WO2020093642A1 - 含金属原子簇的磁性氧化铁纳米颗粒及其制备和应用 - Google Patents

含金属原子簇的磁性氧化铁纳米颗粒及其制备和应用 Download PDF

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WO2020093642A1
WO2020093642A1 PCT/CN2019/078427 CN2019078427W WO2020093642A1 WO 2020093642 A1 WO2020093642 A1 WO 2020093642A1 CN 2019078427 W CN2019078427 W CN 2019078427W WO 2020093642 A1 WO2020093642 A1 WO 2020093642A1
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iron oxide
metal atom
oxide nanoparticles
iron
magnetic
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French (fr)
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樊海明
刘晓丽
彭明丽
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西安超磁纳米生物科技有限公司
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Publication of WO2020093642A1 publication Critical patent/WO2020093642A1/zh

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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
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    • H01F1/0036—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties showing low dimensional magnetism, i.e. spin rearrangements due to a restriction of dimensions, e.g. showing giant magnetoresistivity
    • H01F1/0045—Zero dimensional, e.g. nanoparticles, soft nanoparticles for medical/biological use
    • H01F1/0054—Coated nanoparticles, e.g. nanoparticles coated with organic surfactant
    • H—ELECTRICITY
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    • H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
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    • H01F1/058—Alloys characterised by their composition containing rare earth metals and magnetic transition metals, e.g. SmCo5 and IVa elements, e.g. Gd2Fe14C
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    • H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
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    • H01F1/032—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity of hard-magnetic materials
    • H01F1/10—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity of hard-magnetic materials non-metallic substances, e.g. ferrites, e.g. [(Ba,Sr)O(Fe2O3)6] ferrites with hexagonal structure
    • H01F1/11—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity of hard-magnetic materials non-metallic substances, e.g. ferrites, e.g. [(Ba,Sr)O(Fe2O3)6] ferrites with hexagonal structure in the form of particles
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    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y25/00—Nanomagnetism, e.g. magnetoimpedance, anisotropic magnetoresistance, giant magnetoresistance or tunneling magnetoresistance
    • 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
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    • C01P2002/54—Solid solutions containing elements as dopants one element only
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    • C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
    • C01P2002/72—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by d-values or two theta-values, e.g. as X-ray diagram
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
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    • C01P2004/03—Particle morphology depicted by an image obtained by SEM
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    • C01—INORGANIC CHEMISTRY
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    • C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
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    • C01—INORGANIC CHEMISTRY
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    • C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer
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    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/42—Magnetic properties

Definitions

  • the invention and the technical field of magnetic iron oxide specifically relate to a magnetic iron oxide nanoparticle containing metal atom clusters and its preparation and application.
  • iron oxide as an important magnetic material, has good biocompatibility, except for magnetic fluids, catalysts and magnetic recording materials. In terms of application, it also has a wide range of applications in biological separation, detection, targeted medicine and medical imaging. It has been used in preclinical or clinical iron supplements (such as ferumoxytol), magnetic resonance imaging contrast agents (such as Combidex ), Magnetic hyperthermia agents (such as NanoTherm approved by European regulation) and drug carriers.
  • preclinical or clinical iron supplements such as ferumoxytol
  • magnetic resonance imaging contrast agents such as Combidex
  • Magnetic hyperthermia agents such as NanoTherm approved by European regulation
  • the magnetic iron oxide particles prepared by the above method have uniform size, morphology and stable superparamagnetic properties, these magnetic nanoparticles have low magnetic field response in magnetic resonance imaging, cell tracking and magnetothermal conversion efficiency, and imaging sensitivity Insufficient, low magnetothermal conversion efficiency and other problems. Therefore, how to improve the stability and magnetic properties of iron oxide nanoparticles is still one of the hot spots in the research of magnetic nanomaterials.
  • Common methods for improving the magnetic properties of magnetic iron oxide nanoparticles include: preparing spinel-type structured ferrite nanoparticles; preparing cubic-shaped ferrite nanoparticles; or forming ferrite with an exchange coupling effect Core / shell nanostructures and other strategies.
  • the particles prepared by these methods have some shortcomings, such as: the ferrite or cubic shape has limited improvement in magnetic properties and corresponding application performance; and for the ferrite core / shell nanostructure, due to the complicated preparation process, the reaction The process is not easy to control.
  • the ferrite or cubic shape has limited improvement in magnetic properties and corresponding application performance; and for the ferrite core / shell nanostructure, due to the complicated preparation process, the reaction The process is not easy to control.
  • the present invention provides magnetic iron oxide nanoparticles containing metal atom clusters and preparation and applications thereof.
  • Magnetic iron oxide nanoparticles containing metal atom clusters the metal atom clusters are embedded in the iron oxide crystal matrix, and the content of the metal atom clusters in the magnetic iron oxide nanoparticles containing metal atom clusters is 0.1 -15%.
  • the particle size of the metal atom cluster is 0.2-5 nm, and the particle size range of the iron oxide crystal matrix is 2-100 nm.
  • the iron oxide nanoparticles have a particle size range of 3-50 nm.
