WO2015180205A1 - 稀土基纳米颗粒磁共振造影剂及其制备方法 - Google Patents

稀土基纳米颗粒磁共振造影剂及其制备方法 Download PDF

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WO2015180205A1
WO2015180205A1 PCT/CN2014/079597 CN2014079597W WO2015180205A1 WO 2015180205 A1 WO2015180205 A1 WO 2015180205A1 CN 2014079597 W CN2014079597 W CN 2014079597W WO 2015180205 A1 WO2015180205 A1 WO 2015180205A1
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rare earth
contrast agent
magnetic resonance
resonance contrast
based nanoparticle
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French (fr)
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孙聆东
严纯华
郑晓宇
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Peking University
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Peking University
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Priority to JP2016569952A priority patent/JP2017518993A/ja
Priority to EP14892931.8A priority patent/EP3150232A4/en
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    • 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
    • A—HUMAN NECESSITIES
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K49/00—Preparations for testing in vivo
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    • A61K49/00—Preparations for testing in vivo
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    • 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
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    • A61K49/1806—Suspensions, emulsions, colloids, dispersions
    • A—HUMAN NECESSITIES
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    • 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
    • A61K49/1836—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 carboxylic acid having less than 8 carbon atoms in the main chain
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    • 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
    • A61K49/1854—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 by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly(meth)acrylate, polyacrylamide, polyvinylpyrrolidone, polyvinylalcohol
    • 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

Definitions

  • the invention relates to a rare earth-based nano particle magnetic resonance contrast agent and a preparation method thereof, and belongs to the technical field of nano materials. Background technique
  • Magnetic Resonance Imaging is an important technology in the field of medical diagnosis and molecular imaging. It has the advantages of high tissue resolution, many imaging parameters, and no radiation damage to the human body.
  • contrast agents ContrastAgents
  • the contrast agent can be classified into two types according to the ratio of the transverse and longitudinal relaxation rates: a contrast agent that brightens the local tissue and a T 2 contrast agent that darkens the local tissue.
  • Rare earth ions have an unfilled 4f electron layer, so they have unique optical, electrical and magnetic properties, and have important application value in both magnetic resonance and T 2 imaging.
  • trivalent strontium ions (Gd 3+ ) have the largest number of unpaired electrons, and the electron spin relaxation time is long, which can effectively shorten the longitudinal relaxation time to increase the image brightness, so it is considered to be angiography.
  • the best choice for the agent In order to reduce the risk of toxicity caused by free cesium ions, the most widely used contrast agent is a bismuth-containing paramagnetic chelate in order to reduce its liberation by chelation.
  • such contrast agents generally have a low relaxation rate, limited contrast effects, and large doses, which still pose a certain threat to normal tissues.
  • the contrast agent since the contrast agent is a small molecule, the residence time in the body is short, and the long-term diagnosis cannot be guaranteed.
  • rare earth-based inorganic nanoparticles are expected to be a new generation of high-efficiency magnetic resonance contrast agents, because a single particle contains a large amount of rare earth ions, which can produce more significant signal enhancement, and the rigid framework of inorganic nanostructures can reduce rare earth ions. The possibility of liberation. Since the size of the nanoparticles is larger than the chelate, the circulation time in the body is longer. In addition, the surface of inorganic nanostructures is easy to modify functional groups for active targeting, multimodal imaging, and the like. Therefore, the development and utilization of rare earth-based nanoparticle magnetic resonance contrast agents have the advantages of improving the accuracy of diagnosis and the safety of contrast agents. Significance. Summary of the invention
  • the invention provides a rare earth-based nanoparticle magnetic resonance contrast agent and a preparation method thereof, and the magnetic resonance contrast agent has the characteristics of high relaxation rate, small injection dose, long circulation time in the body, and low possibility of free radical ion release.
  • the rare earth-based nanoparticle magnetic resonance contrast agent of the present invention refers to a rare earth-based inorganic nanoparticle having a surface coated with a hydrophilic ligand.
  • the invention first obtains rare earth-based nanoparticles by high-temperature oil phase reaction, and then coats the surface with a hydrophilic molecule to obtain a rare earth-based nanoparticle magnetic resonance contrast agent.
  • the rare earth element (RE) in the rare earth-based nanoparticle magnetic resonance contrast agent of the present invention includes lanthanum (La), cerium (Ce), praseodymium (Pr), cerium (Nd;), cerium (Sm;), cerium (Eu;) , L(Gd) ⁇ (Tb;), ⁇ (Dy;), ⁇ (Ho), ⁇ (Er;), ⁇ (Tm;), ⁇ (Yb;), ⁇ (Lu), ⁇ (Sc) and One or several of ⁇ (Y).
  • the composition of the rare earth-based nanoparticle in the rare earth-based nanoparticle magnetic resonance contrast agent of the present invention is M a REO b X e , wherein RE represents a rare earth element, M represents an alkali metal or an alkaline earth metal, X represents fluorine or chlorine, 0 ⁇ a ⁇ l, 0 ⁇ b ⁇ 1.5, 0 ⁇ c ⁇ 4.
  • the rare earth-based nanoparticles may also be an inorganic compound doped with a matrix of M a REO b X c , and doping may impart luminescent properties or regulate its magnetic properties.
  • the surface-coated ligand of the rare earth-based nanoparticle magnetic resonance contrast agent of the present invention may be one or more of the following: hydrophilic small molecules such as citric acid and cysteine, and polyvinyl alcohol and polyethylene.
