WO2010151085A2 - Systèmes de séparation magnétique et capteurs magnétiques à base de nanoparticules magnétiques contenant du zinc - Google Patents

Systèmes de séparation magnétique et capteurs magnétiques à base de nanoparticules magnétiques contenant du zinc Download PDF

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WO2010151085A2
WO2010151085A2 PCT/KR2010/004158 KR2010004158W WO2010151085A2 WO 2010151085 A2 WO2010151085 A2 WO 2010151085A2 KR 2010004158 W KR2010004158 W KR 2010004158W WO 2010151085 A2 WO2010151085 A2 WO 2010151085A2
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magnetic
zinc
nanoparticles
nanoparticle
separation system
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PCT/KR2010/004158
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English (en)
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WO2010151085A3 (fr
Inventor
Jin Woo Cheon
Jae Hyun Lee
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Industry-Academic Cooperation Foundation, Yonsei University
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Publication of WO2010151085A2 publication Critical patent/WO2010151085A2/fr
Publication of WO2010151085A3 publication Critical patent/WO2010151085A3/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C1/00—Magnetic separation
    • B03C1/005—Pretreatment specially adapted for magnetic separation
    • B03C1/01—Pretreatment specially adapted for magnetic separation by addition of magnetic adjuvants
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/72—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C2201/00—Details of magnetic or electrostatic separation
    • B03C2201/18—Magnetic separation whereby the particles are suspended in a liquid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C2201/00—Details of magnetic or electrostatic separation
    • B03C2201/26—Details of magnetic or electrostatic separation for use in medical or biological applications

Definitions

  • the present invention relates to zinc-containing magnetic nanopartide-based magnetic separation systems and magnetic sensors.
  • Magnetic nanoparticles have been found to be applied to very numerous application fields.
  • MRI magnetic resonance imaging
  • material separation systems using magnetism include: (a) material separation systems using magnetism; (c) drug delivery systems using magnetism; (d) material sensors using magnetism; and (e) thermotherapies using a high-frequency magnetic field (HFMF).
  • HFMF high-frequency magnetic field
  • iron oxide nanoparticles have some advantages such as (a) feasible synthesis and (b) relatively low cost in its synthesis according to the development of various synthesis methods.
  • a few iron oxide nanoparticles ⁇ e.g., MRI contrast agent) are commercially accessible as iron oxide has been known to exhibit very low toxicity in a human body.
  • a nanoparticle having high saturation magnetism (AZ 5 ) is as follows:
  • MnFe 2 O 4 nanopartides are synthesized by substituting Mn 2+ for Fe 2+ in conventional iron oxide nanopartides.
  • the nanopartides with a size of 12 nm have saturation magnetism of 125 emu/g.
  • FeCo nanopartides (Seo eta/., Nature Materials, 5: 971 (2006))
  • FeCo nanopartides are produced by alloy of iron and cobalt, and their saturation magnetisms are 215 emu/g.
  • nanopartides developed in aforementioned references as MRI contrast agent their contrast effects were improved several ten times compared with iron oxide-based contrast agents, supposing that the nanopartides may be utilized in early diagnosis of diseases such as cancer more excellent than present techniques.
  • Zn ⁇ 4 Fe 2-6 O 4 nanoparticle using a zinc-containing iron oxide have lower toxicity than FeCo nanoparticle, it exhibits the most excellent application probability in human body and bio-experiments.
  • magnetic moment of nanopartides is crucial for enhancement of contrast effect.
  • nanoparticles having high magnetic moment contribute to enhancement of contrast effect in several other application fields including magnetic separation, magnetoresistance sensor, magnetic relaxation sensor, heat release by high- frequency magnetic field, and so forth.
  • the nanoparticle cluster may be utilized.
  • the present inventors have made intensive studies to develop a magnetic separation system having improved separation efficiency for isolating a target material.
  • a magnetic nanoparticle used in the magnetic separation system zinc-containing magnetic nanoparticle having high saturation magnetism or cluster thereof may be applied to the magnetic separation system for providing a magnetic separation system to achieve the aforementioned purpose.
  • a magnetic sensor for detecting or quantitating an analyte in more improved sensitive and accurate manner.
  • a magnetic nanopartide used in the magnetic sensor zinc-containing magnetic nanopartide having specific stoichiometry and high saturation magnetism or cluster thereof may be applied to the magnetic sensor for providing a magnetic sensor to achieve the aforementioned purpose.
  • a zinc-containing magnetic nanopartide-based magnetic separation system or magnetic sensor comprising a zinc-containing magnetic nanopartide represented by the following formula 1 or 2 or a cluster thereof:
  • Zn f M a-f O b (0 ⁇ f ⁇ 8, 0 ⁇ a ⁇ 16, 0 ⁇ b ⁇ 8, 0 ⁇ f/(a-f) ⁇ 10, M represents a magnetic metal atom or an alloy thereof)
  • Zn g M c-g M' d O e (0 ⁇ g ⁇ 8, 0 ⁇ c ⁇ 16, 0 ⁇ d ⁇ 16, 0 ⁇ e ⁇ 8, 0 ⁇ g/ ⁇ (c-g)+d ⁇ 10
  • M represents a magnetic metal atom or an alloy thereof
  • M' represents one or more elements selected from the group consisting of Group 1 elements, Group 2 elements, Group 12 elements, Group 13 elements, Group 14 elements, Group 15 elements, transition metal elements, Lanthanide elements and Actinide elements)
  • the magnetic separation system and magnetic sensor of the present invention exhibit utilize a zinc-containing magnetic nanoparticle having specific stoichiometry and high saturation magnetism or cluster thereof, and both working principles are similar.
  • Zinc-containing magnetic nanoparticles used in the magnetic separation system of the present invention are represented by the following formula 1 or 2:
  • M represents a magnetic metal atom or an alloy thereof
  • M represents a magnetic metal atom or an alloy thereof;
  • M' represents one or more elements selected from the group consisting of Group 1 elements, Group 2 elements, Group 12 elements, Group 13 elements, Group 14 elements, Group 15 elements, transition metal elements, Lanthanide elements and Actinide elements)
  • High saturation magnetism of zinc-containing nanoparticles described in the formula 1 or 2 leads to enhanced separation efficiency on the magnetic separation system to which magnetic field is applied.
  • M represents preferably transition metal elements
  • Lanthanide metal elements and Actinide metal elements more preferably, transition metal elements selected from the group consisting of Ba, Mn, Co, Ni and Fe, Lanthanide metal elements selected from the group consisting of Gd, Er, Ho, Dy, Tb,
  • M' preferably represents one or more elements selected from the group consisting of Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Ra, Ge, Ga, Bi, In, Si, Ge, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, Lanthanide elements and Actinide elements.
  • the zinc-containing magnetic nanopartide used in the magnetic separation system of this invention is represented by the following formula 3:
  • M" represents a magnetic metal atom or an alloy thereof
  • M" represents preferably transition metal elements, Lanthanide metal elements and Actinide metal elements; more preferably, transition metal elements selected from the group consisting of Ba, Mn, Co, Ni and Fe, Lanthanide metal elements selected from the group consisting of Gd, Er, Ho, Dy, Tb, Sm and Nd; and most preferably, Mn, Co, Ni, Fe, Gd, Er, Ho, Dy, Tb, Sm or Nd, or an alloy thereof.
  • the zinc-containing magnetic nanopartide used in the magnetic separation system of this invention is represented by the following formula 4 or 5:
  • a stoichiometric content ratio of zinc and other metals is as follows: 0.001 ⁇ 'zinc/ (entire metal component - zinc)' ⁇ 10, more preferably 0.01 ⁇ 'zinc/ (entire metal component - zinc)' ⁇ 1, and most preferably 0.03 ⁇ 'zinc/ (entire metal component - zinc)' ⁇ 0.5.
  • zinc is contained as the above, high saturation magnetism can be obtained, resulting in significant improvement of separation efficiency in the present magnetic separation system.
  • the zinc-containing magnetic nanopartides contained in the cluster of the present invention are aggregated in a number of preferably 2-10,000, more preferably 2-1,000, and most preferably 2-100.
  • Each zinc-containing magnetic nanoparticles in the cluster is linked to each other by an intermolecular interaction, or encapsulated by an organic or inorganic carrier.
  • a binding agent with a binding affinity to a target material may be linked to the surface of a zinc-containing magnetic nanopartide or cluster thereof used in the present invention, or not.
  • the material of interest may be directly linked to a metal element contained in the zinc-containing magnetic nanopartide of the present invention.
  • nickel may be directly linked to a histidine residue of a protein or peptide, whereby protein is able to be isolated.
  • a gas- selective metal contained in the zinc-containing magnetic nanopartide of the present invention contributes to gas separation without a further binding agent.
  • the gas- selective metal includes Pt, Pd, Au, Ag, Nb, Ir, Rh, Ru and an alloy thereof, but is not limited to.
  • a hydrogen-selective metal includes Pt, Pd, Au, Ag and an alloy thereof.
  • a binding agent with a binding affinity to a target material is linked to the surface of a zinc-containing magnetic nanopartide or cluster thereof.
  • the binding agent is directly or indirectly, covalently or non-covalently linked to the surface of zinc-containing magnetic nanopartide of the present invention.
  • the binding agent may be directly bound to the surface of zinc- containing magnetic nanopartide by a covalent or non-covalent linkage such as an ionic bond, an electrostatic bond, a hydrophobic interaction, a hydrogen bond, a covalent bond, a hydrophilic interaction or a Van der Waal force.