  • the metal atom cluster is an Mx atom cluster formed by a metal atom M, and the range of x is 3-100, and the M is one or two of rare earth metals, fourth-period transition metals and post-transition metals .
  • the M is one or more of Fe, Co, Ni, Mn, Ga, Nd, Sm, Tb, Dy, Ho, Er, Tm, Yb, Ce.
  • the magnetic iron oxide nanoparticles containing metal atom clusters provided by the present invention not only have the advantages of good biocompatibility and stable properties due to the interaction between the metal atom clusters and the iron oxide matrix, but also further improve the saturation magnetization strength.
  • the present invention also provides a method for preparing magnetic iron oxide nanoparticles containing metal atom clusters, which is characterized by comprising the following steps:
  • the metal precursor is an iron-containing organic complex
  • the metal atom cluster precursor is a metal-organic complex
  • the iron-containing organic complex includes: iron erucate, iron acetylacetonate Fe (acac) 3 , oil Iron acid Fe (OA) 3 , pentacarbonyl iron Fe (CO) 5 , nitrosohydroxyaniline iron FeCup 3
  • the metal organic complex includes: acetylacetone iron Fe (acac) 3 , iron oleate Fe ( OA) 3 , iron pentacarbonyl Fe (CO) 5 , nitrosohydroxyaniline iron FeCup 3 , Co 2 (CO) 8 , Co (acac) 2 , Ni (OOCCH 3 ) 2 , Ni (acac) 2 , Rare earth complex of oleic acid and rare earth complex of acetylacetone.
  • the molar ratio of the organic acid to the organic amine is 1: 0.5-10
  • the volume ratio of the organic acid to the organic solvent is 1: 1-100
  • the volume ratio of the organic amine to the organic solvent is 1: 1 -100
  • the concentration of the metal precursor is 0.01-1 mol / L.
  • the organic acid is an organic acid with a carbon chain length of 6-25
  • the organic amine is an organic amine with a carbon chain length of 6-25
  • the organic solvent is a reducing solvent.
  • the organic acid is one of oleic acid, stearic acid and erucic acid
  • the organic amine is one of oleylamine and octadecylamine
  • the organic solvent is trioctylamine and tributylamine One of amine, 1,2-hexadecanediol, and octylamine.
  • the reaction temperature in S2 is 200-360 ° C, and the reaction time is 0.5-8h.
  • the preparation method of the magnetic iron oxide nanoparticles containing metal atom clusters provided by the present invention is based on the metal precursor high-temperature pyrolysis method, through the reduction or doping of the solvent to form the metal atoms embedded in the iron oxide crystals Clusters, thereby obtaining magnetic iron oxide nanoparticles containing metal atom clusters, with simple and controllable characteristics.
  • the invention provides the application of magnetic iron oxide nanoparticles containing metal atom clusters, which can be applied to the fields of magnetic resonance imaging, long-term cell tracking and magnetic nanoparticle imaging.
  • the magnetic iron oxide nanoparticles containing metal atom clusters of the present invention are magnetic nanoparticles in which metal atom clusters are embedded in iron oxide crystals. Due to the chimerism of the metal atom clusters, the magnetic properties of the magnetic iron oxide particles are obtained Obviously improved, and the iron oxide matrix fully guarantees the stability of the properties of the nanoparticles, so it can be better applied in the field of biomedical detection and treatment; 2.
  • the present invention uses the method of metal precursor pyrolysis, by controlling the reactants The concentration, reaction time and reaction temperature can control the size and morphology of the nanoparticles. 3.
  • the magnetic iron oxide nanoparticles containing metal atom clusters of the present invention can be used in fields such as magnetic resonance imaging, long-term cell tracking, and magnetic nanoparticle imaging, and have important practical significance.
  • Example 1 is a transmission electron microscope (TEM) image of magnetic iron oxide nanoparticles containing elemental iron atom clusters according to Example 1 of the present invention
  • Figure 2 shows the magnetic iron oxide nanoparticles containing elemental iron clusters in Example 1 of the present invention.
  • HRTEM High resolution transmission electron microscope
  • Fig. 3 shows the magnetic iron oxide nanoparticles containing elemental iron atom clusters in Example 1 of the present invention.
  • SAED selected area electron diffraction
  • Figure 4 shows the magnetic iron oxide nanoparticles containing elemental iron clusters in Example 1 of the present invention.
  • XRD X-ray diffraction
  • Example 5 is a hysteresis loop of magnetic iron oxide nanoparticles containing elemental iron atom clusters according to Example 1 of the present invention.
  • the invention relates to magnetic iron oxide nanoparticles containing metal atom clusters and preparation methods and applications thereof.
  • metal oxide precursors of iron oxide, organic acids, and organic amines are dissolved in an organic solvent in proportion to form a uniform reaction system; After the reaction system is heated to 150-350 ° C in an inert gas atmosphere, a metal atom cluster precursor is added, and the reaction is heated and refluxed until the precursor is completely decomposed to obtain magnetic nanoparticles containing metal atom clusters;
  • the clustered magnetic nanoparticles are used in magnetic resonance imaging, long-term cell tracking, and magnetic nanoparticle imaging.