  • hydrophilic polymer such as an amine, polyvinylpyrrolidone or polyacrylic acid.
  • the invention provides a preparation method of a rare earth-based nano particle magnetic resonance contrast agent, the steps of which are:
  • the preferred range of the molar ratio of the precursor to the solvent in the step 1) is 1:20-1:200, the rare earth precursor in the precursor is necessary to be added, and whether the rare earth precursor is to be added depends on the composition of the target product.
  • Step 2) preferably performing the vacuuming at 100-140 ° C;
  • Step 3) preferably washing with a large amount of ethanol, preferably washing by centrifugation, preferably 2-6 times;
  • the high boiling organic solvent in the present invention means one of oleic acid, linoleic acid, oleylamine, octadecene, hexadecylamine and octadecylamine. Or a mixed solvent of various compositions.
  • the rare earth precursor in the present invention is a mixture of one or more of the following: rare earth hydroxide, oxalate, acetate, trifluoroacetate, trichloroacetate, acetylacetonate, benzene Acetylacetonate.
  • the non-rare earth precursor in the present invention is a mixture of one or more of the following: fluorides, hydroxides, oxalates, acetates, trifluoroacetates, trichloroethanes of alkali metals and alkaline earth metals Acid salt, acetylacetonate, phenylacetylacetonate.
  • the rare earth-based nanoparticles can adjust the composition, size, morphology and crystallization of the nanoparticles by parameters such as solvent ratio, precursor charge amount, reaction temperature and reaction time. Degree, etc.; and the relaxation property and biocompatibility of the contrast agent can be adjusted by the type and amount of water-soluble molecules in the surface coating process of the hydrophilic ligand.
  • the single particle of the magnetic resonance contrast agent of the present invention contains a large amount of rare earth ions, which can significantly reduce the relaxation time of surrounding protons;
  • the magnetic resonance contrast agent of the present invention is larger in size than the chelate, and has a longer circulation time in the body, which can meet the needs of clinical long-term diagnosis;
  • the magnetic resonance contrast agent of the present invention has a high relaxation rate, which is about ten times higher than that of a conventional contrast agent, and has a better contrast effect under the same concentration condition;
  • the magnetic resonance contrast agent of the present invention possesses a rigid skeleton of inorganic nanostructures, which can reduce the possibility of release of rare earth ions and is safer than the chelate compound;
  • the magnetic resonance contrast agent of the invention has excellent contrast performance, and the required dose can be greatly reduced compared with the current clinical common contrast agent, which can further reduce the risk of damaging normal tissues;
  • the magnetic resonance contrast agent of the present invention has simple reaction, easy control, good repeatability and stable properties.
  • Figure 1 is a comparison of the magnetic resonance images of rare earth-based nanoparticle magnetic resonance contrast agents and five common contrast agents in different concentrations.
  • the scanning sequence used is a T1 weighted sequence with a magnetic field strength of 3 T.
  • Figure 2 is a comparison of the magnetic resonance images of rare earth-based nanoparticle magnetic resonance contrast agents and five common contrast agents in different concentrations.
  • the scanning sequence used is a ⁇ 2 weighted sequence with a magnetic field strength of 3 ⁇ .
  • Figure 3 is a comparison of the magnetic resonance images of rare earth-based nanoparticle magnetic resonance contrast agents and five common contrast agents in different concentrations.
  • the scanning sequence used is ceMRA sequence, and the magnetic field strength is 3 T.
  • Figure 4 is a comparison of magnetic resonance images of rare earth-based nanoparticle magnetic resonance contrast agents and five common contrast agents in different concentrations.
  • the scanning sequence used is LAVA sequence, and the magnetic field strength used is 3 T.
  • Figure 5 is a schematic diagram comparing the relaxation rates of rare earth-based nanoparticle magnetic resonance contrast agents with five commonly used contrast agents in clinical practice. The magnetic field strength used is 3 T.
  • Figure 6 is a comparison of the relaxation rates of rare earth-based nanoparticle magnetic resonance contrast agents at different magnetic field strengths.
  • the rare earth-based nanoparticle magnetic resonance contrast agent and the preparation method thereof described in the application of the present invention are described in conjunction with specific embodiments, in order to better understand the technical content of the public, rather than the technical content.
  • Limitations, in fact, improvements to the composite material and its method of preparation on the same or similar principles are within the technical solutions claimed in the present application.
  • the embodiment will be described by taking a 50 mL capacity reaction system as an example. In the actual preparation, the materials can be scaled up in the same manner.
  • Synthesis of Y 2 0 3 nanoparticles Add 0.5 mmol of cesium hydroxide to a mixed solvent of oleic acid (2 mL), oleylamine (3 mL) and octadecene (5 mL), and heat to 310 ° under inert gas protection. C, maintaining the temperature for 1 h, the reaction solution was cooled to room temperature, a large amount of ethanol was added thereto, and the mixture was washed twice by centrifugation to obtain Y 2 0 3 nanoparticles.
  • Embodiment 6 Synthesis of CeOF nanoparticles: Add 1 mmol of oxalate to a mixed solvent of oleic acid C5 mmol) and hexadecylamine C35 mmol), heat to 320 °C under inert gas, maintain the temperature for 1 h, and cool the reaction to room temperature. A large amount of ethanol was added thereto and washed twice by centrifugation to obtain CeOF nanoparticles.
