prevents magnetic leakage.More select it is excellent a kind of glycol and a kind of triol can be used, such as
Ethylene glycol is used together with butantriol, and preferred molar ratio is 1:2.
Preferably, in step 5), carboxyl modified agent can be glycolic or one or more of amino acid, such as bright
Propylhomoserin, tryptophan, serine, 6- Amino-n-hexanoic acids, arginine, glutamic acid, lysine, glycine or asparatate etc..
Can be amino-polyethyleneglycols carboxyl (polyethylene glycol of Amino End Group one end carboxyl), molecular weight is preferably 200,300,400,
500th, the polyethylene glycol of 600,800,1000,2000 or one terminal hydroxy group one end carboxyl, molecular weight is preferably 200,300,
400th, 500,600,800,1000,2000, it can also be bis- (methylol) propionic acid of 2,2- certainly.Carboxy-functionalized polyurethane packet
Cover the utilization of magnetic microsphere：
Coupling protein：With reaction buffer (0.1mM MES, pH 6.0) prepare protein solution for 1~2 μ g/ μ L and
EDC is 10~20mg/mL.The magnetic bead of 1mL (10mg/mL) is taken according to experimental design, supernatant is abandoned in centrifugation.Add in 1mL go from
Sub- water cleans 1min, and supernatant is abandoned in centrifugation.The reaction buffer cleaning 1min of 1mL is added in, supernatant is abandoned in centrifugation.Addition 50~
100 μ L EDC solutions, 100~200 μ L of buffer solution activate 30min.Then 0.2~1mL protein solution solution is added in, is placed in rotation
Turn on mixed instrument, 12~16h of room temperature.Carboxyl magnetic polyurethane microballoon coupling Streptavidin, Avidin, Protein A,
Protein G, Protein L etc. are applied to the more popular albumen in directions such as protein purification, immunodiagnosis, more select excellent sheet
Carboxyl magnetic polyurethane microballoon coupling Streptavidin is used in magnetic microparticle chemiluminescence and magnetic particle electrochemical luminescence field, carboxyl
Magnetic polyurethane microballoon coupling Protein A can be used for precipitation field is immunized.
Embodiment 1：It is prepared by 3 μm of Monodispersed cross linking polystyrene microsphers
320mL absolute ethyl alcohols and 40mL pure water are measured, pours into beaker and is uniformly mixed.Precise 20g PVP K30
It is added in beaker, above-mentioned mixed solution is poured into flask, open nitrogen deoxygenation, mechanical agitation.Precise 1.0g AIBN
It adds in beaker, then measures styrene 72mL and pour into beaker, the two is uniformly mixed and is poured into flask, after mechanical agitation 1h
50 DEG C are warming up to, causes 30min in advance, after then heating to 65 DEG C of mechanical agitation 4h, by 20mL divinylbenzenes and 50mL benzene second
Alkene, which is dissolved in 20mL ethyl alcohol, to be added dropwise in flask, then heats to 75 DEG C, reacts 16h.After reaction, eccentric cleaning, respectively
With ethyl alcohol, water eccentric cleaning respectively three times, crosslinked polystyrene microsphere drying then will singly be divided to preserve.
Embodiment 2：It is prepared by 0.8 μm of Monodispersed cross linking polystyrene microsphers
300mL absolute ethyl alcohols and 20mL pure water are measured, pours into beaker and is uniformly mixed.Precise 12g PVP K30
It is added in beaker, above-mentioned mixed solution is poured into flask, open nitrogen deoxygenation, mechanical agitation.Precise 2g AIBN add
Enter in beaker, then measure styrene 60mL and pour into beaker, the two is uniformly mixed and is poured into flask, is risen after mechanical agitation 1h
Temperature causes 30min in advance to 50 DEG C, after then heating to 65 DEG C of mechanical agitation 4h, by 40mL divinylbenzenes and 58mL styrene
It is dissolved in 50mL ethyl alcohol and being added dropwise in flask, then heat to 90 DEG C, react 20h.After reaction, eccentric cleaning is used respectively
Ethyl alcohol, water eccentric cleaning respectively three times, then will singly divide crosslinked polystyrene microsphere drying to preserve.