  • the metal precursor is an iron-containing organic complex, including: iron erucate, iron acetylacetonate Fe (acac) 3 , iron oleate Fe (OA) 3 , iron pentacarbonyl Fe (CO) 5 , FeCup 3 nitrosohydroxyaniline iron, but not limited to this.
  • the metal cluster precursors are metal organic complexes, including iron organic complexes, specifically including iron acetylacetonate Fe (acac) 3 , iron oleate Fe (OA) 3 , iron pentacarbonyl Fe (CO) 5 , Nitrohydroxyaniline FeCup 3 ; cobalt organic complexes, including Co 2 (CO) 8 and Co (acac) 2 ; nickel organic complexes, including Ni (OOCCH 3 ) 2 and Ni (acac) 2 , Gadolinium organic complexes: Gd (OA) 3 , Gd (acac) 3 .
  • the metal cluster precursor is not limited to this.
  • the organic acid is an organic acid with a carbon chain length of 6-25, specifically one of oleic acid, stearic acid, and erucic acid;
  • the organic amine is a carbon chain length of 6-25
  • the organic amine is specifically one of oleylamine and octadecylamine, and the organic solvent is a reducing solvent, specifically one of trioctylamine, tributylamine, 1,2-hexadecanediol, and octylamine .
  • the composition of the iron oxide is (Fe 2 O 3 ) r (Fe 3 O 4 ) 1-r , where r is 0 ⁇ 1.
  • iron cluster iron oxide nanoparticles Iron cluster iron oxide nanoparticles (Iron cluster iron oxide, ICIO): iron acetylacetone Fe (acac) 3 (0.4 mmol), oleic acid (6 mmol), oleylamine (6 mmol), Trioctylamine (30 mL) was stirred under a nitrogen atmosphere to obtain a homogeneous mixture. The mixture was heated to 200 ° C for 1 h, and then the nitrogen flow was increased to add iron acetylacetonate Fe (acac) 3 (0.05 mmol) and heated to 340 ° C under reflux for 2 h to obtain a dark brown mixture. The dark brown mixture was naturally cooled to room temperature.
  • Figure 1 is a transmission electron microscope image.
  • Figure 2 is a high-resolution transmission electron microscope image. The lattice fringes can be seen from Fig.
  • FIG. 5 is the VSM characterization results, which shows that the ICIO prepared in this example has elemental iron atom clusters embedded in the iron oxide crystal, so the stability is good, After the sample is left for at least 1 year, the saturation magnetization value is determined to be as high as 120 emu / g, and the iron oxide particles prepared without iron clusters under the same conditions have a saturation magnetization value of only 60 emu / g, further illustrating the method of the present invention Prepared There are clusters of elemental iron magnetic iron oxide nanoparticles having an extremely high saturation magnetization value, and stable, long-term storage.
  • ⁇ T / ⁇ t is the initial slope in the heating curve.
  • mFe is the concentration of iron atoms in the magnetic nanoparticle solution.
  • the test results of the magnetocaloric instrument in this example found that the aqueous solution of magnetic iron oxide nanoparticles containing iron clusters (ICIO) and magnetic iron oxide nanoparticles containing no iron clusters (SPIO) after applying a magnetic field for 30 seconds respectively 27.6oC rose to 44.2 oC and 27.8oC, the calculated SAR values are: 25600W / g and 228, respectively W / g fully shows that the magnetic-heat conversion efficiency of magnetic iron oxide nanoparticles containing iron clusters is much higher than that of magnetic iron oxide nanoparticles not containing iron clusters at the same concentration.
  • the magnetic iron oxide nanoparticles (ICIO) containing iron clusters prepared in Example 1 and the magnetic iron oxide nanoparticles (SPION) containing no iron clusters were dispersed in agarose gel so that their Fe concentrations were 0.01, 0.025, 0.05, 0.1, 0.25, 0.5 mM. Separately, take 15 mL into 20 mL glass vials, take agarose gel as the control sample, and scan with 7 T small animal magnetic resonance imaging system (BioSpec 70/20 USR, Bruker, Germany).
  • iron magnetic iron oxide nanoparticles (Icio) of 2 clusters is no iron magnetic iron oxide nanoparticles (of SPION) of 2 r 5 times or more, indicating that the iron-containing magnetic iron oxide nanoparticles clusters MRI imaging The performance is much higher than that of magnetic iron oxide nanoparticles without iron clusters.
  • the magnetic iron oxide nanoparticles containing iron clusters prepared in Example 1 were used for magnetic nanoparticle imaging, using MPI Scanner (Magnetic Insight Inc, MOMENTUMTM Imager), frequency is 45 KHz, magnetic gradient intensity (magnetic gradient strenght) is 5.7 T / m, and the data is processed with VivoQuant software.
  • MPI Scanner Magnetic Insight Inc, MOMENTUMTM Imager
  • frequency is 45 KHz
  • magnetic gradient intensity magnetic gradient strenght
  • the data is processed with VivoQuant software.
  • the signal intensity measured at the mg / ml concentration can reach 1169, while the signal intensity of the magnetic iron oxide nanoparticles without iron clusters is only 192.
  • the signal intensity of the magnetic iron oxide nanoparticles with iron clusters is a common magnetic iron oxide nanoparticle contrast agent 6 times better imaging performance.

