CN114470221A - Magnetic nano material capable of regulating blood brain barrier and preparation method and application thereof - Google Patents
Magnetic nano material capable of regulating blood brain barrier and preparation method and application thereof Download PDFInfo
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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Abstract
The invention discloses a magnetic nano material capable of regulating and controlling a blood brain barrier, which comprises a magnetic substance, wherein the surface of the magnetic substance is sequentially coated with silicon dioxide and polyethylene glycol from inside to outside. After the magnetic nano material is injected into a body, a magnetic field with certain strength is applied to the brain, on one hand, the opening of a specific position of the brain can be controlled, on the other hand, the instantaneous opening of a blood brain barrier can be controlled, and after the magnetic field is removed, the blood brain barrier recovers the integrity. The process has high safety and almost no influence on blood vessels and corresponding cells. The invention also discloses a preparation method of the magnetic nano material, which has the characteristic of simple operation. The invention also discloses the application of the magnetic nano material, the magnetic nano material can exert a synergistic effect with a medicament to prepare a medicinal composition, and the medicinal composition can regulate and control focus blood brain barrier so as to better exert the medicinal effect. The invention opens up a potential way for safe and efficient administration of the brain treatment drug.
Description
Technical Field
The invention belongs to the technical field of medicine, and relates to a magnetic nano material capable of regulating and controlling a blood brain barrier, and a preparation method and application thereof.
Background
The Blood-Brain Barrier (BBB) is closest to neurons and is therefore considered to be the most important Barrier preventing harmful molecules from reaching the Brain through its extensive capillary network. The blood brain barrier is formed by brain microvascular endothelial cells (BMECs, also known as BMVECs and BECs), which separate blood in capillaries from interstitial fluid (ISF) in the brain cavity. Protection of the blood brain barrier is crucial for optimal functioning of the central nervous system. The blood brain barrier buffers ionic and liquid movement, particularly after meals or physical exercise, to ensure that ISF provides the most favorable conditions for neuronal function. It also provides necessary nutrients to the brain, regulating the continual replacement of cerebrospinal fluid and interstitial fluid which drains waste products. The blood-brain barrier is a physical barrier that strictly monitors and controls the entry of different substances into the brain, and is most notably characterized by the presence of tight junctions between the endothelial cells of the brain microvasculature, the gaps between these tight junctions being between 1.4nm and 1.8nm, through which only particles smaller than 1nm can passively pass. The structure also prevents more than 98 percent of small molecule drugs and nearly 100 percent of large molecule drugs from entering the brain tissues to play corresponding therapeutic functions. Therefore, how to safely, effectively and reversibly improve the permeability of the BBB and further improve the accumulation of the drug in the focus becomes one of the research hotspots of drug delivery in the nervous system.
There are currently three main strategies for the efficient delivery of drug molecules to focal regions of the brain: controlling BBB, drug molecule design modification and nano-material mediated drug delivery. Among the methods for controlling the BBB are mainly the opening of tight junctions, such as increasing the permeability of the BBB by means of injection of hypertonic solutions in the carotid artery, microwave-induced hyperthermia, electromagnetic fields, focused ultrasound, etc. However, the methods have relatively large safety influence on brain tissues, so that how to develop a new and mild transient BBB opening method has certain potential clinical application value.
Disclosure of Invention
In order to overcome the defects of the prior art, one of the purposes of the invention is to provide a magnetic nano material capable of regulating and controlling the blood brain barrier, and after the magnetic nano material is injected into a body, the permeability of the blood brain barrier can be improved by combining an external magnetic field, and the blood brain barrier of a specific position of a brain can be opened; after removal of the magnetic field, the blood-brain barrier can restore its integrity.
The second purpose of the invention is to provide a preparation method of the magnetic nano material capable of regulating and controlling the blood brain barrier.
The invention also aims to provide the application of the magnetic nano material capable of regulating and controlling the blood brain barrier.
One of the purposes of the invention is realized by adopting the following technical scheme:
a magnetic nano material capable of regulating and controlling a blood brain barrier comprises a magnetic substance, wherein the surface of the magnetic substance is sequentially coated with silicon dioxide and polyethylene glycol from inside to outside.
Further, the magnetic substance is FeNi or Fe3O4。
Further, the particle size of the magnetic nano material is 100-1000 nm.
