CN112007035A - Magnetic carrier for targeted medicine and preparation method thereof - Google Patents
Magnetic carrier for targeted medicine and preparation method thereof Download PDFInfo
- Publication number
- CN112007035A CN112007035A CN202010911690.1A CN202010911690A CN112007035A CN 112007035 A CN112007035 A CN 112007035A CN 202010911690 A CN202010911690 A CN 202010911690A CN 112007035 A CN112007035 A CN 112007035A
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- parts
- solution
- magnetic
- drug
- microemulsion
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- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 107
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 229940079593 drug Drugs 0.000 claims abstract description 97
- 239000006249 magnetic particle Substances 0.000 claims abstract description 48
- 229910052681 coesite Inorganic materials 0.000 claims abstract description 42
- 229910052906 cristobalite Inorganic materials 0.000 claims abstract description 42
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 42
- 229910052682 stishovite Inorganic materials 0.000 claims abstract description 42
- 229910052905 tridymite Inorganic materials 0.000 claims abstract description 42
- 238000002156 mixing Methods 0.000 claims abstract description 40
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000011734 sodium Substances 0.000 claims abstract description 25
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- 238000003756 stirring Methods 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 239000002244 precipitate Substances 0.000 claims description 23
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
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- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 5
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 3
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- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Inorganic materials [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 3
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- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
-
- A—HUMAN NECESSITIES
- 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
- 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
- A61K47/06—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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- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
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- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
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Abstract
The invention relates to the technical field of micro-nano preparation, in particular to a preparation method of a magnetic carrier for a targeted drug, which mainly comprises the steps of preparing a hollow framework → preparing magnetic particles → carrying a drug → magnetizing → coating a wall material; by mixing with high drug loadingPEG 6000-sodium glutamate-Fe3O4Magnetic particles and G-mesoporous SiO2Assembling the spheres to obtain a habit drug nano particle with high drug loading, superparamagnetism and good magnetic response; the biocompatibility is good, and the wall material is biodegradable, so the half-life period of drug release can be controlled, magnetic targeting treatment can be carried out on the focus deep in the body of a patient, the toxic and side effects of the drug are reduced, and the concentration of the therapeutic drug in a target area exceeds that of the traditional preparation by hundreds of times, so that the curative effect is enhanced.
Description
Technical Field
The invention relates to the technical field of micro-nano preparation, in particular to a magnetic carrier for targeted drugs and a preparation method thereof.
Background
Over the years, physicians have developed different targeted therapies that can deliver drugs to the affected area, such as puncture delivery, i.e., the delivery of a drug injection to the affected area by puncture. The traditional antitumor drugs are administered through various routes, and reach a certain drug concentration and are distributed throughout the body to generate a treatment effect. The greatest drawback of this treatment is the lack of selectivity and the associated side effects, which make the treatment of tumors less than ideal. In order to improve the targeting effect of chemotherapeutic drugs on tumors and increase the effective utilization rate of the drugs, people propose targeting drugs.
The targeted drug delivery system refers to a drug delivery system in which a carrier enables a drug to be localized in a target tissue, a target organ, a target cell or a cell through local or systemic blood circulation and binary concentration, and is a concrete embodiment of the concept of a drug operation system. The magnetic targeted drug is a novel targeted sustained-release drug delivery system which is researched more in recent years, and the targeted sustained-release mechanism is as follows: the magnetic anticancer nano particles are firstly injected into a human body through an artery, then under the action of an external magnetic field, the magnetic anticancer nano particles are gradually enriched at the target position of a tumor tissue and permeate into tumor cells, and due to the difference of degradation characteristics and different crosslinking degrees of high polymer materials, the drug is released from a carrier in a slow-release and controlled-release manner, so that the pharmacological effect is exerted on the level of cells or subcells, meanwhile, the probability that the drug is phagocytized by a reticuloendothelial system in the body is reduced, and the treatment effect is improved.
Because the magnetic targeting drug is a novel drug delivery system, the optimization of the preparation process, the improvement of the performance, the pharmacokinetics in a human body, the positioning of a magnetic field and the like need to be further improved, and the magnetic targeting drug carrier has important significance for the research of the magnetic targeting drug carrier and the preparation method thereof.
Disclosure of Invention
The magnetic targeting medicine is a magnetic medicine with targeting property, which is formed by coating magnetic nano particles, solid or liquid medicines by utilizing natural or synthetic polymer materials, and can directionally move and target specific tumor cells or biomolecules in vivo and slowly release the medicines under the action of an external magnetic field after being applied to the body.
