US20110171715A1 - Biocompatible polymer and magnetic nanoparticle with biocompatibility - Google Patents

Biocompatible polymer and magnetic nanoparticle with biocompatibility Download PDF

Info

Publication number
US20110171715A1
US20110171715A1 US12/989,402 US98940208A US2011171715A1 US 20110171715 A1 US20110171715 A1 US 20110171715A1 US 98940208 A US98940208 A US 98940208A US 2011171715 A1 US2011171715 A1 US 2011171715A1
Authority
US
United States
Prior art keywords
magnetic nanoparticle
biocompatible polymer
biocompatibility
nanoparticle
coupled
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/989,402
Other languages
English (en)
Inventor
Wen-Hsiang Chang
Wen-Uan Hsieh
Shiu-Hua Huang
Chin-1 Lin
Shian-Jy Jassy Wang
Kelly Teng
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Industrial Technology Research Institute ITRI
Original Assignee
Industrial Technology Research Institute ITRI
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Industrial Technology Research Institute ITRI filed Critical Industrial Technology Research Institute ITRI
Assigned to INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE reassignment INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TENG, KELLY, LIN, CHIN-I, WANG, SHIAN-JY JASSY, HSIEH, WEN-UAN, CHANG, WEN-HSIANG, HUANG, HSIU-HUA
Assigned to INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE reassignment INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNOR'S NAMES PREVIOUSLY RECORDED ON REEL 025637 FRAME 0620. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT SET FORTH IN THE ORIGINAL AND CORRECTED ASSIGNMENT DOCUMENT. Assignors: LIN, CHIN-I, TENG, KELLY, WANG, SHIAN-JY JASSY, HUANG, SHIU-HUA, CHANG, WEN-HSIANG, HSIEH, WEN-UAN
Publication of US20110171715A1 publication Critical patent/US20110171715A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/336—Polymers modified by chemical after-treatment with organic compounds containing silicon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089—Particulate, powder, adsorbate, bead, sphere
    • A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
    • A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
    • A61K49/1848—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule the small organic molecule being a silane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1857—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
    • A61K49/186—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA the organic macromolecular compound being polyethyleneglycol [PEG]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/321—Polymers modified by chemical after-treatment with inorganic compounds
    • C08G65/323—Polymers modified by chemical after-treatment with inorganic compounds containing halogens
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/321—Polymers modified by chemical after-treatment with inorganic compounds
    • C08G65/326—Polymers modified by chemical after-treatment with inorganic compounds containing sulfur
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C08G65/3328—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33303—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group
    • C08G65/33306—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group acyclic
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