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Abstract

提供一种含金属原子簇的磁性氧化铁纳米颗粒，其中金属原子簇嵌合在氧化铁晶体基质中，且金属原子簇的含量占比为0.1-15％。还提供该纳米颗粒的制备方法，包括将氧化铁的金属前驱体、有机酸、有机胺溶于有机溶剂中形成均匀的反应体系，然后将反应体系在惰性气体氛围内加热到150-350℃后，加入金属原子簇前驱体，升温回流反应至金属原子簇前驱体全部分解即可。该纳米颗粒由于金属原子簇的嵌合使得磁性氧化铁颗粒的磁学性质得到提高，而氧化铁又充分保证了纳米颗粒性质的稳定性，因而能够更好的应用于生物医学检测与治疗等领域。

Description

含金属原子簇的磁性氧化铁纳米颗粒及其制备和应用 技术领域
本发明及磁性氧化铁技术领域 ，具体涉及一种含金属原子簇的磁性氧化铁纳米颗粒及其制备和应用。
背景技术
近年来，磁性纳米颗粒的研究在各个学科领域都引起了人们的广泛兴趣，其中氧化铁作为一种重要的磁性材料，具有很好的生物相容性，除了在磁流体、催化剂和磁记录材料方面的应用，在生物分离、检测、靶向药物和医学成像方面也具有广泛的用途，已经在临床前或临床上被用于补铁剂（如ferumoxytol），磁共振成像造影剂（如Combidex ），磁热疗剂（如欧洲监管批准的NanoTherm）以及药物载体。为了制备具有良好的生物学相容性、磁学性质优良且稳定磁性氧化铁纳米颗粒，美国专利号6,262,129，中国发明专利CN200580040484.1发明专利CN200480044382.2发明专利CN02820174.4以及Alivisatos课题组发表的J. Am. Chem. Soc.,1999, 121(49), 11595；Sun课题组发表的J. Am. Chem. Soc.，2002,124, 8204；J. Am. Chem. Soc., 2004, 126(1), 273；Hyeon课题组发表的J. Am. Chem. Soc., 2001, 123(51), 12798；Nat. Mater., 2004, 3(12), 891；Peng，X. Chem. Mater., 2004,16, 393等文件中都公开了利用高温热解法，制备均匀铁氧体、铁氧化物及铁及其合金等磁性纳米颗粒的方法。
虽然通过以上方法制备的磁性氧化铁颗粒具有均一尺寸、形貌和稳定的超顺磁学性质，然而这些磁性纳米颗粒在磁共振成像、细胞跟踪以及磁热转换效率中存在磁场响应低，成像灵敏度不足，磁热转换效率低性能等问题。因此如何提高氧化铁纳米颗粒的稳定性和磁学性能依然是目前磁性纳米材料研究的热点之一。常见的提高磁性氧化铁纳米颗粒的磁学性质的方法包括：制备尖晶石型结构结构的铁氧体纳米颗粒；制备立方形状的铁氧体纳米颗粒；或者形成具有交换耦合作用的铁氧体核/壳纳米结构等策略。
 技术问题
这些方法制备的颗粒均有一些不足，比如：铁氧体或者立方形貌对磁学性质和相应的应用性能提高有限；而对于铁氧体核/壳纳米结构，由于其制备过程复杂，使得反应过程不易控制。
技术方案
为了满足生物医学应用对高饱和磁化强度且性质稳定磁性氧化铁纳米颗粒的需求，本发明提供了一种含金属原子簇的磁性氧化铁纳米颗粒及其制备和应用。
为达到上述目的，本发明的技术方案如下：
含金属原子簇的磁性氧化铁纳米颗粒，所述金属原子簇嵌合在氧化铁晶体基质中，且所述金属原子簇在含金属原子簇的磁性氧化铁纳米颗粒中的的含量占比为0.1-15%。
其中，所述金属原子簇的粒径大小为0.2-5 nm，所述氧化铁晶体基质的粒径范围为2-100 nm。
优选地，所述氧化铁纳米颗粒粒径范围为3-50 nm。
优选地，所述金属原子簇是由金属原子M形成的Mx原子簇，x的范围为3-100，所述M为稀土金属、第四周期过渡金属和后过渡金属中的一种或两种。
更优选地，所述M为Fe、Co、Ni、Mn、Ga、Nd、Sm、Tb、Dy、Ho、Er、Tm、Yb、Ce中的一种或多种。
本发明提供的含金属原子簇的磁性氧化铁纳米颗粒，由于金属原子簇与氧化铁基质的相互作用，使得磁性纳米颗粒不仅具有生物相容性好，性质稳定的优点，而且进一步提高了饱和磁化强度。
为了实现上述目的，本发明还提供了含金属原子簇的磁性氧化铁纳米颗粒的制备方法，其特征在于，包括以下步骤：
S1、将氧化铁的金属前驱体、有机酸、有机胺按照比例溶于有机溶剂中形成均匀的反应体系；