The targeted drugs can be divided into active targeted drugs and passive targeted drugs according to the targeting mechanism, the active targeted drugs realize targeted positioning of the drugs through the specific binding capacity of the drugs or functional groups thereof with specific parts of tumor cells or specific molecules, and the passive targeted drugs realize targeted positioning drug delivery through the accumulation property of the drugs in specific organs or tissues or targeted positioning of the drugs in specific tumor regions under the external action (such as electric fields, magnetic fields and the like). The invention relates to preparation of a passive targeting drug magnetic carrier, which comprises the following specific technical scheme:
the magnetic targeting drug particles designed by the invention consist of the following four parts:
1. skeleton material
The framework material is used for supporting magnetic particles and medicines, and the material has certain characteristics:
(1) has good biocompatibility and little antigenicity, and can not cause immune response.
(2) Has enough binding force with the drug and has larger drug-loading capacity.
Based on the three requirements, the invention designs a preparation method of the framework material, which comprises the following steps:
(1) raw material preparation
The surface of the nano particles prepared by the microemulsion method is coated with a layer of surfactant, so that the particles are not easy to agglomerate, and the surface of the particles can be modified by selecting different surfactant molecules to control the size of the particles, so that the nano hollow material can be prepared.
When the microemulsion is used as a microreactor, the addition modes of reactants mainly include a direct addition method and a blending method, and the reaction mechanism of the method is divided into a permeation reaction mechanism and a fusion reaction mechanism. A + B → C + D is used as a reaction model, A, B is a reaction substance dissolved in water, C is a precipitate insoluble in water, and D is a byproduct.
Direct addition method-osmotic reaction mechanism: first a microemulsion system of the W/O (water-in-oil) type is prepared, solubilizing a, then the reactant B is added thereto, passing through the surfactant membrane by diffusion and osmosis, entering the "water bath" (nanoreactor). A. B, reacting in a water pool to obtain the nano particles. The reaction process is controlled by an osmotic diffusion mechanism.
Blending method-mechanism of fusion reaction: two inverse microemulsions, one solubilization A and one solubilization B, were mixed with the same oil-to-water ratio. The two microemulsion liquid drops are subjected to collision, fusion, separation and recombination to nucleate and grow a product, and finally the nano-particles are obtained.
The invention adopts the mechanism to prepare the microemulsion A, the microemulsion B and the microemulsion C firstly.
Preparing a microemulsion A: 9 parts of Triton X-100, 4 parts of octanol and 60 parts of cyclohexane are mixed and stirred according to volume components until the solution is clear and transparent, and then 2 parts of Cd (NO)3)2And dropwise adding the solution into the system within 20min, mixing and stirring until the solution is clear and transparent to obtain the A microemulsion.
Preparing microemulsion B: 9 parts of Triton X-100, 4 parts of octanol and 60 parts of cyclohexane are mixed and stirred according to volume components until the solution is clear and transparent, and then 2 parts of Na2And dropwise adding the S solution into the system within 20min, mixing and stirring until the solution is clear and transparent, and obtaining the B microemulsion.
Preparing microemulsion C: according to the volume components, 9 parts of Triton X-100, 4 parts of octanol and 60 parts of cyclohexane are mixed and stirred until the solution is clear and transparent, then 5 parts of ammonia water are dripped into the system within 20min, and the mixture is stirred until the solution is clear and transparent, so that the C microemulsion is obtained.
(2) Preparation of hollow skeleton
(21) Preparation of CdS/SiO2Composite core-shell particles:
preparing the microemulsion A, the microemulsion B, the microemulsion C and an acetone aqueous solution for later use;
mixing and stirring 4 parts of A microemulsion and 4 parts of B microemulsion for 15min until the mixture is uniform in terms of volume components, then adding 3 parts of C microemulsion and 2-4 parts of TEOS into the system, and magnetically stirringStirring for 15min, and aging at room temperature for 24 h; adding 2 parts of acetone aqueous solution into the solution system to generate flocculation, standing for 20min, and performing centrifugal separation to obtain a precipitate; washing the precipitate with anhydrous ethanol and deionized water, and vacuum drying at 60 deg.C for 8 hr to obtain CdS/SiO2Composite core-shell particles.
