JP2006328309A - Magnetic polymer particle and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide magnetic polymer particles having uniformity of the length of the grafted polymer chain or the thickness of the polymer layer and a narrow and uniform distribution of particle diameter, functional magnetic polymer particles in which the polymer chain covering the surface of the magnetic particles is formed with a molecular design according to the purpose of use and a method of manufacturing the magnetic particles. <P>SOLUTION: The magnetic polymer particles comprise magnetic particles and polymer chains covering the magnetic particles of a molecular weight distribution index, Mw/Mn, of the polymer chain of ≤1.6. A method of manufacturing the magnetic polymer particles has a process of preparing the magnetic particles and a process of covering the magnetic particles with a polymer, wherein the covering process comprises forming a polymer chain by the living polymerization. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to magnetic polymer particles useful as separation carriers for biological materials such as nucleic acids and proteins, magnetic inks and magnetic toners, MRI contrast agents, antigen-antibody reaction carriers, drug carriers for drug delivery, and the like, and methods for producing the same. is there.

  Conventionally, magnetic polymer particles coated with polymer around magnetic particles have been used in the fields of biology and medicine to take advantage of the fact that particles are easily separated and collected by magnetic force. Use as separation / purification carrier, drug carrier for drug delivery with drug immobilized on polymer chain, catalyst carrier by immobilizing enzyme on polymer chain, carrier for detection of pathogen by antibody / antigen reaction, etc. Yes. In recent years, information recording media have been widely used with remarkable progress in information communication, and these media have a part for storing information. As an information recording method, magnetic recording is a useful recording method along with optical recording, and magnetic polymer particles are widely used for patterning a magnetic recording layer by printing, transfer, ink jet, etc. It has been. Thus, the use of magnetic polymer particles has been widely studied in the fields of biochemical / medical materials and information / communication / electronic materials.

Examples of typical synthesis methods for such magnetic polymer particles include the following. In Patent Document 1, a magnetic substance is dispersed in water, and carboxyl group-containing magnetic particles having a particle diameter of 1 μm or more are obtained by suspension polymerization using an oil-soluble initiator. Further, in Patent Document 2, ferrite fine particles whose core is made of resin are mixed with a double salt of a surfactant and a polymerization initiator and a polymerizable monomer having a glycidyl group, radical polymerization is performed, and protective coating is performed with the polymer. Ferrite magnetic particles are obtained. Patent Document 3 discloses a method for producing magnetic polymer particles in which biotin or avidin is immobilized on magnetic particles via a stimulus-responsive polymer and a method for separating biological substances.
Japanese Patent Laid-Open No. 10-87711 JP 7-82302 A International Publication No. 02/016571 Pamphlet

  However, when these methods are used, since a general-purpose radical polymerization method that is simple for polymer synthesis is used, the structure of the polymer chain of the obtained magnetic polymer particles is generally non-uniform. For the purpose of immobilizing biomaterials, immobilization methods using functional groups randomly distributed in polymer chains grafted on magnetic particles, and polymerization of radically polymerizable monomers containing biomaterials Since the magnetic polymer particles were produced by the above, it was difficult to control the arrangement of the biomaterial in the polymer chain due to the non-uniformity of the polymer chain structure. Further, when a surfactant is used, the polymer chain is physically adsorbed to the magnetic particles, and thus there are problems such as peeling off and dispersibility. As described above, the magnetic polymer particles obtained by the conventional production method have a non-uniform particle size distribution and a non-uniform polymer chain structure (molecular weight, composition, arrangement, etc.). It was difficult to actively control the functional and mechanical properties of the chain.

  An object of the present invention is to solve the above-mentioned problems, and specifically, to provide magnetic polymer particles in which the chain length of the polymer to be grafted or the thickness of the polymer layer is uniform, and thus the particle size distribution is narrow. That is.

  Another object of the present invention is to provide a functional magnetic polymer particle in which the polymer chain covering the surface of the magnetic particle is a block polymer having a molecular design according to the purpose of use, and a method for producing the magnetic polymer particle. .

  According to the present invention, there is provided a magnetic polymer particle comprising a magnetic particle and a polymer chain coated with the magnetic particle, wherein the molecular weight distribution index (Mw / Mn) of the polymer chain is 1.6 or less. The

  According to the present invention, there is provided a magnetic polymer particle comprising a magnetic particle and a polymer chain coated with the magnetic particle, wherein the polymer chain is a block polymer composed of two or more types of blocks. The

According to the present invention, there is also provided a method for producing magnetic polymer particles comprising the steps of preparing magnetic particles and coating the magnetic particles with a polymer,
There is provided a method for producing magnetic polymer particles, wherein the step of coating with a polymer forms a polymer chain by living polymerization.

Furthermore, according to the present invention, there is provided a method for producing magnetic polymer particles comprising the steps of preparing magnetic particles and coating the magnetic particles with a polymer,
Coating with the polymer comprises
Introducing a polymerization initiating group on the surface of the magnetic particles;
A step of grafting the polymer onto the surface of the magnetic particles by homopolymerizing or copolymerizing one or more monomers using the polymerization initiation group as a polymerization initiation source;
A method for producing magnetic polymer particles is provided.