S2、将S1中所述反应体系在惰性气体氛围内加热到150-350℃后，加入金属原子簇前驱体，升温回流反应至前驱体全部分解，即得到含金属原子簇的磁性纳米颗粒。
其中，所述金属前驱体为含铁有机配合物，所述金属原子簇前驱体为金属有机配合物；所述含铁有机配合物包括：芥酸铁、乙酰丙酮铁 Fe(acac)3 、油酸铁Fe(OA)3 、五羰基合铁Fe(CO)5 、亚硝基羟基苯胺合铁FeCup 3 ；所述金属有机配合物包括：乙酰丙酮铁Fe(acac)3 、油酸铁Fe(OA) 3 、五羰基合铁Fe(CO)5 、亚硝基羟基苯胺合铁FeCup3、Co2(CO)8 、Co(acac) 2 、Ni(OOCCH3) 2 、Ni(acac)2 、油酸稀土配合物、乙酰丙酮稀土配合物。
其中，所述有机酸与有机胺的摩尔比为1:0.5-10，所述有机酸与有机溶剂的体积比为1:1-100，所述有机胺与有机溶剂的体积比为1:1-100，所述金属前驱体的浓度为0.01-1 mol/L。
优选地，所述有机酸为碳链长度介于6-25之间的有机酸，所述有机胺为碳链长度介于6-25之间的有机胺，所述有机溶剂为还原性溶剂。
更优选地，所述有机酸为油酸、硬脂酸、芥酸中的一种，所述有机胺为油胺、十八胺中的一种，所述有机溶剂为三辛胺、三丁胺、1,2-十六二醇、辛胺中的一种。
其中，S2中反应温度为200-360℃，反应时间为0.5-8h。
本发明提供的含金属原子簇的磁性氧化铁纳米颗粒的制备方法，是在金属前驱体高温热解方法的基础上，通过溶剂的还原作用或掺杂，形成嵌入在氧化铁晶体中的金属原子簇，从而得到含有金属原子簇的的磁性氧化铁纳米颗粒，具有简单可控的特点。
本发明提供含金属原子簇的磁性氧化铁纳米颗粒的应用，可以应用于磁共振成像、细胞长期跟踪以及磁纳米颗粒成像领域。
 有益效果
1、本发明的含金属原子簇的磁性氧化铁纳米颗粒是一种将金属原子簇嵌入到氧化铁晶体中的磁性纳米颗粒，由于金属原子簇的嵌合使得磁性氧化铁颗粒的磁学性质得到明显的提高，而氧化铁基质又充分保证了纳米颗粒性质的稳定性，因而能够更好的应用于生物医学检测与治疗等领域；2、本发明利用金属前驱热解的方法，通过控制反应物浓度、反应时间和反应温度，可以对纳米颗粒尺寸以及形貌进行控制。3、本发明的含金属原子簇的磁性氧化铁纳米颗粒可以应用于磁共振成像、细胞长期跟踪以及磁纳米颗粒成像等领域，具有重要的现实意义。
附图说明
图1为本发明实施例1的 含 单质铁原子簇的磁性氧化铁纳米颗粒 的 透射电镜（TEM）图；
图 2 为 本发明实施例1的 含 单质铁原子簇的磁性氧化铁纳米颗粒 的的 高分辨透射电镜（HRTEM）图；
图 3 为 本发明实施例1的 含 单质铁原子簇的磁性氧化铁纳米颗粒 的 选区电子衍射（SAED）图；
图 4 为 本发明实施例1的 含 单质铁原子簇的磁性氧化铁纳米颗粒 的 X射线衍射（XRD）图；
图 5 为 本发明实施例1的 含 单质铁原子簇的磁性氧化铁纳米颗粒 的磁滞回线。
 最佳实施例
本发明涉及含金属原子簇的磁性氧化铁纳米颗粒及其制备方法和应用，首先将氧化铁的金属前驱体、有机酸、有机胺按照比例溶于有机溶剂中形成均匀的反应体系；然后将所述反应体系在惰性气体氛围内加热到150-350℃后，加入金属原子簇前驱体，升温回流反应至前驱体全部分解，即得到含金属原子簇的磁性纳米颗粒；最后将得到的含金属原子簇的磁性纳米颗粒应用于磁共振成像、细胞长期跟踪以及磁纳米颗粒成像等领域。
在本发明中，所述金属前驱体为含铁有机配合物，包括：芥酸铁、乙酰丙酮铁Fe(acac) 3 、油酸铁Fe(OA) 3 、五羰基合铁Fe(CO) 5 、亚硝基羟基苯胺合铁FeCup 3 ，但是并不局限于此。
所述金属原子簇前驱体为金属有机配合物，包括铁有机配合物，具体包括乙酰丙酮铁Fe(acac) 3 、油酸铁Fe(OA) 3 、五羰基合铁Fe(CO) 5 、亚硝基羟基苯胺合铁FeCup 3 ；钴有机配合物，具体包括Co 2 (CO) 8 、Co(acac) 2 ；镍有机配合物，具体包括：Ni(OOCCH 3 ) 2 、Ni(acac) 2 、钆有机配合物：Gd(OA) 3 、Gd(acac) 3 。所述金属原子簇前驱体并不局限于此。
所述有机酸为碳链长度介于6-25之间的有机酸，具体为油酸、硬脂酸、芥酸中的一种；所述有机胺为碳链长度介于6-25之间的有机胺具体为油胺、十八胺中的一种，所述有机溶剂为还原性溶剂，具体为三辛胺、三丁胺、1,2-十六二醇、辛胺中的一种。