(22) Preparation of mesoporous SiO2Ball:
mixing the above CdS/SiO2Adding the composite core-shell particles into deionized water, stirring to obtain slurry, treating with concentrated hydrochloric acid to remove the CdS core, and centrifuging the solution to obtain precipitate; washing the precipitate with absolute ethyl alcohol and deionized water, and vacuum drying at 60 deg.C for 8 hr to obtain mesoporous SiO2A ball.
Mesoporous SiO2The mechanism of sphere formation is as follows:
containing Cd2+、S2-The reverse micelle is subjected to collision and aggregation to perform substance exchange and reaction, and first, homogeneous nucleation is performed in the reverse micelle to generate CdS seed crystals; then adding S containing2-(or containing Cd2+) After micro-emulsifying, the reverse micelle of the whole system is subjected to the same process, the generated CdS in the reverse micelle is used as a growth seed crystal, and after a reaction species is added, the CdS grows into larger particles through a heterogeneous nucleation process; after TEOS addition, CdS particles as SiO2The TEOS grows on the surface of the CdS crystal grains, and the CdS/SiO is obtained by hydrolysis and polycondensation reaction2Composite core-shell particles. The CdS core reacts with hydrochloric acid when the particles are treated by the hydrochloric acid to generate Cd2+、NO3-And H2S, etc. products from SiO2Diffusing out from the pore canal of the shell layer to obtain mesoporous SiO2A ball.
(23) Preparation of G-mesoporous SiO2Ball with ball-shaped section
The mesoporous SiO is prepared2Adding the ball and the gold nanorod into methanol acidified by hydrochloric acid, and stirring and mixing uniformly; heating the mixed solution at 60 ℃ for 8h under reflux, centrifuging to obtain a precipitate, and washing with methanol and deionized water to obtain a product; adding the above product and ammonia water into CTAB micelle system, adding TEOS dropwise at 45 deg.C, mixing and reacting for 40min, centrifuging to obtain precipitate, adding methanol and ammonia waterWashing with deionized water to obtain G-mesoporous SiO2A ball.
Tetraethyl orthosilicate (TEOS) is hydrolyzed and polymerized into SiO in reverse micelle2The mechanism of (1) is as follows:
in the presence of alkaline catalyst, the anion is 0H-The radius is small (0.09nm), nucleophilic attack is directly initiated on a silicon atom, and a 5-coordination transition state is formed. 0H of particle-Attack, negatively charging the silicon nucleus and causing electron cloud to the OR of the other side-The Si-O bond of the group is weakened and eventually cleaved, completing the hydrolysis reaction.
The micro-emulsion method for preparing mesoporous SiO2The ball material can be summarized in two steps:
(1) by adjusting the concentration and the dosage of reactants and the rigidity of a microemulsion interface membrane, particles (CdS inner cores) with uniform granularity and smaller particle size than the radius of a microemulsion water core are formed; the resulting particles can serve as core centers to initiate the second reaction.
(2) Core-shell composite particles (Cds/SiO) obtained by the above reaction2Composite core-shell particles) is etched or calcined to remove the core, and then the hollow sphere (mesoporous SiO) is obtained2A ball).
2. Magnetic fine particles
The magnetic particles provide magnetism for the targeted drug and also act as a drug carrier. The magnetic materials commonly used are pure iron powder, hydroxyl iron, magnetite, ferrate and other ferrite materials. The magnetic particles used for preparing magnetic medicine are required to have higher magnetic conductivity, are nontoxic to organisms, can be positioned and concentrated without coagulation and precipitation under the induction of an external magnetic field, can be fixed at tumor positions, and can be regularly and safely discharged out of the body of an organism without causing immune reaction.
Fe3O4The fine particles have a strong tendency to agglomerate because of their extremely small particle size, large specific surface area and high surface energy, and must be stably dispersed in an aqueous phase by means of a surfactant. Thus, to obtain stable Fe3O4The magnetic particles must be selected from a desired surfactant.
Based on the above requirements, the invention designs a preparation method of magnetic particles, which comprises the following steps:
(1) preparation of sodium glutamate-Fe3O4Magnetic particles:
calculated by mol components, 1-6 parts of sodium glutamate, 5 parts of NaOH and 20 parts of NaNO3Mixing; mixing 1 part of the mixture with 1 part of deionized water, and heating to 100 ℃; mixing 1 part of the above mixed solution with 1 part of FeSO4Mixing the solutions, reacting at 100 ℃ for 1h, and then cooling to room temperature; separating the solution by magnetic separation method, and washing the precipitate with deionized water to obtain sodium glutamate-Fe3O4Magnetic particles.
