CN102078623B - Amorphous state iron-based nano magnetic resonance contrast agent material and preparation method thereof - Google Patents

Abstract

The invention relates to the field of amorphous nanometer materials, and discloses a preparation method of an amorphous iron-based nanometer magnetic resonance contrast agent material. The technical scheme is: (1) dissolving the ferrous salt, the divalent manganese salt or the divalent nickel salt, and the coating agent to form solution I; (2) adding the reducing agent solution dropwise to the solution I under anaerobic conditions, Ultrasonic treatment for 10-60 minutes; take the precipitate to obtain amorphous iron-based nano-magnetic resonance contrast agent material, with an average particle size of 5-15nm, high saturation magnetic susceptibility, and superparamagnetic properties; good dispersibility, low toxicity, and Very good water solubility and biocompatibility. The preparation method has very low requirements on experimental operation and equipment, the required raw materials are cheap, the operation is simple and convenient, and the by-products are pollution-free.

Description

A kind of amorphous iron-based nano magnetic resonance contrast agent material and preparation method thereof

technical field

The invention relates to the field of amorphous nanometer materials, in particular to an amorphous iron-based nanometer magnetic resonance contrast agent material and a preparation method thereof.

Background technique

Amorphous Alloy (Amorphous Alloy) was first prepared by Brenner of the American Bureau of Standards and Measures in 1947 by electrolysis and electroless plating. In 1960, Dwuez et al. prepared Au-S amorphous alloy for the first time by melting and quenching. , In the future, amorphous alloys will develop into a new discipline rapidly.

Amorphous alloys are different from crystalline metals in structure and are in an unstable or metastable state in thermodynamics. They have characteristics that general alloys do not have, such as high strength, corrosion resistance, superconductivity and other excellent mechanical properties. Magnetic, electrical and other chemical properties, and can be widely used in various aspects of the national economy.

Due to its unique amorphous structure of long-range disorder and short-range order, amorphous alloy nanoparticles lead to excellent catalytic activity and selectivity, especially the characteristics of less environmental pollution and high catalytic efficiency during the preparation process, and The very good biocompatibility after modification has attracted more and more people's attention. Although the research on amorphous alloy materials is not long, a large number of experimental data have shown that it has good application prospects in industrialization and biomedicine. Amorphous nanoparticles can be used to construct NMR contrast agents due to their superparamagnetic properties. In the experimental preparation process, the surface of the amorphous nanomaterials is coated with dextran macromolecules, which greatly improves the biocompatibility of the materials and the retention time of the materials in the living body. has become a major aspect of research in the field. At present, the preparation methods of amorphous magnetic nanoparticles mainly include co-precipitation method, physical ball milling method, hydrothermal emulsion method, etc., but most of the nanoparticles obtained by these methods have uneven particle size, poor biocompatibility, and poor dispersion. or reunion.

There are many preparation methods for amorphous alloy nanomaterials. Among them, the gas phase evaporation and condensation method is still the current method for industrial batch preparation of amorphous alloy nanomaterials because of its high purity, high activity and continuous production. main method. Liquid-phase chemical reduction method, inverse microemulsion method and electrochemical method have the advantages of simple process, low cost, easy control of purity, and easy promotion in industrial production. They are currently the most researched and promising methods for preparing amorphous Methods for Alloying Nanoparticles.

After the 1970s, the preparation technology and process of amorphous alloys continued to improve, and various rapid condensation techniques in gas phase or liquid phase were widely used in the preparation of amorphous alloys, and various amorphous alloys were prepared, and realized It has achieved remarkable success in industrialized production. Smiht published the first paper on the use of amorphous alloys as catalysts at the Seventh International Conference on Catalysis, showing the bright prospects of this new type of catalytic material, which has aroused widespread attention and interest in materials and catalytic science circles in various countries. 80 Since the 1990s, the catalytic properties of amorphous alloys have been widely studied at home and abroad. At present, the methods for preparing amorphous alloy nanoparticles are mainly gas-phase evaporation condensation method and chemical reduction. The chemical reduction method has the characteristics of simple equipment requirements and convenient operation. It is used by more and more people and has attracted attention at home and abroad.

In the fields of molecular imaging and biomedicine, amorphous magnetic nanoparticles must be monodisperse, water-soluble and stable in order to have good reproducibility, high saturation magnetic susceptibility and good biocompatibility sex.