  • the binding agent may be indirectly bound to the surface of zinc-containing magnetic nanopartide through an intervening agent.
  • target material refers to a material in a sample to be separated (or separated and detected, or separated, detected or quantified).
  • the target material includes, but is not limited to, a nucleic acid molecule (DNA or RNA), a protein, a peptide, an antigen, a sugar, a lipid, a bacterium, a virus, a cell, an organic compound, an inorganic compound, a metal and an inorganic ion.
  • the sample includes a biological sample, a chemical sample and an environmental sample, but is not limited to.
  • the biological sample includes blood, plasma, serum, virus, bacterium, tissue, cell, lymph, bone marrow, saliva, milk, urine, feces, eyeball fluid, seminal fluid, brain extract, spinal fluid, synovial fluid, thymus fluid, ascites, amniotic fluid, cell tissue fluid and cell culture, but is not limited to.
  • binding agent means a substance having a specific affinity to a target material to be separated. Any material having a binding affinity to a target material to be separated may be utilized as the binding agent.
  • a non- limiting example of a binding agent includes a nucleic acid molecule (DNA or RNA), a protein, an antibody, an antigen, an aptamer (RNA, DNA and peptide aptamer), a receptor, a hormone, a streptavidin, an avidin, a biotin, a lectin, a ligand, an agonist, an antagonist, an enzyme, a coenzyme, an inorganic ion, a cofactor, a sugar, a lipid, a substrate for an enzyme, a hapten, a neutravidin, a protein A, a protein G, a selectin, calcium sulfate, a gas binding agent (example: Pt, Pd, Au, Ag, Nb, Ir, Rh and Ru).
  • the binding agent is bound to the surface of zinc-containing magnetic nanopartide or cluster thereof through an intervening agent.
  • the intervening agent includes various linkers and nanopartide-coating materials known to those ordinarily skilled in the art.
  • the surface of the zinc-containing magnetic nanopartides or cluster thereof is coated with a water-soluble multifunctional ligand for nanopartide solubilization, whereby the binding agent is linked to nanopartide.
  • water-soluble multi-functional ligand refers to a ligand that may be bound to zinc-containing nanoparticles or cluster thereof to solublize in water and stabilize the nanoparticles, and may allow the nanoparticles to be bound by binding agent having a specific affinity to a target material.
  • the water-soluble multi-functional ligand can include (a) an adhesive region (Li), and further can include (b) a binding region (L M ), (c) a cross-linking region (Lm ), or (d) a binding & cross-linking region (L M -Lm) which includes both the binding region (L n ) and the cross-linking region (L,,,).
  • an adhesive region Li
  • L M an adhesive region
  • L M a binding region
  • Lm cross-linking region
  • Lm binding & cross-linking region
  • the term "adhesive region (U)" refers to a portion of a multi-functional ligand including a functional group capable of binding to the nanoparticles, and preferably to an end portion of the functional group. Accordingly, it is preferable that the adhesive region including the functional group should have high affinity with the surface of the nanoparticles.
  • the nanopartide can be attached to the adhesive region by an ionic bond, a covalent bond, a hydrogen bond, a hydrophobic interaction or a metal-ligand coordination bond.
  • the adhesive region of the multifunctional ligand may be varied depending on the substances constituting the nanoparticles.
  • binding region (Ln) means a portion of the multi-functional ligand containing a functional group capable of binding to binding agents having a specific affinity to a target material, and preferably the other end portion located at the opposite side from the adhesive region.
  • the functional group of the reactive region may be varied depending on the type of binding agents and their chemical formulae (Table 2).
  • cross-linking region (Lm) refers to a portion of the multi-functional ligand including a functional group capable of cross-linking to an adjacent multifunctional ligand, and preferably a side chain attached to a central portion.
  • cross-linking means that the multi-functional ligand is bound to another adjacent multi-functional ligand by intermolecular interaction.
  • the intermolecular interaction includes, but is not limited to, a hydrophobic interaction, a hydrogen bond, a covalent bond ⁇ e.g., a disulfide bond), a Van der Waals force and an ionic bond. Therefore, the cross-linkable functional group may be variously selected according to the kind of the intermolecular interaction.
  • the compound which originally contains the above-described functional group may be used as a water-soluble multi-functional ligand, but a compound modified or prepared so as to have the above-described functional group by a chemical reaction known in the art may be also used as a water-soluble multifunctional ligand.
  • the preferable multi-functional ligand of the present invention includes a monomer, a polymer, a carbohydrate, a protein, a peptide, a nucleic acid, a lipid or an amphiphilic ligand.
  • one example of the preferable multi-functional ligand is a monomer which contains the functional group described above, and preferably dimercaptosuccinic acid, since it originally contains the adhesive region, the cross-linking region and the binding region. That is, -COOH on one side of dimercaptosuccinic acid is bound to the magnetic nanoparticle, and -COOH and -SH on the other end portion functions to bind to a binding agent.
  • -SH of dimercaptosuccinic acid acts as the cross-linking region by disulfide bond with another -SH.
  • dimercaptosuccinic acid in addition to the dimercaptosuccinic acid, other compounds having -COOH as the functional group of the adhesive region and - COOH, -NH 2 or -SH as the functional group of the binding region may be utilized as the preferable multi-functional ligand, but not limited to.
  • Still another example of the preferable water-soluble multi-functional ligand according to the present invention includes, but not limited to, one or more polymers selected from the group consisting of polyphosphagen, polylactide, polylactide-co- glycolide, polycaprolactone, polyanhydride, polymaleic acid, a derivative of polymaleic acid, polyalkylcyanoacrylate, polyhydroxybutylate, polycarbonate, polyorthoester, polyethylene glycol, poly-L-lysine, polyglycolide, polymethyl methacrylate and polyvinylpyrrolidone.
  • polymers selected from the group consisting of polyphosphagen, polylactide, polylactide-co- glycolide, polycaprolactone, polyanhydride, polymaleic acid, a derivative of polymaleic acid, polyalkylcyanoacrylate, polyhydroxybutylate, polycarbonate, polyorthoester, polyethylene glycol, poly-L-lysine, polyglycolide, polymethyl
  • preferable other examples of the multi-functional ligand are a peptide.
  • Peptide is oligomer/polymer consisting of several amino acids. Since the amino acids have -COOH and -NH 2 functional groups in both ends thereof, peptides naturally have the adhesive region and the binding region.
  • the peptide that contains one or more amino acids having one or more of -SH, -COOH, -NH 2 and -OH as the side chain may be utilized as the preferable water-soluble multifunctional ligand.
  • still another example of the preferable multi-functional ligand is a protein.
  • Protein is a polymer composed of more amino acids than peptides, that is, composed of several hundreds to several hundred thousands of amino acids. Proteins contains -COOH and -NH 2 functional group at both ends, and also contains a lot of functional groups such as -COOH, -NH 2 , -SH, -OH, -CONH 2 , and so on. Proteins may be used as the water-soluble multi-functional ligand because they naturally contain the adhesive region, the cross-linking region and the binding region according to its structure as the above-described peptide.
  • the representative examples of proteins which are preferable as the water-soluble multi-functional ligand include a structural protein, a storage protein, a transport protein, a hormone protein, a receptor protein, a contraction protein, a defense protein and an enzyme protein, and more specifically, albumin, antibody, antigen, avidin, cytochrome, casein, myosin, glycinin, carotene, collagen, globular protein, light protein, streptavidin, protein A, protein G, protein S, lectin, selectin, angiopoietin, anti-cancer protein, antibiotic protein, hormone antagonist protein, interleukin, interferon, growth factor protein, tumor necrosis factor protein, endotoxin protein, lymphotoxin protein, tissue plasminogen activator, urokinase, streptokinase, protease inhibitor, alkyl phosphocholine, surfactant, cardiovascular pharmaceutical protein, neuro pharmaceuticals protein and gastrointestinal pharmaceuticals, but not limited to.
  • nucleic acid is oligomer consisting of many nucleotides. Since the nucleic acids have -PO 4 " and -OH functional groups in their both ends, they naturally have the adhesive region and the binding region (L 1 - L n ), or the adhesive region and the cross-linking region (L r L m ). Therefore, the nucleic acids may be useful as the water-soluble multi-functional ligand in this invention. In some cases, the nucleic acid is preferably modified to have the functional group such as -SH, -NH 2 , -COOH or -OH at 3'- or 5'-terminal ends.
  • the preferable multi-functional ligand is an amphiphilic ligand including both a hydrophobic and a hydrophilic region.
  • hydrophobic ligands having long carbon chains coat the surface.
  • the hydrophobic region of the amphiphilic ligand and the hydrophobic ligand on the nanoparticles are bound to each other through intermolecular interaction to stabilize the nanoparticles.
  • the outermost part of the nanoparticles shows the hydrophilic functional group, and consequently water-soluble nanoparticles can be prepared.
  • the intermolecular interaction includes a hydrophobic interaction, a hydrogen bond, a Van der Waals force, and so forth.
  • the portion which binds to the nanoparticles by the hydrophobic interaction is an adhesive region (Li), and further the binding region (Ln) and the cross-linking region (Lm) can be introduced therewith by an organo-chemical method.
  • an adhesive region Li
  • the binding region (Ln) and the cross-linking region (Lm) can be introduced therewith by an organo-chemical method.
  • amphiphilic polymer ligands with multiple hydrophobic and hydrophilic regions can be used.
  • Cross-linking between the amphiphilic ligands can be also performed by a linker for enhancement of stability in an aqueous solution.