Embodiment 3：It is prepared by 5 μm of Monodispersed cross linking polystyrene microsphers
It measures 200mL absolute ethyl alcohols to pour into beaker, precise 5g PVP K30 are added in beaker, by above-mentioned mixing
Solution is poured into flask, opens nitrogen deoxygenation, mechanical agitation.Precise 0.6g AIBN are added in beaker, then measure benzene second
Alkene 60mL is poured into beaker, and the two is uniformly mixed and is poured into flask, and 50 DEG C are warming up to after mechanical agitation 1h, causes 30min in advance,
After then heating to 65 DEG C of mechanical agitation 4h, 25mL divinylbenzenes and 18mL styrene are dissolved in 45mL ethyl alcohol and are added dropwise to burning
In bottle, 85 DEG C are then heated to, reacts 18h.After reaction, eccentric cleaning, respectively with ethyl alcohol, water eccentric cleaning respectively three times,
Then crosslinked polystyrene microsphere drying will singly be divided to preserve.It is crosslinked polystyrene manufactured in the present embodiment as shown in Fig. 2 (a)
The scanning electron microscope diagram of microballoon, uniform particle diameter, monodisperse, microsphere surface smoother.
Embodiment 4：It is prepared by sulfonic group crosslinked polystyrene microsphere
3 μm of Monodispersed cross linking polystyrene microsphers 10g of the drying from embodiment 1 is added in 30min to 5 DEG C
In the 200mL concentrated sulfuric acids, 90 DEG C are heated to, 4h is reacted, mixed liquor is poured onto 1L on ice, is cleaned with deionized water to neutrality,
Obtain 3 μm of sulfonic group crosslinked polystyrene microspheres.
Embodiment 5：It is prepared by sulfonic group crosslinked polystyrene microsphere
0.8 μm of Monodispersed cross linking polystyrene microsphers 5g of the drying in embodiment 2 is dispersed to 100mL ethyl alcohol
In, it adds in 10g allyl glycidyl ethers and 0.5g AIBN reacts 8h at 70 DEG C and obtain epoxy-modified crosslinking polyphenyl second
Alkene microballoon is dispersed in 50mL ethyl alcohol and 30mL deionized waters after ethyl alcohol eccentric cleaning, adds in 5.6g sodium sulfites, 3.5g tetrems
Base niter cake and 0.2g magnesia, react 12h at 75 DEG C, obtain sulfonic group crosslinked polystyrene microsphere.
Embodiment 6：It is prepared by carboxyl crosslinked polystyrene microsphere
5 μm of the Monodispersed cross linking polystyrene microsphers 12g in embodiment 3 is dispersed in 100mL deoxidation methanol,
20mL acrylic acid, 2mL ethylene glycol dimethacrylates and the 0.8gAIBN of addition react 12h at 75 DEG C and obtain carboxyl friendship
Polystyrene microballoon.
Embodiment 7：Microballoon magnetizes
25g FeSO47H2O and 50g FeCl36H2O are dissolved in 200mL deoxygenation deionized waters, are added to 10g
From in 0.8 μm of granules of polystyrene suspension of the sulfonic group of embodiment 5, wherein the suspension contains 10g particles and 300mL
Water.1g PVPK12 are added, 30min is stirred at room temperature in suspension.The ammonium hydroxide of 25g 25% is added in, temperature is risen to 80
DEG C continue 2h.Suspension is cooled down, Magnetic Isolation washing particle, finally drying preserves.