However, the result is not ideal when only sodium glutamate is used as a surfactant, and the efficiency of drying and then re-dispersing the prepared magnetic particles into water is not high, so that a second surfactant PEG6000 is required to be added. Dried PEG 6000-sodium glutamate-Fe3O4The magnetic particles can be easily re-dispersed into the water phase and still remain unsettled for a long time.
(2) Preparation of PEG 6000-sodium glutamate-Fe3O4Magnetic particles:
mixing the above sodium glutamate-Fe3O4Adding the magnetic particles into PEG6000 solution with mass concentration of 0.1g/mL, stirring and mixing uniformly, and drying to obtain PEG 6000-sodium glutamate-Fe3O4And (4) magnetic particles.
The reaction mechanism of the above operation is:
Fe3O4the surface is positively charged, the sodium glutamate is negatively charged in aqueous solution, and the sodium glutamate can be adsorbed to Fe due to electrostatic action3O4On the surface, sodium glutamate is adsorbed to Fe due to its extremely strong hydrophilicity of hydroxyl and carboxyl groups3O4After the surface is added with Fe3O4Is hydrophilic and blocks Fe3O4The growth of the particles is continued, so that Fe can be controlled3O4The size of the particle size.
But after drying due to the action of hydroxyl and hydrophobic groupsWith Fe3O4The nanoparticles can aggregate and are difficult to redisperse in water. However, after PEG6000 is added, the hydroxyl group and ether bond of PEG6000 can be adsorbed on Fe through hydrogen bond3O4The hydroxyl bond of sodium glutamate on the surface and the ether oxygen bond of PEG6000 can be bonded with water through hydrogen bonds, so that Fe is generated3O4The hydrophilicity of (2) is improved.
3. Wall material
Wall materials, as materials for enclosing drugs, generally need to possess certain characteristics:
(1) has good biocompatibility, very small antigenicity and biodegradability, can not cause immune reaction, and can be gradually degraded and eliminated in vivo through metabolism.
(2) Must have some permeability for the release of the coated drug.
Based on the above two requirements, the currently common wall materials are all polymer materials, mainly including: albumin, latex, gelatin, polyethylene glycol, neutral dextran, phosphatidylcholine, polyalkylcyanoacrylate, ethyl cellulose, red blood cells, and the like. The invention selects gelatin as wall material.
4. Medicine
The drug in the magnetically targeted drug particles must also possess certain characteristics:
(1) does not react with the framework material and the magnetic material.
(2) The half-life period is short, frequent administration is needed, and the half-life period is less than 1 hour or more than 24 hours, so that the magnetic targeting drug particles are not suitable to be prepared.
(3) The dosage is small, the drug effect is stable, and the solubility is good; the medicine with large dosage, violent drug effect and poor solubility is not suitable for preparing the magnetic particles.
(4) The dosage of the medicine does not need to be precisely adjusted, and medicines such as antihypertensive medicines, antiarrhythmic medicines, histamine medicines, anti-psychotic medicines and the like which need to be precisely adjusted are not suitable for preparing the magnetic particles.
The mercaptopurine selected by the invention is mainly used for clinically treating acute leukemia, chorionic adenomatosis, malignant hydatidiform mole and the like. Can also be used as immunosuppressant, mainly used for treating autoimmune diseases, preventing immune rejection after tissue organ transplantation, and treating thrombocytopenic purpura and lupus erythematosus, but has the side effects of inhibiting bone marrow, damaging liver and the like, so the application of the immunosuppressant is greatly limited. Because the half-life of the mercaptopurine is 3h, the therapeutic dose is usually 6-6.5mg/(kg d), and the required dose is small, the method is suitable for preparing the magnetic nano-drug and realizes the therapeutic function of the magnetic nano-drug on the premise of reducing the side effect of the magnetic nano-drug.
Since the thiol group of mercaptopurine interacts with the hydroxyl group of PEG6000, PEG6000 has solubilization, emulsifying and dispersing effects on mercaptopurine. Therefore, when the magnetic gelatin targeting drug containing mercaptopurine is prepared, mercaptopurine is firstly added into magnetic particles containing PEG6000, and the mercaptopurine is dispersed in the magnetic particles through ultrasonic oscillation.