所述氧化铁的成分为(Fe2O3)r(Fe3O4)1-r，其中r 为0~1。
接下来通过具体实施例对本发明进行详细说明。
实施例1
含铁原子簇的磁性氧化铁纳米颗粒（Iron cluster iron oxide, ICIO）的制备方法：将乙酰丙酮铁 Fe(acac)3（0.4 mmol），油酸（6 mmol），油胺（6 mmol），三辛胺（30 mL），在氮气氛围下搅拌充分得到均匀的混合物。将混合物加热到200℃保持1 h，然后加大氮气流量加入乙酰丙酮铁Fe(acac)3（0.05 mmol）再加热到340 ℃回流2 h得到黑棕色混合物，将黑棕色混合物自然冷却到室温。取10 mL酒精加到黑棕色混合物中，黑色物质被沉淀，然后进行离心分离，将离心分离得到的黑色物质溶解于10 mL正己烷中，并以5000 rpm转速离心处理10 min 除去未分散的剩余物；离心得到的产物用酒精沉淀，并以5000 rpm转速离心处理10 min 除去溶剂，得到含铁原子簇的磁性氧化铁纳米颗粒。
对制备的含铁原子簇的磁性氧化铁纳米颗粒进行一系列表征，具体是将含铁原子簇的磁性氧化铁纳米颗粒分散在正己烷中，取2 L分散有纳米颗粒的正己烷溶液滴在镀有碳膜的Cu网上，自然干燥后做表征。图1为透射电镜图，从图1中可以看出，单质铁原子簇的磁性氧化铁纳米颗粒大小形貌均一，具有单分散性，尺寸在 20 nm 左右；图2是高分辨透射电镜图，从图2中可以看到晶格fringes，表明此纳米颗粒结晶度很高，晶格间距为 0.258 nm，符合（311）面晶面垂直间距，表明该纳米颗粒为氧化铁纳米颗粒，更重要的是，发现有Fe原子簇镶嵌在氧化铁纳米颗粒晶格中；图3为选区电子衍射，从图3中进一步证实氧化铁颗粒中有Fe原子簇；图4为XRD图，表明此纳米颗粒结晶很好，有Fe相的峰和反结晶Fe3O4相的峰；图5为VSM表征结果，说明本实施例制备的ICIO由于有单质铁原子簇嵌入氧化铁晶体内，因此稳定性好，样品放置至少1年后，测定其饱和磁化值仍高达120 emu/g，而相同条件下制备的不含铁原子簇的氧化铁颗粒，其饱和磁化值只有60 emu/g，进一步说明本发明方法制备的含有单质铁原子簇的磁性氧化铁纳米颗粒具有极其高的饱和磁化值，且性质稳定，可以长期保存。
 实施例
实施例2
含铁原子簇的磁性氧化铁纳米颗粒（Iron cluster iron oxide, ICIO）的制备方法：将油酸铁Fe(OA) 3 （0.4 mmol），芥酸（8 mmol），十八胺（4 mmol），辛胺（40 mL），在氮气氛围下搅拌充分得到均匀的混合物。将混合物加热到150 ℃加入 保持1 h，然后加大氮气流量加入乙酰丙酮铁Fe(acac) 3 （0.05 mmol）再加热到200 ℃ 回流8h得到黑棕色混合物，将黑棕色混合物自然冷却到室温。后续处理过程与实施例1相同。
实施例3
含铁原子簇的磁性氧化铁纳米颗粒（Iron cluster iron oxide, ICIO）的制备方法：五羰基合铁Fe(CO) 5 （0.04 mmol），硬脂酸（1mmol），油胺（10mmol），三丁胺（40 mL），在氮气氛围下搅拌充分得到均匀的混合物。将混合物加热到300 ℃加入 保持1 h，然后加大氮气流量加入油酸铁Fe(OA) 3 （0.005 mmol）再加热到360 ℃ 回流0.5 h得到黑棕色混合物，将黑棕色混合物自然冷却到室温。后续处理过程与实施例1相同。
实施例 4
含钴原子簇的磁性氧化铁纳米颗粒（Cobalt cluster iron oxide, CCIO）的制备方法：将乙酰丙酮铁 Fe(acac) 3 （8 mmol），油酸（6 mmol），油胺（6 mmol），三辛胺（30 mL），在氮气氛围下搅拌充分得到均匀的混合物。将混合物加热到200 ℃ 保持1 h，然后加大氮气流量加入羰基钴 Co 2 (CO) 8 （1 mmol）再加热到340 ℃ 回流2 h得到黑棕色混合物，将黑棕色混合物自然冷却到室温后进行后续处理。后续处理过程与实施例1相同，后续处理后即得到含钴原子簇的磁性氧化铁纳米颗粒。
实施例 5
含镍原子簇的磁性氧化铁纳米颗粒（ Nickel cluster iron oxide, NCIO）的制备方法：将乙酰丙酮铁 Fe(acac) 3 （8 mmol），油酸（6 mmol），油胺（6 mmol），三辛胺（30 mL），在氮气氛围下搅拌充分得到均匀的混合物。将混合物加热到200 ℃ 保持1 h，然后加大氮气流量加入乙酰丙酮镍Ni(acac) 2 （1 mmol），再加热到340 ℃ 回流2 h得到黑棕色混合物，将黑棕色混合物自然冷却到室温后进行后续处理。后续处理过程与实施例1相同，后续处理后即得到含镍原子簇的磁性氧化铁纳米颗粒。