Although great progress has been made in the preparation and application of amorphous alloy nanoparticles, there are still many problems to be studied. Problems such as easy aggregation of particles, easy oxidation of the surface, how to functionalize the surface, and decreased activity during use have not been effectively resolved. How to functionalize the surface of amorphous alloys without reducing their magnetic properties and solve the problems of high toxicity and easy agglomeration is one of the current research hotspots. When applied to the fields of catalysis and biomedicine, magnetic nanoparticles must be monodisperse and water-soluble in order to have good reproducibility and good biocompatibility under biological conditions.

Contents of the invention

The invention aims to provide an amorphous iron-based nano magnetic resonance contrast agent material.

The present invention also provides a preparation method of the above-mentioned contrast agent material.

Its technical solution is:

(1) ferrous salt, divalent nickel salt or divalent manganese salt (all soluble salts), coating agent are dissolved in water and made into solution I,

(2) Add a reducing agent solution dropwise to solution I under anaerobic conditions, while stirring; then ultrasonically treat for 10 to 60 minutes; take the precipitate to obtain an amorphous iron-based nano-magnetic resonance contrast agent material;

The molar ratio of divalent iron ions to divalent nickel ions or divalent manganese ions is 1: 0.95 to 2.5, preferably 1: 1 to 2;

The molar ratio of divalent iron ion and reducing agent is 1: 0.2～0.5;

The dosage ratio of coating agent and Fe ²⁺ is 0.5～2.5g/mmol;

The encapsulating agent can be selected from dextran, chitosan or polyvinylpyrrolidone (PVP);

The reducing agent is borohydride, which can be potassium borohydride or sodium borohydride;

The divalent iron salt used is ferrous sulfate, ferrous nitrate or ferrous chloride; the divalent nickel salt used is nickel sulfate, nickel nitrate or nickel chloride, and the divalent manganese salt used is manganese sulfate, manganese nitrate or manganese chloride.

The molecular weight of dextran, chitosan or polyvinylpyrrolidone is 10000-30000.

The concentration of Fe ²⁺ in solution I is 0.005-0.02M.

The concentration of the reducing agent solution in step (2) is 5-20 mM.

In step (1), the solution I is heated to 60-98° C. and stirred to fully dissolve the ferrous salt, nickel salt or manganese, and the encapsulating agent.

In step (2), an inert gas such as nitrogen, helium, neon or argon is used as a protective gas to exclude oxygen in the reaction system.

The amorphous iron-based nano magnetic resonance contrast agent material obtained by the above method has an average particle size of 5-15 nm, a high saturation magnetic susceptibility, and superparamagnetic properties; good dispersion, low toxicity, good water solubility and Biocompatibility.

In the present invention, common soluble ferrous salts, manganese salts or nickel salts are used as raw materials, water is used as a solvent, and dextran, chitosan or PVP are stirred and dissolved in water, and then a strong reducing agent is added for hydroboration The monodisperse, amorphous, water-soluble and biocompatible magnetic nano-resonance contrast agent can be directly obtained under ultrasonic conditions. Dextran, chitosan or PVP is used as the encapsulating agent. After stirring and dissolving, fresh strengthening agent is added dropwise, and ferrous borohydride ions, divalent manganese ions or nickel ions are reduced to simple substances to obtain amorphous iron-based nanoparticles. Magnetic resonance contrast agent material; due to the weak coordination between the hydroxyl group on the wrapping agent and the metal and the wrapping effect of the non-chemical bond between the organic polymer and the nano-particles of the wrapping agent under ultrasonic conditions, an amorphous state with good dispersion can be prepared. Good magnetic nanoparticles. Because the outside is coated with substances such as dextran, the nanoparticles have good water solubility and biocompatibility.

The present invention can prepare amorphous alloy nanoparticles with good dispersion, uniform particle size, good water solubility and biocompatibility under simple and common experimental device conditions and simple ultrasonic conditions, greatly reducing the number of nanomaterials toxicity. This preparation method has relatively low requirements on experimental operation and equipment, short reaction time, common and easily available raw materials, and low price. The operation process is simple and convenient, and the by-products are pollution-free. The invention provides an economical and usable new method for studying the synthesis and preparation of amorphous alloy nanoparticles, and provides a good platform for studying amorphous nanoparticles in the field of catalysis and biomedicine.

Description of drawings

Fig. 1 is a transmission electron microscope (TEM) photo of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) in Example 1. It can be seen from the figure that the size of the nanoparticles is relatively uniform and has good monodispersity.

Fig. 2 is a particle size distribution diagram of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) in Example 1. It can be seen from the figure that the average size of the nanoparticles is about 10 nm.