Secondly, the invention synthesizes the components into a final finished product by the following steps
1. Magnetization
Based on volume components, 1 part of the drug-loaded magnetic particles and 20 parts of G-SiO2Mixing the solution with a ball solvent, standing the obtained solution for 1h for electrostatic self-assembly to obtain the drug-loaded magnetic SiO2A fluid.
2. Coating wall material
(1) 2 parts of the drug-loaded magnetic SiO at 35 ℃ by volume2Dispersing the fluid in 8 parts of gelatin solution with the mass concentration of 5-20%, and centrifugally separating the drug-loaded magnetic SiO which is not dispersed in the gelatin solution2A fluid.
Because the magnetic targeting drug needs to have good magnetic responsiveness under a certain magnetic field to achieve the purpose of magnetic targeting, the entrapment rate of the magnetic particles is more than 20%. Since gelatin is a macromolecule, it can stabilize the colloid at high concentrations, but at lower concentrations it can cause the colloid to coagulate and settle. Therefore, the invention carries medicine magnetic SiO2Adding the fluid into a gelatin solution with the concentration of 5-20% to study the gelatin concentration on drug-loaded magnetic SiO2Influence of fluid suspensibility.
(2) Adding 2-5 parts of isopropanol into the mixed solution under the condition of water bath at 40 ℃, stirring until gelatin is formed, adding glutaraldehyde with the mass fraction of 30% for curing, stirring at a high speed for 4h, washing with isopropanol, and finally drying in vacuum at 55 ℃ to obtain the magnetic drug nanoparticles.
The curing agent is isopropanol, which is prepared by reacting aldehyde with amino on lysine or hydroxy lysine residue in gelatin molecule to obtain G-mesoporous SiO2The surface of the ball is solidified by forming a high density of cross-links.
Compared with the existing magnetic carrier of the targeted drug, the invention has the beneficial effects that:
the invention is prepared by adding PEG 6000-sodium glutamate-Fe with high drug loading3O4Magnetic particles and G-mesoporous SiO2Assembling the spheres to obtain a habit drug nano particle with high drug loading, superparamagnetism and good magnetic response; the biocompatibility is good, and the wall material is biodegradable, so the half-life period of drug release can be controlled, magnetic targeting treatment can be carried out on the focus deep in the body of a patient, the toxic and side effects of the drug are reduced, and the concentration of the therapeutic drug in a target area exceeds that of the traditional preparation by hundreds of times, so that the curative effect is enhanced.
Detailed Description
In order to further illustrate the manner in which the present invention is made and the effects obtained, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments.
Example one
The embodiment is prepared by taking one mixture ratio in the whole scheme of the invention as a standard, and the specific scheme is as follows:
the magnetic targeting drug particles designed by the invention consist of the following four parts:
1. skeleton material
(1) Raw material preparation
Preparing a microemulsion A: 9mL Triton X-100, 4mL octanol and 60mL cyclohexane were mixed and stirred until the solution was clear and transparent, then 2mL Cd (NO)3)2And dropwise adding the solution into the system within 20min, mixing and stirring until the solution is clear and transparent to obtain the A microemulsion.
Preparing microemulsion B: 9mL Triton X-100, 4mL octanol and 60mL cyclohexane were mixed and stirred until the solution was clear and transparent, then 2mL Na2And dropwise adding the S solution into the system within 20min, mixing and stirring until the solution is clear and transparent, and obtaining the B microemulsion.
Preparing microemulsion C: and (3) mixing and stirring 9mL of Triton X-100, 4mL of octanol and 60mL of cyclohexane until the solution is clear and transparent, then dropwise adding 5mL of ammonia water into the system within 20min, and mixing and stirring until the solution is clear and transparent to obtain the C microemulsion.
An aqueous acetone solution was prepared for use.
(2) Preparation of hollow skeleton
(21) Preparation of CdS/SiO2Composite core-shell particles:
mixing and stirring 80mL of A microemulsion and 80mL of B microemulsion for 15min until the mixture is uniform, then adding 60mL of C microemulsion and 40mL of TEOS into the system, magnetically stirring for 15min, and aging for 24h at room temperature; adding 40mL of acetone aqueous solution into the solution system to generate flocculation, standing for 20min, and performing centrifugal separation to obtain a precipitate; washing the precipitate with anhydrous ethanol and deionized water, and vacuum drying at 60 deg.C for 8 hr to obtain CdS/SiO2Composite core-shell particles.