  • LiTmF 4 nanoparticles Add 1 mmol of lithium trifluoroacetate and 1 mmol of trifluoroacetic acid to a mixed solvent of oleic acid C20 mmol) and octadecene C20 mmol), and heat to 320 °C under inert gas to maintain At this temperature for 15 h, the reaction solution was cooled to room temperature, a large amount of ethanol was added thereto, and the mixture was washed by centrifugation six times to obtain LiTmF 4 nanoparticles.
  • the surface of the particles was coated with citric acid.
  • the upper suspension liquid is taken, centrifuged with a large amount of ethanol, and the obtained precipitate is dispersed in pure water to obtain a nanoparticle magnetic resonance contrast agent.
  • Coating the surface of the particles with polyvinyl alcohol The CeOF nanoparticles (0.1 mmol) obtained in Example 6 were dispersed in 10 mL of cyclohexane, and 10 mL of N,N-dimethylformamide and 50 mg of nitrosyltetrafluoroborate were added. Gun, stir vigorously for not less than 1 h. The lower layer was taken, centrifuged with a large amount of toluene, and the resulting precipitate was again dissolved in 10 mL of N,N-dimethylformamide, and 50 mg of polyvinyl alcohol was added thereto, and stirred for not less than 4 hours. Then, a large amount of acetone was added to the solution, and the resulting precipitate was dispersed in pure water to obtain a nanoparticle magnetic resonance contrast agent.
  • the surface of the particles was coated with polyethyleneimine: LaF 3 nanoparticles (0.2 mmol) obtained in Example 5 were dispersed in 10 mL of cyclohexane, and 10 mL of N,N-dimethylformamide and 50 mg of tetrafluoroborate were added. Nitrogen gun, stirring vigorously for not less than 1 h. The lower layer of the liquid was taken, centrifuged with a large amount of toluene, and the resulting precipitate was again dissolved in 10 mL of N,N-dimethylformamide, and 50 mg of polyethyleneimine was added thereto, and stirred for not less than 4 hours. A large amount of acetone is then added to the solution, centrifuged, and the resulting precipitate is dispersed in pure water to obtain a nanoparticle magnetic resonance contrast agent.
  • Polyvinylpyrrolidone coated on the surface of the particles: NaDyF 4 :Yb,Er nanoparticles (0.2 mmol) obtained in Example 8 were dispersed in 10 mL of cyclohexane, and 10 mL of N,N-dimethylformamide and 50 mg were added. Fluorite tetrafluoroborate gun, stirring vigorously for not less than lh. The lower layer liquid was taken, centrifuged with a large amount of toluene, and the resulting precipitate was again dissolved in 10 mL of N,N-dimethylformamide, and polyvinylpyrrolidone 50 mg was added thereto, and stirred for not less than 4 hours.
  • nanoparticle magnetic resonance contrast agent 1 to 4 are magnetic resonance images of rare earth-based nanoparticle magnetic resonance contrast agents obtained in Example 12 and clinically used five contrast agents at different concentrations, and the magnetic field strengths used are 3 T.
  • the scan sequence used in Figure 1 is a 1-weighted sequence; the scan sequence used in Figure 2 is a weighted sequence; the scan sequence used in Figure 3 is the ceMRA sequence; and the scan sequence used in Figure 4 is the LAVA sequence. It can be seen from FIG. 1 to FIG.
  • the rare earth-based nanoparticle magnetic resonance contrast agent obtained in the embodiment 12 has better imaging performance than the commonly used contrast agent under the same concentration condition, and the contrast effect is significantly improved with the increase of the concentration ( The brighter the image in Fig. 1, Fig. 3, and Fig. 4, the better the contrast effect, and the darker the image in Fig. 2, the better the contrast effect).
  • the image darkening of the rare earth-based nanoparticle magnetic resonance contrast agent in Figure 1 is due to the existence of the "saturation effect", that is, the T1 contrast effect has reached the limit, and the T2 contrast effect at high concentration.
  • Fig. 5 is a schematic view showing the comparison of the relaxation rates of the rare earth-based nanoparticle magnetic resonance contrast agent obtained in the twelfth embodiment and the five commonly used contrast agents in the clinical use, and the magnetic field strength used is 3 T. It can be seen from FIG. 5 that the longitudinal and transverse relaxation rates of the rare earth-based nanoparticle magnetic resonance contrast agent obtained in the embodiment 12 are higher than those of the commonly used contrast agents.
  • Fig. 6 is a comparison of the relaxation ratios of the rare earth-based nanoparticle magnetic resonance contrast agents obtained in Example 12 under different magnetic field strengths. As can be seen from Fig. 6, the rare earth-based nanoparticle magnetic resonance contrast agent obtained in Example 12 exhibited high longitudinal and transverse relaxation rates at both high magnetic field strength and low magnetic field strength.
  • the rare earth-based nanoparticle magnetic resonance contrast agent of the present invention can significantly reduce the relaxation time of surrounding protons, thereby greatly improving the contrast of local tissues.
  • the rare earth-based nanoparticle magnetic resonance contrast agent described in the application has the characteristics of high relaxation rate, long residence time in the body, low injection dose, and low possibility of free radical ion release, and can effectively improve the accuracy of diagnosis and the contrast agent. safety.