  The magnetic polymer particles obtained by the living radical polymerization method of the present invention can be provided with a uniform magnetic polymer particle comprising a graft layer having an unprecedented uniform polymer chain length, and thus a narrow particle size distribution. Moreover, if the polymerization method of this invention is used, the magnetic polymer particle which makes a block polymer a graft chain can also be manufactured easily. In the resulting block polymer, the arrangement of the functional groups can be controlled, so that the optimum arrangement can be controlled even in the immobilization of biomaterials and drugs in the magnetic particles, and the introduction of a stimulus-responsive block allows the polymer chain to respond to stimulation. It is possible to autonomously control the stabilization of these biomaterials and the release of the drug due to the contraction and aggregation of the. In addition, when used as a magnetic ink, ink properties having optimal ink viscosity and fixability can be imparted by the above stimulation, and it can be suitably used as highly functional functional magnetic polymer particles. The utility value is extremely high.

  Hereinafter, the present invention will be described in detail. FIG. 1 is a view showing magnetic polymer particles of the present invention. The magnetic polymer particles in the present invention are composed of magnetic particles 1 and polymer chains 2 covering the periphery thereof. More specifically, the polymer chain 2 is grafted onto the surface of the magnetic particle 1 via a polymerization initiating group.

  The method for producing a polymer grafted on the surface of the magnetic particle of the present invention is based on a living radical polymerization method, a step of introducing a polymerization initiating group to the surface of the magnetic particle, and radical polymerization using the polymerization initiating group as a polymerization initiating source. And a step of grafting the polymer onto the surface of the magnetic particles. Various techniques have been developed in recent years for the living radical polymerization method, and examples include the following. For example, Macromol. Chem. RapidCommun. 1982, Volume 3, page 133, Iniferter Polymerization, Journal of the American Chemical Society (J. Am. Chem. Soc.), 1994, Volume 116, page 7943 One using a cobalt porphyrin complex, one using a radical scavenger such as a nitroxide compound as shown in Macromolecules, 1994, 27, 7228, Journal of the American Chemical Society (J. Am. Chem. Soc.), 1995, 117, 5614, “Atom Transfer Radical Polymerization” using an organic halide as an initiator and a transition metal complex as a catalyst (Atom Transfer Radical Polymerization). ATRP), and Macromolecules (Macromolecules), 1998 years, Vol. 31, shown on pages 5559 "RAFT: Reversible Addition-Fragmentation chain Transfer polymerization", and the like. Among these, although the present invention is not particularly limited, a synthesis method using a radical scavenger such as a nitroxide compound or a synthesis method by an atom transfer radical polymerization method is particularly preferably used.

  First, the polymerization initiating group introduced into the magnetic particle surface will be described. In the synthesis method using the nitroxide compound, compounds represented by the following general formulas (1) to (2) are preferable as the polymerization initiation group to be introduced onto the surface of the magnetic particles.

In the above formulas, R ^{1 to} R ¹⁰ and R ¹² are the same or different and each is a (halogenated) alkyl group having 1 to 10 carbon atoms such as a hydrogen atom, a methyl group, an ethyl group, a propyl group and a trifluoromethyl group, Group, p-fluorophenyl group, naphthyl group, tolyl group, biphenyl group, benzyl group and other aromatic substituted alkyl groups, hydroxylalkyl group, alkoxyalkyl group, cyano group, carboxyl group, alkylcarbonyloxy group, alkyloxycarbonyl group , A hydroxyl group, an amino group, a carbonyl group, a mercapto group, an aldehyde group, an amide group or a sulfonyl group. R ¹¹ represents an alkylene group, an alicyclic alkylene group, an alkylene arylene alkylene group, an arylene group, an alkylsilylene group, or a single bond, and the alkylene group has a —O—, —CO—, —COO—, or OCOO— bond. May be included. Y is a substituent selected from a carboxyl group, a phosphine group, an alkoxysilyl group or a halogenated silyl group.

  Specific examples of the nitroxide compound include 2,2,6,6-tetramethylpiperidine-1-oxyl (hereinafter also referred to as “TEMPO”), 4-hydroxy-TEMPO, 4-amino-TEMPO, 4-acetamido-TEMPO. 4-aminomethyl-TEMPO, 4-methoxy-TEMPO, 4-t-butyl-TEMPO, 3-hydroxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl, 3-amino-2,2, 5,5-tetramethylpyrrolidine-1-oxyl, 3-acetamido-2,2,5,5-tetramethylpyrrolidine-1-oxyl, 3-methoxy-2,2,5,5-tetramethylpyrrolidine-1- Oxyl, 3- (aminomethyl) -2,2,5,5-tetramethylpyrrolidine-1-oxyl, and 3-t-butyl-2, , 5,5-tetramethyl-1-oxyl, and the like.

  In addition, as a polymerization initiating group in the atom transfer radical polymerization method, an organic halide or a sulfonyl halide compound having at least one halogen as a polymerization starting point, which is a functional group that binds to or interacts with the magnetic particle surface. Although it will not specifically limit if it contains, It is a compound which has one or two halogen which becomes a starting point normally, and the compound represented by following General formula (3)-(5) is especially preferable.

In the above formula, R ¹³ is a substituent selected from an alkoxy group or a halogen atom, and R ¹⁴ is an alkylene group, an alicyclic alkylene group, an alkylene arylene alkylene group, an arylene group, an alkylsilylene group, or a single bond. All of the above groups may contain a —O—, —CO—, —COO— or OCOO— bond. X represents a halogen atom.