  • hydrophobic region of the amphiphilic ligand can be a linear or branched structure composed of chains containing two or more carbon atoms, more preferably an alkyl functional group such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, icosyl, tetracosyl, dodecyl, cyclopentyl or cyclohexyl; a functional group having an unsaturated carbon chain containing a carbon-carbon double bond, such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, octenyl, decenyl or oleyl; or a functional group having an unsaturated carbon chain containing a carbon-carbon triple bond, such as propyl
  • examples of the hydrophilic region include a functional group being neutral at a specific pH, but being positively or negatively charged at a higher or lower pH such as -SH, -COOH, -NH 2 , -OH, -PO 3 H, -PO 4 H 2 , -SO 3 H, -OSO 3 H-NR 3 + X ' and so on.
  • preferable examples thereof include a polymer and a block copolymer, wherein monomers used therefor include ethylglycol, acrylic acid, alkylacrylic acid, ataconic acid, maleic acid, fumaric acid, acrylamidomethylpropane sulfonic acid, vinylsulfonic acid, vinylphophoric acid, vinyl lactic acid, styrenesulfonic acid, allylammonium, acrylonitrile, N-vinylpyrrolidone and N-vinylformamide, but not limited to.
  • monomers used therefor include ethylglycol, acrylic acid, alkylacrylic acid, ataconic acid, maleic acid, fumaric acid, acrylamidomethylpropane sulfonic acid, vinylsulfonic acid, vinylphophoric acid, vinyl lactic acid, styrenesulfonic acid, allylammonium, acrylonitrile, N-vinylpyrrolidone and N-vinyl
  • the preferable water-soluble multi-functional ligand in the nanoparticle of the present invention is a carbohydrate. More preferably, the carbohydrate includes, but not limited to, glucose, mannose, fucose, N-acetyl glucomine, N-acetyl galactosamine, N-acetylneuraminic acid, fructose, xylose, sorbitol, sucrose, maltose, glycoaldehyde, dihydroxyacetone, erythrose, erythrulose, arabinose, xylulose, lactose, trehalose, mellibose, cellobiose, rafflnose, melezitose, maltoriose, starchyose, estrodose, xylan, araban, hexosan, fructan, galactan, mannan, agaropectin, alginic acid, carrageenan, hemicelluloses, hyprome
  • the surface of the zinc-containing magnetic nanoparticles used in the present invention is coated with a water-soluble multi-functional organic ligand, and linked to the binding agent having a specific affinity to a target material through the binding region (Lu).
  • the zinc-containing nanoparticles may be synthesized according to various methods.
  • the zinc-containing nanoparticles of the present invention may be produced using a nanoparticle synthesis method in gas phase or in liquid phase ⁇ e.g., aqueous solution, organic solution or multiple solution system, etc.) known to those ordinarily skilled in the art.
  • the water-soluble zinc-containing nanoparticle coated with a water-soluble multi-functional organic ligand may be synthesized according to a chemical reaction in an aqueous solution.
  • This method is to synthesize the zinc- containing water-soluble metal oxide nanoparticles by adding zinc ion precursor materials to the reaction solution containing the water-soluble multi-functional ligand. It may be performed according to a synthesis method ⁇ e.g., a coprecipitation method, a sol-gel method, a micelle method, etc.) of a conventional water-soluble nanoparticle known to those skilled in the art.
  • a metal nitrate-based compound, a metal sulfate-based compound, a metal acetylacetonate-based compound, a metal fluoroacetoacetate-based compound, a metal halide-based compound, a metal perchlorate-based compound, a metal alkyloxide-based compound, a metal sulfamate-based compound, a metal stearate-based compound, a metal alkoxide- based compound or an organometallic compound may be used, but not limited to.
  • a benzene-based solvent a hydrocarbon solvent, an ether-based solvent, a polymer solvent, an ionic liquid solvent, an alcohol-based solvent, a sulfoxide-based solvent or water
  • benzene, toluene, halobenzene, octane, nonane, decane, benzyl ether, phenyl ether, hydrocarbon ether, a polymer solvent, diethylene glycol (DEG), water or an ionic liquid solvent may be used, but not limited to.
  • the zinc-containing metal oxide nanopartides according to the above- described method have a uniform size distribution ( ⁇ ⁇ 10%) and a high crystallinity.
  • zinc-content in the nanoparticle may be precisely controlled. In other words, by changing the ratio of zinc to other metal precursor material, the zinc-content in the nanoparticle can be controlled between 0.001 ⁇ 'zinc/(entire metal material - zinc)' ⁇ 10 in a stiochiometric ratio.
  • the hydrodynamic diameter of the final nanopartides prepared by the present invention is in a size range of preferably 1-1000 nm, more preferably 1-800 nm, much more preferably 2-100 nm and most preferably 10-50 nm.
  • the hydrodynamic diameter of the final nanoparticle clusters prepared by the present invention is in a size range of preferably 1-1000 nm, more preferably 1-800 nm, much more preferably 2-100 nm and most preferably 10-50 nm.
  • the nanoparticles of this invention have a saturation magnetization (M s ) value in a range of 100-200 emu/g and more preferably 120-200 emu/g.
  • the zinc-containing magnetic nanoparticle-based magnetic separation system further includes a magnetic field- generating means.
  • the magnetic field-generating means include a conventional magnet such as a permanent magnet and electromagnet known to those ordinarily skilled in the art.
  • the permanent magnet and electromagnet may be modified depending on a separation system, and have a magnetic field strength of preferably 10-10,000 mT, more preferably 100-5,000 mT, and most preferably 200-1,000 mT.
  • a method for separating a target material in a sample comprising the steps of:
  • M represents a magnetic metal atom or an alloy thereof
  • M represents a magnetic metal atom or an alloy thereof
  • M' represents one or more elements selected from the group consisting of Group 1 elements, Group 2 elements, Group 12 elements, Group 13 elements, Group 14 elements, Group 15 elements, transition metal elements, Lanthanide elements and Actinide elements) (2);
  • the zinc-containing magnetic nanopartide-target material complex is separated from other components in the sample by induction of magnetic field.
  • the complex may be removed from other components in the sample by various methods (pipetting, draining, skimming, pouring, etc.) to obtain a sample concentration solution containing only the zinc-containing magnetic nanopartide-target material complex.
  • various methods pipetting, draining, skimming, pouring, etc.
  • zinc-containing magnetic nanopartides may be added to a reactor containing a sample and mixed, they may be separated in a portion of the reactor by induction of magnetic field.
  • only the zinc-containing magnetic nanopartides may be separated by pipetting the sample under magnetic field induction.
  • the zinc-containing magnetic nanopartides are washed and resuspended in a suitable solvent, enabling to produce a sample concentration solution containing only the zinc-containing magnetic nanopartide-target material complex.
  • the separation method of the present invention may be combined with a detection or quantification process.
  • the method of the present invention further includes a step (c) which detects a formation of the zinc-containing magnetic nanopartide-target material complex in the sample.
  • a method to detect a formation of the zinc-containing magnetic nanopartide- target material complex in the sample may be carried out according to the conventional methods known to those ordinarily skilled in the art. For instance, the detection described above may be accomplished by measuring an absorbance change for a sample containing the zinc-containing magnetic nanopartide-target material complex. In addition, the zinc-containing magnetic nanoparticle complex conjugated with a signal generating label may be detected by measuring the fluorescent signal.
  • the signal generating label includes, but is not limited to, chemical labels
  • biotin ⁇ e.g., biotin
  • enzyme labels ⁇ e.g., alkaline phosphatase, peroxidase, ⁇ -galactosidase and ⁇ -glucosidase
  • radioisotopes ⁇ e.g., I 125 and C 14
  • fluorescent labels e.g., luminescent labels, chemiluminescent labels, FRET (fluorescence resonance energy transfer) labels and heavy metals ⁇ e.g., gold).
  • the non-limiting example of the above-described fluorescent label includes fluorescein, rhodamine, lucifer yellow, B-phytoerythrin, 9-acrydine isothiocyanate, lucifer yellow VS, 4-acetamido-4'-isothio-cyanatostilbene-2,2'-disulfonate, 7- diethylamino-3-(4'-isothiocyatophenyl)-4-methylcoumarin, succinimidyl- pyrenebutyrate, 4-acetoamido-4'-isothio-cyanatostilbene-2,2'-disulfonate derivatives, LCTM-Red 640, LCTM-Red 705, Cy5, Cy5.5, resamine, isothiocyanate, erythrin isothiocyanate, diethyltriamine pentaacetate, l-dimethylaminonaphthyl-5-sulfonate, l
  • a method to detect the formation of zinc-containing magnetic nanoparticle-target material complex conjugated with the label may be carried out according to the methods such as fluorometer, spectrophotometer, colorimetric detection or radioactivity detection.
  • the present invention may be used in separation, concentration and detection of a specific target material in a sample.
  • Using zinc-containing magnetic nanoparticles synthesized depending on a type of binding agent to be bound to a target material an economic system may be designed to separate and/or detect various target materials in a high efficient manner. According to the present invention, it is also unnecessary to perform further procedures such as complicated pre-enrichment, purification or processing needed in common detection.
  • the nanopartides of the present invention may be rapidly distributed into a biological sample (generally, an aqueous sample), i.e., numerous opportunities to contact a target material in an aqueous sample by Brown's diffusion, and furthermore may be harvested/separated under magnetic field induction.
  • a biological sample generally, an aqueous sample
  • numerous opportunities to contact a target material in an aqueous sample by Brown's diffusion and furthermore may be harvested/separated under magnetic field induction.