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  • Magnetic Resonance Imaging Apparatus (AREA)

Abstract

一种稀土基纳米颗粒磁共振造影剂及其制备方法。该稀土基纳米颗粒磁共振造影剂是表面包覆亲水性配体的稀土基无机纳米颗粒，其通过如下方法制备而成：首先通过高温油相反应获得稀土基纳米颗粒，然后在其表面包覆亲水性分子后即得。该磁共振造影剂与现有临床造影剂相比，弛豫率大大提高，成像效果好，所需注射剂量低，且体内停留时间较长。此外，无机纳米颗粒的刚性结构可有效降低钆离子游离可能。

Description

稀土基纳米颗粒磁共振造影剂及其制备方法
技术领域
本发明涉及一种稀土基纳米颗粒磁共振造影剂及其制备方法， 属于纳米材料技术领域。 背景技术
磁共振成像 （Magnetic Resonance Imaging, MRI) 是医学诊断与分子成像领域中的一项 重要技术， 具有组织分辨率高、 成像参数多、 对人体无辐射损伤等优点。 但由于 MRI技术 灵敏度较低， 临床上常采用造影剂 （ContrastAgents) 来提高成像对比度和图像质量。 造影 剂可根据横、 纵向弛豫率的比值高低分为两类： 使局部组织变亮的 造影剂和使局部组织 变暗的 T2造影剂。 稀土离子具有未充满的 4f电子层， 因此具有独特的光、 电、 磁学特性， 在磁共振 与 T2造影方面都具有重要的应用价值。
在1 造影剂方面，三价的钆离子 (Gd3+)具有最多的未成对电子数，且电子自旋弛豫时间 长， 可以有效缩短纵向弛豫时间来增加图像亮度， 因此被认为是 造影剂的最佳选择。 为 了降低游离的钆离子带来毒性的风险， 当前应用最为广泛的 造影剂是含钆的顺磁性螯合 物， 以期通过螯合的方式降低其游离的可能。 然而， 该类造影剂通常弛豫率较低， 造影效 果有限， 且所需剂量大， 对于正常组织仍有一定的威胁。 此外， 由于该类造影剂属于小分 子， 体内停留时间短， 无法保证长时间的诊断效果。
在 T2造影剂方面， 具有超顺磁性的氧化铁纳米颗粒造影剂已经实现了商业化， 但遗憾 的是， 此类造影剂在较低的磁场强度下 （1.5 Τ) 便已达到饱和磁化强度， 在更高磁场强度 下的造影效果较差 （NaDyF4 Nanoparticles as T-2 Contrast Agents for Ultrahigh Field Magnetic Resonance Imaging, Frank C. J. M. van Veggel, et al. J. Phys. Chem. Lett. 2012, 3, 524—529)。 而 稀土离子 （如铽 Tb3+、 镝 Dy3+、 铁 Ho3+、 铒 Er3+) 具有较大的磁矩以及较短的电子自旋弛 豫时间， 有望满足高磁场强度下的造影需求。
综上所述， 稀土基的无机纳米颗粒有望成为新一代高效的磁共振造影剂， 因为单个颗 粒包含大量的稀土离子， 可产生更加显著的信号增强， 且无机纳米结构的刚性骨架可以降 低稀土离子游离的可能性。 又由于纳米颗粒的尺寸大于螯合物， 其体内循环时间较长。 此 外， 无机纳米结构的表面易于修饰功能性基团以达到主动靶向、 多模式成像等目的。 因此， 稀土基纳米颗粒磁共振造影剂的开发与利用对于提高诊断的准确性及造影剂的安全性具有 重要的意义。 发明内容
本发明提出了一种稀土基纳米颗粒磁共振造影剂及其制备方法， 该磁共振造影剂具有 弛豫率高、 注射剂量小、 体内循环时间较长、 稀土离子游离可能性低等特点。
本发明的稀土基纳米颗粒磁共振造影剂指的是表面包覆亲水性配体的稀土基无机纳米 颗粒。 本发明首先通过高温油相反应获得稀土基纳米颗粒， 然后在其表面包覆亲水性分子 后得到稀土基纳米颗粒磁共振造影剂。
本发明的稀土基纳米颗粒磁共振造影剂中稀土元素 (RE)包括镧 (La)、 铈 (Ce)、 镨 (Pr)、 钕 (Nd；)、 钐 (Sm；)、 铕 (Eu；)、 L(Gd) 铽 (Tb；)、 镝 (Dy；)、 钬 (Ho)、 铒 (Er；)、 铥 (Tm；)、 镱 (Yb；)、 镥 (Lu)、 钪 (Sc)和钇 (Y)中的一种或几种。
本发明的稀土基纳米颗粒磁共振造影剂中稀土基纳米颗粒的组成是 MaREObXe， 其中 RE代表稀土元素， M代表碱金属或碱土金属， X代表氟或氯， 0≤a≤l， 0≤b≤1.5， 0≤c≤4。 此外， 稀土基纳米颗粒还可以是以 MaREObXc为基质进行掺杂的无机化合物， 进行掺杂的 作用是赋予其发光性质或调控其磁性。
本发明的稀土基纳米颗粒磁共振造影剂的表面包覆配体可以采用下列中的一种或多 种： 柠檬酸、 半胱氨酸等亲水性小分子， 以及聚乙烯醇、 聚乙烯亚胺、 聚乙烯吡咯烷酮、 聚丙烯酸等亲水性高分子。
本发明提出一种稀土基纳米颗粒磁共振造影剂的制备方法， 其步骤为：
1 ) 在高沸点有机溶剂中， 加入一定量的稀土前驱体或者稀土前驱体与非稀土前驱体的 混合物， 得到溶液 A;
2) 对溶液 A抽真空以除去水分， 然后在惰性气体保护下升温至 250-340 V ， 维持 15 min-24 h, 然后冷却至室温， 得到溶胶 B;
3 ) 对溶胶 B进行离心分离， 对所得沉淀物进行洗涤， 再对沉淀物的表面进行亲水性配 体的包覆；
4) 将包覆后的颗粒分散于溶剂中， 即得到造影剂。
