JP2016211938A - Magnetic composite particle - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a magnetic composite particle having high dispersion stability and high detection sensitivity.SOLUTION: A magnetic composite particle 6 includes magnetic substance particles 8 and an organic polymer material 7 enclosing the magnetic substance particles 8. The magnetic composite particle has a shape in which the ratio of the major axis to the minor axis is greater than 1. At least one of the bottom surface 15 and top surface 16 as surfaces crossing the minor axis 12 has a connectivity to an analyte higher than that of a side surface 15 as a surface crossing the major axis 13.SELECTED DRAWING: Figure 1

Description

  The present invention relates to magnetic composite particles.

  In recent years, research and development related to composite particles have been actively conducted for application to various industrial fields. For example, magnetic composite particles composed of a polymer compound and a magnetic material are expected to have a wide variety of uses. In particular, attention has been drawn to the use as a base in the medical / diagnosis field, such as pharmaceuticals and diagnostic agents. Yes. An example of applying magnetic composite particles to the medical / diagnosis field is a magnetic biosensor. Magnetic biosensor is one of the recently proposed high-sensitivity sensing methods that detects the presence and concentration of a target substance in a sample liquid by detecting the presence and number of magnetic composite particles located near the surface of the detection unit. To do.

  FIG. 4 shows an example of a conventional biosensor measurement technique using magnetic composite particles 4. The substrate 1 is provided with a sensor unit 2 (magnetic sensor) made of a GMR element, a Hall element or the like. Then, the specimen 3 is fixed on the upper part of the sensor unit 2. The magnetic composite particle 4 has a surface functional group so as to bind to the specimen 3, and is fixed so that the magnetic composite particle 4 is caught by the specimen 3, and the magnetic flux 5 from the fixed magnetic composite particle 4 is detected by the sensor. Measured by the unit 2.

Patent Document 1 discloses a composite having a small particle size and excellent monodispersibility used in these magnetic biosensors, a high magnetic substance content for each particle, a large saturation magnetization, excellent dispersion stability, and nonspecific adsorption inhibiting ability. Particles and methods for their production are disclosed.

Patent Document 2 discloses a flat-shaped magnetic polymer particle that is excellent in magnetic separation and has a large amount of binding with a biological substance and a method for producing the same.

Japanese Unexamined Patent Publication No. 2009-300239 JP 2007-256151 A

  However, in practice, increasing the magnetic substance content rate has a trade-off relationship with dispersion stability because the specific gravity of the composite particles increases and the dispersion stability decreases. The flat magnetic polymer particle 18 has a large surface area and high dispersion stability. However, when the magnetic polymer particle 18 is bound to the specimen in an inverted state with respect to the sensor unit 2 like the magnetic polymer particle 18 shown on the left side of FIG. There is a problem that becomes low. An object of the present invention is to provide magnetic composite particles having high dispersion stability and detection sensitivity.

  The magnetic composite particle of the present invention that achieves the above object includes a magnetic particle and an organic polymer material that includes the magnetic particle, and has a shape with a major axis / minor axis larger than 1, and a surface that intersects the minor axis It is characterized in that at least one of the bottom surface and the top surface is a higher binding property to the specimen than the side surface that is the surface that intersects the major axis.

In the present invention, the “major axis” of a shape refers to the largest diameter of the cross section passing through the center of the shape, and the “minor diameter” of the shape refers to the smallest of the diameters of the cross section passing through the center of the shape. This means the diameter.

Since the magnetic flux density is rapidly attenuated by the distance from the magnetic material, when the magnetic composite particles are detected by a magnetic sensor, the magnetic particles in the magnetic composite particles are close to the magnetic sensor, and the contribution ratio to the magnetic detection is high. Magnetic particles far from the magnetic sensor have a low contribution rate. By making the shape of the magnetic composite particle larger than 1 in the major axis / minor axis, the contribution to magnetic detection can be increased even if the number of magnetic particles in the magnetic composite particle is the same, so the number of magnetic particles is increased. Even without this, the detection sensitivity can be improved. In addition, the bottom or top surface of the magnetic composite particles can be selectively bonded to the specimen, and the magnetic composite particles can be prevented from binding to the specimen in an inverted state. Can be combined with the analyte. Therefore, magnetic composite particles having high dispersion stability and detection sensitivity can be provided.