Embodiment 8：Polyurethane coating coat and it is carboxy-functionalized
0.5g magnetic microspheres in embodiment 7 are scattered in 90mLDMF, the logical nitrogen 10min of flask sealing, by MDI
250mg is dissolved in 5mL DMF, is added in flask, 80 DEG C of reaction 2h.Finally MDI 500mg are dissolved in 5mL DMF, adds in and burns
Then bottle adds in PEG300300 μ L, 490 μ L of tetraethylene glycol are added in into flask.80 DEG C of reaction condition leads to nitrogen, reacts 16h.So
Glycolic 680mg and MDI 250mg are dissolved in 5mLDMF afterwards, add in flask, the reaction was continued 4h, with second alcohol and water repeatedly finally
Cleaning, drying preserve, and about 1 μm of carboxyl polyurethane coated magnetic microballoon is prepared.As shown in Figure 1, it is the present embodiment carboxyl
The synthesis schematic diagram of functionalized polyurethane coated magnetic microballoon.
Embodiment 9：Polyurethane coating coat and it is carboxy-functionalized
1g magnetic microspheres in embodiment 7 are scattered in 90mL ether, the logical nitrogen 10min of flask sealing, by MDI
300mg is dissolved in 5mL ether, is added in flask, 80 DEG C of reaction 2h.Finally MDI 700mg are dissolved in 6mL ether, adds in and burns
Then bottle adds in pentaerythrite 400mg, 410 μ L of ethylene glycol are added in into flask.85 DEG C of reaction condition leads to nitrogen, reacts 16h.
Then aspartic acid 600mg and MDI 300mg are dissolved in 8mL ether, add in flask, the reaction was continued 8h, finally with ethyl alcohol and
Water cleans repeatedly, and drying preserves, and about 1 μm of carboxyl polyurethane coated magnetic microballoon is prepared.
Embodiment 10：It is coupled Streptavidin SA
It is 2 μ g/ μ L and EDC is 10mg/ to prepare Streptavidin with reaction buffer (0.1mM MES, pH 6.0)
mL.Carboxyl magnetic bead prepared by the embodiment 8 of 1mL (10mg/mL) is taken according to experimental design, supernatant is abandoned in centrifugation.Add in going for 1mL
Ionized water cleans 1min, and supernatant is abandoned in centrifugation.The reaction buffer cleaning 1min of 1mL is added in, supernatant is abandoned in centrifugation.Add in 100 μ
LEDC solution, 100 μ L of buffer solution activate 30min.Then 500 μ LSA solution are added in, are placed on rotary mixer, are reacted at room temperature
16h.It is 78 μ g/mg with Streptavidin package amount on spectrophotometric determination magnetic bead.
Embodiment 11：Microballoon magnetizes
20g FeCl24H2O and 45g FeCl36H2O are dissolved in 100mL deoxygenation deionized waters, are added to 5g
From in 3 μm of granules of polystyrene suspension of the sulfonic group of embodiment 4, wherein the suspension contains 5g particle 200mL water.Again
0.4g PVP K12 are added in, 30min is stirred at room temperature in suspension.The ammonium hydroxide of 10g 25% is added in, temperature is risen to 80 DEG C
Continue 1h.Suspension is cooled down, Magnetic Isolation washing particle, finally drying preserves.
Embodiment 12：Polyurethane coating coat and it is carboxy-functionalized
0.5g magnetic microspheres prepared by embodiment 11 are scattered in 50mLDMAC, the logical nitrogen 10min of flask sealing will
HDI 250mg are dissolved in 5mLDMAC, are added in flask, 80 DEG C of reaction 2h.HDI 500mg are finally dissolved in 7mLDMAC, are added in
Then flask adds in 200 μ L of 1,2-PD, pentaerythrite 460mg is added in into flask.80 DEG C of reaction condition leads to nitrogen, instead
It answers 18 hours.Then amino-polyethyleneglycols carboxyl (Mw=300) 480mg and HDI 250mg are dissolved in 6mL DMAC, add in and burn
Bottle, the reaction was continued 4h are finally cleaned repeatedly with second alcohol and water, and drying preserves, and about 3.1 μm of carboxyl polyurethane cladding is prepared
Magnetic microsphere.