  • the present invention may be utilized in various application fields including: (a) diagnosis - disease-related substances (for example, proteins, antigens, nucleic acid molecules, viruses, bacteria, carbohydrates and lipids) may be separated/detected by applying the zinc-containing magnetic nanopartides to a biological sample; (b) separation - a final product may be separated by applying the nanopartides to a synthesis of a chemical compound; (c) water or seawater desalination using zinc-containing magnetic nanopartides modified with a chelating /complexing agent to selectively remove a specific salt, ion or metal.
  • diagnosis - disease-related substances for example, proteins, antigens, nucleic acid molecules, viruses, bacteria, carbohydrates and lipids
  • separation - a final product may be separated by applying the nanopartides to a synthesis of a chemical compound
  • water or seawater desalination using zinc-containing magnetic nanopartides modified with a chelating /complexing agent to selectively remove a specific salt, ion or metal
  • the present magnetic separation system using the same has much more improved separation efficiencies.
  • an economic system may be designed to separate and/or detect various target materials in a high efficient manner. According to the present invention, it is also unnecessary to perform further procedures such as complicated pre-enrichment, purification or processing needed in common detection.
  • a zinc-containing magnetic nanopartide-based magnetic sensor comprising: (a) a zinc-containing magnetic nanopartide or a cluster thereof represented by the following formula 1 or 2:
  • Zn f M a-f O b (0 ⁇ f ⁇ 8, 0 ⁇ a ⁇ 16, 0 ⁇ b ⁇ 8, 0 ⁇ f/(a-f) ⁇ 10, M represents a magnetic metal atom or an alloy thereof)
  • Zn g M c-g M' d O e (0 ⁇ g ⁇ 8, 0 ⁇ c ⁇ 16, 0 ⁇ d ⁇ 16, 0 ⁇ e ⁇ 8, 0 ⁇ g/ ⁇ (c-g)+d ⁇ 10
  • M represents a magnetic metal atom or an alloy thereof
  • M' represents one or more elements selected from the group consisting of Group 1 elements, Group 2 elements, Group 12 elements, Group 13 elements, Group 14 elements, Group 15 elements, transition metal elements, Lanthanide elements and Actinide elements)
  • the present magnetic sensor comprises the zinc-containing magnetic nanoparticles described in the magnetic separation system of this invention, the common descriptions between them, are omitted in order to avoid undue redundancy leading to the complexity of this specification.
  • the zinc-containing magnetic nanopartide or the cluster thereof used in the magnetic sensor of this invention plays a role in a signal generator.
  • the zinc-containing magnetic nanopartide used in the magnetic sensor of this invention is represented by the following formula 1 or 2:
  • M represents a magnetic metal atom or an alloy thereof
  • M represents a magnetic metal atom or an alloy thereof;
  • M' represents one or more elements selected from the group consisting of Group 1 elements, Group 2 elements, Group 12 elements, Group 13 elements, Group 14 elements, Group 15 elements, transition metal elements, Lanthanide elements and Actinide elements) (2) Since the zinc-containing magnetic nanoparticles of the formula 1 or 2 have high saturation magnetism, the present magnetic sensor using the same may exhibit much more enhanced sensitivity under magnetic field induction.
  • M represents preferably transition metal elements, Lanthanide metal elements and Actinide metal elements; more preferably, transition metal elements selected from the group consisting of Ba, Mn, Co, Ni and Fe, Lanthanide metal elements selected from the group consisting of Gd, Er, Ho, Dy, Tb, Sm and Nd; and most preferably, Mn, Co, Ni, Fe, Gd, Er, Ho, Dy, Tb, Sm or Nd, or an alloy thereof.
  • M' preferably represents one or more elements selected from the group consisting of Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Ra, Ge, Ga, Bi, In, Si, Ge, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, Lanthanide elements and Actinide elements.
  • the zinc-containing magnetic nanoparticle used in the magnetic sensor of this invention is represented by the following formula 3:
  • M'V k FeiO j (0 ⁇ k ⁇ 8, 0 ⁇ h ⁇ 16, 0 ⁇ i ⁇ 8, 0 ⁇ j ⁇ 8, 0 ⁇ k/ ⁇ (h-k)+i ⁇ 10, M" represents a magnetic metal atom or an alloy thereof)
  • M represents preferably transition metal elements, Lanthanide metal elements and Actinide metal elements; more preferably, transition metal elements selected from the group consisting of Ba, Mn, Co, Ni and Fe, Lanthanide metal elements selected from the group consisting of Gd, Er, Ho, Dy, Tb, Sm and Nd; and most preferably, Mn, Co, Ni, Fe, Gd, Er, Ho, Dy, Tb, Sm or Nd, or an alloy thereof. More preferably, the zinc-containing magnetic nanoparticle used in the magnetic sensor of this invention is represented by the following formula 4 or 5:
  • a stoichiometric content ratio of zinc and other metals is as follows: 0.001 ⁇ 'zinc/ (entire metal component - zinc)' ⁇ 10, more preferably 0.01 ⁇ 'zinc/ (entire metal component - zinc)' ⁇ 1, and most preferably 0.03 ⁇ 'zinc/ (entire metal component - zinc)' ⁇ 0.5.
  • zinc is contained as the above, high saturation magnetism can be obtained, resulting in remarkable improvement of sensor sensitivity in the present magnetic sensor.
  • the zinc-containing magnetic nanopartides contained in the cluster of the present invention are clustered in the number of preferably 2-10,000, more preferably 2-1,000, and most preferably 2-100.
  • Each zinc-containing magnetic nanopartides in the duster is linked each other by their intermolecular interactions, or encapsulated by organic or inorganic carrier.
  • the surface of the zinc-containing magnetic nanopartides or cluster thereof is coated with a water-soluble multi- functional ligand.
  • water-soluble multi-functional ligand refers to a ligand that may be bound to zinc-containing nanopartides or cluster thereof to solublize in water and stabilize the nanopartides, and may allow the nanopartides to be bound by binding agent having a specific affinity to an analyte.
  • the water-soluble multi-functional ligand can include (a) an adhesive region
  • the compound which originally contains the above-described functional group may be used as a water-soluble multi-functional ligand, but a compound modified or prepared so as to have the above-described functional group by a chemical reaction known in the art may be also used as a water-soluble multifunctional ligand.
  • the preferable multi-functional ligand of the present invention includes a monomer, a polymer, a carbohydrate, a protein, a peptide, a nucleic acid, a lipid or an amphiphilic ligand.
  • the hydrodynamic diameter of the final nanopartides prepared by the present invention is in a size range of preferably 1-1000 nm, more preferably 1-800 nm, much more preferably 2-100 nm and most preferably 10-50 nm.
  • the hydrodynamic diameter of the final nanopartide clusters prepared by the present invention is in a size range of preferably 1-1000 nm, more preferably 1-800 nm, much more preferably 2-100 nm and most preferably 10-50 nm.
  • the nanopartides of this invention have a saturation magnetization ( ⁇ / s ) value in a range of 100-300 emu/g and more preferably 120-200 emu/g.
  • the zinc-containing magnetic nanopartide used in the present invention is linked to a binding agent having a binding affinity to an analyte. More preferably, the zinc-containing magnetic nanopartide used in the present invention is coated with a water-soluble multifunctional organic ligand, and linked to the binding agent having a specific affinity to an analyte through the binding region (Ln).
  • analyte refers to a substance or chemical constituent in a sample ⁇ e.g., a liquid or gas sample, preferably a liquid sample, and most preferably an aqueous sample) to be separated (detected or quantified).
  • the analyte includes a nucleic acid molecule (DNA or RIMA), a protein, a peptide, an antigen, a bacterium, a virus, a sugar, a lipid, an organic compound ⁇ e.g., chiral compounds, therapeutic compounds), an inorganic compound, a metal and an inorganic ion, but is not limited to.
  • binding agent means a substance having a specific affinity to an analyte to be separated. Any material having a binding affinity to a target material to be separated may be utilized as the binding agent.
  • a non-limiting example of a binding agent includes a nucleic acid molecule (DNA or RNA), an antibody, an aptamer, a receptor, a streptavidin, an avidin, a biotin, a lectin, a ligand, an enzyme, a coenzyme, an inorganic ion, a cofactor, a sugar, a lipid, a substrate for an enzyme, a hapten, a neutravidin, a protein A, a protein G, a selectin, an inorganic compound, a metal, a semiconductor and an organic compound.
  • the magnetic sensor of this invention may be prepared as a variety of methods.
  • the zinc-containing magnetic nanopartide-based magnetic sensor includes all types of sensors containing magnetic nanoparticles such as a magneto-resistance sensor, a magnetic relaxation sensor, a magnetic micro- cantilever sensor, a magneto-electronic sensor and magnetophoresis sensor.
  • the magnetic sensor of the present invention may further include a signal processing means.
  • the signal processing means may include at least one amplifier.
  • the signal processing means may further include a linearizing circuit, and thus have potential to normalize a non-linear R-H property of a sensor device.
  • a magnetic sensor device, a signal processing means and a magnetic field-generating means may be composed as a single integrated circuit.
  • the magnetic field-generating means may include a conductor and a current source to generate current through the conductor.
  • the sensor of the present invention further includes a means measuring current via a magnetic sensor device.
  • the present invention using a magnetic sensor as a magneto-resistance sensor includes the steps of: (a) generating magnetic field in the vicinity of a magnetic sensor device; (b) inducing regular voltage across the magnetic sensor device; and (c) measuring total signal currents of the magnetic sensor device.