实施例6
含铁镍原子簇的磁性氧化铁纳米颗粒的制备方法：将乙酰丙酮铁 Fe(acac) 3 （8 mmol），油酸（6 mmol），油胺（6 mmol），三辛胺（30 mL），在氮气氛围下搅拌充分得到均匀的混合物。将混合物加热到200 ℃ 保持1 h，然后加大氮气流量加入乙酰丙酮镍Ni(acac) 2 （0.5 mmol）、乙酰丙酮铁Fe(acac) 3 （0.5 mmol）再加热到340 ℃ 回流2 h得到黑棕色混合物，将黑棕色混合物自然冷却到室温后进行后续处理。后续处理过程与实施例1相同，后续处理后即得到含钴原子簇的磁性氧化铁纳米颗粒。
实施例7
取1 mL实施例1制备的含铁原子簇磁性氧化铁纳米颗粒（ICIO，20 nm）的水溶液，其中铁含量为 0.1 mg/mL；另取1 mL不含铁原子簇磁性氧化铁纳米颗粒（SPIO，20 nm）的水溶液，其中铁含量同样为 0.1 mg/mL，分别加入到15 mL试管中，并将试管放置于磁热仪的磁线圈里，从而在试管外部加上中频交变磁场（频率为488 kHz，场强为600 Oe），利用光纤热电偶探头来测量温度变化，测定磁性纳米颗粒的比吸收速率（SAR），SAR 的定义是在单位时间内，单位质量的铁在交变磁场中所能产生的热量，单位是瓦特/克（Watt/g），计算如公式（1）所示，该计算值可以评价磁性纳米颗粒的磁热转换效率。本实施例中所用的磁热仪器由深圳市双平电源技术有限公司生产，型号为SPG-10AB-II，该仪器同时还与光纤探头连接，以测试样品溶液的温度。
比吸收速率(SAR)的计算：
实施例7
取1 mL 实施例1制备的 含铁原子簇磁性氧化铁纳米颗粒（ICIO，20 nm）的水溶液，其中铁含量为 0.1 mg/mL；另取1 mL不含铁原子簇磁性氧化铁纳米颗粒（SPIO，20 nm）的水溶液，其中铁含量同样为 0.1 mg/mL，分别加入到15 mL试管中，并将试管放置于磁热仪的磁线圈里，从而在试管外部加上中频交变磁场（频率为488 kHz，场强为600 Oe），利用光纤热电偶探头来测量温度变化，测定磁性纳米颗粒的比吸收速率（SAR），SAR 的定义是在单位时间内，单位质量的铁在交变磁场中所能产生的热量，单位是瓦特/克（Watt/g），计算如公式（1）所示，该计算值可以评价磁性纳米颗粒的磁热转换效率。本实施例中所用的磁热仪器由深圳市双平电源技术有限公司生产，型号为SPG-10AB-II，该仪器同时还与光纤探头连接，以测试样品溶液的温度。
比吸收速率(SAR)的计算：
Figure ZXF16087-appb-I000002
式（1）
其中：C 为水溶液的比热容（Cwater = 4.18 J/(g·℃)），ΔT/Δt为升温曲线中的初始斜率。mFe为磁性纳米颗粒溶液中铁原子的浓度。本实施例中磁热仪器的测试结果发现含有铁原子簇磁性氧化铁纳米颗粒（ICIO）和不含铁原子簇磁性氧化铁纳米颗粒（SPIO）水溶液在加磁场30秒后，水溶液的温度分别由27.6ºC上升至44.2 ºC和27.8ºC，计算得到SAR值分别为：25600W/g和228 W/g，充分说明含有铁原子簇磁性氧化铁纳米颗粒磁热转换效率远远高于相同浓度的不含有铁原子簇磁性氧化铁纳米颗粒。
实施例8
将 实施例1制备的 含有铁原子簇磁性氧化铁纳米颗粒（ICIO）和不含铁原子簇磁性氧化铁纳米颗粒（SPION）分散在琼脂糖凝胶中，使其Fe浓度分别为0.01, 0.025, 0.05, 0.1, 0.25, 0.5 mM。分别取15 mL装入20 mL玻璃瓶中，以琼脂糖凝胶为对照样品，使用7 T小动物磁共振成像仪（BioSpec 70/20 USR, Bruker, Germany）进行扫描。MRI扫描参数为：TR= 2900 ms, TE= 40.06 ms, field of view= 35 mm×35 mm, matrix size= 256×256, flip angle= 90º and NEX= 3。得到样品磁共振扫描图像后，采用Matlab软件，使用Levenberg-Margardt法计算出不同浓度梯度样品的弛豫时间T 2 值，进而求出弛豫速率r 2 =1/T 2 。经计算含有铁原子簇磁性氧化铁纳米颗粒（ICIO）和不含铁原子簇磁性氧化铁纳米颗粒（SPION）的r 2 分别为1060 mM -1 S -1 和185 mM -1 S -1 ，说明含有铁原子簇磁性氧化铁纳米颗粒（ICIO）的r 2 是不含铁原子簇磁性氧化铁纳米颗粒（SPION）的r 2 的5倍以上，说明含铁原子簇磁性氧化铁纳米颗粒MRI的成像性能远远高于不含铁原子簇磁性氧化铁纳米颗粒。