Embodiment 13：It is coupled Protein A
It is 1 μ g/ μ L and EDC is 10mg/mL to prepare Protein A with reaction buffer (0.1mM MES, pH 6.0).
12 magnetic bead of embodiment of 2mL (10mg/mL) is taken according to experimental design, supernatant is abandoned in centrifugation.Add in the deionized water cleaning of 1mL
Supernatant is abandoned in 1min, centrifugation.The reaction buffer cleaning 1min of 1mL is added in, supernatant is abandoned in centrifugation.100 μ LEDC solution are added in,
100 μ L of buffer solution activate 30min.Then 1mL Protein solution As are added in, are placed on rotary mixer, room temperature 16h.With point
The package amount that light photometer measures Protein A is 65 μ g/mg.
Embodiment 14：Polyurethane coating coat and it is carboxy-functionalized
Magnetic microsphere 2g prepared by embodiment 11 is scattered in 80mLDMF, the logical nitrogen 10min of flask sealing, by MDI
400mg is dissolved in 8mL DMF, is added in flask, 80 DEG C of reaction 2h.Finally MDI 800mg are dissolved in 10mL DMF, adds in and burns
Then bottle adds in 200 μ L of PEG300,365 μ L of glycerine are added in into flask.80 DEG C of reaction condition leads to nitrogen, is stirred overnight
18h.6- Amino-n-hexanoic acids 500mg, glycine 500mg and MDI300mg were dissolved in 10mL DMF in second day, add in flask, after
Continuous reaction 4h, is finally cleaned repeatedly with second alcohol and water, and drying preserves, and about 3.1 μm of carboxyl polyurethane coated magnetic is prepared
Microballoon.
Embodiment 15：It is coupled Protein G
It is 2 μ g/ μ L and EDC is 10mg/mL to prepare Protein G with reaction buffer (0.1mM MES, pH 6.0).
The magnetic bead of 1mL (10mg/mL) is taken according to experimental design, supernatant is abandoned in centrifugation.Add in the deionized water cleaning 1min of 1mL, centrifugation
Abandon supernatant.The reaction buffer cleaning 1min of 1mL is added in, supernatant is abandoned in centrifugation.Add in 100 μ LEDC solution, 100 μ of buffer solution
L activates 30min.Then 1mL Protein G solution is added in, is placed on rotary mixer, room temperature 10h.It is measured with spectrophotometric
The package amount for determining Protein G is 122 μ g/mg.
Embodiment 16：Microballoon magnetizes
25g FeSO47H2O and 52g FeCl36H2O are dissolved in 200mL deoxygenation deionized waters, are added to 10g
From in 5 μm of granules of polystyrene suspension of the carboxylated of embodiment 6, wherein the suspension contains 10g particles and 300mL water.
0.1g PVP K12 are added, 30min is stirred at room temperature in suspension.The ammonium hydroxide of 50g 25% is added in, temperature is risen to 70
DEG C continue 1h.Suspension is cooled down, Magnetic Isolation washing particle, finally drying preserves.It is this implementation as shown in Fig. 2 (b), (c)
The scanning electron microscope diagram of crosslinked polystyrene magnetic microsphere prepared by example, uniform particle diameter, monodisperse, microsphere surface uniformly cover
Lid magnetisable material.