  • the zinc-containing magnetic nanoparticles are preferably used as a label of an analyte.
  • the sample containing an analyte is reacted with the zinc- containing magnetic nanopartides coated with a binding agent having a specific affinity to the analyte for labeling, and then the signal from the magnetic nanopartides is measured to determine the presence or amount of the analyte in the sample.
  • an antibody immobilized on a substrate is contacted with a sample containing an analyte, and washed.
  • the substrate is reacted with a detecting antibody linked to the surface of zinc-containing magnetic nanoparticle, and then washed. After stopping reaction, it may be concluded that the analyte is involved in the sample with the proviso that the signal from the zinc-containing magnetic nanopartides is detected (by the magnetic sensor device).
  • the changes in the Tl relaxation time are measured to determine contacting between zinc-containing magnetic nanopartides and a reactant, i.e., the presence or amount of a reactant).
  • a reactant i.e., the presence or amount of a reactant.
  • the reactants are linked to the binding agents on the surface of nanopartides, leading to form nanoparticle aggregates.
  • the magnetic moment of nanoparticle is changed, and T2 relaxation time of water is decreased.
  • the changes in the T2 relaxation time may be measured using a MR (magnetic resonance) imaging machine. It may be concluded that the analyte is involved in the sample with the proviso that the changes in the T2 relaxation time are detected.
  • the amount of reactants may be easily determined.
  • the changes in the Tl relaxation time may be measured using T2-weighted spin echo sequence and 1.5 T superconduction magnet under the condition of fixed echo time (TE) and repetition time (TR).
  • MR imaging instruments may be utilized as a magnetic sensor device and magnetic field-generating means in a magnetic relaxation sensor.
  • MR imaging method and devices are disclosed in D. M. Kean and M. A. Smith,
  • a magnetic micro-cantilever sensor is composed of a micro-sized cantilever and magnetic nanopartides conjugated with a substance ⁇ e.g., antigen) capable of binding to a reactant of interest.
  • the reactant in a sample is attached to the cantilever and nanopartides according to a sandwich method.
  • the cantilever is bent by the magnetic nanopartides under magnetic field induction. The bending force is measured as current by a piezoelectric device, enabling to determine exact amount of reactant.
  • a magnetophoresis sensor is a sensor employing the motion of dispersed magnetic nanopartides relative to a fluid under the influence of a magnetic field.
  • the movement of magnetic particles can be used to detect or isolate specific components in the fluid, using specific binding and/or capture.
  • the magnetophoresis sensor using the magnetic nanopartide or cluster thereof of the present invention is described in Example 8.
  • the sensors using magnetic nanopartides include, but is not limited to, a Maxwell bridge, a frequency dependent magnetometer, a magnetic remanence measurement using a superconducting quantum interference device, a Hall effect measurement, a micro fluidic system, and so forth.
  • the magnetic field-generating means used in the present invention may include a permanent magnet and electromagnet and may be varied by modulation depending on the morphology and size of nanoparticle.
  • Zn f M a - f O b (0 ⁇ f ⁇ 8, 0 ⁇ a ⁇ 16, 0 ⁇ b ⁇ 8, 0 ⁇ f/(a-f) ⁇ 10, M represents a magnetic metal atom or an alloy thereof)
  • Zn g M c-g M' d O e (0 ⁇ g ⁇ 8, 0 ⁇ c ⁇ 16, 0 ⁇ d ⁇ 16, 0 ⁇ e ⁇ 8, 0 ⁇ g/ ⁇ (c-g)+d ⁇ 10
  • M represents a magnetic metal atom or an alloy thereof
  • M' represents one or more elements selected from the group consisting of Group 1 elements, Group 2 elements, Group 12 elements, Group 13 elements, Group 14 elements, Group 15 elements, transition metal elements, Lanthanide elements and Actinide elements) (2); and
  • the present method comprises the magnetic sensor of this invention described above, the common descriptions between them are omitted in order to avoid undue redundancy leading to the complexity of this specification.
  • the zinc-containing magnetic nanoparticle-based magnetic sensor of the present invention may be utilized in various application fields including molecular diagnosis, analysis for a biological sample and chemical sample, and so on. Since the magnetic sensor of the present invention utilizes zinc-containing magnetic nanopartide having very high saturation magnetism, it may exhibit much more enhanced sensitivity under magnetic field induction and detect an infinitesimal amount of analytes ⁇ e.g., proteins or nucleic acid molecules in blood).
  • the present magnetic sensor using the same may detect analytes in a much more sensitive manner.
  • the nanopartides having improved sensitivity ⁇ e.g., sensitivity in fM level) prepared by the present invention may permit to detect a trace amount of analytes such as anti-cancer marker proteins or nucleic acid molecules, and prion proteins in blood.
  • the present sensor may be constituted by all types of sensors including a magneto-resistance sensor, a magnetic relaxation sensor, a magnetic micro-cantilever sensor, a magnetophoresis sensor, a magneto-electronic sensor, and so forth.
  • Fig. Ia shows a TEM (transmission electron microscope) image of synthesized Zno. 4 Fe 2 . 6 O 4 nanopartides.
  • Fig. Ib shows a high resolution TEM image of synthesized Zn 0-4 Fe 2-6 O 4 nanopartides.
  • the internal image of Fig. Ib is a FFT (fast fourier transformation) image of the high resolution TEM image.
  • Fig. Ic is a XRD (X-ray diffraction) pattern of synthesized Zn 0-4 Fe 2-6 O 4 nanopartides.
  • Fig. 2 represents TEM images of (A) ZnxMn 1-x Fe 2 0 4 and (B) Zn x Fe 3-x 0 4 .
  • the zinc content ratio (x) may be modulated from 0 to 0.8.
  • Fig. 3 is a graph representing a saturation magnetism of zinc-containing magnetic nanopartides and several nanopartides containing no zinc.
  • Fig. 4 represents a TEM image of synthesized zinc-containing nanopartide cluster.
  • the cluster is prepared by encapsulating zinc-containing nanopartides in a micelle consisting of polystyrene-polyacryl acid copolymers.
  • Fig. 5 is a graph measuring a magnetic field strength depending on the distance from the surface of NdFeB magnet used as external magnetic field- generating means.
  • Fig. 6 schematically represents the principle of a magnetic separation system using zinc-containing magnetic nanoparticles.
  • a solution containing a target material is mixed with magnetic nanoparticles conjugated with a binding agent capable of selectively binding to the target material, resulting in binding of the target material and magnetic nanoparticles. Afterwards, the target material may be separated by magnet attraction.
  • Fig. 7 shows a graph comparing separation efficiency of a fluorescent material (rhodamine) using zinc-containing nanoparticles (Zno. 4 Fe 2 .eO 4 ) or nanoparticles containing no zinc (Fe 3 O 4 ).
  • Fig. 7A represents a graph measuring the fluorescent material (rhodamine) absorbance at 580 nm depending on magnetic separation time
  • Fig. 7B represents a graph measuring separation efficiency of the fluorescent material (rhodamine) with the passage of time.
  • Fig. 8 is a graph comparing magnetic separation efficiency between zinc- containing nanoparticles (Zn 0-4 Fe 2-6 O 4 ) and nanoparticles containing no zinc (Fe 3 O 4 ) according to changes of external magnetic field strength.
  • Fig. 9 shows a graph comparing antibody separation using nanoparticles containing no zinc and zinc-containing nanoparticles.
  • Fig. 10 represents results comparing: (A) cell amounts separated with the passage of time in zinc-containing nanoparticles and nanoparticles containing no zinc; and (B) cell separation efficiency of zinc-containing nanoparticles and nanoparticles containing no zinc.
  • Fig. lla shows a TEM image of synthesized Zn 0-4 Fe 2-6 O 4 nanoparticles.
  • Fig. lib shows a high resolution TEM image of synthesized Zn 0-4 Fe 2-6 O 4 nanoparticles.
  • the internal image of Fig. Ib is a FFT (fast fourier transformation) image of the high resolution TEM image.
  • Fig. lie is a XRD (X-ray diffraction) pattern of synthesized Zn 0-4 Fe 2-6 O 4 nanoparticles.
  • Fig. 12 represents TEM images of (A) ZnxMni -x Fe 2 0 4 and (B) Zn x Fe 3-x 0 4 .
  • the zinc content ratio (x) may be modulated from 0 to 0.8.
  • Fig. 13 is a graph analyzing a saturation magnetism of zinc-containing magnetic nanoparticles and several nanoparticles containing no zinc.
  • Fig. 14 represents a TEM image of synthesized zinc-containing nanopartide cluster.
  • the cluster is prepared by encapsulating zinc-containing nanoparticles in a micelle consisting of polystyrene-polyacryl acid copolymers.
  • Fig. 15 schematically represents the principle of a magnetic relaxation sensor using zinc-containing magnetic nanoparticles.
  • the magnetic nanoparticles exhibit high spin-spin relaxation time (T2) due to rare interaction each other at a distance enough to be dispersed, but the formation of magnetic nanopartide aggregates mediated by samples of interest allows magnetic particles having very low TZ relaxation time.
  • T2 relaxation time may be measured using MRI or magnetic relaxation system.
  • Fig. 16 shows DNA detection using in zinc-containing nanoparticles
  • Fig. 16A represents a colorimetric MRI image merging ⁇ T2 with image measured by MRI in each nanoparticles.