The second purpose of the invention is realized by adopting the following technical scheme:
a preparation method of a magnetic nano material capable of regulating and controlling a blood brain barrier comprises the following steps:
adding absolute ethyl alcohol into the magnetic substance, performing ultrasonic treatment, then adding ethanol, ammonia water and tetraethoxysilane, stirring for reaction, and washing and drying after the reaction is finished to obtain an intermediate product; and then dissolving the intermediate product and polyethylene glycol in deionized water, heating and refluxing for reaction, cooling to room temperature after the reaction is finished, carrying out magnetic separation on the product, washing and drying to obtain the final product.
Further, the adding ratio of the magnetic substance to the tetraethoxysilane is 1mg:1-50 mu L; the mass ratio of the intermediate product to the polyethylene glycol is 1: 35-40.
Further, the heating temperature is 90-100 ℃, and the time is 3-24 h.
Further, the magnetic substance FeNi is prepared as follows: dissolving ferric salt and nickel salt into glycerol, and stirring to obtain a uniformly mixed solution; then adding a hydrazine hydrate mixed solution containing NaOH, stirring, carrying out hydrothermal reaction, carrying out magnetic separation after the reaction is finished, washing, and freeze-drying to obtain a magnetic substance FeNi;
magnetic substance Fe3O4The preparation process comprises the following steps: adding ferric salt and sodium acetate into ethylene glycol, mixing and stirring uniformly, carrying out hydrothermal reaction, washing and drying a product after the reaction is finished, and obtaining a magnetic substance Fe3O4。
Further, the iron source is FeCl3·6H2O, the nickel source is NiCl2·6H2O。
The adding proportion of the iron source, the nickel source and the glycerol is 0.1-2mmol:0.2-4mmol:35mL, and the adding proportion of the iron salt, the sodium acetate and the ethylene glycol is 1-5mmol:2-20mmol:16 mL.
Further, the hydrothermal temperature in the preparation process of the magnetic substance FeNi is 180-; magnetic substance Fe3O4The hydrothermal temperature in the preparation process is 180 ℃ and 220 ℃, and the time is 8-24 h.
The third purpose of the invention is realized by adopting the following technical scheme:
the application of the magnetic nano material capable of regulating and controlling the blood brain barrier can be used for exerting a synergistic effect with a medicament to prepare a medicinal composition capable of regulating and controlling the blood brain barrier.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a magnetic nano material capable of regulating and controlling a blood brain barrier, which comprises a magnetic substance, wherein the surface of the magnetic substance is sequentially coated with silicon dioxide and polyethylene glycol from inside to outside. After the magnetic nano material is injected into a body, a magnetic field with certain strength is applied to the brain, on one hand, the opening of a specific position of the brain can be controlled, on the other hand, the instantaneous opening of a blood brain barrier can be controlled, and after the magnetic field is removed, the blood brain barrier recovers the integrity. The process has high safety and almost no influence on blood vessels and corresponding cells. The invention also provides a preparation method of the magnetic nano material capable of regulating the blood brain barrier, and the preparation method has the characteristic of simple operation. The invention provides the application of the magnetic nano material, the magnetic nano material can exert a synergistic effect with a medicament to prepare a medicinal composition, and the medicinal composition can regulate and control focus blood brain barrier so as to better exert the medicinal effect. The invention provides a new drug administration method with physical control, and opens up a potential way for safe and efficient administration of brain treatment drugs.