Embodiment 17：Carboxyl polyurethane coats
1g magnetic microspheres prepared by embodiment 16 are scattered in 60mL acetone, the logical nitrogen 10min of flask sealing, by MDI
250mg is dissolved in 6mL acetone, is added in flask, and 80 DEG C are reacted 2 hours.Finally by 200 μ L of triethylene glycol, 400 μ L of PEG 800
It is dissolved in 6mL acetone with MDI 500mg, adds in flask, 80 DEG C of reaction condition leads to nitrogen, is stirred overnight 20h；Second day by 2,
Bis- (methylol) propionic acid 1g and the MDI 250mg of 2- are dissolved in 5mL acetone, add in flask, the reaction was continued 6h, finally with second alcohol and water
It cleans repeatedly, drying preserves.It is carboxy-functionalized polyurethane coated magnetic microballoon manufactured in the present embodiment as shown in Fig. 2 (d)
Scanning electron microscope diagram, it is seen that microsphere surface cover aggregation object figure layer.
Embodiment 18：Magnetic microparticle chemiluminescence is tested
Embodiment 8 and embodiment 12 are prepared into carboxyl polyurethane coated magnetic microballoon and existing commercialization
DynabeadsTMMyOneTMCarboxylic Acid (Invitrogen companies) and Magnosphere MS160/Carboxyl
The carboxyl magnetic bead of (JS Life Sciences companies) carries out the contrast test of magnetic microparticle chemiluminescence.By four kinds of magnetic beads according to reality
The mode of example 13 is applied to antibody anti-tsh monoclonal antibody (HyTest, Ltd, a clone：It 10C7) is fixed, fixed amount point
It Wei not 45,35,32,15 μ g/mg, human serum TSH antigens sample (50 μ by the above-mentioned particle of 60 μ g and at various concentrations
L), 20min is reacted at 37 DEG C, Magnetic Isolation TB buffer solution for cleaning 3 times, then two identified with alkaline phosphatase (ALP)
Secondary antibody (HyTest, Ltd, clone：It 105E8) is reacted, chemiluminescence amount is surveyed after addition substrate solution (AMPPD)
It is fixed, see from table 1, the interference of the magnetic bead of embodiment 8 in antigen concentration 0u IU/mL is consistent with Magnosphere magnetic beads, is
The 1/2 of Dynabeads, in addition the signal strength in antigen 200u IU/mL is about 2 times of Magnosphere, is
Dynabeads1.4 times, about Magnosphere2.0 times of high sensitivity can be obtained as noise S/N ratios, is
Dynabeads2.8 times of high sensitivity.Interference of the magnetic bead of embodiment 12 in antigen concentration 0u IU/mL be
Magnosphere magnetic beads 2/3 are the 2/5 of Dynabeads, and in addition the signal strength in antigen 200u IU/mL is about
1.3 times of Magnosphere are the 90% of Dynabeads, and about Magnosphere1.9 times can be obtained as noise S/N ratios
High sensitivity, be Dynabeads2.3 times of high sensitivity.
Table 1：Luminous value of the different carboxyl magnetic beads under different antigen concentrations
Although the embodiments of the present invention have been disclosed as above, but its be not restricted in specification and embodiment it is listed
With it can be fully applied to various fields suitable for the present invention, for those skilled in the art, can be easily
Realize other modification, therefore without departing from the general concept defined in the claims and the equivalent scope, it is of the invention and unlimited
In specific details and legend shown and described herein.
Claims (8)
1. a kind of preparation method of carboxy-functionalized polyurethane coated magnetic microballoon, which is characterized in that include the following steps：
1) crosslinked polystyrene microsphere is prepared：By azodiisobutyronitrile, styrene, polyvinylpyrrolidone, absolute ethyl alcohol and water
Cause 10-30min in advance at 45-55 DEG C, after being warming up to 60-65 DEG C of reaction 2-4h, add divinylbenzene and styrene, and
70-90 DEG C is warming up to, reacts 16~20h；After reaction, eccentric cleaning is dried to obtain crosslinked polystyrene microsphere；
2) surface functionalization：By the crosslinked polystyrene microsphere that step 1) obtains by surface modified into amino, carboxyl, sulphur
One kind in acyl group, methoxyl group or chloromethyl；
3) magnetize：Step 2) is taken to be dispersed in iron salt solutions by the crosslinked polystyrene microsphere of surface functionalization, adds in and stablizes
Agent reacts at room temperature 10-200min, adds in ammonium hydroxide, is warming up to 60-80 DEG C of reaction 1-2h；Cooling, Magnetic Isolation are obtained through magnetized
Crosslinked polystyrene microsphere；
4) polyurethane coating coats：Step 3) is scattered in through magnetized crosslinked polystyrene microsphere in organic solvent, is added in more
Isocyanates reacts 2-4h in 80 DEG C；Polyisocyanates and at least one non-monohydric alcohol are then added in again in 70-90 DEG C of reaction
16-20h；
5) it is carboxy-functionalized：Carboxyl modified agent and polyisocyanates are added in into the reaction system of step 4) the reaction was continued 4-8h,
Carboxy-functionalized polyurethane coated magnetic microballoon is made after washing and drying.
2. preparation method as described in claim 1, which is characterized in that in step 1), the dosage of azodiisobutyronitrile accounts for total amount
0.1-0.5%, the dosage of divinylbenzene accounts for the 10~70% of total amount.
3. preparation method as described in claim 1, which is characterized in that in step 3), the iron salt solutions for divalent iron salt and
The molar ratio of the mixed liquor of trivalent iron salt, divalent iron salt and trivalent iron salt is 1: 1-3, and divalent iron salt is hydrated selected from ferrous sulfate seven
Object, iron ammonium sulfate hexahydrate, frerrous chloride tetrahydrate, anhydrous frerrous chloride or combination；Trivalent iron salt is selected from chlorination
Iron hexahydrate, ferric sulfate, ferric nitrate nonahydrate or combination；The stabilizer is selected from PVP K12, PVP K15, PVP
One or two kinds of mixing in K17.
4. preparation method as described in claim 1, which is characterized in that the organic solvent in step 4) is does not send out with isocyanates
The organic solvent of raw reaction.
5. preparation method as described in claim 1, which is characterized in that step 4) and 5) in polyisocyanates be selected from methylene
Diisocyanate, 2,4 toluene diisocyanate or its isomers, 4,4 '-oxygen bis- (phenyl isocyanates), 4,4 '-diphenylmethyl
Alkane diisocyanate, isoflurane chalcone diisocyanate, phenylene vulcabond, 2,4- diphenyl diisocyanates, methylene
Biscyclohexyl diisocyanate, hexamethylene diisocyanate, the own ester of 1,6- diisocyanates, 1,5 naphthalene diisocyanate ester, to four
In methylxylene diisocyanate, trans-cyclohexane -1,4- diisocyanate and tetramethylxylene diisocyanate
It is one or more.
6. preparation method as described in claim 1, which is characterized in that in step 4), the non-monohydric alcohol is selected from ethylene glycol, one
Contracting dipropylene glycol, triethylene glycol, 1,2- propylene glycol, ten glycol, 1,2- hexylene glycols, 2- methyl-1,3-propanediols, 1,4- fourths two
Alcohol, diethylene glycol (DEG), seven glycol, tetraethylene glycol, polypropylene glycol 200,1,6-HD, polypropylene glycol 400, polyethylene glycol, glycerine, fourth
In triol, three (methylol) aminomethanes, oxyhydroquinone, glycerine, 2- amino-2-methyl -1,3- propylene glycol, pentaerythrite
It is one or more.
7. preparation method as described in claim 1, which is characterized in that in step 5), the carboxyl modified agent be selected from glycolic,
Leucine, tryptophan, serine, 6- Amino-n-hexanoic acids, arginine, glutamic acid, lysine, glycine, asparatate, amino
It is one or more in bis- (methylol) propionic acid of polyethylene glycol carboxyl, 2,2-.
8. a kind of carboxy-functionalized polyurethane cladding made from preparation method using as described in any one of claim 1-7
Magnetic microsphere.
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Application publication date: 20180622 |