其中， 步骤 1 ) 中前驱体与溶剂摩尔比的优选范围是 1 :20-1 :200， 前驱体中稀土前驱体 是必须要加入的， 而非稀土前驱体是否要加入取决于目标产物的组成； 步骤 2) 优选在 100-140 °C下进行所述抽真空； 步骤 3 ) 优选采用大量乙醇进行洗涤， 洗涤方式优选为离心 洗涤， 洗涤次数优选为 2-6次； 步骤 4) 所述溶剂优选为水或生理盐水。
本发明中的高沸点有机溶剂指油酸、 亚油酸、 油胺、 十八烯、 十六胺和十八胺中的一种 或多种组成的混合溶剂。
本发明中的稀土前驱体是下列中的一种或多种的混合： 稀土的氢氧化物、 草酸盐、 乙酸 盐、 三氟乙酸盐、 三氯乙酸盐、 乙酰丙酮盐、 苯基乙酰丙酮盐。
本发明中的非稀土前驱体是下列中的一种或多种的混合： 碱金属与碱土金属的氟化物、 氢氧化物、 草酸盐、 乙酸盐、 三氟乙酸盐、 三氯乙酸盐、 乙酰丙酮盐、 苯基乙酰丙酮盐。
本发明的稀土基纳米颗粒磁共振造影剂的制备方法中， 稀土基纳米颗粒可通过溶剂比 例、 前驱体投料量、 反应温度、 反应时间等参数调节纳米颗粒的组成、 尺寸、 形貌、 晶化 程度等； 并可通过亲水性配体的表面包覆过程中水溶性分子的种类、 投料量等调节造影剂 的弛豫性质、 生物相容性等。
本发明的稀土基纳米颗粒磁共振造影剂具有以下优点：
1.本发明的磁共振造影剂单个颗粒包含大量的稀土离子，可显著降低周围质子的弛豫时 间；
2.本发明的磁共振造影剂尺寸大于螯合物， 体内循环时间较长， 可满足临床上长时间诊 断的需要；
3.本发明的磁共振造影剂弛豫率较高， 与临床常用造影剂相比可高出约十倍， 同浓度条 件下造影效果更好；
4.本发明的磁共振造影剂拥有无机纳米结构的刚性骨架， 可减小稀土离子游离的可能， 与螯合物相比更安全；
5.本发明的磁共振造影剂由于造影性能优异，所需剂量与当前临床常用造影剂相比可大 幅减少， 可进一步降低损伤正常组织的风险；
6.本发明的磁共振造影剂反应操作简单， 易于控制， 重复性良好， 性质稳定。 附图说明
图 1 是稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂在不同浓度条件下的磁共 振图像对比， 所用扫描序列为 T1加权序列， 所用磁场强度为 3 T。
图 2是稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂在不同浓度条件下的磁共 振图像对比， 所用扫描序列为 Τ2加权序列， 所用磁场强度为 3 Τ。
图 3 是稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂在不同浓度条件下的磁共 振图像对比， 所用扫描序列为 ceMRA序列， 所用磁场强度为 3 T。
图 4是稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂在不同浓度条件下的磁共 振图像对比， 所用扫描序列为 LAVA序列， 所用磁场强度为 3 T。 图 5 是稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂的弛豫率对比示意图， 所 用磁场强度为 3 T。
图 6是稀土基纳米颗粒磁共振造影剂在不同磁场强度下的弛豫率对比。 具体实施方式
以下结合具体的实施方式， 对本发明申请所述的稀土基纳米颗粒磁共振造影剂及其制 备方法进行描述， 目的是为了公众更好地理解所述的技术内容， 而不是对所述技术内容的 限制， 事实上， 在以相同或近似的原理对所述复合材料及其制备方法进行的改进， 都在本 发明申请所要求保护的技术方案之内。 以下仅以 50 mL容量反应体系为例对实施方式进行 说明， 实际制备中可采用各物料同比例放大方式加以实施。
实施例一
Gd203纳米颗粒的合成： 向油酸 (4 mL)、 油胺 (12 mL)的混合溶剂中加入 0.5 mmol乙酰 丙酮钆， 惰性气体保护下加热至 340 °C， 维持该温度 15 min， 将反应液冷却至室温， 向其 中加入大量的乙醇， 离心洗涤两次， 得到 Gd203纳米颗粒。
实施例二
Pr203纳米颗粒的合成：向油酸 (6 mL)、油胺 (12 mL)的混合溶剂中加入 0.5 mmol乙酸镨， 惰性气体保护下加热至 340 °C， 维持该温度 2 h， 将反应液冷却至室温， 向其中加入大量的 乙醇， 离心洗涤两次， 得到 Pr203纳米颗粒。
实施例三
Er203纳米颗粒的合成： 向油酸 (6 mL)、 油胺 (8 mL)的混合溶剂中加入 0.5 mmol苯基乙 酰丙酮铒， 惰性气体保护下加热至 310 °C， 维持该温度 l h， 将反应液冷却至室温， 向其中 加入大量的乙醇， 离心洗涤两次， 得到 Er203纳米颗粒。
实施例四
Y203纳米颗粒的合成： 向油酸 (2 mL)、油胺 (3 mL)与十八烯 (5 mL)的混合溶剂中加入 0.5 mmol氢氧化钇， 惰性气体保护下加热至 310 °C， 维持该温度 1 h， 将反应液冷却至室温， 向其中加入大量的乙醇， 离心洗涤两次， 得到 Y203纳米颗粒。
实施例五
LaF3纳米颗粒的合成： 向油酸 (20 mmol)与十八烯 (20 mmol)的混合溶剂中加入 1 mmol 三氟乙酸镧与 0.5 mmol氟化锂， 惰性气体保护下加热至 260 °C， 维持该温度 4 h， 将反应 液冷却至室温， 向其中加入大量的乙醇， 离心洗涤两次， 得到 LaF3纳米颗粒。