Definitions

  • the invention relates to a biocompatible polymer and in particular to a biocompatible polymer for covalently modifying magnetic nanoparticles.
  • Magnetic resonance imaging is an appealing noninvasive approach for early cancer diagnostics and therapeutics.
  • MRI utilizes radio frequency pulses and magnetic field gradients applied to a subject in a strong field to produce images.
  • MRI is capable of showing several different characteristics of tissues.
  • the level of tissue magnetization at specific signal recording periods during the MR imaging cycle generally determines the brightness of a particular tissue in the MRI images. Contrast is produced when tissues do not have the same level of magnetization.
  • the magnetic nanoparticle can be modified with a biocompatible polymer to prolong the particle circulation time in blood and reduce immunogenicity. Furthermore, the magnetic nanoparticle can be modified with a fluorescent dye and a specific targeting agent to provide fluorescent properties and specific targeting functions.
  • U.S. Patent Publication No. 20070148095 discloses a multi-modality contrast agent with specificity for both magnetic and optical imaging.
  • the multi-modality contrast agent includes a magnetic nanoparticle, a biocompatible polymer chemically modifying the magnetic nanoparticle, a fluorescent dye coupled to the biocompatible polymer, and a specific targeting agent coupled to the biocompatible polymer.
  • the biocompatible polymers include polyethylene glycol (PEG), polylactic acid (PLA), PLA-PEG, poly(glycolic acid) (PGA), poly( ⁇ -caprolactone) (PCL), poly(methyl methacrylate) (PMMA), and the like.
  • U.S. Patent Publication No. 20070148095 discloses a silane compound for modifying magnetic nanoparticle and a method for using the nanoparticle to detect and treat tissues of interest.
  • MRI contrast enhancement agents include Feridex® (dextran-coated iron oxide) and Resovist® (carboxydextran-coated iron oxide).
  • the invention provides a biocompatible polymer of formula (I),
  • R 1 is alkyl, aryl, carboxyl, or amino
  • R 2 is alkyl or aryl
  • n is an integer from 5 to 1000
  • m is an integer from 1 to 10.
  • the invention provides a magnetic nanoparticle with biocompatibility, comprising a magnetic nanoparticle and a biocompatible polymer of formula (II) covalently coupled to the magnetic nanoparticle,
  • R 1 is alkyl, aryl, carboxyl, or amino
  • n is an integer from 5 to 1000
  • m is an integer from 1 to 10.
  • FIG. 1 is a schematic drawing showing the synthesis of the biocompatible polymer of the invention.
  • FIG. 2 is a schematic drawing showing a magnetic nanoparticle modified with the biocompatible polymer of the invention.
  • biocompatible polymer of the invention is represented by general formula (I),
  • FIG. 1 is a schematic drawing showing the synthesis of the biocompatible polymer of the invention, wherein R1, R2, n, and m have the same meaning as described above.
  • the synthetic scheme involves converting the hydroxyl end group of polyethylene glycol (PEG) to a carboxyl group by using a succinic anhydride compound, and coupling a silane group to the PEG.
  • Suitable alkyl groups for R 1 and R 2 include C 1 -C 20 straight chain or branched alkyl groups.
  • each of R 1 and R 2 independently, is a C 1 -C 6 straight chain or branched alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, and isohexyl.
  • Suitable aryl groups for R 1 and R 2 include C 6 -C 12 substituted or unsubstituted aryl groups such as phenyl, biphenyl, and naphthyl, and examples of substituents thereof include hydroxyl, haloalkyl, alkoxyl, cyano, nitro, amino, or alkylamino.
  • the number of methylene units m is preferably an integer from 1 to 10.
  • the number of oxyethylene units n is preferably an integer from 5 to 1000, equivalent to a molecular weight of about 200-50000 g/mole of the PEG. In one embodiment, m is about 3, and n is about 15.
  • the biocompatible polymer synthesized in FIG. 1 is useful in that it can chemically modify the surface of the iron oxide nanoparticle to increase biocompatibility.
  • the biocompatible polymer is useful in that it can label particles (e.g., nanoparticles, magnetic particles, magnetic nanoparticles, superparamagnetic particles), to render the particles to be further reactive toward one or more targeting, fluorescent, therapeutic, or diagnostic agents.
  • the invention also provides a magnetic nanoparticle with biocompatibility, comprising a magnetic nanoparticle; a biocompatible polymer of formula (II) covalently coupled to the magnetic nanoparticle,
  • FIG. 2 is a schematic drawing showing a magnetic nanoparticle modified with the biocompatible polymer of the invention.
  • the magnetic nanoparticle is preferably made of at least one of Fe, Co, Ni, and oxides thereof. It will be appreciated that the nanoparticle can be made of any single or composite magnetic material, although superparamagnetic materials are particularly preferred.
  • the terminal groups R 1 are transformed into active functional groups such as carboxyl or amino groups to allow coupling with fluorescent dye and/or specific targeting agents.
  • R 1 is not alkyl or aryl, since alkyl or aryl are not capable of coupling with targeting agents or fluorescent dye.
  • R 1 is a carboxyl group.
  • the number of methylene units m is preferably an integer from 1 to 10.