Further, in the magnetic composite particle of the present invention, the organic polymer material enclosing the magnetic particle is a surface where the major axis / minor axis of the outer shape is larger than 1 and intersects the minor axis of the organic polymer material. A selective binding group to the specimen is added to at least one of the bottom surface and the top surface.

According to this, it is possible to provide magnetic composite particles with high dispersion stability and high detection sensitivity more easily.

Furthermore, the magnetic composite particle of the present invention is characterized in that the side surface is hydrophilic.

In the present invention, “hydrophilic” means that the contact angle of pure water is 40 ° or less.

According to this, it is possible to provide magnetic composite particles having a low binding property between the specimen and the side surface, a higher inversion prevention effect, and a high detection sensitivity.

  The present invention can provide magnetic composite particles having high dispersion stability and high detection sensitivity.

FIG. 1 is a schematic diagram showing the configuration of magnetic composite particles in the embodiment. FIG. 2 is a schematic cross-sectional view of a biosensor using magnetic composite particles in the embodiment. FIG. 3 is a process diagram showing an example of a production process of magnetic composite particles in the embodiment. FIG. 4 is a schematic view of a biosensor using conventional magnetic composite particles. FIG. 5 is a schematic diagram of a biosensor using conventional magnetic composite particles.

Hereinafter, modes for carrying out the present invention will be described. This embodiment is an example for carrying out the present invention, and the present invention is not limited to this embodiment.

(Basic composition of magnetic composite particles)
A schematic diagram of the magnetic composite particle 6 of the present embodiment is shown in FIG. The magnetic composite particle 6 includes a magnetic particle 8 and an organic polymer material 7 containing the magnetic particle 8. The organic polymer material 7 including the magnetic particles 8 has a shape whose major axis / minor axis is larger than 1, and the magnetic composite particle 6 has a shape whose major axis / minor axis is larger than 1. ing. The shapes of the organic polymer material 7 and the magnetic composite particles 6 are, for example, a substantially disk shape or a spheroid shape. A selective binding group 14 to the specimen 3 is added to at least one of the bottom surface 15 and the top surface 16 that are surfaces intersecting the minor axis of the organic polymer material 7, and the magnetic composite particle 6 intersects the minor axis 12. At least one of the bottom surface 15 and the top surface 16 that is the surface has a higher binding property to the specimen than the side surface 17 that is the surface that intersects the major axis 13. The selective binding group 14 has a higher binding property to the specimen than the surface functional group present on the surface of the organic polymer material 7 (side surface 17 of the magnetic composite particle 6). In order to further reduce the binding between the side surface of the magnetic composite particle 6 and the specimen 3, the side surface 17 of the magnetic composite particle 6 is preferably hydrophilic. Here, hydrophilicity means that the contact angle of pure water is 40 ° or less.

Here, the specimen 3 is a protein capable of protein-protein interaction, such as a receptor protein having a ligand capable of binding, an adhesion protein, an antigen or an antibody, and is associated with a disease. Such proteins include proteins that can be used to diagnose disease, such as proteins whose increase or decrease in their amount suggests the presence of a disease, such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF) Growth factors such as brain-derived growth factor (BDGF) or vascular endothelial growth factor (VEGF), cell adhesion factors such as fibronectin, laminin or vitronectin, hormones such as insulin, somatostatin, somatothrombin or gonadotropin releasing factor, LDL, etc. Lipoproteins, various tumor markers or antibodies. Alternatively, a virus such as HIV or HBV, or a DNA / RNA such as a bacterium or an oncogene can be used as the specimen 3. In addition, the sample 3 is not limited to the sample molecule exemplified above, but should be a molecule that binds to the sample molecule as exemplified above or a molecule that is unevenly distributed in the vicinity of the sample molecule as exemplified above. You can also.

(Organic polymer material)
As the organic polymer material 7, a known thermoplastic polymer, thermosetting polymer, or a mixture thereof can be used. Examples of the thermoplastic polymer include polyester resins such as polyethylene, polypropylene, polyethylene propylene, polystyrene, polymethyl methacrylate, polyvinyl alcohol, polyvinyl chloride, polycarbonate, polyethylene terephthalate, polybutylene terephthalate, polypropylene terephthalate or polynaphthalene terephthalate. , Polyamides such as nylon 6, nylon 66, nylon 12 or nylon 4, poly-4-methylpentene, acrylonitrile-butadiene-styrene copolymer, acrylic / styrene copolymer, chlorinated polyethylene, allyl resins, ethylene-vinyl acetate -Vinyl chloride copolymer, ethylene-vinyl chloride copolymer, methacryl-styrene copolymer, acrylonitrile resin, olefin Vinyl alcohol copolymer, petroleum resin, polyacetal, polyallyl sulfone, polybenzimidazole, polybutylene, polyether ether ketone, polyether ketone, polyether nitrile, polyether sulfone, polyketone, polymethylpentene, polyphenylene ether, polyphenylene sulfide, Examples thereof include polysulfone, butadiene-styrene resin, polyurethane, polyvinylidene chloride, silicone resin, polyvinyl acetate, ethylene propylene diene, chloroprene, butadiene, nitrile rubber, natural rubber, acrylonitrile butadiene rubber, and butyl rubber.

Examples of the thermosetting polymer include known polymers such as unsaturated polyester, phenolic, melamine, urea, diallyl phthalate, and polyimide polymers.

The magnetic composite particles 6 preferably have a specific gravity close to 1 in order to prevent sedimentation and aggregation when dispersed in an aqueous solution. For this reason, the organic polymer material 7 is preferably selected from those insoluble in water and having a small specific gravity. Further, in the aqueous solution, the hydrophobic group of the specimen 3 and the hydrophobic group of the organic polymer material 7 are likely to be bonded by a hydrophobic interaction. In order to further reduce the binding between the side surface of the magnetic composite particle 6 and the specimen 3, a polymer that easily obtains a hydrophilic surface is used as the organic polymer material 7, and the outer surface of the organic polymer material 7 (particularly, the major diameter and It is preferable to make the side surface which intersects) hydrophilic. Examples of the polymer that easily obtains a hydrophilic surface include polyvinyl alcohol, polyurethane, and polyamides.

(Magnetic particles)
The magnetic particle 8 is a ferromagnetic material that can be detected by a magnetic sensor or the like, and preferably has a high magnetization (saturation magnetization) when an external magnetic field is applied to improve detection sensitivity. In order to reduce this, it is preferable that the magnetization (residual magnetization) when the external magnetic field is removed is small.

Examples of such ferromagnetic materials include ferromagnetic metals such as iron, manganese, cobalt, nickel, and gadolinium, or alloys or oxides containing at least one of them. Specifically, magnetic steel containing iron as a main component and added with cobalt, tungsten, chromium, nickel or aluminum, an alloy of iron and platinum and / or neodymium and / or samarium, an alloy of samarium and cobalt, Various ferrites such as iron oxide (Fe ₃ O ₄ ), CoFe ₂ O _{4, and} γ-iron sesquioxide (γ-Fe ₂ O ₃ ) are included. Further, since the magnetic composite particles 6 are dispersed in an aqueous solution and the surface thereof is modified with an antibody or the like, it is preferable that the magnetic particles 8 have poor reactivity, for example, ferrites. Fe ₃ O ₄ (magnetite) is preferred.

(Biosensor)
A schematic diagram of a biosensor using magnetic composite particles 6 is shown in FIG. The substrate 1 is provided with a sensor unit 2 (magnetic sensor) made of a GMR element, a Hall element or the like. Then, the specimen 3 is fixed on the upper part of the sensor unit 2. The bottom surface 15 or the top surface 16 of the magnetic composite particle 6 has a selective binding group 14 so as to bind to the specimen 3, and the magnetic composite particle 6 is fixed on the bottom surface 15 or the top surface 16 by the specimen 3, and the fixed magnetism is fixed. The magnetic flux 5 from the composite particle 6 is measured by the sensor unit 2.

FIG. 2 is a schematic diagram when an external magnetic field having a component parallel to the surface (sensing surface) of the sensor unit 2 is applied to the magnetic composite particles 6. Since the magnetic flux density is rapidly attenuated by the distance from the magnetic material, the magnetic particles 8 in the magnetic composite particles 6 that are close to the sensor unit 2 have a high contribution rate to magnetic detection, and the magnetic particles 8 far from the sensor unit 2. Has a low contribution rate. Since the magnetic composite particles 6 are fixed on the bottom surface 15 or the top surface 16, the magnetic particles 8 exist at a position close to the sensor unit 2 even if the number of the magnetic particles is the same, and the contribution ratio is increased. Detection sensitivity can be improved without increasing the number. Further, in an inverted state where the magnetic composite particles 6 are fixed to the specimen 3 on the side surface 17, the number of magnetic particles 8 at a position far from the sensor unit 2 increases, and the detection sensitivity decreases. Since at least one of the bottom surface 15 and the top surface 16 of the magnetic composite particle 6 has a higher binding property to the sample 3 than the side surface 17, the bottom surface 15 or the top surface 16 of the magnetic composite particle 6 selectively becomes the sample 3. Since the binding can prevent the magnetic composite particle 6 from binding to the specimen 3 in an inverted state, the magnetic composite particle 6 can be more reliably bound to the specimen with high detection sensitivity.