实施例六 CeOF纳米颗粒的合成： 向油酸 C5 mmol)与十六胺 C35 mmol)的混合溶剂中加入 1 mmol 草酸铈， 惰性气体保护下加热至 320 °C， 维持该温度 l h， 将反应液冷却至室温， 向其中加 入大量的乙醇， 离心洗涤两次， 得到 CeOF纳米颗粒。
实施例七
EuOCl纳米颗粒的合成：向油胺 (20 mmol)与十八烯 (20 mmol)的混合溶剂中加入 1 mmol 三氯乙酸铕， 惰性气体保护下加热至 330 °C， 维持该温度 l h， 将反应液冷却至室温， 向其 中加入大量的乙醇， 离心洗涤两次， 得到 EuOCl纳米颗粒。
实施例八
NaDyF4:Yb,Er纳米颗粒的合成： 向油酸 (10 mmol)、十八胺（10 mmol)与十八烯 (20 mmol) 的混合溶剂中加入 0.78 mmol三氟乙酸镝、 0.20 mmol三氟乙酸镱、 0.02 mmol三氟乙酸铒 与 1 mmol三氟乙酸钠， 惰性气体保护下加热至 250 °C， 维持该温度 0.5 h， 将反应液冷却 至室温， 向其中加入大量的乙醇， 离心洗涤四次， 得到 NaDyF4:Yb,Er纳米颗粒。
实施例九
LiTmF4纳米颗粒的合成： 向油酸 C20 mmol)与十八烯 C20 mmol)的混合溶剂中加入 1 mmol三氟乙酸锂与 1 mmol三氟乙酸铥，惰性气体保护下加热至 320 °C，维持该温度 15 h， 将反应液冷却至室温， 向其中加入大量的乙醇， 离心洗涤六次， 得到 LiTmF4纳米颗粒。
实施例十
KYb2F7纳米颗粒的合成： 向油酸 C20 mmol)与十八烯 C20 mmol)的混合溶剂中加入 1 mmol三氟乙酸钾与 1 mmol三氟乙酸镱， 惰性气体保护下加热至 310 °C， 维持该温度 2 h， 将反应液冷却至室温， 向其中加入大量的乙醇， 离心洗涤六次， 得到 KYb2F7纳米颗粒。
实施例十一
BaYF5纳米颗粒的合成： 向亚油酸 (10 mmol)、 油酸 (10 mmol)与十八胺 (20 mmol)的混合 溶剂中加入 1 mmol草酸钡与 1 mmol三氟乙酸钇， 惰性气体保护下加热至 340 °C， 维持该 温度 24 h， 将反应液冷却至室温， 向其中加入大量的乙醇， 离心洗涤六次， 得到 BaYF5纳 米颗粒。
实施例十二
颗粒表面包覆柠檬酸： 将实施例一得到的 Gd203纳米颗粒 (0.1 mmol)分散于 5 mL氯仿 中， 加入柠檬酸水溶液 (n/n=20)， 室温下剧烈搅拌至少 6 h。 取上层悬浊液体， 加入大量乙 醇离心， 将所得沉淀分散于纯水中即得纳米颗粒磁共振造影剂。
实施例十三
颗粒表面包覆半胱氨酸：将实施例四得到的 Y203纳米颗粒 (0.1 mmol)分散于 5 mL氯仿 中， 加入半胱氨酸水溶液 (n/n=30)， 室温下剧烈搅拌至少 6 h。 取上层悬浊液体， 加入大量 乙醇离心， 将所得沉淀分散于纯水中即得纳米颗粒磁共振造影剂。
实施例十四
颗粒表面包覆聚乙烯醇： 将实施例六得到的 CeOF纳米颗粒 (0.1 mmol)分散于 10 mL环 己烷中， 加入 10 mL N,N-二甲基甲酰胺与 50 mg四氟硼酸亚硝鎗， 剧烈搅拌不少于 1 h。 取 下层液体， 加入大量甲苯离心， 将所得沉淀再次溶于 10 mL N,N-二甲基甲酰胺， 并加入聚 乙烯醇 50 mg， 搅拌不少于 4 h。 然后向该溶液中加入大量丙酮， 离心， 将所得沉淀分散于 纯水中即得纳米颗粒磁共振造影剂。
实施例十五
颗粒表面包覆聚乙烯亚胺：将实施例五得到的 LaF3纳米颗粒 (0.2 mmol)分散于 10mL环 己烷中， 加入 10 mL N,N-二甲基甲酰胺与 50 mg四氟硼酸亚硝鎗， 剧烈搅拌不少于 1 h。 取 下层液体， 加入大量甲苯离心， 将所得沉淀再次溶于 10 mL N,N-二甲基甲酰胺， 并加入聚 乙烯亚胺 50 mg， 搅拌不少于 4 h。 然后向该溶液中加入大量丙酮， 离心， 将所得沉淀分散 于纯水中即得纳米颗粒磁共振造影剂。
实施例十六
颗粒表面包覆聚乙烯吡咯烷酮： 将实施例八得到的 NaDyF4:Yb,Er纳米颗粒 (0.2 mmol) 分散于 10 mL环己烷中， 加入 10 mL N,N-二甲基甲酰胺与 50 mg四氟硼酸亚硝鎗， 剧烈搅 拌不少于 l h。 取下层液体， 加入大量甲苯离心， 将所得沉淀再次溶于 10 mL N,N-二甲基甲 酰胺， 并加入聚乙烯吡咯烷酮 50 mg， 搅拌不少于 4 h。 然后向该溶液中加入大量丙酮， 离 心， 将所得沉淀分散于纯水中即得纳米颗粒磁共振造影剂。 图 1-图 4是实施例十二得到的稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂在 不同浓度条件下的磁共振图像对比， 所用磁场强度均为 3 T。 图 1所用扫描序列为 1 加权 序列； 图 2所用扫描序列为 加权序列； 图 3所用扫描序列为 ceMRA序列； 图 4所用扫 描序列为 LAVA序列。 由图 1-图 4可以看出， 实施例十二得到的稀土基纳米颗粒磁共振造 影剂在相同浓度的条件下， 成像效果优于临床常用造影剂， 且造影效果随浓度增加而显著 提高（图 1、图 3、图 4中图像越亮表示造影效果越好， 图 2中图像越暗表示造影效果越好）。 需要说明的是， 图 1 中稀土基纳米颗粒磁共振造影剂在较高浓度下图像变暗是由于 "饱和 效应" 的存在， 即此时 T1造影效果已达到极限， 而高浓度下 T2造影效果将增强并部分抵 消 T1造影效果，该结果表明稀土基纳米颗粒磁共振造影剂在浓度低于临床常用造影剂的条 件下即可达到相同的造影效果。 图 5 是实施例十二得到的稀土基纳米颗粒磁共振造影剂与临床五种常用造影剂的弛豫 率对比示意图， 所用磁场强度为 3 T。 由图 5可以看出， 实施例十二得到的稀土基纳米颗粒 磁共振造影剂的纵向和横向弛豫率均高于临床常用造影剂。