  An example of such an initiating group is (4a) synthesized by the method shown below, but the initiating group of the present invention is not limited thereto.

On the other hand, as the magnetic particles for introducing a polymerization initiating group in the present invention, basically, iron ore, magnetic iron oxide, magnetite, ferrite, nickel oxide, cobalt oxide or the like can be used, but drug delivery, separation carrier, In applications such as diagnosis, particles having a strong magnetic force tend to be required, so among them, those classified as ferromagnetic materials are preferred, ferrites are more preferred, and Fe ₃ O ₄ is particularly preferred.

  The average particle diameter of the magnetic particles used as a raw material can be properly used depending on the application. For example, when it is used in a living body, it is smaller than 400 nm, which is recognized as a foreign substance in a blood vessel and causes a risk of occlusion of the blood vessel, for example, preferably 2 to 200 nm. On the other hand, when used as a magnetic information recording medium, when using magnetic unevenness, the particle size of the magnetic particles is 1 μm or more, which is a relatively large particle size for creating magnetic unevenness, while high density and high definition are required. In consideration, about 5 nm to 1 μm is preferable. When the magnetic polymer particle exceeds 40 μm, it becomes a protrusion when it is formed into a coating film, and the substrate characteristics as a medium such as lamination property, running property, and slipping property may be deteriorated.

  In the step of introducing a polymerization initiating group onto the surface of the magnetic particles, the magnetic particles as the raw material and the compound to be the polymerization initiating group are mixed. At this time, the carboxyl group, phosphine group, alkoxysilyl group, halogenated silyl group and the like contained in the polymerization initiating group react and adsorb on the surface of the magnetic particle, and the polymerization initiating group is introduced on the surface of the magnetic particle. In this step, the dispersibility of the magnetic particles can be increased or the introduction of a polymerization initiating group can be promoted by ultrasonic treatment, heat treatment, microwave treatment, or the like, if necessary.

  Next, a process of performing polymerization using the initiating group as a polymerization initiation source and grafting a polymer chain onto the magnetic particle surface will be described. The radical polymerization and atom transfer radical polymerization by the nitroxide compound in the present invention can be carried out in various forms, and examples thereof include solution polymerization, suspension polymerization, emulsion polymerization and bulk polymerization. In the case of other than bulk polymerization, any type of solvent can be used as long as it does not inhibit radical polymerization. As the radical polymerizable monomer and the polymerization solvent used in the radical polymerization, the compounds described below can be used.

  In carrying out the present invention, in radical polymerization and atom transfer radical polymerization with a nitroxide compound, there are no particular restrictions on the addition procedure of the polymerization reagent, but after the addition of the reagent, deaeration and substitution with an inert gas are performed as necessary. After performing, it sets to predetermined | prescribed temperature and is made to react.

  In the case of a synthesis method using a nitroxide compound, the above-mentioned polymerization initiator group-introduced magnetic particles are mixed with a radical polymerizable monomer, an appropriate solvent is added as necessary, and polymerization is performed at a predetermined temperature. . The polymerization temperature is usually selected between 20 and 140 ° C, preferably between 40 and 120 ° C. When the polymerization temperature is less than 20 ° C., the polymerization reaction is extremely slow, which is not industrially preferable. On the other hand, when the polymerization temperature exceeds 140 ° C., the molecular weight distribution tends to be widened, which is not preferable.

  When the atom transfer radical polymerization method is used, the radical polymerizable monomer is subjected to living radical polymerization using a halogen-containing metal complex as a catalyst together with the polymerization initiating group. As the metal catalyst, a catalyst composed of a metal complex in which at least one transition metal (M) selected from Groups 7 to 11 of the periodic table is a central metal is used. Is a metal selected from the group consisting of Cu, Ni, Pd, Pt, Rh, Co, Ir, Fe, Ru, Re and Mn. Among them, Cu, Ru, Fe and Ni are preferable, and copper is particularly preferable. . When copper is used as the central metal of the halogen-containing metal complex, cuprous chloride and cuprous bromide are particularly preferably used as the halogen-containing copper complex, but are not particularly limited thereto.

  An organic ligand is used for the above metal complex. Organic ligands are used to enable solubilization in polymerization solvents and reversible redox reactions of metal complexes. Examples of the coordination atom to the metal include a nitrogen atom, an oxygen atom, a phosphorus atom, and a sulfur atom, and a nitrogen atom is preferable. Specific examples of the organic ligand include 2,2′-bipyridyl and derivatives thereof, tetramethylethylenediamine, pentamethyldiethylenetriamine, hexamethyltriethylenetetraamine, tris (dimethylaminoethyl) amine, and triphenylphosphine. However, it is not limited to these.

  In the case of the atom transfer radical polymerization method, the magnetic particles into which the polymerization initiating group has been introduced, the radical polymerizable monomer, the metal catalyst and, if necessary, the ligand thereof are mixed, and if necessary, an appropriate solvent is added. The polymerization may be performed at a predetermined temperature. The polymerization temperature is usually selected between 5 and 140 ° C, preferably between 20 and 120 ° C. When the polymerization temperature is less than 5 ° C., the polymerization reaction is extremely slow, which is not industrially preferable. On the other hand, when the polymerization temperature exceeds 140 ° C., the tendency of the molecular weight distribution to become wide is increased, which is not preferable.