  • Fig. 16B is a graph expressing Fig. 16A numerically (i.e., ⁇ T2 value to
  • Fig. 17 shows protein (avidin) detection using in zinc-containing nanoparticles
  • Fig. 17A represents a colorimetric MRI image merging ⁇ T2 with image measured by MRI in each nanoparticles.
  • Fig. 17B is a graph expressing Fig. 17A numerically (i.e., ⁇ T2 value to protein amount analyzed).
  • Fig. 18 schematically represents a magnetophoresis sensor using zinc- containing magnetic nanoparticles.
  • Fig. 19 represents a graph analyzing a cell migration rate (panel A) and attractive force toward a magnetic tip (panel B).
  • Fig. 20 shows microscopic images observing practical operation of the magnetophoresis sensor. It could be appreciated that the cells bound with zinc- containing magnetic nanoparticles are migrated toward a magnetic tip more rapidly than those bound with magnetic nanoparticles containing no zinc.
  • DMSA Dimercaptosuccinic Acid
  • ZnCI 2 Aldrich, USA
  • FeCI 2 Aldrich, USA
  • MnCI 2 Aldrich, USA
  • Fe(acac) 3 Aldrich, USA
  • the synthesized zinc-containing ferrite nanoparticles were precipitated by excess ethanol and then the precipitated nanoparticles were again dispersed in toluene, obtaining a colloid solution.
  • nanoparticles synthesized according to the method aforementioned have globular structure with a homogeneous size of 15 nm (size distribution s ⁇ 10%). As demonstrated in a high resolution electron microscope (Fig.
  • the nanoparticles exhibit higher crystallinity as a spinel structure.
  • the amount of zinc was determined using Inductively Coupled Plasma- Atomic Emission Spectroscopy (ICP-AES, OPTIMA-3000, Perkin Elmer) and Energy Dispersive X-ray (EDAX, Gatan).
  • nanoparticles with different sizes ⁇ e.g., 9 or 12 nm
  • equal amount of precursors were mixed with trioctylamine solvent containing various ratios of oleic acid and oleylamine depending on the sizes of nanoparticles, and the same process described above was carried out.
  • the synthesized nanoparticles (20 mg/ml in toluene) were mixed with DMSO solution containing excess DMSA, and incubated for 2 hrs. Subsequently, the nanoparticles were centrifuged and re-dispersed in water. As results, the synthesized nanoparticles have globular structure with a homogeneous size, and their zinc contents were analyzed using ICP-MS and EDAX.
  • ZnCI 2 , CoCI 2 or NiCI 2 , and Fe(acac) 3 as precursors of nanoparticles were added to trioctylamine solvent containing 20 mmol oleic acid and 20 mmol oleylamine as capping molecules.
  • M Co or Ni
  • the synthesized nanoparticles (20 mg/ml in toluene) were mixed with DMSO solution containing excess DMSA, and incubated for 2 hrs. Subsequently, the nanoparticles were centrifuged and re-dispersed in water. As results, the nanoparticles have globular structure with a homogeneous size, and zinc contents were analyzed using ICP-MS and EDAX.
  • the synthesized nanopartides (50 mg/ml in 1 ml toluene) were precipitated by excess ethanol and then the precipitated nanopartides were again dispersed in 5 ml TMAOH solution, obtaining a soluble solution.
  • the synthesized nanopartides have the composition of Zn 0-4 M 26 O 4 , Zn 0 . 2 Co 0 . 8 ⁇ or Zn 0-2 Ni 0-8 O with the core size of 6, 7 or 10 nm, respectively.
  • Zinc contents were analyzed using ICP-MS and EDAX.
  • each saturation magnetization of zinc-containing nanopartides, conventionally accessible metal oxide nanopartides, CLJO (cross-linked iron oxide) and FeridexTM (Taejoon Co Ltd.), and several ferrite nanopartides containing no zinc was measured at room temperature.
  • CLJO was synthesized according to the method described in Weissleder et a/., Journal of Magnetic Resonance in Medicine 29: 599 (1993).
  • Several ferrite nanopartides were produced according to the method described in Korean Pat. Nos. 10-0604975, 10-0652251 and 10-0713745, PCT/KR2004/002509, Korean Pat. No.
  • saturation magnetization of each zinc-containing nanoparticles, Zn 0-4 Fe 2 ⁇ O 4 and Zn 0-4 Mn 0-6 Fe 2 O 4 was 161 and 175 emu/g higher than that of conventionally accessible metal oxide nanoparticles ⁇ e.g., CLIO, 64 emu/g;
  • Feridex 82 emu/g. Furthermore, these values are enhanced to 47 and 61 emu/g compared with nanoparticles containing no zinc, Fe 3 O 4 and MnFe 2 O 4 , respectively.
  • zinc-containing nanoparticles having enhanced saturation magnetization may highly increase conventional sensor sensitivity in the senses that saturation magnetization is proportional to the square of sensor sensitivity.
  • Exemplified nanoparticle cluster using zinc-containing nanoparticles includes a magnetic nanoparticle cluster which is encapsulated in micelles prepared by polystyrene-polyacryl acid copolymers.
  • Basic preparation method of polymer and cluster used was carried out according to the method described in Taton et a/. Nano Leters 5: 1987 (2005).
  • Zinc-containing nanoparticles coated with oleic acid and oleylamine were prepared according to the method described in Korean Pat. Nos. 10- 0604975, 10-0652251 and 10-0713745, PCT/KR2004/002509, Korean Pat. No. 10- 0604975, PCT/KR2004/003088, PCT/KR2007/001001, and Korean Pat. Appln. No.
  • the polystyrene-polyacryl acid copolymers were dissolved in dimethylformamide (DMF; Aldrich) at a concentration of 0.1 mg/ml, and further added with tetrahydrofuran (THF; Aldrich) to be at a final concentration of 50%.
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • the solution was vigorously stirred and the nanoparticles were gradually added to be at a concentration of 0.1 mg/ml, followed by adding 40 ml water at a rate of 5 ml/hr.
  • micelles are stabilized in a soluble solution due to exposure of carboxylic acid on their surface, which serves as a functional group to attach a binding agent such as antibodies.
  • the micelles were cross-linked to enhance their stability and dispersion in solution.
  • 5 mM EDC 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide; Sigma
  • 2 mM sulfo-NHS N- hydroxysulfosuccinimide; Sigma
  • 5 mM 2,2'-(ethylenedioxy)bis(ethylamine) Aldrich
  • the synthesized micelles have a total size of about 120 nm, and contain numbers of 15 zinc-containing nanoparticles. As described above, it is expected that the synthesized nanoparticle clusters exhibit enhanced saturation magnetization, leading to significantly improve separation efficiencies of magnetic separation systems.
  • EXAMPLE 7 Magnetic Field Measurement of NdFeB Magnets Used as a Means for Generating External Magnetic Field
  • NdFeB magnets were used in the magnetic separation system of the present invention.
  • the magnetic separation system used in the present invention has a working principle shown in Fig. 6. Through mixing a solution containing materials of interest with magnetic nanoparticles including binding agents capable of selectively binding to materials of interest, they may be linked to magnetic nanoparticles, enabling to be separated by intermolecular interaction of magnets.
  • Each zinc-containing nanoparticles and nanoparticles containing no zinc were synthesized according to the methods described in Example 1 and Korean Pat. Nos. 10-0604975, 10-0652251 and 10- 0713745, PCT/KR2004/002509, Korean Pat. No.
  • each nanoparticles were solubilized in water by surface modifications with TMAOH according to the method described in Example 4. Afterwards, these nanoparticles were coated with bovine serum albumin (BSA) according to the methods described in Korean Pat. Nos. 10-0604975, 10-0652251 and 10-0713745.
  • BSA bovine serum albumin
  • fluorescent dye rhodamine; Pierce
  • Fig. 7 represents a graph measuring rhodamine absorbance at 580 nm by monitoring with the passage of time.
  • rhodamine molecules in solution are decreased with the passage of time, resulting in gradual reduction of their absorbance.
  • almost all rhodamine molecules were separated at about 4 min in zinc- containing nanoparticles, and their absorbance was measured in the level of approximate 0.02.
  • the absorbance of rhodamine was unchangeable until 6 min in nanoparticles containing no zinc, and was reduced at 10 min to the level of about 0.12, reaching at the level of almost 0.02 after 50 min.
  • Fig. 7B is a graph representing separation rate (%) of Fig. 7A.
  • Zinc-containing magnetic nanoparticles and magnetic nanoparticles containing no zinc with a concentration 0.2 mg/ml was added to MACS ® column under external magnetic fields, respectively.
  • the magnetic nanoparticles were captured in MACS ® column by external magnetic fields, and the removal of external magnetic fields causes their release from the column.
  • nanoparticle magnetism is varied depending on a type of nanoparticle, the amount of nanoparticles captured in the column is different.
  • the captured nanoparticles were quantified using an absorption spectrophotometer.
  • Fig. 8 is a graph comparing magnetic separation efficiency between zinc- containing nanoparticles (Zn 0-4 Fe 2-6 O 4 ) and nanoparticles containing no zinc (Fe 3 O 4 ) according to changes of external magnetic field strength. As shown in Fig. 8, the amount of both separated magnetic nanoparticles was similar under very strong external magnetic fields (300 mT). However, the separated amount of zinc- containing nanoparticles or nanoparticles containing no zinc was significantly different depending on reduction of external magnetic field. That is, the amount of zinc-containing nanoparticles captured in the column was increased in 17% and 22% under external magnetic fields of 150 and 100 mT higher than that of nanoparticles containing no zinc, respectively.