图 6 是实施例十二得到的稀土基纳米颗粒磁共振造影剂在不同磁场强度下的弛豫率对 比。 由图 6可以看出， 实施例十二得到的稀土基纳米颗粒磁共振造影剂在高磁场强度和低 磁场强度下均表现出较高的纵向和横向弛豫率。
本发明的稀土基纳米颗粒磁共振造影剂可以显著降低周围质子的弛豫时间， 从而可以 大幅提高局域组织的对比度。 本发明申请所述的稀土基纳米颗粒磁共振造影剂具有弛豫率 高、 体内停留时间较长、 注射剂量低、 稀土离子游离可能性小等特点， 可以有效提高诊断 的准确性及造影剂的安全性。
虽然本发明以前述的实施例公开如上， 然其并非用以限定本发明。 本发明所属技术领 域中的技术人员， 在不脱离本发明的精神和范围内， 当可做些许之更改与润饰。 因此本发 明的保护范围以权利要求书为准。

Claims

权 利 要 求 书
、 一种稀土基纳米颗粒磁共振造影剂， 其特征在于， 其为包覆亲水性配体的稀土基无机纳 米颗粒。
、 根据权利要求 1所述的稀土基纳米颗粒磁共振造影剂， 其特征在于， 所述稀土基无机纳 米颗粒的组成是 1¾0 ， 其中 RE代表稀土元素， M代表碱金属或碱土金属， X代表氟 或氯， 0V/aV/ l， OV/bV/ 1. 5, OV/cV/4; 或者所述稀土基无机纳米颗粒是以所述 MaRE0bX。 为基质进行掺杂的无机化合物。
、 根据权利要求 1所述的稀土基纳米颗粒磁共振造影剂， 其特征在于， 所述稀土元素包括 镧、 铈、 镨、 钕、 钐、 铕、 钆、 铽、 镝、 钬、 铒、 铥、 镱、 镥、 钪和钇中的一种或多种。 、 根据权利要求 1所述的稀土基纳米颗粒磁共振造影剂， 其特征在于， 所述稀土基无机纳 米颗粒的表面包覆配体是下列中的一种或多种： 柠檬酸、 半胱氨酸、 聚乙烯醇、 聚乙烯 亚胺、 聚乙烯吡咯烷酮、 聚丙烯酸。
、 一种权利要求 1所述稀土基纳米颗粒磁共振造影剂的制备方法， 其特征在于， 包括如下 步骤：
1 ) 在高沸点有机溶剂中， 加入一定量的稀土前驱体或者稀土前驱体与非稀土前驱体的 混合物， 得到溶液 A;
2) 对溶液 A抽真空以除去水分， 然后在惰性气体保护下升温至 250-340 V , 维持 15 min-24 h， 然后冷却至室温， 得到溶胶 B;
3) 对溶胶 B进行离心分离， 对所得沉淀物进行洗涤， 再对沉淀物的表面进行亲水性配 体的包覆；
4) 将包覆后的颗粒分散于溶剂中， 即得到造影剂。
、 根据权利要求 5所述的方法， 其特征在于： 所述高沸点有机溶剂指油酸、亚油酸、油胺、 十八烯、 十六胺和十八胺中的一种或多种组成的混合溶剂。
、 根据权利要求 5所述的方法， 其特征在于： 所述稀土前驱体是下列中的一种或多种的混 合： 稀土的氢氧化物、 草酸盐、 乙酸盐、 三氟乙酸盐、 三氯乙酸盐、 乙酰丙酮盐、 苯基 乙酰丙酮盐； 所述非稀土前驱体是下列中的一种或多种的混合： 碱金属与碱土金属的氟 化物、 氢氧化物、 草酸盐、 乙酸盐、 三氟乙酸盐、 三氯乙酸盐、 乙酰丙酮盐、 苯基乙酰 丙酮盐。
、 根据权利要求 5 所述的方法， 其特征在于： 步骤 1 ) 中前驱体与溶剂的摩尔比是 1 : 20-1 : 200； 步骤 2)在 100-140 °C 下进行所述抽真空； 步骤 3) 采用大量乙醇进行洗 涤。 、 根据权利要求 5所述的方法， 其特征在于： 步骤 3 ) 采用的洗涤方式为离心洗涤， 洗涤 次数为 2-6次。
0、 根据权利要求 5所述的方法， 其特征在于： 步骤 4) 所述溶剂为水或生理盐水。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113440623A (zh) * 2021-02-10 2021-09-28 天津市中西医结合医院（天津市南开医院） 一种Au NRs@Gd2O3复合材料的制备方法
CN117089350A (zh) * 2023-07-21 2023-11-21 中国科学院福建物质结构研究所 一种高光效稀土纳米荧光材料及其制备方法和在造影剂中的应用

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104371714B (zh) * 2014-11-28 2016-03-16 赵兵 一种三氧化钼-氧化石墨烯复合材料及其制备方法
CN104371727B (zh) * 2014-11-28 2016-06-22 赵兵 一种水溶性上转换纳米颗粒及其制备方法
CN104371715B (zh) * 2014-11-28 2016-06-22 赵兵 一种水溶性三氧化钼上转换纳米材料及其制备方法
CN104449714B (zh) * 2014-11-28 2016-06-22 赵兵 一种上转换纳米颗粒-氧化石墨烯复合材料及其制备方法
US10714224B2 (en) 2015-01-29 2020-07-14 Framatome Gmbh Method of preparing of irradiation targets for radioisotope production and irradiation target