  • the number of oxyethylene units n is preferably an integer from 5 to 1000. In one embodiment, m is about 3, and n is about 15.
  • the biocompatible polymer is preferably coated on the entire surface of the magnetic nanoparticle to form a core-shell structure. More preferably, the biocompatible polymer forms a monolayer coating on the magnetic nanoparticle.
  • the biocompatible polymer of the invention may increase the r2 value of the magnetic nanoparticle to about 2 times that of commercial contrast agents, Feridex® and Resovist®. Accordingly, the magnetic nanoparticle may provide greater contrast enhancement when being used as an MRI contrast agent.
  • the targeting agent is preferably coupled to the biocompatible polymer via covalent bonds.
  • targeting agents include an antibody, a protein, a peptide, an enzyme, a carbohydrate, a glycoprotein, a nucleotide, and a lipid.
  • the magnetic nanoparticle may have a diameter of about 3-500 nm after coupling with the targeting agent.
  • folic acid can be used to specify breast cancer cells with a folate receptor.
  • the structure of the folic acid allows coupling with an amine-terminated or carboxy-terminated biocompatible polymer.
  • the folic acid allows coupling with the amine-terminated biocompatible polymer by forming a —CONH— linkage.
  • a fluorescent dye may be further coupled to the magnetic nanoparticle to provide an optical signal for optical imaging techniques such as NIR imaging, thus allowing real-time monitoring of foci by different imaging techniques.
  • the fluorescent dye is coupled to the biocompatible polymer via covalent bonds.
  • Suitable fluorescent dyes include organic or inorganic dyes and organometallic complexes.
  • the excitation and emission wavelengths of the fluorescent dye may be ultraviolet (UV), near-infrared (NIR), or visible (VIS) light.
  • the magnetic nanoparticle coupled with the targeting agent and fluorescent dye preferably has a diameter of about 15-200 nm.
  • the reaction mixture was added to 9 L of isopropyl ether for re-precipitation, and the precipitates were collected, re-dissolved in 500 ml of toluene, and centrifuged at 5000 rpm for 5 minutes to collect a supernatant. The supernatant was again, added to 9 L of isopropyl ether for re-precipitation. Brown oily liquid was collected and dried under vacuum to obtain the biocompatible polymer, mPEG-silane.
  • the reaction mixture was added to 9 L of isopropyl ether for re-precipitation, and the precipitates were collected, re-dissolved in 500 ml of toluene, and centrifuged at 5000 rpm for 5 minutes to collect a supernatant. The supernatant was again, added to 9 L of isopropyl ether for re-precipitation. Brown oily liquid was collected and dried under vacuum, thus obtaining the biocompatible polymer, COOH-PEG-silane.
  • solution A 2895 ⁇ l (half-volume) of solution A was added to solution B and stirred for 8 hours.
  • the resulting solution was added into a dialysis membrane (Mw: 3000) and water was used for dialysis. Then, the solution was concentrated to 2 ml by an ultra-filtration device to obtain iron oxide nanoparticles coupled with a targeting agent.
  • Example 5 The iron oxide nanoparticles coupled with folate (2 mg/ml) of Example 5 were dissolved in 10 ml of deionized water, followed by addition of 10 ⁇ 6 mole of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). After the mixture was stirred for one hour, 10 ⁇ 6 mole of N-hydroxysuccinimide (NHS) was added and stirred for another hour, thus giving a solution D.
  • EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
  • Solution C was added to solution D and stirred for 8 hours.
  • the resulting solution was added into a dialysis membrane (Mw: 3000) and water was used for dialysis. Then, the solution was concentrated to 2 ml by an ultra-filtration device to obtain iron oxide nanoparticles coupled with a targeting agent and a fluorescent dye.
  • the modified iron oxide nanoparticles of Example 5 were compared for the r1 and r2 relaxivity with the product of U.S. Patent Publication No. 2006/0216239 and commercial contrast agents, i.e., Feridex® and Resovist®.
  • Iron oxide solutions of various concentrations were prepared and measured for the T1 or T2 relaxation time by a Minispec mq 20 from the Bruker Corporation.
  • a linear relationship was established between the reciprocal of relaxation time as the ordinate axis and the concentration of the solution as the abscissa axis.
  • the slope of the linear relationship was the r1 and r2 relaxivity.
  • the r2 relaxivity of the modified iron oxide nanoparticles of the invention was about 2 times that of Feridex® and Resovist®, and about 1.4 times that of the prior art product of U.S. Patent Publication No. 2006/0216239. Accordingly, the contrast enhancement was improved due to the higher r2 relaxivity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nanotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Polymers & Plastics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medical Informatics (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
US12/989,402 2008-04-22 2008-04-22 Biocompatible polymer and magnetic nanoparticle with biocompatibility Abandoned US20110171715A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2008/000823 WO2009129649A1 (en) 2008-04-22 2008-04-22 Biocompatible polymer and magnetic nanoparticle with biocompatibility