(22) Preparation of mesoporous SiO2Ball:
mixing the above CdS/SiO2Adding the composite core-shell particles into deionized water, stirring to obtain slurry, treating with concentrated hydrochloric acid to remove the CdS core, and centrifuging the solution to obtain precipitate; washing the precipitate with absolute ethyl alcohol and deionized water, and vacuum drying at 60 deg.C for 8 hr to obtain mesoporous SiO2A ball.
(23) Preparation of G-mesoporous SiO2Ball with ball-shaped section
The mesoporous SiO is prepared2Adding the ball and the gold nanorod into methanol acidified by hydrochloric acid, and stirring and mixing uniformly; heating the mixed solution at 60 ℃ for 8h under reflux, centrifuging to obtain a precipitate, and washing with methanol and deionized water to obtain a product; adding the above product and ammonia water into CTAB micelle system, adding TEOS dropwise at 45 deg.C, mixing and reacting for 40min, centrifuging to obtain precipitate, precipitating with methanol and deionizingWashing with water to obtain G-mesoporous SiO2A ball.
2. Magnetic fine particles
(1) Preparation of sodium glutamate-Fe3O4Magnetic particles:
1mmol of sodium glutamate, 5mmol of NaOH and 0.2mol of NaNO3Mixing; mixing 0.1mol of the mixture with 18mL of deionized water, and heating to 100 ℃; 18mL of the above mixture was mixed with 1mL of FeSO4Mixing the solutions, reacting at 100 ℃ for 1h, and then cooling to room temperature; separating the solution by magnetic separation method, and washing the precipitate with deionized water to obtain sodium glutamate-Fe3O4Magnetic particles.
(2) Preparation of PEG 6000-sodium glutamate-Fe3O4Magnetic particles:
mixing the above sodium glutamate-Fe3O4Adding the magnetic particles into PEG6000 solution with mass concentration of 0.1g/mL, stirring and mixing uniformly, and drying to obtain PEG 6000-sodium glutamate-Fe3O4And (4) magnetic particles.
3. Wall material
The invention selects gelatin as wall material.
4. Medicine
The invention selects mercaptopurine as the loaded drug of the magnetic targeting nano-carrier.
Secondly, the invention synthesizes the components into a final finished product by the following steps
1. Magnetization
Based on volume components, 1mL of the drug-loaded magnetic particles and 20mL of the G-SiO2Mixing the solution with a ball solvent, standing the obtained solution for 1h for electrostatic self-assembly to obtain the drug-loaded magnetic SiO2A fluid.
2. Coating wall material
(1) At 35 ℃, 2mL of the drug-loaded magnetic SiO2Dispersing the fluid in 8mL of gelatin solution with the mass concentration of 5-20%, and centrifugally separating the drug-loaded magnetic SiO which is not dispersed in the gelatin solution2A fluid.
(2) Adding 5mL of isopropanol into the mixed solution under the condition of 40 ℃ water bath, stirring until gelatin is formed, adding glutaraldehyde with the mass fraction of 30% for curing, stirring at a high speed for 4h, washing with isopropanol, and finally drying in vacuum at 55 ℃ to obtain the magnetic drug nanoparticles.
Example two
Example two and example one except that the amount of tetraethyl orthosilicate (TEOS) surfactant added was different, the remaining portions were the same, and the comparison of TEOS usage to mesoporous SiO was made2The effect of the ball structure is shown in table 1:
TABLE 1 TEOS dosage vs. mesoporous SiO2Influence of ball structure
As can be seen from the data in Table 1, with the increase of the amount of TEOS used as a surfactant, the entire mesoporous SiO obtained2The size of the ball and the hollow part are reduced to a certain extent, especially the whole mesoporous SiO2The variation in size of the ball is particularly significant.
The reason for the above phenomenon is that with the increase of the amount of the surfactant, the original free water is gradually surrounded by the increased surfactant to restrict the water conversion, and the reduction of the free water makes the interface arrangement compact, which is not beneficial to the proceeding of TEOS hydrolysis reaction, thereby resulting in mesoporous SiO2The size of the ball and hollow portion is reduced. Therefore, the optimal amount of TEOS used as the surfactant of the present invention is 40 mL.