CN108245689A (zh) * 2016-12-29 2018-07-06 国家纳米科学中心 用于提高核磁共振检测精确度的造影剂、制备方法及应用
GB201915715D0 (en) * 2019-10-30 2019-12-11 Univ Oxford Innovation Ltd Ionic liquids in lithium ion batteries
CN113082228A (zh) * 2021-04-14 2021-07-09 山东建筑大学 一种基于单核多模态成像用于诊断乳腺癌的造影剂
CN114533905A (zh) * 2022-01-14 2022-05-27 南京工业大学 一种可生物降解的t1-mri纳米造影剂及其制备方法
CN114906874B (zh) * 2022-06-17 2023-07-25 中国科学院高能物理研究所 一种氧化铪纳米颗粒及其制备方法和应用
CN115246653B (zh) * 2022-07-12 2023-10-17 中南大学 纳米氧化镝及其制备方法与应用
CN116789160B (zh) * 2023-06-15 2026-04-21 上海大学 一种超小稀土氧化钆纳米材料的制备方法
WO2025244582A1 (en) * 2024-05-20 2025-11-27 National University Of Singapore Metal oxides nanoparticles and uses thereof
CN119551682B (zh) * 2024-11-29 2025-12-05 苏州大学 一种多金属硼酸盐纳米颗粒及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103275722A (zh) * 2013-06-20 2013-09-04 南京大学 一种磁光双模态成像探针稀土纳米微粒及其制法和用途
CN103623436A (zh) * 2012-08-22 2014-03-12 北京万德高科技发展有限公司 生物相容性磁性稀土纳米颗粒、其制备及磁共振成像应用
CN103623435A (zh) * 2012-08-20 2014-03-12 苏州迈格锐意医药科技有限公司 纳米磁共振造影材料和造影剂及其制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0400235D0 (en) * 2004-01-07 2004-02-11 Univ Sunderland Nanoparticles as agents for imaging finger prints
JP2008513053A (ja) * 2004-09-14 2008-05-01 オプトクリツト・アー・ベー 超常磁性ガドリニウム酸化物ナノスケール粒子およびそのような粒子を含む組成物
CA2575649C (en) * 2006-01-25 2015-04-14 University Of Victoria Innovation And Development Corporation Lanthanide rich nanoparticles, and their investigative uses in mri and related technologies
US20130320263A1 (en) * 2012-05-29 2013-12-05 Rutgers, The State University Of New Jersey Surfactant effects on efficiency enhancement of luminescent particles
CN103638532B (zh) * 2013-11-28 2015-07-01 首都医科大学 一种氧化钆靶向磁共振造影剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103623435A (zh) * 2012-08-20 2014-03-12 苏州迈格锐意医药科技有限公司 纳米磁共振造影材料和造影剂及其制备方法
CN103623436A (zh) * 2012-08-22 2014-03-12 北京万德高科技发展有限公司 生物相容性磁性稀土纳米颗粒、其制备及磁共振成像应用
CN103275722A (zh) * 2013-06-20 2013-09-04 南京大学 一种磁光双模态成像探针稀土纳米微粒及其制法和用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3150232A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113440623A (zh) * 2021-02-10 2021-09-28 天津市中西医结合医院（天津市南开医院） 一种Au NRs@Gd2O3复合材料的制备方法
CN117089350A (zh) * 2023-07-21 2023-11-21 中国科学院福建物质结构研究所 一种高光效稀土纳米荧光材料及其制备方法和在造影剂中的应用

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