  • EXAMPLE 10 Comparison and Quantification of Magnetic Separation Efficiency in Zinc-Containing Nanoparticles and Nanoparticles Containing no Zinc for Anti-Mouse IgG-FITC in the Presence of External Magnetic Field
  • MACS ® column (Miltenyi Biotech, Germany) was used as a magnetic separation system.
  • Nanopartides containing no zinc and zinc-containing nanopartides are Fe 3 O 4 and Zn 0-4 Fe 2-6 O 4 , respectively. Both nanopartides were particles with a diameter of 15 nm.
  • the surface of each nanopartides was coated with dimercaptosuccinic acid (DMSA) and then linked to protein A (Sigma).
  • DMSA dimercaptosuccinic acid
  • the synthesis of nanopartides was carried out according to the method described in Example 1. To bind protein A on the surface of nanopartides, it was reacted with sulfo-SMCC (Sulfosuccinimidyl-4-(N- maleimidomethyl)cydohexane-l-carboxylate; Pierce) for 30 min, and then mixed with nanopartides.
  • sulfo-SMCC Sulfosuccinimidyl-4-(N- maleimidomethyl)cydohexane-l-carboxylate; Pierce
  • Target protein of the present invention is goat anti-mouse IgG-FlTC (Sigma). Under the condition of external magnetic field, each zinc-containing nanopartides (0.08 mg/ml) and nanopartides containing no zinc (0.08 mg/ml) were added to MACS ® column, and subsequently to antibody protein (1 ml of 0.01 M anti-mouse IgG-FITC) labeled with fluorescent dye, resulting in binding of antibody protein on the surface of nanopartides by specific interactions between antibody protein and protein A coated on the surface of nanopartides.
  • Magnetic nanopartides are captured in MACS ® column due to external magnetic field, and thus the removal of external magnetic field allows magnetic nanopartides to be released from the column.
  • the captured nanopartides may be quantified using an absorption spectrophotometer.
  • the amount of separated nanoparticles may be inversely determined by measuring fluorescent signal intensity as antibody protein with fluorescent dye is bound to the surface of captured nanoparticles. Consequently, separation efficiency to antibody protein may be analyzed by measuring magnetic values of two nanoparticles.
  • Fig. 9 is a graph comparing magnetic separation efficiency between zinc- containing nanoparticles (Zno.
  • the higher fluorescence intensity refers to the large amount of nanoparticles.
  • FITC has physical potential to emit the strongest fluorescence intensity at 521 nm by absorbing the light with a wavelength of 495 nm.
  • each zinc-containing nanoparticles and nanoparticles containing no zinc was coated with dimercaptosuccinic acid (DMSA) and bound to antibody proteins.
  • DMSA dimercaptosuccinic acid
  • the antibody proteins utilized Cetuximab (Merck) conventionally known as Erbitux, which is capable of binding to an EGFR receptor on the surface of U87MG cells.
  • antibody proteins were activated using sulfo-SMCC (Pierce) and then mixed with nanoparticles coated with DMSA according to the method described in Example 10.
  • sulfo-SMCC Pieris-maleimidomab
  • DMSA DMSA
  • Each nanoparticles linked to Cetuximab was incubated with cells in PBS buffer at room temperature for 1 hr, followed by adding external magnetic field. Afterwards, Cetuximab antibodies on the nanoparticles were bound to cells. Cells were attracted toward magnetic field under external magnetic field by the nanoparticles bound to the surface of cells. Thus, samples in reaction solution were harvested depending on time in certain region apart from magnets, and cell number was observed.
  • Fig. 10 is graphs comparing cell separation using zinc-containing nanoparticles (Zno. 4 Fe 2 .eO 4 ) and nanoparticles containing no zinc (Fe 3 ⁇ 4 ) as described above. Since magnetism of zinc-containing nanoparticles is higher than that of nanoparticles containing no zinc, cells were attracted in stronger and faster manner. Therefore, it could be appreciated that cell number separated from solution to a region adjacent to magnet were much more rapidly increased with the passage of time (Fig. 10A).
  • Fig. 1OB represents cell separation efficiency which is determined by counting cell number separated at 5 min after addition of external magnetic field. The cell separation efficiency is calculated by a ratio of cell number after to cell number before cell separation. It was demonstrated that the efficiency of cell separation in zinc-containing nanoparticles may be about 2.9-fold higher than that in nanoparticles containing no zinc, and the amount of separated cells may be quantified using a hematocytometer.
  • ZnCI 2 Aldrich, USA
  • FeCI 2 Aldrich, USA
  • MnCI 2 Aldrich, USA
  • Fe(acac) 3 Aldrich, USA
  • the synthesized zinc-containing ferrite nanoparticles were precipitated by excess ethanol and then the precipitated nanoparticles were again dispersed in toluene, obtaining a colloid solution.
  • nanoparticles synthesized according to the method aforementioned have globular structure with a homogeneous size of 15 nm (size distribution s ⁇ 10%). As demonstrated in a high resolution electron microscope (Fig.
  • the nanoparticles exhibit higher cr ⁇ stallinity as a spinel structure.
  • the amount of zinc was determined using Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES, OPT ⁇ MA-3000, Perkin Elmer) and Energy Dispersive X-ray (EDAX, Gatan).
  • nanopartides with different sizes e.g., 9 or 12 nm
  • equal amount of precursors were mixed with trioctylamine solvent containing various ratios of oleic acid and oleylamine depending on the sizes of nanopartides, and the same process described above was carried out.
  • the synthesized nanopartides (20 mg/ml in toluene) were mixed with DMSO solution containing excess DMSA, and incubated for 2 hrs. Subsequently, the nanopartides were centrifuged and re-dispersed in water. As results, the synthesized nanopartides have globular structure with a homogeneous size, and their zinc contents were analyzed using ICP-MS and EDAX.
  • ZnCI 2 , CoCI 2 or NiCI 2 , and Fe(acac) 3 as precursors of nanopartides were added to trioctylamine solvent containing 20 mmol oleic acid and 20 mmol oleylamine as capping molecules.
  • M Co or Ni
  • a ratio of ZnCI 2 , CoCI 2 or NiCI 2 as precursors of nanoparticles was modulated depending on the composition of Zn.
  • the synthesized nanoparticles (20 mg/ml in toluene) were mixed with DMSO solution containing excess DMSA, and incubated for 2 hrs. Subsequently, the nanoparticles were centrifuged and re-dispersed in water. As results, the nanoparticles have globular structure with a homogeneous size, and zinc contents were analyzed using ICP-MS and EDAX.
  • the synthesized nanoparticles (50 mg/ml in 1 ml toluene) were precipitated by excess ethanol and then the precipitated nanoparticles were again dispersed in 5 ml TMAOH solution, obtaining a soluble solution.
  • the synthesized nanoparticles have the composition of Zn 0-4 M 2-6 O 4 , Zn 0-2 Co 0-8 O or Zn 0 2 Ni 0-8 O with the core size of 6, 7 or 10 nm, respectively.
  • Zinc contents were analyzed using ICP-MS and EDAX.
  • each saturation magnetization of zinc-containing nanoparticles, conventionally accessible metal oxide nanoparticles, CLJO and FeridexTM, and several ferrite nanoparticles containing no zinc was measured at room temperature.
  • CLJO was synthesized according to the method described in Weissleder et a/., Journal of Magnetic Resonance in Medicine 29: 599 (1993).
  • Several ferrite nanoparticles were produced according to the method described in Korean Pat. Nos. 10-0604975, 10- 0652251 and 10-0713745, PCT/KR2004/002509, Korean Pat. No.
  • saturation magnetization of each zinc-containing nanoparticles was 161 and 175 emu/g higher than that of conventionally accessible metal oxide nanoparticles ⁇ e.g., CLJO, 64 emu/g; Feridex, 82 emu/g). Furthermore, these values are enhanced to 47 and 61 emu/g compared with nanoparticles containing no zinc, Fe 3 O 4 and MnFe 2 O 4 , respectively.
  • zinc-containing nanoparticles having enhanced saturation magnetization may highly increase conventional sensor sensitivity in the senses that saturation magnetization is proportionate to the square of sensor sensitivity.
  • Exemplified nanoparticle cluster using zinc-containing nanoparitldes includes a magnetic nanoparticle cluster which is encapsulated in micelles prepared by polystyrene-polyacryl acid copolymers.
  • Basic preparation method of polymer and cluster used was carried out according to the method described in Taton et a/. Nano Leters 5: 1987 (2005).
  • Zinc-containing nanopartides coated with oleic acid and oleylamine were prepared according to the method described in Korean Pat. Nos. 10- 0604975, 10-0652251 and 10-0713745, PCT/KR2004/002509, Korean Pat. No. 10- 0604975, PCT/KR2004/003088, PCT/KR2007/001001, and Korean Pat. Appln. No.
  • the polystyrene-polyacryl acid copolymers were dissolved in dimethylformamide (DMF; Aldrich) at a concentration of 0.1 mg/ml, and further added with tetrahydrofuran (THF; Aldrich) to be at a final concentration of 50%.
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • the solution was vigorously stirred and the nanopartides were gradually added to be at a concentration of 0.1 mg/ml, followed by adding 40 ml water at a rate of 5 ml/hr.
  • micelles are stabilized in a soluble solution due to exposure of carboxylic acid on their surface, which serves as a functional group to attach a binding agent such as antibodies.
  • the micelles were cross-linked to enhance their stability and dispersion in solution.