Drawings
FIG. 1 is a physicochemical property characterization of a product obtained in example 1 of the present invention, wherein FIG. 1A is a TEM image of FeNi, and FIG. 1B is FeNi @ SiO2TEM image of-PEG, FIG. 1C being FeNi @ SiO2-transmission electron microscopy particle size distribution plot of PEG, fig. 1D is hysteresis plot of FeNi;
FIG. 2 is a physicochemical property characterization of the product obtained in example 2 of the present invention, wherein FIG. 2A is Fe3O4TEM of (2B) is Fe3O4The particle size distribution of the transmission electron microscope is shown in FIG. 2C as Fe3O4The hysteresis curve of (1);
FIG. 3 shows the condition of the magnetic nanomaterial injected into the mouse body and the staining of the mouse brain by the staining agent Evans blue under the action of the magnetic field in the experimental example 1 of the present invention;
FIG. 4 shows the staining of mouse brain by evans blue, a staining agent, in comparative example 1 of the present invention, in the absence of magnetic nano-materials and magnetic field;
FIG. 5 shows the staining of the mouse brain by injecting Evans blue into the mouse after removing the magnetic field in comparative example 2 of the present invention;
FIG. 6 shows the staining of mouse brain with evans blue after omitting the injection of magnetic nanomaterial in the mouse of comparative example 3 of the present invention;
FIG. 7 is a graph showing the results of imaging the blood brain barrier opening condition of mice and imaging major organs with different magnetic nanomaterials in Experimental example 1 of the present invention;
FIG. 8 is an immunofluorescence staining pattern of the present invention after injecting magnetic nanomaterial into a mouse, which affects mouse microglia under magnetic field and no magnetic field;
FIG. 9 is an immunofluorescence staining pattern of the present invention after injecting magnetic nanomaterial into a mouse, which affects mouse glial cells under magnetic field and no magnetic field;
FIG. 10 is a graph showing the immunofluorescence staining of the effect of Cy5 on blood vessels in mice according to the present invention under different conditions;
FIG. 11 is a TEM image of a brain slice sample of a mouse of the present invention under different conditions.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and the detailed description, and it should be noted that any combination of the embodiments or technical features described below can be used to form a new embodiment without conflict.
Example 1
A magnetic nano material capable of regulating and controlling blood brain barrier is prepared by the following steps:
preparation of magnetic substance FeNi: 0.181g of FeCl3·6H2O and 0.317g NiCl2·6H2Dissolving O in 35mL of glycerol, heating and stirring for 30min at 50 ℃ in a water bath to completely dissolve O to obtain a uniform solution. Then 5.3mL of hydrazine hydrate solution containing 0.4g of NaOH was added dropwise to the above homogeneous solution, after vigorous stirring for 5min, the mixture was transferred to a 60mL polytetrafluoroethylene-lined reaction vessel, put into a steel jacket, screwed down, reacted at 200 ℃ for 2h, and naturally cooled to room temperature. And performing magnetic separation on the final product by a magnet, ultrasonically washing the product for a plurality of times by using deionized water and ethanol, and freeze-drying the product overnight to obtain the magnetic substance FeNi.
The preparation of the magnetic nano material comprises the following steps: 1) FeNi @ SiO2Synthesizing: taking out 50mg of the freeze-dried product FeNi, adding the product FeNi into 20mL of absolute ethyl alcohol, performing ultrasonic treatment for 10min, adding 60mL of ethyl alcohol, 2mL of ammonia water and 500 mu L of TEOS (adding 20 mu L of TEOS every 1 min), stirring at 800rpm for 10h, performing ultrasonic washing on the obtained product with deionized water and ethanol for several times, and performing freeze-drying overnight.
2)FeNi@SiO2-PEG synthesis: taking the FeNi @ SiO obtained in the step 1)240mg and 1.5g PEG 8000 are dissolved in 30mL deionized water, heated and refluxed for 3h at 100 ℃, cooled to room temperature, and finally the product is magnetically separated by a magnet, washed by deionized water for a plurality of times and freeze-dried overnight to obtain the magnetic nano material FeNi @ SiO2-PEG。
Example 2
A magnetic nano material capable of regulating blood brain barrier is prepared by the following steps:
example 2 differs from example 1 in that: magnetic substance adjusted to Fe3O4The remainder was the same as in example 1, to obtain Fe3O4@SiO2-PEG。
Magnetic substance Fe3O4The preparation of (1): to 16mL of ethylene glycol was added 0.54g (2mmol) FeCl3·6H2O and 0.93g (11mmol) NaAc gave a mixture which was then mixed well by stirring at 700rpm for 30min, and the solution was then transferred to a Teflon lined stainless steel autoclave with a volume of 50mL, which was then sealed and heated in an oven at 200 ℃ for 8 h. Centrifuging the black product, washing with deionized water and ethanol for three times, and standing overnight in a vacuum drier to obtain magnetic substance Fe3O4。
Experimental example 1
Application of magnetic nano material capable of regulating blood brain barrier
The experimental process for verifying that the magnetic nano material improves blood brain barrier permeability is as follows:
the magnetic nano material FeNi @ SiO prepared in the example 12PEG in PBS, FeNi @ SiO2PEG particle size of 200-1000nm and concentration of 20mg/kg of injected mouse body weight. A cube N52 Ru Feibao magnet with the side length of 5mm is pasted on the brain of a mouse, the magnetic nano material with the weight of 20mg/kg and evans blue with the weight of 2mg/25g of the mouse are injected into the body of the mouse in a tail vein injection mode to serve as an experimental group (MF + NP), and the action time of a magnetic field is 4 hours.