EXAMPLE III
Example three and example one the same as except that the amount of sodium glutamate was varied, in order to compare the amount of sodium glutamate used to PEG 6000-sodium glutamate-Fe3O4The influence of the magnetic particle size is specifically shown in table 2:
TABLE 2 influence of sodium glutamate dosage on magnetic particle size
From Table 2As can be seen from the data, the PEG 6000-sodium glutamate-Fe is increased along with the increase of the dosage of the sodium glutamate3O4The particle size of the magnetic particles is reduced significantly, and when the amount of sodium glutamate is 6mmol, the size of the magnetic particles reaches the level of several nanometers.
The reason for this is that sodium glutamate is a low molecular weight aminocarboxylate, in which a portion of the carboxylic acid groups in the molecule can replace Fe3O4Abundant hydroxyl and Fe on surface3+The magnetic particles are combined to form monomolecular layer adsorption, and after adsorption, the surfaces of the magnetic particles are charged with negative charges and repel each other, so that the magnetic particles play a role in dispersion. With the increase of the dosage of sodium glutamate, the sodium glutamate is adsorbed on Fe3O4The amount of sodium glutamate on the surface will increase, so that Fe3O4The density of negative charges charged on the surface increases, the degree of mutual aggregation of particles decreases, and the dispersibility improves, thereby decreasing the particle size.
By combining the data of the first, second and third embodiments, the invention can be obtained by combining the magnetic particles and the mesoporous SiO2The spheres are better combined, and the optimal dosage of the sodium glutamate is selected to be 4 mmol.
Example four
Example four is the same as example one except that the concentration of gelatin is different, and the effect of the concentration of gelatin on the drug loading rate and the encapsulation rate is compared at the addition of 5mL of isopropanol, and the calculation formula of the drug loading rate and the encapsulation rate is as follows:
in this example, 0.3g mercaptopurine and 3mL of magnetic SiO carrying drug were added2The fluids were added to the following sets of gelatin solutions of different concentrations, respectively, and the mass specific data are shown in table 3:
TABLE 3 Effect of gelatin concentration on drug Loading
As can be seen from the data in table 3, when the gelatin concentration is 1%, 5mL of isopropanol does not allow gelatin to be precipitated from the aqueous solution, and thus magnetic drug nanoparticles are not obtained at this concentration.
When the gelatin concentration is gradually increased from 5% to 10%, 5mL of isopropanol can separate out a small amount of gelatin from the aqueous solution to generate a condensed phase, and the magnetic drug nanoparticles are obtained through the solidification of glutaraldehyde.
When the concentration of the gelatin reaches 15%, 5mL of isopropanol can enable the precipitation amount of the gelatin to be remarkably increased, and correspondingly, the drug loading rate and the coating rate of the magnetic drug nanoparticles are also high.
However, it is worth noting that when the gelatin concentration reaches 20%, the drug loading rate and the encapsulation rate of the magnetic drug nanoparticles are decreased, and the reason for this phenomenon is probably because the amount of the coacervate phase generated by 5mL of isopropanol is increased with the increase of the gelatin concentration, the yield of the obtained magnetic drug nanoparticles is increased, the wall material thickness is increased, the particle size is increased, and the drug-loaded magnetic particles and the G-SiO particles are hindered2Electrostatic assembly between spheres to result in mercaptopurine-carrying drug-loaded magnetic SiO2The amount of fluid binding is reduced, resulting in a reduction in the final drug load and encapsulation.
Therefore, the optimal gelatin concentration of the invention is 15%, under the concentration, the drug loading rate of the magnetic drug nanoparticles is 26.2%, the coating rate is 80.1%, and compared with similar products on the market, the magnetic drug nanoparticles have great competitive potential.