  In the step of grafting on the surface of the magnetic particles of the present invention, as for the monomer that can be used, when using the above nitroxide compound or when using the atom transfer radical polymerization method, a known radical polymerizable monomer is used. Can do. Examples of the unsaturated monomer that can be used in the radical polymerization method of the present invention include the following, but are not particularly limited thereto.

  Styrene, α-, o-, m-, p-alkyl of styrene, alkoxyl, halogen, haloalkyl, nitro, cyano, amide, ester substituted product; styrene sulfonic acid, 2,4-dimethylstyrene, paradimethylaminostyrene, vinyl Polymerizable unsaturated aromatic compounds such as benzyl chloride, vinylbenzaldehyde, indene, 1-methylindene, acenaphthalene, vinylnaphthalene, vinylanthracene, vinylcarbazole, 2-vinylpyridine, 4-vinylpyridine, 2-vinylfluorene;

Alkyl (meth) acrylates such as methyl (meth) acrylate, ethyl (meth) acrylate, n-propyl acrylate, n-butyl acrylate, 2-ethylhexyl (meth) acrylate, stearyl (meth) acrylate; methyl crotonic acid, crotonic acid Unsaturated monocarboxylic acid esters such as ethyl, methyl cinnamate and ethyl cinnamate; fluoroalkyl (meta) such as trifluoroethyl (meth) acrylate, pentafluoropropyl (meth) acrylate and heptafluorobutyl (meth) acrylate ) Acrylates; trimethylsiloxanyldimethylsilylpropyl (meth) acrylate, tris (trimethylsiloxanyl) silylpropyl (meth) acrylate, di (meth) acryloylpropyldimethylsilylate Siloxanyl compounds such as 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, hydroxyalkyl (meth) acrylates such as 3-hydroxypropyl (meth) acrylate; dimethylaminoethyl (meth) acrylate, Amine-containing (meth) acrylates such as diethylaminoethyl (meth) acrylate and t-butylaminoethyl (meth) acrylate; 2-hydroxyethyl crotonic acid, 2-hydroxypropyl crotonic acid, 2-hydroxypropyl cinnamate, etc. Hydroxyalkyl esters of saturated carboxylic acids; unsaturated alcohols such as (meth) allyl alcohol; unsaturated (mono) carboxylic acids such as (meth) acrylic acid, crotonic acid and cinnamic acid; glycidyl (meth) acrylate, α- Glycidyl ethyl acrylate, glycidyl α-n-propyl acrylate, glycidyl α-n-butyl acrylate, (meth) acrylic acid-3,4-epoxybutyl, (meth) acrylic acid-6,7-epoxyheptyl, α -Ethylacrylic acid-6,7-epoxyheptyl, o-vinylbenzyl glycidyl ether, m-vinylbenzyl glycidyl ether, p-vinylbenzyl glycidyl ether, (meth) acrylic acid-β-methylglycidyl, (meth) acrylic acid- β-ethylglycidyl, (meth) acrylic acid-β-propylglycidyl, α-ethylacrylic acid-β-methylglycidyl, (meth) acrylic acid-3-methyl-3,4-epoxybutyl, (meth) acrylic acid- 3-ethyl-3,4-epoxybutyl, 4-methyl-4 (meth) acrylate , 5-epoxypentyl, (meth) acrylic acid-5-methyl-5,6-epoxyhexyl, (meth) acrylic acid-β-methylglycidyl, (meth) acrylic acid-3-methyl-3,4-epoxybutyl Epoxy group-containing (meth) acrylic esters such as mono- and diesters thereof;

In addition, N-alkyl-substituted (meth) acrylamides such as N, N-dimethylacrylamide and N-isopropylacrylamide; N-methylolacrylamide, N-methylolmethacrylamide, N-vinylpyrrolidone, (anhydrous) maleic acid, fumaric acid, (Anhydrous) Unsaturated polycarboxylic acids (anhydrides) such as itaconic acid and citraconic acid, vinyl chloride, vinyl acetate and the like.

  For the purpose of improving the dispersibility of the magnetic polymer particles obtained, macromonomers having a polymerizable functional group such as a vinyl group or a methacryloyl group in a high molecular weight segment such as polyvinylpyrrolidone, polyoxyethylene, or polyacrylamide are suitable. It can also be used.

  Furthermore, in addition to the above monomer, a polyfunctional compound that can serve as a crosslinking agent may coexist. Examples of the polyfunctional compound include N-methylol acrylamide, N-ethanol acrylamide, N-propanol acrylamide, N-methylol maleimide, N-ethylol maleimide, N-methylol maleamic acid, N-methylol maleamic acid ester. N-alkylolamide of vinyl aromatic acid (for example, N-methylol-p-vinylbenzamide), N- (isobutoxymethyl) acrylamide and the like. Furthermore, among the above monomers, divinylbenzene, divinylnaphthalene, divinylcyclohexane, 1,3-dipropenylbenzene, ethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, butylene glycol, Polyfunctional monomers such as trimethylolethane tri (meth) acrylate and pentaerythritol tetra (meth) acrylate can also be used as a crosslinking agent. The monomers and macromonomers exemplified above can be used alone or in combination of two or more.