  • 5 mM EDC 1- ethyl-3-(3-dimethylaminopropyl) carbodiimide; Sigma
  • 2 mM sulfo-NHS N- hydroxysulfosuccinimide; Sigma
  • 5 mM 2,2'-(ethylenedioxy)bis(ethylamine) Aldrich
  • the synthesized micelles have a total size of about 120 nm, and contain 15 numbers of zinc-containing nanopartides. As described above, it is expected that the synthesized nanopartide clusters exhibit enhanced saturation magnetization, leading to significantly improve separation efficiencies of magnetic sensor systems.
  • the magnetic relaxation sensor system used in the present invention has a working principle shown in Fig. 15.
  • the magnetic nanoparticles have high spin-spin relaxation time (T2) at a distance enough to be dispersed, whereas the aggregation of magnetic nanoparticles through samples of interest allows magnetic particles having very low T2 relaxation time.
  • T2 relaxation time The presence and quantification of samples of interest may be determined by measurement of T2 relaxation time using MRI or magnetic relaxation system.
  • Each zinc-containing nanoparticles and nanoparticles containing no zinc was synthesized according to the methods described in Example 1 and Korean Pat. Nos. 10-0604975, 10-0652251 and 10-0713745, PCT/KR2004/002509, Korean Pat. No. 10-0604975,
  • each nanoparticles were solubilized in water by surface modifications with dimercaptosuccinic acid according to the method described in
  • DNAl or DNA2 having a nucleotide sequence complementary to DNA of interest is bound to the surface of nanoparticles to produce nanopartide 1 or nanopartide 2, respectively.
  • the nucleotide sequence of DNA to be analyzed, and DNAl and DNA2 complementary to DNA are as follows:
  • DNA of interest 5'-TAC GAG TTG AGA ATC CTG AAT GCG-3'
  • DNAl HS-(CH 2 ) 6 -5'-CGC ATT CAG GAT-3'
  • DNA2 HS-(CH 2 ) 6 -3'-ATG CTC AAC TCT-5'
  • T2 time changes were measured using MRI (See, Rg. 16).
  • 3T system (Acheiva; Philips Medical Systems. Best, the Netherlands) equipped with sense-flex-M coil was used for MRI analysis.
  • Fig. 16A represents a colorimetric plot merging ⁇ T2 with image measured by MRI.
  • T2 time changes depending on addition of DNA to be analyzed, red and blue color indicate low and high ⁇ T2, respectively.
  • ⁇ T2 was changed to yellow color in zinc-containing nanopartides (Zn 0-4 Fe 2 ⁇ O 4 ) by addition of 10 fmol DNA.
  • ⁇ T2 was gradually enhanced depending on increase of DNA amounts (from 100 to 2,000 fmol), leading to color changes from yellow color to green or blue color.
  • the color was unchanged in nanopartides containing no zinc (Fe 3 O 4 ) by addition of DNA (10-100 fmol), and slightly changed to yellow color by treatment of 1000 fmol DNA.
  • FIG. 16B is a graph expressing Fig. 16A numerically, suggesting that the use of zinc- containing nanopartides in a magnetic relaxation sensor contributes to striking enhancement of sensor sensitivity.
  • ⁇ T2 of about 10 is measured in zinc- containing nanopartides by addition of 10 fmol DNA, whereas in nanopartides containing no zinc by treatment of 1000 fmol DNA. Consequently, it could be appreciated that the sensor sensitivity of zinc-containing nanopartides is enhanced 100-fold higher than that of nanopartides containing no zinc.
  • Fig. 17A represents a colorimetric plot merging ⁇ T2 with image measured by
  • EXAMPLE 8 Magnetophoresis Sensor Using Zinc-Containing Magnetic Nanopartides; Comparison of Magnetic Potential Strength between Zinc- Containing Magnetic Nanopartides and Magnetic Nanopartides Containing No Zinc by Measuring Migration Rate of Cells Bound with Magnetic Nanopartides in the Presence of External Magnetic Field
  • Zinc-containing nanopartides and nanopartides containing no zinc used in the sensor of the present invention are Zn 0 ⁇ Fe 26 O 4 and Fe 3 O 4 , respectively.
  • DMSA dimercaptosuccinic acid
  • sulfo-SMCC Sulfosuccinimidyl-4-(N-maleimidomethyl)cydohexane-l- carboxylate; Pierce
  • the antibody proteins enable to bind to a EGFR receptor on the surface of U87MG cells.
  • Cell migration toward a magnetic tip was recorded as a video using a computer linked with a microscope. Further, a positioning coordinate of a specific cell was observed in a frame with regular interval to measure migration distance depending on the time.
  • Fig. 19A is a graph representing mean of cell migration rate obtained from 20 specific cells using zinc-containing magnetic nanoparticles and magnetic nanoparticles containing no zinc.
  • the cell migration rate of cells bound with zinc- containing magnetic nanoparticles was attracted toward a magnetic tip about 4.14- fold more rapid than that that of cells bound with magnetic nanoparticles containing no zinc.
  • Fig. 19B is a graph calculating the strength by stokes' law to determine how powerful cells bound with magnetic nanoparticles are practically affected by a magnetic tip.
  • the magnetic attraction of cells bound with zinc-containing magnetic nanoparticles was about 4.12-fold stronger than that that of cells bound with magnetic nanoparticles containing no zinc.
  • Fig. 19A is a graph representing mean of cell migration rate obtained from 20 specific cells using zinc-containing magnetic nanoparticles and magnetic nanoparticles containing no zinc.
  • the cell migration rate of cells bound with zinc- containing magnetic nanoparticles was attracted toward a magnetic tip about 4.14- fold more rapid than that that

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Abstract

L'invention concerne des systèmes de séparation magnétique et des capteurs magnétiques à base de nanoparticules magnétiques contenant du zinc (de préférence ces nanoparticules comportent, lié à la surface, un agent de liaison à affinité de liaison avec un matériau cible ou analyte). De tels systèmes de séparation et capteurs contiennent une nanoparticule ou un groupe de nanoparticules de ce type. Puisque ces nanoparticules ont un magnétisme à très forte saturation, les systèmes de séparation décrits qui les utilisent offrent une efficacité largement accrue. Le magnétisme à saturation supérieure des nanoparticules magnétiques contenant du zinc rendent un capteur magnétique les utilisant capable de détecter des analytes de façon bien plus sensible. Les nanoparticules à sensibilité améliorée (par exemple, sensibilité en niveau fM) selon l'invention permettent la détection de quantité trace d'analytes du type protéines marqueurs anticancéreux ou molécules d'acides nucléiques, et protéines prions dans le sang.
PCT/KR2010/004158 2009-06-25 2010-06-25 Systèmes de séparation magnétique et capteurs magnétiques à base de nanoparticules magnétiques contenant du zinc WO2010151085A2 (fr)

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WO2012125932A2 (fr) * 2011-03-17 2012-09-20 The Board Of Trustees Of The University Of Illinois Procédé, dispositif et système de séparation de nanostructures à champ magnétique asymétrique
WO2014120794A1 (fr) * 2013-01-29 2014-08-07 Massachusetts Institute Of Technology Séparation magnétique à l'aide de nanoparticules
WO2015166415A1 (fr) 2014-04-28 2015-11-05 Universidade De Aveiro Nanoparticules chélatrices de silice magnétique modifiée, leur utilisation et leur préparation
US9409148B2 (en) 2013-08-08 2016-08-09 Uchicago Argonne, Llc Compositions and methods for direct capture of organic materials from process streams
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US20070258888A1 (en) * 2003-11-17 2007-11-08 Claus Feldmann Contrast Agent for Medical Imaging Techniques and Usage Thereof
KR100851933B1 (ko) * 2005-12-02 2008-08-12 연세대학교 산학협력단 망간 산화물 나노입자를 포함하는 자기공명 영상제
KR20080092870A (ko) * 2007-04-12 2008-10-16 연세대학교 산학협력단 아연이 함유된 금속 산화물 자성 나노 입자를 포함하는자기 공명 영상제

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WO2012125932A2 (fr) * 2011-03-17 2012-09-20 The Board Of Trustees Of The University Of Illinois Procédé, dispositif et système de séparation de nanostructures à champ magnétique asymétrique
WO2012125932A3 (fr) * 2011-03-17 2012-12-13 The Board Of Trustees Of The University Of Illinois Procédé, dispositif et système de séparation de nanostructures à champ magnétique asymétrique
WO2014120794A1 (fr) * 2013-01-29 2014-08-07 Massachusetts Institute Of Technology Séparation magnétique à l'aide de nanoparticules
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WO2015166415A1 (fr) 2014-04-28 2015-11-05 Universidade De Aveiro Nanoparticules chélatrices de silice magnétique modifiée, leur utilisation et leur préparation
ES2785774A1 (es) * 2019-04-03 2020-10-07 Consejo Superior Investigacion Catalizador biologico reciclable obtenido a partir de masa negra de pilas desechadas para la sintesis de esteres alquilicos de acidos grasos volatiles
WO2020201607A1 (fr) * 2019-04-03 2020-10-08 Consejo Superior De Investigaciones Científicas (Csic) Catalyseur biologique recyclable à partir de masse noire de piles jetées pour la synthèse d'esters alkyliques d'acides gras volatils
CN113376371A (zh) * 2021-05-10 2021-09-10 华中农业大学 一种铂壳金核纳米酶介导的磁弛豫传感信号放大系统的构建方法及其应用
CN113376371B (zh) * 2021-05-10 2024-01-30 华中农业大学 一种铂壳金核纳米酶介导的磁弛豫传感信号放大系统的构建方法及其应用

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