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2008/000823 A-371-Of-International WO2009129649A1 (en) 2008-04-22 2008-04-22 Biocompatible polymer and magnetic nanoparticle with biocompatibility

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/600,209 Division US8741615B2 (en) 2008-04-22 2012-08-30 Magnetic nanoparticle with biocompatibility

Publications (1)

Publication Number Publication Date
US20110171715A1 true US20110171715A1 (en) 2011-07-14

Family

ID=41216385

Family Applications (2)

Application Number Title Priority Date Filing Date
US12/989,402 Abandoned US20110171715A1 (en) 2008-04-22 2008-04-22 Biocompatible polymer and magnetic nanoparticle with biocompatibility
US13/600,209 Active US8741615B2 (en) 2008-04-22 2012-08-30 Magnetic nanoparticle with biocompatibility

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/600,209 Active US8741615B2 (en) 2008-04-22 2012-08-30 Magnetic nanoparticle with biocompatibility

Country Status (8)

Country Link
US (2) US20110171715A1 (zh)
EP (1) EP2285423B1 (zh)
CN (1) CN102112158B9 (zh)
ES (1) ES2787502T3 (zh)
HU (1) HUE049091T2 (zh)
PL (1) PL2285423T3 (zh)
PT (1) PT2285423T (zh)
WO (1) WO2009129649A1 (zh)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140228552A1 (en) * 2013-02-08 2014-08-14 National Cheng Kung University Mri contrast enhancing agent
US9492399B2 (en) * 2014-07-11 2016-11-15 Megapro Biomedical Co., Ltd. Method of treating iron deficiency
US10359678B2 (en) 2014-04-07 2019-07-23 The Regents Of The University Of California Highly tunable magnetic liquid crystals
TWI745272B (zh) * 2014-07-14 2021-11-11 巨生生醫股份有限公司 免疫細胞追蹤方法

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2387787B1 (en) 2008-12-19 2018-09-12 Ferronova Pty Ltd Magnetic nanoparticles
JP5751580B2 (ja) * 2011-04-28 2015-07-22 国立研究開発法人産業技術総合研究所 メトキシオリゴエチレングリコール−シラン化合物表面修飾材料
CN102420172B (zh) * 2011-05-13 2014-02-05 上海华力微电子有限公司 用于提高半导体器件性能的在浅沟槽上形成接触孔的方法
CN105936820B (zh) * 2016-04-20 2019-07-12 北京工商大学 一种水溶性生物相容性荧光磁性纳米团簇及其制备方法
GB201607902D0 (en) * 2016-05-05 2016-06-22 Revolymer U K Ltd Adhesion promoters
CN110157000B (zh) * 2018-02-12 2022-05-31 巨生生医股份有限公司 生物相容性磁性材料
BR112024002150A2 (pt) 2021-08-03 2024-04-30 Pharmacosmos Holding As Compostos de complexo de ferro para uso subcutâneo na terapia de deficiência de ferro em animais de companhia

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040096507A1 (en) * 2002-11-08 2004-05-20 Sunbio Inc. Novel hexa-arm polyethylene glycol and its derivatives and the methods of preparation thereof
US20060216239A1 (en) * 2005-03-18 2006-09-28 Washington, University Of Magnetic nanoparticle compositions and methods
US20070148095A1 (en) * 2005-12-23 2007-06-28 Industrial Technology Research Institute Fluorescent magnetic nanoparticles with specific targeting functions
US20070254005A1 (en) * 2004-08-26 2007-11-01 Pathak Chandraskekhar P Implantable Tissue Compositions and Method
US20080089836A1 (en) * 2006-10-12 2008-04-17 Nanoprobes, Inc. Functional associative coatings for nanoparticles

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1724076A (zh) * 2005-06-10 2006-01-25 中南大学 核磁共振成像造影剂及其制备方法
US9913917B2 (en) * 2005-12-22 2018-03-13 Visen Medical, Inc. Biocompatible fluorescent metal oxide nanoparticles

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040096507A1 (en) * 2002-11-08 2004-05-20 Sunbio Inc. Novel hexa-arm polyethylene glycol and its derivatives and the methods of preparation thereof
US20070254005A1 (en) * 2004-08-26 2007-11-01 Pathak Chandraskekhar P Implantable Tissue Compositions and Method
US20060216239A1 (en) * 2005-03-18 2006-09-28 Washington, University Of Magnetic nanoparticle compositions and methods
US20070148095A1 (en) * 2005-12-23 2007-06-28 Industrial Technology Research Institute Fluorescent magnetic nanoparticles with specific targeting functions
US20080089836A1 (en) * 2006-10-12 2008-04-17 Nanoprobes, Inc. Functional associative coatings for nanoparticles

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140228552A1 (en) * 2013-02-08 2014-08-14 National Cheng Kung University Mri contrast enhancing agent
US10359678B2 (en) 2014-04-07 2019-07-23 The Regents Of The University Of California Highly tunable magnetic liquid crystals
US9492399B2 (en) * 2014-07-11 2016-11-15 Megapro Biomedical Co., Ltd. Method of treating iron deficiency
TWI745272B (zh) * 2014-07-14 2021-11-11 巨生生醫股份有限公司 免疫細胞追蹤方法

Also Published As

Publication number Publication date
CN102112158A (zh) 2011-06-29
EP2285423B1 (en) 2020-03-18
WO2009129649A8 (en) 2009-12-23
EP2285423A1 (en) 2011-02-23
ES2787502T3 (es) 2020-10-16
PL2285423T3 (pl) 2020-08-24
WO2009129649A1 (en) 2009-10-29
CN102112158B9 (zh) 2018-04-06
US8741615B2 (en) 2014-06-03
EP2285423A4 (en) 2014-12-03
HUE049091T2 (hu) 2020-08-28
PT2285423T (pt) 2020-05-07
US20120329129A1 (en) 2012-12-27
CN102112158B (zh) 2012-09-05