  As the polymerization solvent used in the present invention, any type of solvent can be used as long as it does not inhibit radical polymerization. Among them, the solvent is compatible with the monomer used for polymerization and efficiently disperses the magnetic particles described below. It is advantageous in terms of polymerization control to select a solvent that can be used. Specific examples of the specific polymerization solvent include water; methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol, tert-butyl alcohol, and 1-pentanol. 2-pentanol, 3-pentanol, 2-methyl-1-butanol, isopentyl alcohol, tert-pentyl alcohol, 1-hexanol, 2-methyl-1-pentanol, 4-methyl-2-pentanol, Alcohols such as 2-ethylbutanol, 1-heptanol, 2-heptanol, 3-heptanol, 2-octanol, 2-ethyl-1-hexanol, benzyl alcohol, cyclohexanol; methyl cellosolve, ethyl cellosolve, isopropyl cellosolve, butyl celloso Ethers such as butyl and diethylene glycol monobutyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone; esters such as ethyl acetate, butyl acetate, ethyl propionate and cellosolve acetate; pentane, 2-methylbutane, n- Hexane, cyclohexane, 2-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, heptane, n-octane, isooctane, 2,2,3-trimethylpentane, decane, nonane, cyclopentane, methylcyclopentane , Methylcyclohexane, ethylcyclohexane, p-menthane, dicyclohexyl, benzene, toluene, xylene, ethylbenzene, anisole (methoxybenzene) and other aliphatic or aromatic hydrocarbons Halogenated hydrocarbons such as carbon tetrachloride, trichloroethylene, chloroform, dichloromethane, 1,2-dichloroethane, dichlorobenzene, chlorobenzene and tetrabromoethane; ethers such as ethyl ether, dimethyl ether, trioxane and tetrahydrofuran; methylal, diethyl acetal, etc. Acetals; fatty acids such as formic acid, acetic acid and propionic acid; sulfur such as nitropropene, nitrobenzene, dimethylamine, monoethanolamine, pyridine, dimethylformamide, dimethyl sulfoxide, acetonitrile, and nitrogen-containing organic compounds. These are not particularly limited except for the above solvent conditions, and a solvent suitable for the use of the polymerization method may be selected as appropriate. These may be used alone or in combination of two or more.

  In the present invention, the polymer chain length to be grafted or the thickness of the polymer layer in the magnetic polymer particle is uniform, and the grafted polymer is cut out from the core magnetic particle and measured by recovery / gel permeation chromatography (GPC). This is confirmed by the molecular weight distribution index (Mw / Mn) obtained. That is, it is suggested that the smaller the value of the molecular weight distribution index (Mw / Mn), the more uniform the chain length of the grafted polymer. The molecular weight distribution index (Mw / Mn) must be 1.6 or less, and preferably 1.4 or less. When the molecular weight distribution index (Mw / Mn) is 1.6 or less, a graft layer having a uniform polymer chain length can be obtained, and a uniform magnetic polymer having a narrow particle size distribution can be obtained.

  The second invention of the present invention is a magnetic polymer particle characterized in that the polymer chain grafted onto the surface of the magnetic particle is a block polymer chain composed of two or more types of blocks. Since the present invention uses a production method based on the living radical polymerization method, nitroxide (in the case of nitroxide polymerization) or halogen X (in the case of atom transfer radical polymerization) is bonded to the polymerizable radical terminal to temporarily polymerize. After stopping, the radical end can be generated again from the nitroxide end or the halogen end to start the polymerization, or the polymerization can be freely started and ended. Furthermore, since the polymer obtained by the production method of the present invention has a nitroxide or halogen-terminated X capable of initiating further polymerization, the first monomer is consumed in the polymerization and the first After forming the block chain, a second monomer can be added to form a second block chain that grows from the end of the first block chain. Further, a multi-block copolymer can be produced. In addition, the polymer obtained by the production method of the present invention can be converted into a polymer having another functional group of interest by subjecting it to a modification step and reacting with a compound having a halogen terminal and a functional group. .

  That is, after introducing a polymerization initiating group on the surface of the magnetic particle and forming the first block chain by living radical polymerization using it as a starting source, another monomer is added and the function is different from that of the first block chain. It is possible to provide functional magnetic polymer particles by forming a block chain having a structure. Specifically, as a block chain having a different function from the first block chain, functions such as a polymer chain imparted with a function of dispersion stability and a polymer chain that causes volume change and structural change in response to various stimuli The magnetic polymer particles are preferably used, but the type of block polymer chain is not limited to the above, and the number of blocks is not particularly limited, and a multi-block polymer chain composed of two or more types of blocks can be synthesized. it can.

  For example, in order to impart a function of dispersion stability, it is preferable to use a hydrophilic monomer or a macromonomer when the use environment is an aqueous system. As the hydrophilic macromonomer, a macromonomer having a polymerizable vinyl group at the terminal and having a hydrophilic property and a molecular weight of 300 to 3000 is preferable, and specific examples thereof include polyethylene glycol, polyvinyl pyrrolidone, and polyacrylamide. However, it is not limited to these.

  Examples of the stimulus given to the stimulus-responsive polymer include light, temperature, pH, and electric field.