Fig. 3 is an EDS energy spectrum diagram of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) in Example 1. From the energy spectrum, it can be seen that the iron and nickel elements of the nanoparticles and the presence of dextran on the surface.

Fig. 4 is a high-resolution transmission electron microscope (HR-TEM) photo of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) in Example 1. It can be seen from the figure that the synthesized Fe-Ni-B nanoparticles are amorphous nanoparticles.

Fig. 5 is a selected area electron diffraction (SAED) photo of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) in Example 1. This figure and Figures 1 and 4 are all from. From this figure, it can be proved that the synthesized Fe-Ni-B nanoparticles are amorphous nanoparticles.

Fig. 6 is an X-ray electron diffraction pattern (XRD) of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) in Example 1. It is obtained by DMAX 2000 X-ray diffractometer, which is Cu/Kα-radiation (λ=0.15405nm) (40kV, 40mA). This figure further illustrates that the synthesized amorphous alloy nanomaterial Fe-Ni-B is amorphous.

Fig. 7 is the hysteresis loop of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) in Example 1 at room temperature. It is the change relationship between the magnetic induction intensity and the magnetic field intensity of Fe-Ni-B amorphous alloy nanomaterials measured under normal temperature conditions, the abscissa is the magnetic field, and the ordinate is the magnetic induction intensity. It can be seen from the figure that the material has superparamagnetism, and the saturation magnetic susceptibility is 21emu/g.

Fig. 8 is the Fourier transform-infrared (FT-IR) figure of embodiment 1 amorphous iron-based nano magnetic resonance contrast agent material (Fe-Ni-B nanoparticle) and pure dextran, it is obvious from the figure It is found that both Fe-Ni-B nanoparticles and pure dextran have a peak at 1028cm ^-1 , which is the peak position of COC on dextran. From the FT-IR figure, it can be proved that the surface of the nanoparticle is Coated with dextran.

Fig. 9 is the thermal gravimetric analysis (TGA) figure of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) of Example 1. It can be observed from the figure that there is an obvious gradient at 200°C to 400°C. Weight loss, this is the weight loss peak of dextran, indicating that the surface of Fe-Ni-B nanoparticles is coated with dextran.

Fig. 10 is the solubility and dispersion of Example 1 amorphous iron-based nano magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) in aqueous solution, PBS buffer solution, ethanol solution, and water and cyclohexane mixed solution From the photo, it can be seen that Fe-Ni-B nanoparticles are insoluble in organic solvents and are very stable and well dispersed in aqueous solution, PBS buffer solution and ethanol solution.

Figure 11 shows the toxicity test of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) coated with dextran on HeLa cells at a concentration of 0 μg/mL to 100 μg/mL.

Fig. 12 is an MRI weighted imaging image of amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) coated with dextran on the surface at different concentrations.

Fig. 13 is a fitting straight line of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) r ₂ coated with dextran in Example 1.

Fig. 14 is the hysteresis loop of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Mn-B nanoparticles) in Example 2 at room temperature.

Detailed ways

Example 1

Weigh NiCl ₂ 6H ₂ O (0.2377g, 1mmol), FeSO ₄ 7H ₂ O (0.2780g, 1mmol) and dissolve in 100ml water, then add 1.000g dextran (molecular weight 20000, English name is dextran, China Produced by Sinopharm Chemical Reagent Co., Ltd., solid white powder with a purity greater than 97.0%), magnetically stirred at 90°C for 20 minutes to completely dissolve the dextran;

Then use nitrogen to remove oxygen from the reaction system. Under anaerobic conditions, use nitrogen as a protective gas, then add fresh NaBH ₄ (40mL, 10mM) aqueous solution drop by drop, and finally ultrasonically disperse for 30min under ultrasonic conditions, and then centrifuge. The amorphous iron-based nano magnetic resonance contrast agent material (Fe-Ni-B nanoparticle) is obtained.

The transmission electron microscope (TEM) photo is shown in Figure 1, and it can be seen from the figure that the size of the nanoparticles is relatively uniform and has good monodispersity.

Figure 2 is a particle size distribution diagram. It can be seen from the figure that the average size of the nanoparticles is about 10 nm.

Fig. 3 is an EDS energy spectrum, and it can be seen that the iron and nickel elements of the nanoparticles and the presence of dextran on the surface.

Figure 4 is a high-resolution transmission electron microscope (HR-TEM) photo, it can be seen that the synthesized Fe-Ni-B nanoparticles are amorphous nanoparticles.