Comparative example 1
Comparative example 1(Control) differs from experimental example 1 in that: the mouse body is not injected with magnetic nano materials, and a magnetic field is not arranged. The rest of the experimental example 1 was the same.
Comparative example 2
Comparative example 2(After MF + NP) differs from Experimental example 1 in that: magnetic nano material FeNi @ SiO2PEG tail vein injection into mice, after the magnetic field is removed, Evans blue staining agent is injected. The rest of the ingredients are mixed with the fruitThe experimental example 1 is the same.
Comparative example 3
Comparative example 3(MF) differs from experimental example 1 in that: the evans blue is injected into a mouse body, and the step of injecting the magnetic nano material is omitted. The rest is the same as in experimental example 1.
The experimental results are as follows:
1. characterization of the magnetic nanomaterials obtained in examples 1-2
FIG. 1 and FIG. 2 are physicochemical property representations of the products obtained in examples 1 and 2 of the present invention, respectively, in which FeNi and Fe are shown3O4Shows good magnetism, and the prepared magnetic substances FeNi and Fe3O4The distribution is uniform, and the spherical shape is uniform in size. FeNi @ SiO2PEG with Fe3O4Has a more concentrated particle size distribution, wherein the particle size distribution is FeNi @ SiO2The particle size distribution range of-PEG is 100-500nm, Fe3O4The particle size distribution range is within the range of 100-300 nm.
2. Evaluation of magnetic nanomaterial on improvement of blood brain barrier permeability of mouse
The invention verifies that the magnetic nano material improves the permeability of the blood brain barrier through an experimental example 1 and comparative examples 1 to 3, anesthetizes a mouse by chloral hydrate after the experiment is finished, performs heart perfusion by using physiological saline, and dissects and takes out the brain.
FIG. 3 is a diagram of a brain picture of a mouse in an experimental group, wherein the permeability of a blood brain barrier of the mouse can be improved in the magnetic field action process, the blood brain barrier of the mouse is opened, and an Evans blue coloring agent can enter the brain of the mouse to successfully dye the brain of the mouse. Fig. 4 is a comparative mouse brain picture of comparative example 1 in which neither magnetic nanomaterial was injected nor a magnetic field was applied to the brain of the mouse, and it can be seen from the figure that the blood brain barrier of the mouse is intact and evans blue dye cannot enter the brain of the mouse. Fig. 5 shows the treatment of the mice of comparative example 2, in which evans blue dye is injected after the magnetic field is removed, although the mice are injected with the magnetic nanomaterial and the magnetic field is applied, and evans blue cannot enter the brains of the mice, indicating that the blood brain barrier of the mice recovers the integrity after the magnetic field is removed. FIG. 6 shows that in comparative example 3, when the magnetic nanomaterial is not injected into the mouse, no staining of the brain of the mouse by the staining agent is observed despite the action of the applied magnetic field, indicating that the omission of the magnetic nanomaterial can not open the blood brain barrier and improve the permeability of the mouse.
3. Test of effects of different magnetic nano materials combined with drugs on permeability of blood brain barrier of mouse and accumulation conditions of drugs in different organs
The invention adopts magnetic nano materials to act on the brain of a mouse in combination with a magnetic field, and simultaneously injects Cy 5-labeled Bovine Serum Albumin (BSA) simulation antibody drugs into the mouse to verify the blood brain barrier opening condition of the mouse and the influence on different organs of the mouse. The experimental group is that Cy5-BSA and Fe3O4Or FeNi is injected into the body of the mouse together with the blood, the magnet is removed after 4 hours of action of the magnet, and then fluorescence imaging is carried out by using a small animal imager.
The results show that FIG. 7A shows that when the magnetic nano material FeNi @ SiO is injected into the body of the mouse2PEG (abbreviated FeNi in the figure) and Fe3O4@SiO2PEG (abbreviated symbol in the figure as Fe)3O4) When the magnetic nano material is used, Cy5-BSA can enter the mouse brain, and the fluorescence shows red, which indicates that the magnetic nano material FeNi @ SiO is2-PEG and Fe3O4@SiO2PEG is capable of opening the blood brain barrier in mice in the presence of PEG. Sham (Sham) mice showed no red light in the brain. FIG. 7B is a graph showing the effect of magnetic treatment on different organs in mice, wherein the organs represented by English letters are Heart (Heart), Spleen (Spleen), Brain (Brain), Liver (Liver), Kidney (Kidney), and lung (lung), respectively. As can be seen from FIG. 7B, Cy5-BSA regulated the accumulation of blood-brain barrier in the mouse brain to produce aggregation in the experimental group, which was more significant than the aggregation in other organs, compared to the control group.
4. Safety experiment of magnetic nano material under magnetic field effect
4.1 influence of magnetic nanomaterial on mouse microglia and neuroglia under action of magnetic field
The invention adopts an immunofluorescence staining method to verify the safety influence of the magnetic nano material on mouse microglia (Iba-1) and glial cells (GFAP) under the action of a magnetic field and a non-magnetic field. The experimental procedure involved is as follows: after the brain tissues of the mice in the magnetic treatment group and the normal group are taken out, the mice are firstly soaked in 4% paraformaldehyde overnight, then are subjected to gradient dehydration in 20% sucrose solution and 30% sucrose solution respectively, are subjected to OCT embedding, and finally are frozen sections are prepared by using a freezing microtome.
The dyeing process specifically comprises the following steps:
1) the frozen sections were removed, fixed with cold acetone for 10min, washed 3 times with PBS, 10min each.
2) 0.3% PBST for 30 min.
3) Blocking with goat serum for 1 h.
4) Add GFAP/IBA-1 primary antibody and incubate overnight at 4 ℃.
5) Wash 3 times with PBS for 10min each.
6) A fluorescent secondary antibody Alexa Fluor-IgG was added and incubated for 1 h. PBS was washed three times for 10min each.
7) Add CD31 primary antibody and incubate overnight at 4 ℃.
8) Wash 3 times with PBS. Each time for 10 min.
9) A fluorescent secondary antibody FITC-IgG was added and incubated for 1 h. PBS was washed three times for 10min each.
10) Nuclei were stained with 5 μ M DAPI for 30min and washed three times with PBS for 10min each.
11) Glycerol mounting followed by observation under confocal microscopy.
As can be seen from fig. 8 and 9, compared with the blank control group, the magnetic nanomaterial prepared in example 1 of the present invention has less influence on mouse microglia and glial cells under the action of magnetic field and no magnetic field, and has higher safety.
4.2 influence of magnetic nanomaterial on cerebral blood vessel of mouse under action of magnetic field
The invention adopts an immunofluorescence staining method and a TEM to verify the safety influence of the magnetic nano material on the cerebral vessels of the mice under the action of a magnetic field. The magnetic nano material prepared in the example 1 and Cy5 dye are injected into a mouse body at the same time, a directional magnetic field (experimental group: MF + NP + Cy5) is applied to the brain of the mouse, and after 4 hours of action, the safety of the method is represented by immunofluorescence staining and TEM. In the MF + NP (Cy5) group for comparison, the MF + NP (Cy5) group was prepared by injecting the magnetic nanoparticles first, removing the magnet after 4 hours of magnet action, then injecting Cy5, and recycling for 1 hour. Sham group is the Sham group. Immunofluorescent staining was performed on the three groups of treated samples as described in reference to 3.1.
The result is shown in fig. 10, and the immunofluorescence staining result shows that after the blood brain barrier of the MF + NP + Cy5 group is opened, Cy5 enters the brain of the mouse, and the blood vessels in the brain of the mouse still keep the integrity, thereby proving the safety of the experimental scheme of the invention. Whereas the MF + NP (Cy5) group showed that after removal of the magnetic field, the blood brain barrier recovered integrity, and that post-injection Cy5 failed to cross the blood brain barrier. The MF + NP + Cy5 group showed no significant difference in vascular integrity compared to the MF + NP (Cy5) group, Sham group.
TEM images of the experimental and Sham-treated groups shown in fig. 11, in which fig. 11C and 11D are enlarged views of dashed boxes in fig. 11A and 11B, respectively. The NP + MF group is FeNi @ SiO injection2PEG nanoparticles, cardiac perfusion (2.5% glutaraldehyde) after 4h with magnetite and brain extraction; in the Sham group, PBS alone was injected, and then the brains were harvested after 4h of magnet exposure by heart perfusion (2.5% glutaraldehyde) in mice. The sample is then sent to a plant stress emphasis laboratory of the university of Henan for TEM sample preparation, the slice thickness is 80 μm, the slice is stained with uranium acetate for 15 minutes and then with lead citrate for 10 minutes in a copper mesh, and finally the slice is photographed by using a transmission electron microscope. In the figure, L represents the Lumen of a blood vessel (Lumen), EC is an Endothelial cell (Endothelial-cell), and T-J is a Tight junction (light-junction). The graph shows that Cy5 entered the mouse brain after the blood brain barrier was opened in the experimental group, and the arrows indicate tight junctions, which are known to maintain the integrity of the tight junctions in the experimental group compared to the sham group.
In summary, after the magnetic nanomaterial capable of regulating blood brain barrier provided by the invention is injected into a body, a magnetic field with a certain strength is applied to the brain, so that the opening of the blood brain barrier at a specific site of the brain can be controlled, the opening of the blood brain barrier can be controlled, and the blood brain barrier can recover integrity after the magnetic field is removed. The method provided by the invention has almost no influence on blood vessels and corresponding cells, and has higher safety.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (10)
1. The magnetic nano material capable of regulating and controlling the blood brain barrier is characterized by comprising a magnetic substance, wherein the surface of the magnetic substance is sequentially coated with silicon dioxide and polyethylene glycol from inside to outside.
2. The magnetic nanomaterial capable of regulating blood brain barrier of claim 1, wherein the magnetic substance is FeNi or Fe3O4。
3. The blood brain barrier regulating magnetic nanomaterial as claimed in claim 1, wherein the particle size of the magnetic nanomaterial is 100-1000 nm.
4. The method for preparing magnetic nano material capable of regulating blood brain barrier according to any one of claims 1 to 3, comprising the following steps:
adding absolute ethyl alcohol into the magnetic substance, performing ultrasonic treatment, then adding ethanol, ammonia water and tetraethoxysilane, stirring for reaction, and washing and drying after the reaction is finished to obtain an intermediate product; and then dissolving the intermediate product and polyethylene glycol in deionized water, heating and refluxing for reaction, cooling to room temperature after the reaction is finished, carrying out magnetic separation on the product, washing and drying to obtain the final product.
5. The method of claim 4, wherein the ratio of the magnetic substance to the tetraethoxysilane is 1mg:1-50 μ L; the mass ratio of the intermediate product to the polyethylene glycol is 1: 35-40.
6. The method of claim 4, wherein the heating is performed at 90-100 ℃ for 3-24 hours.
7. The method according to claim 4, wherein the step of preparing the magnetic nanomaterial capable of regulating blood-brain barrier,
the magnetic substance FeNi is prepared by the following steps: dissolving ferric salt and nickel salt into glycerol, and stirring to obtain a uniformly mixed solution; then adding a hydrazine hydrate mixed solution containing NaOH, stirring, carrying out hydrothermal reaction, carrying out magnetic separation after the reaction is finished, washing, and freeze-drying to obtain a magnetic substance FeNi;
magnetic substance Fe3O4The preparation process comprises the following steps: adding ferric salt and sodium acetate into ethylene glycol, mixing and stirring uniformly, carrying out hydrothermal reaction, washing and drying a product after the reaction is finished, and obtaining a magnetic substance Fe3O4。
8. The method of claim 7, wherein the iron source is FeCl3·6H2O, the nickel source is NiCl2·6H2O；
The adding proportion of the iron source, the nickel source and the glycerol is 0.1-2mmol:0.2-4mmol:35mL, and the adding proportion of the iron salt, the sodium acetate and the ethylene glycol is 1-5mmol:2-20mmol:16 mL.
9. The method for preparing a magnetic nano material capable of regulating and controlling the blood brain barrier according to claim 7, wherein the hydrothermal temperature in the preparation process of the magnetic substance FeNi is 180-200 ℃ and the time is 2-8 h; magnetic substance Fe3O4The hydrothermal temperature in the preparation process is 180 ℃ and 220 ℃, and the time is 8-24 h.
10. The use of the magnetic nanomaterial capable of regulating blood-brain barrier according to any of claims 1 to 3, wherein the magnetic nanomaterial can act synergistically with a drug to prepare a pharmaceutical composition capable of regulating blood-brain barrier.
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