  For example, as the photoresponsive polymer, a polymer containing an azobenzene derivative, a spiropyran derivative, or a triarylmethane derivative that undergoes an isomerization reaction by light can be used.

  Further, as the temperature-responsive polymer, a polymer having LCST (lower critical solution temperature) is preferable, and poly N-alkyl substituted (meta-N-isopropylacrylamide, poly-N-isopropylmethacrylamide, poly-N-vinylisobutyramide, etc.). ) Acrylamide or polyvinyl methyl ether is particularly preferably used.

  The pH-responsive polymer is preferably a polymer having a carboxyl group or an amino group as a functional group, specifically, a polymer electrolyte is preferred, and poly (meth) acrylic acid or a salt thereof, (meth) acrylic acid And (meth) acrylamide, hydroxyethyl (meth) acrylate, (meth) acrylic acid alkyl ester and other copolymers and salts, maleic acid and (meth) acrylamide, (meth) acrylic acid alkyl ester, etc. Examples thereof include coalesced or a salt thereof, polyvinyl sulfonic acid, polystyrene sulfonic acid and polyvinyl benzene sulfonic acid or a salt thereof, polyacrylamide alkyl sulfonic acid or a salt thereof, polydimethylaminopropyl (meth) acrylamide or a salt thereof.

  The polymer that responds by oxidation / reduction by an electric field is preferably a cationic electrolyte polymer, and is preferably used as a CT complex (charge transfer complex) in combination with an electron-accepting compound. Examples of cationic electrolyte polymers include polyamino-substituted (meth) acrylamides such as polydimethylaminopropyl acrylamide, polydimethylaminoethyl (meth) acrylate, polydiethylaminoethyl (meth) acrylate, polydimethylaminopropyl (meth) acrylate, and other poly ( A meta-acrylic acid amino-substituted alkyl ester, polyvinyl pyridine, polyvinyl carbazole, polydimethylaminostyrene, or the like can be used. Examples of electron accepting compounds include quinones such as benzoquinone, diphenoquinone, 1,4-naphthoquinone and anthraquinone, 7,7,8,8-tetracyanoquinodimethane (TCNQ), methylene blue, tetrabutylammonium perchlorate, tetra Cyanoethylene, chloranil, trinitrobenzene, maleic anhydride, iodine or the like is preferably used.

  Although the polymer chain containing these repeats aggregation and contraction with respect to various stimuli, the stimulus-responsive polymer is not particularly limited thereto.

  Furthermore, when a biomaterial such as protein or a drug is introduced into a polymer chain, a method of reacting with a functional group of a polymer side chain is known as a known technique for immobilizing a biomaterial. When the radical polymerization method is used, the position at which these functional groups are immobilized, such as the first block or the second block, can be controlled. Examples of these functional groups include a glycidyl group, a carboxyl group, and an amino group. As the radical polymerizable monomer having these functional groups, those selected from the above monomers are preferably used. .

  As biomaterials such as enzymes, proteins, nucleic acids, and sugars to be introduced into the polymer chain, various conventionally known substances can be used depending on the application, and are not particularly limited. For example, as the enzyme, an optimum enzyme according to the target enzyme reaction is appropriately adopted, and glucose oxidase, lipase, amylase, urease, protease, isomerase, pepsin, papain, α-chymotrypsin, hydrase, desmolase, cytochrome C, hemoglobin Lysozyme, nogen peroxidase, tyrosinase, acid phosphatase and alkaline phosphatase.

  EXAMPLES Next, although an Example demonstrates this invention still in detail, this invention is not restrict | limited to a following example, unless the summary is exceeded.

Example 1
This example is an example of producing magnetic polymer particles in which polystyrene is grafted by living radical polymerization. A magnetic fluid (trade name: Ferricolloid HC-50, Taiho Kogyo Co., Ltd.) was heated and concentrated to remove the solvent kerosene, and then a concentrated ferrite-based superparamagnetic magnetic material was obtained. After 3.0 g of this magnetic material was ultrasonically dispersed in toluene / methanol (4/1, v / v), 5.0 g of 2- (4-chlorosulfonylphenyl) ethyltrimethoxysilane was added and the mixture was refluxed. The reaction was performed for 24 hours, and a step of introducing a polymerization initiating group onto the surface of the magnetic particles was performed. After the reaction, the particles were thoroughly washed with toluene, and the magnetic particles were collected by centrifugation, followed by vacuum drying to obtain magnetic particles having a polymerization initiation group introduced therein. 0.7 g of the magnetic particles introduced with this polymerization initiating group are well dispersed in 6.1 g of styrene and 3.0 g of xylene, and 45 mg of copper (I) bromide, 4,4′-dinonyl-2,2′-bipyridyl. After mixing 251 mg, the dissolved oxygen was replaced with nitrogen, polymerization was performed at 110 ° C. for 10 hours, and grafted onto the surface of the magnetic particles. After completion of the reaction, toluene washing and centrifugation were repeated to obtain 3.5 g of magnetic polymer particles grafted with polystyrene.

  When the particle size of the magnetic particles obtained was measured in tetrahydrofuran (manufactured by Malvern, HPPS), the average particle size was 80 nm, and the particle size range was 60 nm to 95 nm. The obtained magnetic polymer particles were added to concentrated hydrochloric acid (37%), reacted at room temperature for 3 hours, and the grafted polystyrene was recovered by dissolving and removing the core iron oxide. When the grafted polystyrene was measured by GPC, the number average molecular weight Mn was 9700, and Mw / Mn was 1.30, indicating a narrow molecular weight distribution.

(Example 2)
This example is an example of producing magnetic polymer particles in which polymethyl methacrylate is grafted by living radical polymerization. 1.0 g of phosphine derivative introduced with the polymerization initiating group represented by formula (4a) and 1.0 g of ferrite Fe ₃ O ₄ fine particles (manufactured by Toda Kogyo Co., Ltd.) in tetrahydrofuran were added to tetrahydrofuran and well ultrasonically dispersed at room temperature. . The reaction solution was repeatedly washed with ethanol and centrifuged to obtain magnetic particles into which a polymerization initiating group had been introduced. 0.5 g of the magnetic particles were well dispersed in 5 g of methyl methacrylate and 5 g of anisole, and 28 mg of copper (I) chloride and 30 mg of pentamethyldiethylenetriamine were further added. Dissolved oxygen was replaced with nitrogen, and polymerization was performed at 90 ° C. for 10 hours. Then, washing with toluene and centrifugation were repeated to obtain 3.0 g of magnetic polymer particles grafted with polymethyl methacrylate.

  When the particle size distribution and GPC in tetrahydrofuran were measured in the same manner as in Example 1, the average particle size was 100 nm, the particle size range was 85 nm to 120 nm, Mn of the grafted polymethyl methacrylate was 15000, and Mw / Mn was It was narrow like 1.26 and Example 1.

(Example 3)
This example is an example of producing magnetic polymer particles in which polybenzyl methacrylate is grafted by living radical polymerization. Similarly to Example 2, magnetic particles having a polymerization initiating group introduced therein were obtained using the phosphine derivative represented by the formula (4a) and ferrite Fe ₃ O ₄ fine particles (manufactured by Toda Kogyo Co., Ltd.) by the synthesis method. 0.5 g of this magnetic particle was well dispersed in 8.1 g of benzyl methacrylate and 7.5 g of anisole, and further 20 mg of copper (I) chloride and 21 mg of pentamethyldiethylenetriamine were added. After replacing the dissolved oxygen with nitrogen and performing polymerization at 30 ° C. for 1 hour, toluene washing and centrifugation were repeated to obtain 4.3 g of magnetic polymer particles grafted with polybenzyl methacrylate.

  When the particle size distribution and GPC in tetrahydrofuran were measured in the same manner as in Example 1, the average particle size was 105 nm, the particle size range was 80 nm to 127 nm, the Mn of the grafted polybenzyl methacrylate was 17500, and the Mw / Mn was 1 .35 and the same narrowness as in Example 1.

(Comparative Example 1)
General-purpose radical copolymerization was carried out using the same magnetic particles as in Example 1 as raw materials to produce magnetic polymer particles. In the same manner as in Example 1, a ferrite-based superparamagnetic material was obtained from a magnetic fluid (Ferricolloid HC-50, manufactured by Taiho Industries). After 7 g of styrene and 1 g of methacrylic acid were added to 3 g of this magnetic material and dispersed uniformly, 0.5 g of benzoyl peroxide was dissolved. This was added to 800 ml of water in which 0.4 g of polyvinyl alcohol (trade name: PVA217EE, manufactured by Kuraray Co., Ltd.) was dissolved, and subjected to ultrasonic dispersion to obtain a suspension. Thereafter, this suspension was polymerized at 80 ° C. for 5 hours under a nitrogen atmosphere to obtain magnetic polymer particles.

  The average particle diameter of the obtained magnetic polymer particles was 1.7 μm, the particle diameter range was about 0.3 to 5 μm, and the grafted polymer had Mn of 6700 and Mw / Mn of 3.55. Compared to ˜3, the molecular weight distribution was wide. In this aqueous dispersion of magnetic polymer particles, some large magnetic polymer particles precipitated after standing for 1 day. As is clear from these results, the polymer of the magnetic polymer particles synthesized by the production method of the present invention has a uniform polymer chain length and particle size as compared with Comparative Example 1, and the magnetic polymer particles are well dispersed. It was confirmed to show sex.

Example 4
In this example, magnetic polymer particles grafted with a block polymer whose polymer chain structure changes with stimulation (pH) are prepared. 2.5 g of the magnetic polymer particles obtained in Example 2 were ultrasonically dispersed in 4 g of 1,2-dichlorobenzene and 4.6 g of dimethylaminoethyl methacrylate, and further 12 mg of copper (I) chloride and hexamethyltriethylenetetraamine 26 .7 mg was mixed. This mixed solution was substituted with nitrogen for dissolved oxygen, and polymerized at 90 ° C. for 10 hours to obtain magnetic polymer particles in which the graft polymer chain was a block polymer. The reaction solution was repeatedly washed with toluene and centrifuged to obtain 4.2 g of magnetic polymer particles grafted with a block polymer (polymethyl methacrylate-b-polydimethylaminoethyl methacrylate).

  The particle size distribution in tetrahydrofuran and GPC were measured in the same manner as in Example 1. As a result, the average particle size was 150 nm, the particle size range was 130 nm to 175 nm, and the grafted block polymer (polymethyl methacrylate-b-polydimethylamino Ethyl methacrylate) had a Mn of 24,000 and Mw / Mn of 1.32 as narrow as the precursor polymethyl methacrylate of Example 2. While the magnetic polymer particles were dispersed in an aqueous solution having a pH of 2, they partially precipitated at a pH of 11. Thus, since the charged state of polydimethylaminoethyl methacrylate changes depending on the pH, the structure of the polymer chain can be controlled by the pH.

(Example 5)
In this example, magnetic polymer particles were prepared by grafting a block polymer including a block in which a hydrophilic macromonomer was incorporated in a polymer chain and an enzyme was immobilized in order to improve dispersion stability in water. It is an example. 3.0 g of the magnetic polymer particles obtained in Example 3 were ultrasonically dispersed in 4.0 g of anisole and 4.5 g of methyl methacrylate, and further 1 g of polyethylene glycol methyl ether methacrylate (macromonomer, Mn˜480), copper chloride ( I) 25 mg and pentamethyldiethylenetriamine 36 mg were mixed. This mixed solution was substituted with nitrogen for dissolved oxygen, and polymerized at 50 ° C. for 3 hours to obtain magnetic polymer particles in which the graft polymer chain was a block polymer. The reaction solution was repeatedly washed with toluene and centrifuged to obtain 4.8 g of magnetic polymer particles grafted with a block polymer {polybenzyl methacrylate-b- (polymethyl methacrylate-co-polyethylene glycol methyl ether methacrylate)}.

  When the particle size distribution and GPC in tetrahydrofuran were measured in the same manner as in Example 1, the average particle size was 170 nm and the particle size range was 145 nm to 190 nm. The grafted block polymer {polybenzyl methacrylate-b- (polymethacrylic acid) Methyl of methylmethyl-co-polyethylene glycol methyl ether methacrylate)} was 34,000, and Mw / Mn was 1.30, which was as narrow as the precursor polybenzyl methacrylate of Example 2.

  Polybenzyl methacrylate in this block polymer is converted to polymethacrylic acid having carboxylic acid by catalytic hydrogen reduction using palladium / carbon, and further, using the carboxyl group in the obtained polymethacrylic acid, derived from horseradish Peroxidase was immobilized. That is, the magnetic polymer particles grafted with {polymethacrylic acid-b- (polymethylmethacrylate-co-polyethyleneglycolmethylethermethacrylate)} obtained above were adjusted to a solid content concentration of 3%. Dispersed in 01M borate buffer pH 8.2. To 2 ml of this magnetic polymer particle-containing dispersion, water-soluble carbodiimide (manufactured by DOJIN, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 10 mg / ml, 0.01 M borate buffer pH 8.2) 0.4 ml of horseradish peroxidase (hereinafter referred to as HRP, 54 mg / ml, specific activity 250 to 350 U / mg, 0.01 M borate buffer pH 8.2) 1.2 ml was added and reacted at 4 ° C. for 12 hours. As a result, an amide bond was formed, and HRP was immobilized on the methacrylic acid block. In this magnetic polymer particle, since the HRP-immobilized methacrylic acid block is located inside the particle and protected by the outer block chain, the activity of HRP was kept stable. Furthermore, since a hydrophilic polyethylene glycol macromonomer is present outside the particle and plays a role of a dispersant in water, the dispersibility in an aqueous system was good.

It is a schematic sectional drawing of the magnetic polymer particle of this invention.

Explanation of symbols

1 Magnetic particle 2 Polymer layer

Claims (8)

  A magnetic polymer particle comprising a magnetic particle and a polymer chain coated with the magnetic particle, wherein the molecular weight distribution index (Mw / Mn) of the polymer chain is 1.6 or less.   A magnetic polymer particle comprising a magnetic particle and a polymer chain coated with the magnetic particle, wherein the polymer chain is a block polymer composed of two or more types of blocks.   The magnetic polymer particle according to claim 2, wherein one block is a block polymer composed of blocks containing polymer chains that contribute to dispersion stability.   3. The magnetic material according to claim 2, wherein one block is a block polymer composed of a block containing a polymer chain whose structure or volume changes in response to a stimulus selected from the group consisting of light, temperature, pH and electric field. Polymer particles.   The magnetic polymer particle according to claim 2, wherein one block is a block polymer composed of a block containing a polymer chain to which a biomaterial selected from the group consisting of protein, enzyme, nucleic acid and sugar is immobilized. A method for producing magnetic polymer particles comprising the steps of preparing magnetic particles and coating the magnetic particles with a polymer,
A process for producing magnetic polymer particles, wherein the polymer coating step forms a polymer chain by living polymerization. A method for producing magnetic polymer particles comprising the steps of preparing magnetic particles and coating the magnetic particles with a polymer,
Coating with the polymer comprises
Introducing a polymerization initiating group on the surface of the magnetic particles;
A step of grafting the polymer onto the surface of the magnetic particles by homopolymerizing or copolymerizing one or more monomers using the polymerization initiation group as a polymerization initiation source;
A method for producing magnetic polymer particles, comprising:   The method for producing magnetic polymer particles according to claim 7, wherein the polymerization initiating group has a living radical polymerization initiating ability, and the polymerization is living radical polymerization or living radical copolymerization.

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