(Selective linking group)
The selective binding group 14 is not particularly limited, and is an active functional group such as an aldehyde group or an amino group. Since the amino group introduction site is positively charged, it can bind to the negatively charged specimen 3 by electrostatic interaction. For example, amino group introduction methods include treatment with aminoalkylsilane, plasma treatment under nitrogen atmosphere, coating of amino group-containing polymer material, or coating of poly-L-lysine.

(Production method)
The method for producing the magnetic composite particles 6 is not particularly limited. For example, as shown in FIG. 3, a synthesis step for synthesizing the spherical magnetic composite particles 9, an application step for applying the spherical magnetic composite particles 9 to the glass substrate 11a, It can be produced by a hot press process. More specifically, it can be produced by the following method.

(Synthesis process)
First, spherical magnetic composite particles 9 containing magnetic particles 8 are produced. These can be made using known techniques. Lauroyl peroxide as a polymerization initiator is dissolved in a styrene monomer, and a dispersion in which commercially available Fe ₃ O ₄ is dispersed is prepared. Next, a dispersion in which pure water and Fe ₃ O ₄ are dispersed is placed in a container equipped with a stirrer, and polymerization is performed at a temperature of about 60 ° C. for about 20 hours while stirring to synthesize spherical magnetic fine particles 9. The polymerized spherical magnetic fine particles 9 are separated and purified by magnetic separation. As a result, spherical magnetic fine particles 9 in which Fe ₃ O ₄ as the magnetic particles 8 is encapsulated with polystyrene as the organic polymer 7 are synthesized.

(Coating process)
The spherical magnetic composite particles 9 produced in the synthesis step are dispersed in ethanol, applied to a flat glass substrate 11a on which the selective bonding group 14 has been introduced, and dried to form a single layer of the spherical magnetic composite particles 9.

(Hot press process)
By superposing the glass substrate 11b on which the selective bonding group 14 has been introduced on the glass substrate 11a on which the spherical magnetic composite particles 9 have been applied, and heating to 100 ° C., which is the softening point temperature of polystyrene, The magnetic composite particle 6 having the selective binding group 14 transferred to the bottom surface 15 and the top surface 16 can be formed. Thus, the magnetic composite particle 6 in which the selective binding group 14 to the specimen is added to at least one of the bottom surface 15 and the top surface 16 of the organic polymer material 7 can be produced by a simple method.

The magnetic composite particles 6 described above can be changed as appropriate. For example, in the magnetic composite particle 6 described above, the selective binding group 14 to the specimen is added to at least one of the bottom surface 15 and the top surface 16 of the organic polymer material 7. By physically processing at least one of the top surface and the top surface, the surface state is changed, so that at least one of the bottom surface and the top surface of the magnetic composite particle binds to the specimen rather than the side surface without adding the selective binding group 14. May be made higher.

DESCRIPTION OF SYMBOLS 1 Substrate 2 Sensor part 3 Specimen 4 Magnetic composite particle 5 Magnetic flux 6 Magnetic composite particle 7 Organic polymer material 8 Magnetic body particle 9 Spherical magnetic composite particle 11a Glass substrate 11b Glass substrate 12 Minor axis 13 Major axis 14 Selective binding group 15 Bottom surface 16 Top surface 17 Side surface 18 Magnetic polymer particles

Claims (3)

Including a magnetic particle and an organic polymer material enclosing the magnetic particle, wherein the major axis / minor axis has a shape larger than 1.
A magnetic composite particle, wherein at least one of a bottom surface and a top surface, which are surfaces intersecting with a minor axis, has a higher binding property to a specimen than a side surface, which is a surface intersecting with a major axis. The organic polymer material containing the magnetic particles has a major axis / minor axis greater than 1 in its outer shape,
2. The magnetic composite particle according to claim 1, wherein a selective binding group to a specimen is added to at least one of a bottom surface and an upper surface, which are surfaces intersecting with the minor axis of the organic polymer material.   The magnetic composite particle according to claim 1, wherein the side surface is hydrophilic.

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