实施例9
将 实施例1制备的 含有铁原子簇磁性氧化铁纳米颗粒用于磁纳米颗粒成像，利用MPI 扫描仪（Magnetic Insight Inc, MOMENTUMTM Imager），频率是45 KHz、磁梯度强度（magnetic gradient strenght ）为5.7 T/m，数据用VivoQuant 软件处理。在 0.5 mg/ml浓度下测得样品信号强度可以达到1169，而不含铁原子簇磁性氧化铁纳米颗粒信号强度只有192，含有铁原子簇磁性氧化铁纳米颗粒信号强度是普通磁性氧化铁纳米颗粒造影剂的6倍，成像性能优越。
应当指出，对于本领域的普通技术人员来说，在不脱离本 发明 创造构思的前提下，还可以做出若干变形和改进，这些都属于本 发明 的保护范围。

Claims (10)

  1. 含金属原子簇的磁性氧化铁纳米颗粒，其特征在于，所述金属原子簇嵌合在氧化铁晶体基质中，且所述金属原子簇在含金属原子簇的磁性氧化铁纳米颗粒中的含量占比为0.1-15%。
  2. 根据权利要求1所述的含金属原子簇的磁性氧化铁纳米颗粒，其特征在于，所述金属原子簇的粒径大小为0.2-5 nm，所述氧化铁晶体基质的粒径范围为2-100 nm。
  3. 根据权利要求1所述的含金属原子簇的磁性氧化铁纳米颗粒，其特征在于，所述金属原子簇是由金属原子M形成的Mx原子簇，x的范围为3-100，所述M为稀土金属、第四周期过渡金属和后过渡金属中的一种或两种。
  4. 根据权利要求3所述的含金属原子簇的磁性氧化铁纳米颗粒，其特征在于，所述M为Fe、Co、Ni、Mn、Ga、Nd、Sm、Tb、Dy、Ho、Er、Tm、Yb、Ce中的一种或两种。
  5. 权利要求1-4任一项所述的含金属原子簇的磁性氧化铁纳米颗粒的制备方法，其特征在于，包括以下步骤：
    S1、将氧化铁的金属前驱体、有机酸、有机胺按照比例溶于有机溶剂中形成均匀的反应体系；
    S2、将S1中所述反应体系在惰性气体氛围内加热到150-350℃后，加入金属原子簇前驱体，升温回流反应至金属原子簇前驱体全部分解，即得到含金属原子簇的磁性纳米颗粒。
  6. 根据权利要求5所述的含金属原子簇的磁性氧化铁纳米颗粒的制备方法，其特征在于，所述金属前 驱体 为含铁有机配合物，所述金属原子簇前 驱体 为金属有机配合物； 其中，所述含铁有机配合物包括：芥酸铁、乙酰丙酮铁Fe(acac) 3 、油酸铁Fe(OA) 3 、五羰基合铁Fe(CO) 5 、亚硝基羟基苯胺合铁FeCup 3；其中，所述金属有机配合物包括：乙酰丙酮铁Fe(acac) 3 、油酸铁Fe(OA) 3 、五羰基合铁Fe(CO) 5 、亚硝基羟基苯胺合铁FeCup 3 、Co 2 (CO) 8 、Co(acac) 2 、Ni(OOCCH 3 ) 2 、Ni(acac) 2 、油酸稀土配合物、乙酰丙酮稀土配合物。
  7. 根据权利要求5所述的含金属原子簇的磁性氧化铁纳米颗粒的制备方法，其特征在于，所述有机酸与有机胺的摩尔比为1:0.5-10；所述有机酸与有机溶剂的体积比为1:1-100；所述有机胺与有机溶剂的体积比为1:1-100；所述金属前驱体的浓度为0.01-1 mol/L。
  8. 根据权利要求7所述的含金属原子簇的磁性氧化铁纳米颗粒的制备方法，其特征在于，所述有机酸为碳链长度介于6-25之间的有机酸，所述有机胺为碳链长度介于6-25之间的有机胺，所述有机溶剂为还原性溶剂。
  9. 根据权利要求5所述的含金属原子簇的磁性氧化铁纳米颗粒的制备方法，其特征在于，S2中反应温度为200-360 ℃，反应时间为0.5-8h。
  10. 含金属原子簇的磁性氧化铁纳米颗粒的应用，其特征在于，将权利要求1-4任一所述的含金属原子簇的磁性氧化铁纳米颗粒用于共振成像、细胞长期跟踪以及磁纳米颗粒成像领域。
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