Figure 5 is a selected area electron diffraction (SAED) photo, which can prove that the synthesized Fe-Ni-B nanoparticles are amorphous nanoparticles. Figures 1, 4, and 5 are obtained by JEOL JEM-2100 high-resolution transmission electron microscope.

Fig. 6 is X-ray electron diffraction pattern (XRD), tests with DMAX 2000 X-ray diffractometer, and this diffractometer is Cu/Kα-radiation (λ=0.15405nm) (40kV, 40mA). It further illustrates that the synthesized amorphous alloy nanomaterial Fe-Ni-B is amorphous.

Figure 7 is the hysteresis loop at room temperature. It is the change relationship between the magnetic induction intensity and the magnetic field intensity of Fe-Ni-B amorphous alloy nanomaterials measured under normal temperature conditions, the abscissa is the magnetic field, and the ordinate is the magnetic induction intensity. It can be seen from the figure that the material has superparamagnetism, and the saturation magnetic susceptibility is 21emu/g.

Figure 8 is a Fourier transform-infrared (FT-IR) figure. It can be clearly seen that both Fe-Ni-B nanoparticles and pure dextran have a peak at 1028cm ^-1 , which is the peak of the COC on the dextran. From the peak position, it can be proved from the FT-IR image that the surface of the nanoparticles is coated with dextran.

Figure 9 is a thermogravimetric analysis (TGA) figure. It can be observed from the figure that there is an obvious weight loss between 200°C and 400°C. polysaccharides.

As shown in FIG. 10 , this contrast agent material is insoluble in cyclohexane, has good dispersibility and can exist stably in aqueous solution, PBS buffer solution, and ethanol solution.

Fig. 11 is a diagram of the toxicity test results of the MTT method. It can be clearly seen that Fe-Ni-B nanoparticles have very little toxicity to HeLa cells at a concentration of 0 μg/mL to 100 μg/mL.

Figure 12 is an MRI weighted imaging image of amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticles) coated with dextran on the surface at different concentrations. From the results, the T2 weighted Imaging is very good.

Fig. 13 is the fitting straight line of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Ni-B nanoparticle) _r2 of surface wrapping dextran in embodiment 1, namely magnetic nanoparticle in PBS buffer solution The straight line of T ₂ relaxation rate (1/T ₂ ) versus Fe element concentration. The abscissa is the Fe element concentration in the iron-based nano-magnetic resonance material, the ordinate is the T ₂ relaxation rate (1/T ₂ ), and the slope is the transverse relaxation rate r ₂ . It can be seen from the figure that the iron-based nano-magnetic resonance material has a strong relaxation ability, and the transverse relaxation rate r ₂ =16.21mM ^-1 s ^-1 .

Ferrous sulfate heptahydrate can be replaced by an equimolar amount of ferrous chloride tetrahydrate with the same result.

Sodium borohydride can be replaced by equimolar amount of potassium borohydride with the same effect.

Dextran can be replaced by chitosan or polyvinylpyrrolidone (PVP) with a molecular weight of 10,000 to 30,000, and the effect is the same.

Example 2

Weigh NiCl ₂ 6H ₂ O (0.2377g, 1mmol), FeSO ₄ 7H ₂ O (0.1390g, 0.5mmol) and dissolve them in 100ml of water, then add 0.800g of dextran, and stir magnetically at 90°C for 20min Completely dissolve dextran;

Then use nitrogen to remove oxygen from the reaction system. Under anaerobic conditions, use nitrogen as a protective gas, then add fresh NaBH ₄ (40mL, 10mM) aqueous solution drop by drop, and finally ultrasonically disperse for 30min under ultrasonic conditions, and then centrifuge. The amorphous iron-based nano magnetic resonance contrast agent material (Fe-Ni-B nanoparticle) is obtained.

After testing, the nanoparticles are amorphous, the size is relatively uniform, the particle size distribution is about 10nm, and it has good monodispersity; its surface is coated with dextran; EDS energy spectrum analysis shows that it contains iron and nickel elements and dextran; with superparamagnetism, good T2-weighted imaging effect; insoluble in cyclohexane, good dispersion and stable existence in aqueous solution, PBS buffer and ethanol solution. Low toxicity to HeLa cells at concentrations of 0 μg/mL to 100 μg/mL.

Example 3

Weigh MnCl ₂ 4H ₂ O (0.1979g, 1mmol), FeSO ₄ 7H ₂ O (0.2780g, 1mmol) and dissolve them in 100ml of water, then add 1.000g of dextran, and stir magnetically at 90°C for 20min Completely dissolve dextran;

Then use nitrogen to remove oxygen from the reaction system. Under anaerobic conditions, use nitrogen as a protective gas, then add fresh NaBH ₄ (40mL, 10mM) aqueous solution drop by drop, and finally ultrasonically disperse for 30min under ultrasonic conditions, and then centrifuge. The amorphous iron-based nano magnetic resonance contrast agent material (Fe-Mn-B nanoparticle) is obtained.

Fig. 14 is the hysteresis loop of the amorphous iron-based nano-magnetic resonance contrast agent material (Fe-Mn-B nanoparticles) in Example 3 at room temperature. It is the change relationship between the magnetic induction intensity and the magnetic field intensity of Fe-Mn-B amorphous alloy nanomaterials measured under normal temperature conditions, the abscissa is the magnetic field, and the ordinate is the magnetic induction intensity. It can be seen from the figure that the material has superparamagnetism, and the saturation magnetic susceptibility is 86emu/g.

After testing, the nanoparticles are amorphous, relatively uniform in size, particle size distribution is about 10nm, and have good monodispersity; the surface is coated with dextran; EDS energy spectrum analysis shows that it contains iron and manganese and dextran; with superparamagnetism, good T2-weighted imaging effect; insoluble in cyclohexane, good dispersion and stable existence in aqueous solution, PBS buffer and ethanol solution. Low toxicity to HeLa cells at concentrations of 0 μg/mL to 100 μg/mL.

Claims (10)

1. the method for preparing of an amorphous state iron-based nano magnetic resonance contrast agent material is characterized in that, comprises the steps:

(1) with divalent iron salt, divalent nickel salt and coating agent, perhaps divalent iron salt, manganous salt and coating agent are dissolved in water wiring solution-forming I,

(2) under oxygen free condition, in solution I, drip reductant solution, stir simultaneously; Supersound process is 10～60 minutes then; Get deposition, obtain amorphous state iron-based nano magnetic resonance contrast agent material;

The mol ratio of ferrous ion and bivalent nickel ion or divalent manganesetion is 1: 0.95～2.5;

The mol ratio of ferrous ion and Reducing agent is 1: 0.2～0.5;

Coating agent and Fe ²⁺Amount ratio be 0.5～2.5g/mmol;

Coating agent is glucosan, chitosan or polyvinyl pyrrolidone; Reducing agent is a boron hydride.

2. the method for preparing of the said amorphous state iron-based of claim 1 nano magnetic resonance contrast agent material is characterized in that, the mol ratio of said ferrous ion and bivalent nickel ion or divalent manganesetion is 1: 1～2.

3. the method for preparing of the said amorphous state iron-based of claim 1 nano magnetic resonance contrast agent material is characterized in that, said divalent iron salt is ferrous sulfate, ferrous nitrate or ferrous chloride; Said divalent nickel salt is nickel sulfate, nickel nitrate or Nickel dichloride.; Said manganous salt is manganese sulfate, manganese nitrate or manganese chloride.

4. the method for preparing of the said amorphous state iron-based of claim 1 nano magnetic resonance contrast agent material is characterized in that Fe in the said solution I ²⁺Concentration be 5～20mM.

5. the method for preparing of the said amorphous state iron-based of claim 1 nano magnetic resonance contrast agent material is characterized in that, the concentration of reductant solution is 5～20mM in the step (2).

6. the method for preparing of the said amorphous state iron-based of claim 1 nano magnetic resonance contrast agent material; It is characterized in that, in the step (1), solution I is heated to 60～98 ℃ and stirring; Make divalent iron salt, divalent nickel salt and coating agent, perhaps divalent iron salt, manganous salt and coating agent dissolving are fully.

7. the method for preparing of the said amorphous state iron-based of claim 1 nano magnetic resonance contrast agent material is characterized in that, in the step (2), as protective gas, gets rid of the oxygen in the reaction system with nitrogen, helium, neon or argon.

8. the method for preparing of the said amorphous state iron-based of claim 1 nano magnetic resonance contrast agent material is characterized in that, the molecular weight of said glucosan, chitosan or polyvinyl pyrrolidone is 10000～30000.

9. the method for preparing of the said amorphous state iron-based of claim 1 nano magnetic resonance contrast agent material is characterized in that, said boron hydride is sodium borohydride or potassium borohydride.

10. an amorphous state iron-based nano magnetic resonance contrast agent material prepares through each said method of claim 1～9.

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