Similar Documents

Publication Publication Date Title
US8741615B2 (en) Magnetic nanoparticle with biocompatibility
Kim et al. A cancer-recognizable MRI contrast agents using pH-responsive polymeric micelle
US20070148095A1 (en) Fluorescent magnetic nanoparticles with specific targeting functions
Li et al. Superparamagnetic iron oxide nanoparticles as MRI contrast agents for non-invasive stem cell labeling and tracking
Yang et al. Targeted dual-contrast T1-and T2-weighted magnetic resonance imaging of tumors using multifunctional gadolinium-labeled superparamagnetic iron oxide nanoparticles
CA2827752C (en) Mri contrast agent for lymphography based on iron oxide nanoparticles and method for imaging lymph node using the same
CN103143043B (zh) 一种Fe3O4/Au复合纳米颗粒的制备方法
CN104689338B (zh) 肿瘤靶向性酸敏前药与磁性纳米粒子偶联物的制法及应用
Lee et al. Amphiphilic hyaluronic acid-based nanoparticles for tumor-specific optical/MR dual imaging
Yang et al. Cross-linked magnetic nanoparticles with a biocompatible amide bond for cancer-targeted dual optical/magnetic resonance imaging
US20090226376A1 (en) Novel Mixed Ligand Core/Shell Iron Oxide Nanoparticles for Inflammation Imaging
Yang et al. Folate-conjugated cross-linked magnetic nanoparticles as potential magnetic resonance probes for in vivo cancer imaging
Xiong et al. Gd-Chelated poly (propylene imine) dendrimers with densely organized maltose shells for enhanced MR imaging applications
An et al. Multifunctional Magnetic Gd3+‐Based Coordination Polymer Nanoparticles: Combination of Magnetic Resonance and Multispectral Optoacoustic Detections for Tumor‐Targeted Imaging in vivo
KR101729710B1 (ko) 물에 안정하게 분산되는 멜라닌 나노입자를 포함하는 핵자기 공명 영상 조영제
Yin et al. Fluorescent oligo (p-phenyleneethynylene) contained amphiphiles-encapsulated magnetic nanoparticles for targeted magnetic resonance and two-photon optical imaging in vitro and in vivo
Yang et al. Cross-linked magnetic nanoparticles from poly (ethylene glycol) and dodecyl grafted poly (succinimide) as magnetic resonance probes
Jiang et al. Tumor-microenvironment relaxivity-changeable Gd-loaded poly (L-lysine)/carboxymethyl chitosan nanoparticles as cancer-recognizable magnetic resonance imaging contrast agents
CN102058891A (zh) 聚乙二醇修饰的荧光磁性硅纳米载体及制法和应用
Mondjinou et al. Gd3+: DOTA-modified 2-hydroxypropyl-β-cyclodextrin/4-sulfobutyl ether-β-cyclodextrin-based polyrotaxanes as long circulating high relaxivity MRI contrast agents
Huang et al. Gadolinium-conjugated star-block copolymer polylysine-modified polyethylenimine as high-performance T 1 MR imaging blood pool contrast agents
KR20140131938A (ko) Peg 치환된 알파-히드록시 포스포네이트 셸을 가지는 초상자성 나노입자
TWI361082B (en) Biocompatible polymer and magnetic nanoparticle with biocompatibilities
KR101729711B1 (ko) 물에 안정하게 분산되는 멜라닌 나노입자를 포함하는 핵자기 공명 영상 조영제
Sun et al. Dendrimer-based nanodevices as contrast agents for mr imaging applications

Legal Events

Date Code Title Description
AS Assignment

Owner name: INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE, TAIWAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CHANG, WEN-HSIANG;HSIEH, WEN-UAN;HUANG, HSIU-HUA;AND OTHERS;SIGNING DATES FROM 20101118 TO 20101223;REEL/FRAME:025637/0620

AS Assignment

Owner name: INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE, TAIWAN

Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNOR'S NAMES PREVIOUSLY RECORDED ON REEL 025637 FRAME 0620. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT SET FORTH IN THE ORIGINAL AND CORRECTED ASSIGNMENT DOCUMENT;ASSIGNORS:CHANG, WEN-HSIANG;HSIEH, WEN-UAN;HUANG, SHIU-HUA;AND OTHERS;SIGNING DATES FROM 20110303 TO 20110314;REEL/FRAME:026073/0354

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION