Method for preparing ion-doped iron-based magnetic nanoparticles through coprecipitation

Abstract

The invention discloses a method for preparing ion-doped iron-based magnetic nanoparticles by coprecipitation, which comprises the following steps: (1) dissolving ferric salt, ferrous salt and transition metal salt in deionized water, adding into a jacketed reactor, and carrying out the whole reaction process in a closed device under the protection of inert gas; (2) firstly introducing a circulating ice-water bath with the temperature not higher than 0 DEG C into an interlayer cavity of the jacketed reactor, then slowly dropwise adding an ammonia water solution into the jacketed reactor, and starting an alternating magnetic field after dropwise adding is completed; (3) at a low-temperature nucleation stage, enabling the temperature of the solution in the jacketed reactor to be 0-4 DEG C through a circulating ice-water bath and an alternating magnetic field; after low-temperature nucleation is completed, the temperature of the circulating water bath is adjusted to 28-30 DEG C, then the temperature of the circulating water bath is adjusted to 58-60 DEG C, finally, the temperature of the circulating water bath is adjusted to 78-80 DEG C, and the particle growth stage is completed in a gradual temperature rising mode; (4) after the growth stage of the particles is completed, adding a ligand solution into the jacketed reactor at the circulating water bath temperature of 78-80 DEG C, curing the particles after dropwise adding, and closing the alternating magnetic field after the curing stage of the particles is completed; and (5) washing and centrifuging a product obtained after the reaction to obtain the transition metal ion doped ferroferric oxide magnetic nanoparticles.

Description

Technical Field

[0001] The invention relates to a method for preparing ion-doped iron-based magnetic nanoparticles by coprecipitation. Background Art

[0002] Iron-based magnetic nanoparticles are particles with a size between 1 and 100 nanometers, mainly composed of iron or its compounds, and have magnetic characteristics. Iron-based magnetic nanoparticles have good biocompatibility, narrow size distribution, high crystallinity, excellent magnetic properties, and can be mass-produced, and can be used for magnetic imaging diagnosis in vivo.

[0003] At present, the main methods for preparing iron-based magnetic nanoparticles are high-temperature pyrolysis, hydrothermal method, polyol method, and sol-gel method. The above methods all have problems such as dependence on organic solvents, poor product stability, and poor repeatability. In contrast, the chemical coprecipitation method, as the simplest and most effective synthesis method, has the characteristics of green environmental protection, mild reaction conditions, and low production cost during the reaction process, and has broad application prospects in industry. Although iron oxide magnetic nanoparticles have been used as a drug in clinical practice, from the perspective of magnetic materials, the iron-based magnetic nanoparticles prepared by the existing chemical coprecipitation method have the problems of low magnetic saturation intensity, relatively uneven size distribution, and poor crystallinity, which limits the further application of magnetic nanoparticle drugs in clinical practice. Summary of the invention

[0004] Purpose of the invention: The purpose of the present invention is to provide a method for preparing ion-doped iron-based magnetic nanoparticles by coprecipitation. The iron-based magnetic nanoparticles prepared by this method have high magnetic saturation intensity, good crystallinity and uniform particle size.

[0005] Technical solution: The method for preparing ion-doped iron-based magnetic nanoparticles by coprecipitation of the present invention comprises the following steps:

[0006] (1) dissolving ferric salt, ferrous salt and transition metal salt in deionized water and adding the mixture into a jacketed reactor, wherein the entire reaction process is carried out in a closed device under the protection of an inert gas;

[0007] (2) firstly introduce a circulating ice water bath into the jacketed reactor, wherein the temperature of the circulating ice water bath is not higher than 0° C., and then slowly drip an ammonia solution into the jacketed reactor. After the dripping is completed, an alternating magnetic field is turned on;

[0008] (3) In the low-temperature nucleation stage, the temperature of the solution in the jacketed reactor is kept at 0-4°C by circulating an ice water bath and an alternating magnetic field; after the low-temperature nucleation is completed, the temperature of the circulating water bath is first adjusted to 28-30°C, then to 58-60°C, and finally to 78-80°C, and the particle growth stage is completed by gradually increasing the temperature;

[0009] (4) After the particle growth stage is completed, the ligand solution is added to the jacketed reactor at a circulating water bath temperature of 78 to 80° C., and the particles are ripened after the addition. After the particle ripening stage is completed, the alternating magnetic field is turned off;

[0010] (5) Washing and centrifuging the product obtained after the reaction to obtain transition metal ion-doped ferroferric oxide magnetic nanoparticles.

[0011] Wherein, in step (1), the transition metal salt is one of manganese chloride tetrahydrate, zinc chloride or cobalt chloride hexahydrate; and the molar ratio of the iron salt to the transition metal salt is 1:0.1-0.3.

[0012] Wherein, in step (1), the molar ratio of the ferric salt to the ferrous salt is 1:0.2-0.4.

[0013] Wherein, in step (2), the magnetic field frequency is 313kHz and the magnetic field current is 15 to 25A.

[0014] Wherein, in step (2), Fe 3+ and OH - The ammonia solution is added in a molar ratio of 1:3-5; the mass fraction of the ammonia solution is 25%-28%; and the dripping acceleration rate is not higher than 100 microliters / second.

[0015] Among them, in step (3), the time of the low-temperature nucleation stage is 55 to 60 minutes; the time of the particle growth stage is 55 to 60 minutes; and the time of the particle maturation stage is 55 to 60 minutes.

[0016] Wherein, in step (3), the temperature of the circulating water bath is first adjusted to 30°C, and then adjusted to 60°C after 18 to 20 minutes, and then adjusted to 80°C after 18 to 20 minutes, and the particle growth stage is completed after 18 to 20 minutes.

[0017] Wherein, in step (4), the ligand solution is a glycine solution or a citric acid solution.

[0018] When the ligand solution is a citric acid solution, the citric acid solution is added at a molar ratio of iron salt to citric acid of 1:0.5-1; the concentration of the citric acid solution is 0.5-0.55 g / mL.

[0019] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the transition metal ion-doped ferroferric oxide magnetic nanoparticles prepared by the present invention have the advantages of high magnetic saturation intensity, good crystallinity and uniform particle size, and can effectively enhance the imaging effect of magnetic nanoparticles in magnetic resonance imaging and magnetic particle imaging. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 A schematic diagram of the structure of the reaction device used in the method of the present invention;

[0021] Figure 2 Transmission electron microscope images and element mapping images of iron-based magnetic nanoparticles doped with different metal ions prepared in Examples 1 to 3 (a is Example 1; b is Example 2; c is Example 3);

[0022] Figure 3 The XRD diagram of the FeO4 magnetic nanoparticles doped with metal ions and the pure FeO4 magnetic nanoparticles;

[0023] Figure 4 TEM images of the iron-based magnetic nanoparticles prepared in Comparative Examples 1 and 2. DETAILED DESCRIPTION

[0024] Build as Figure 1 The reaction device shown in the figure comprises a magnetic induction device and a jacketed three-neck reactor fixed in the center of the coil of the magnetic induction device, the water in the interlayer cavity of the jacketed three-neck reactor and the water in the external condensation water pool form a circulating fluid; the middle opening of the reactor is used to place a stirring device; sealing rubber pads are provided at the openings on both sides, one of which is used to input nitrogen into the reactor and to add alkali solution and ligand solution; the other opening is used to discharge the gas in the reactor; the entire reaction process is carried out in a closed environment and under the protection of inert gas; a temperature sensor is also provided in the jacketed three-neck reactor to monitor the temperature of the liquid in the reactor.

[0025] Example 1

[0026] The method of Example 1 adopts Figure 1 The preparation method specifically comprises the following steps:

[0027] (1) 0.004 mol of ferric chloride hexahydrate, 0.0008 mol of ferrous sulfate heptahydrate, and 0.0012 mol of manganese chloride tetrahydrate were completely dissolved in 40 mL of deionized water. The reaction solution was then transferred into a jacketed three-necked reactor. The reactor was kept sealed and N was always introduced. 2 Protection; first, a circulating ice-water bath is introduced into the interlayer cavity of the jacketed three-neck reactor, the temperature of the circulating ice-water bath is not higher than 0°C, and then 2 mL of ammonia solution (analytical grade, 25% to 28%) is slowly added dropwise into the jacketed reactor at a rate of 100 μL / s; after the addition is completed, the magnetic induction device is turned on to generate an alternating magnetic field, the current is 15A, and the magnetic field frequency is 313kHz;

[0028] (2) In the low-temperature nucleation stage, the temperature of the reaction solution in the jacketed three-neck reactor is kept at no more than 4°C by circulating an ice water bath and an alternating magnetic field, and the low-temperature nucleation is performed for 60 minutes. After the low-temperature nucleation is completed, the circulating water bath temperature is first adjusted to 30°C, and then adjusted to 60°C after 20 minutes, and then adjusted to 80°C after 20 minutes. The reaction is carried out at a circulating water bath temperature of 80°C for 20 minutes, and the particle growth stage is completed by gradually increasing the temperature. The particle growth stage is 60 minutes.

[0029] (3) After the particle growth stage is completed, 0.5 mL of 0.5 g / mL citric acid solution is added to the jacketed three-necked reactor at a circulating water bath temperature of 80° C., and the particles are ripened after dropwise addition. The particle ripening stage is 60 min, and the temperature of the circulating water bath during the particle ripening stage is 80° C.; after the particle ripening stage is completed, the alternating magnetic field is turned off;

[0030] (4) After natural cooling, the reaction solution is placed in a static magnetic field for adsorption, and the solid product is separated, washed and vacuum dried to obtain manganese-doped ferroferric oxide magnetic nanoparticle powder, which is recorded as MION.

[0031] TEM and elemental mapping images of MION Figure 2 (a) As shown in the TEM image, it can be seen that the particle size uniformity is good, and it is observed that Mn can be more concentratedly distributed in the area where the nanoparticles are aggregated in the element mapping, which further proves that Mn ions are successfully doped into the crystal structure of ferroferric oxide nanoparticles.

[0032] The hydrodynamic particle size of the MION nanoparticles obtained in Example 1 was 123.0 nm, the PDI (polymer dispersibility index) was 0.161, and the M s (saturation magnetization) is 80.3emu / g, r 2 147.03mM -1 ·s -1 The lower the PDI, the better the particle size uniformity; s A higher value indicates that the particles have excellent magnetic properties; r 2 The higher T2 contrast agent than commercial ones indicates that the particles have strong paramagnetic characteristics, which is of great significance in contrast-enhanced T2-weighted imaging.

[0033] Example 2

[0034] The method of Example 2 also adopts Figure 1 The preparation method specifically comprises the following steps:

[0035] (1) 0.004 mol of ferric chloride hexahydrate, 0.0008 mol of ferrous sulfate heptahydrate, and 0.0012 mol of zinc chloride were completely dissolved in 40 mL of deionized water. The reaction solution was then transferred into a jacketed three-necked reactor. The reactor was kept sealed and N was always introduced. 2 Protection; first, a circulating ice-water bath is introduced into the interlayer cavity of the jacketed three-neck reactor, the temperature of the circulating ice-water bath is not higher than 0°C, and then 2 mL of ammonia solution (analytical grade, 25% to 28%) is slowly added dropwise into the jacketed reactor at a rate of 100 μL / s; after the addition is completed, the magnetic induction device is turned on to generate an alternating magnetic field, the current is 15A, and the magnetic field frequency is 313kHz;

[0036] (2) In the low-temperature nucleation stage, the temperature of the reaction solution in the jacketed three-neck reactor is kept at no more than 4°C by circulating an ice water bath and an alternating magnetic field, and the low-temperature nucleation is performed for 60 minutes. After the low-temperature nucleation is completed, the circulating water bath temperature is first adjusted to 30°C, and then to 60°C after 20 minutes, and then to 80°C after 20 minutes. The reaction is continued at a circulating water bath temperature of 80°C for 20 minutes, and the particle growth stage is completed by gradually increasing the temperature. The particle growth stage is 60 minutes.

[0037] (3) After the particle growth stage is completed, 0.5 mL of 0.5 g / mL citric acid solution is added to the jacketed three-necked reactor at a circulating water bath temperature of 80° C., and the particles are ripened after dropwise addition. The particle ripening stage is 60 min, and the temperature of the circulating water bath during the particle ripening stage is 80° C.; after the particle ripening stage is completed, the alternating magnetic field is turned off;

[0038] (4) After natural cooling, the reaction solution is placed in a static magnetic field for adsorption, and the solid product is separated, washed and vacuum dried to obtain zinc-doped ferroferric oxide magnetic nanoparticle powder, which is denoted as ZION.

[0039] TEM and elemental mapping images of ZION Figure 2 (b) As shown in the TEM image, it can be seen that the particle size is uniform, and it is observed in the element mapping that Zn can be distributed more concentratedly in the area where the nanoparticles are gathered, proving the successful doping of Zn ions.

[0040] The hydrodynamic particle size of the ZION nanoparticles obtained in Example 2 was 91.8 nm, the PDI was 0.114, and the M s 98.3emu / g, r 2 190.71mM -1 ·s -1 The lower the PDI, the better the particle size uniformity; sA higher value indicates that the particles have excellent magnetic properties; r 2 A higher value indicates that the particle has stronger paramagnetic characteristics, which is important in contrast-enhanced T2-weighted imaging.

[0041] Example 3

[0042] The method of Example 3 also adopts Figure 1 The preparation method specifically comprises the following steps:

[0043] (1) 0.004 mol of ferric chloride hexahydrate, 0.0016 mol of ferrous sulfate heptahydrate, and 0.0004 mol of cobalt chloride hexahydrate were completely dissolved in 40 mL of deionized water. The reaction solution was then transferred into a jacketed three-necked reactor. The reactor was kept sealed and N2 was always introduced. 2 Protection; first, a circulating ice-water bath is introduced into the interlayer cavity of the jacketed three-neck reactor, the temperature of the circulating ice-water bath is not higher than 0°C, and then 2 mL of ammonia solution (analytical grade, 25% to 28%) is slowly added dropwise into the jacketed reactor at a rate of 100 μL / s; after the addition is completed, the magnetic induction device is turned on to generate an alternating magnetic field, the current is 15A, and the magnetic field frequency is 313kHz;

[0044] (2) In the low-temperature nucleation stage, the temperature of the reaction solution in the jacketed three-neck reactor is kept at no more than 4°C by circulating an ice water bath and an alternating magnetic field, and the low-temperature nucleation is performed for 60 minutes. After the low-temperature nucleation is completed, the circulating water bath temperature is first adjusted to 30°C, and then to 60°C after 20 minutes, and then to 80°C after 20 minutes. The reaction is continued at a circulating water bath temperature of 80°C for 20 minutes, and the particle growth stage is completed by gradually increasing the temperature. The particle growth stage is 60 minutes.

[0045] (3) After the particle growth stage is completed, 0.5 mL of 0.5 g / mL citric acid solution is added to the jacketed three-necked reactor at a circulating water bath temperature of 80° C., and the particles are ripened after dropwise addition. The particle ripening stage is 60 min, and the temperature of the circulating water bath during the particle ripening stage is 80° C.; after the particle ripening stage is completed, the alternating magnetic field is turned off;

[0046] (4) After natural cooling, the reaction solution is placed in a static magnetic field for adsorption, and the solid product is separated, washed and vacuum dried to obtain cobalt-doped ferroferric oxide magnetic nanoparticle powder, which is recorded as CION.

[0047] TEM and elemental mapping images of CION Figure 2(c) As shown in the TEM image, it can be seen that the particle size is uniform, and it is observed in the element mapping that Co can be distributed more concentratedly in the area where the nanoparticles are gathered, proving the successful doping of Co ions.

[0048] The hydrodynamic particle size of the CION nanoparticles obtained in Example 3 was 123.0 nm, the PDI was 0.133, and the M s 90.4emu / g, r 2 130.50mM -1 ·s -1 The lower the PDI, the better the particle size uniformity; s A higher value indicates that the particles have excellent magnetic properties; r 2 A higher value indicates that the particle has stronger paramagnetic characteristics, which is important in contrast-enhanced T2-weighted imaging.

[0049] Comparative Example 1

[0050] The preparation method of Comparative Example 1 is basically the same as that of Example 2, except that zinc chloride is not added in step (1) and the alternating magnetic field is not turned on; the obtained ferroferric oxide magnetic nanoparticles are denoted as IONP. The hydrodynamic particle size of the obtained IONP nanoparticles is 134.3 nm, the PDI is 0.189, and the M s 78emu / g, r 2 74.04mM -1 ·s -1 .

[0051] Comparative Example 2

[0052] The preparation method of comparative example 2 is basically the same as that of example 2, except that in steps (1) to (3), the water bath process is not a circulating water bath, but a conventional water bath (i.e., the water in the jacketed three-neck reactor interlayer cavity and the water in the external condensation water pool form a circulating fluid, but the reactor is directly placed in a water bath); zinc-doped ferroferric oxide nanoparticles are obtained, denoted as ZION-NC. The hydrodynamic particle size of the obtained ZION-NC nanoparticles is 160.7 nm, PDI is 0.220, Ms is 72.2 emu / g, r 2 126.30mM -1 ·s -1 .

[0053] Figure 3 This indicates that the crystallinity of the ferroferric oxide magnetic nanoparticles doped with metal ions is better than that of the pure magnetic ferroferric oxide nanoparticles. Figure 3In (a), the number 6 in MION-6 represents that the molar ratio of manganese ion to (ferrous ion + manganese ion) is 0.6:1. The product obtained in Example 2 corresponds to Figure 3 In (c), ZION-6, the number 6 represents that the molar ratio of zinc ion to (ferrous ion + zinc ion) is 0.6:1. The product obtained in Example 3 corresponds to Figure 3 In (b), the number 2 in CION-2 represents that the molar ratio of cobalt ion to (ferrous ion + cobalt ion) is 0.2:1. Figure 4 It can be seen that obvious agglomeration occurs in Comparative Example 1 (a) and Comparative Example 2 (b), indicating that the particle size uniformity obtained in Comparative Examples 1 and 2 is poor.

[0054] The present invention significantly improves the crystallinity (the crystallinity can be characterized by TEM and XRD methods, and the improvement of crystallinity can improve the biocompatibility and stability of magnetic nanoparticles in in vivo magnetic imaging diagnosis) and magnetic properties of the prepared metal ion-doped ferroferric oxide magnetic nanoparticles by doping transition metal ions to change the lattice structure during the coprecipitation preparation process, and combines a circulating water bath and an alternating magnetic field to assist endogenous heating.

Claims

1. A method for preparing ion-doped iron-based magnetic nanoparticles by coprecipitation, characterized in that: The steps include: (1) dissolving ferric salt, ferrous salt and transition metal salt in deionized water and adding the mixture into a jacketed reactor, wherein the entire reaction process is carried out under the protection of an inert gas; (2) firstly introduce a circulating ice water bath into the jacketed reactor, wherein the temperature of the circulating ice water bath is not higher than 0° C., and then slowly drip an ammonia solution into the jacketed reactor. After the dripping is completed, an alternating magnetic field is turned on; (3) In the low-temperature nucleation stage, the temperature of the solution in the jacketed reactor is kept at 0-4°C by circulating an ice water bath and an alternating magnetic field; after the low-temperature nucleation is completed, the temperature of the circulating water bath is first adjusted to 28-30°C, then to 58-60°C, and finally to 78-80°C, and the particle growth stage is completed by gradually increasing the temperature; (4) After the particle growth stage is completed, the ligand solution is added to the jacketed reactor at a circulating water bath temperature of 78 to 80° C., and the particles are ripened after the addition. After the particle ripening stage is completed, the alternating magnetic field is turned off; (5) Washing and centrifuging the product obtained after the reaction to obtain transition metal ion-doped ferroferric oxide magnetic nanoparticles.

2. The method according to claim 1, characterized in that: In step (1), the transition metal salt is one of manganese chloride tetrahydrate, zinc chloride or cobalt chloride hexahydrate; and the molar ratio of the iron salt to the transition metal salt is 1:0.1-0.

3.

3. The method according to claim 1, characterized in that: In step (1), the molar ratio of the iron salt to the ferrous salt is 1:0.2-0.

4.

4. The method according to claim 1, characterized in that: In step (2), the alternating magnetic field is turned on, the magnetic field frequency is 313kHz, and the magnetic field current is 15-25A.

5. The method according to claim 1, characterized in that: In step (2), Fe 3+ and OH - Ammonia solution is added to the reaction solution at a molar ratio of 1:3-5; the mass fraction of the ammonia solution is 25%-28%; and the dripping acceleration rate of the ammonia solution is not higher than 100 microliters / second.

6. The method according to claim 1, characterized in that: In step (3), the time of the low-temperature nucleation stage is 55 to 60 minutes; the time of the particle growth stage is 55 to 60 minutes; and the time of the particle maturation stage is 55 to 60 minutes.

7. The method according to claim 1, characterized in that: In step (3), the temperature of the circulating water bath is first adjusted to 30°C, and then adjusted to 60°C after 18 to 20 minutes, and then adjusted to 80°C after 18 to 20 minutes, and the particle growth stage is completed after 18 to 20 minutes.

8. The method according to claim 1, characterized in that: In step (4), during the particle maturation stage, the temperature of the circulating water bath is 78-80°C.

9. The method according to claim 1, characterized in that: In step (4), the ligand solution is a glycine solution or a citric acid solution.

10. The method according to claim 9, characterized in that: When the ligand solution is a citric acid solution, the citric acid solution is added at a molar ratio of iron salt to citric acid of 1:0.5-1; the concentration of the citric acid solution is 0.5-0.55 g / mL.

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