Claims (5)
1. A preparation method of a magnetic carrier for targeted drugs is characterized by mainly comprising the following steps:
s1: preparing a hollow framework:
s11: using a reverse microemulsion method on Triton X-100/octanol/cyclohexane/H2In O system, with Cd (NO)3)2And Na2S is used as raw material to synthesize nano-scaleCdS; hydrolyzing TEOS as a silicon source under the catalysis of ammonia water to synthesize CdS/SiO in situ2Composite core-shell particles; finally, removing the CdS core by concentrated hydrochloric acid treatment to obtain the nano-scale mesoporous SiO with uniform particle size2A ball;
s12: preparing the mesoporous SiO prepared in the step S112The ball and the gold nanorod are subjected to cross-linking reaction to obtain the silicon-grafted gold nanomaterial G-mesoporous SiO2A ball;
s2: preparing magnetic particles:
using a one-step synthesis method for Fe3O4Surface modification of magnetic particles: sodium glutamate is used as a first layer wrapping modifier, PEG6000 is used as a second layer wrapping modifier, and PEG 6000-sodium glutamate-Fe which can be highly dispersed and stably exist in an aqueous solution is obtained3O4Magnetic particles;
s3: carrying out medicine loading:
adding the medicine into PEG 6000-sodium glutamate-Fe prepared in the step S23O4Carrying out ultrasonic oscillation on the magnetic particles to obtain medicine-carrying magnetic particles; the G-mesoporous SiO prepared in the step S122The spheres are dispersed in H2In O, G-SiO was obtained at a concentration of 0.3mg/mL2A ball solution;
s4: magnetization:
1 part of the drug-loaded magnetic particles prepared in step S3 and 20 parts of the G-SiO prepared in step S3 were mixed by volume component2Mixing the solution with a ball solvent, standing the obtained solution for 1h for electrostatic self-assembly to obtain the drug-loaded magnetic SiO2A fluid;
s5: coating wall materials:
s51: 2 parts by volume of the drug-loaded magnetic SiO prepared in the step S42Dispersing the fluid in 8 parts of gelatin solution with the mass concentration of 5-20%, and centrifugally separating the drug-loaded magnetic SiO which is not dispersed in the gelatin solution2A fluid;
s52: adding 5 parts of isopropanol into the mixed solution prepared in the step S51 under the condition of water bath at 40 ℃, stirring until gelatin is formed, adding glutaraldehyde with the mass fraction of 30% for curing, stirring at a high speed for 4h, washing with the isopropanol, and finally drying in vacuum at 55 ℃ to obtain the magnetic drug nanoparticles.
2. The method for preparing a magnetic carrier for a targeted drug according to claim 1, wherein the step S11 is to prepare mesoporous SiO2The specific steps of the ball are as follows:
s111: preparation of CdS/SiO2Composite core-shell particles:
s1111: preparing the microemulsion A, the microemulsion B, the microemulsion C and an acetone aqueous solution for later use;
s1112: mixing and stirring 4 parts of A microemulsion and 4 parts of B microemulsion for 15min by volume until the mixture is uniform, then adding 3 parts of C microemulsion and 2-4 parts of TEOS into the system, magnetically stirring for 15min, and aging for 24h at room temperature;
s1113: adding 2 parts of acetone aqueous solution into the solution system prepared in the step S1112, flocculating, standing for 20min, and performing centrifugal separation to obtain a precipitate;
s1114: washing the precipitate prepared in the step S1113 with absolute ethyl alcohol and deionized water, and then drying the precipitate for 8 hours in vacuum at the temperature of 60 ℃ to obtain CdS/SiO2Composite core-shell particles;
s112: preparation of mesoporous SiO2Ball:
s1121: the CdS/SiO prepared in step S11142Adding the composite core-shell particles into deionized water, stirring to obtain slurry, treating with concentrated hydrochloric acid to remove the CdS core, and centrifuging the solution to obtain precipitate;
s1122: washing the precipitate prepared in the step S1121 with absolute ethyl alcohol and deionized water, and then drying for 8 hours in vacuum at the temperature of 60 ℃ to obtain mesoporous SiO2A ball.
3. The method for preparing a magnetic carrier for a targeted drug according to claim 2, wherein in step S1111, the a microemulsion, the B microemulsion and the C microemulsion are prepared as follows:
s11111: preparing a microemulsion A: 9 parts of Triton X-100, 4 parts of octanol and 60 parts of cyclohexane are mixed and stirred according to volume components until the solution is clear and transparent, and then 2 parts of Cd (NO)3)2The solution is added dropwise into the system within 20minMixing and stirring until the solution is clear and transparent to obtain A microemulsion;
s11112: preparing microemulsion B: 9 parts of Triton X-100, 4 parts of octanol and 60 parts of cyclohexane are mixed and stirred according to volume components until the solution is clear and transparent, and then 2 parts of Na2Dropwise adding the S solution into the system within 20min, mixing and stirring until the solution is clear and transparent to obtain a B microemulsion;
s11113: preparing microemulsion C: according to the volume components, 9 parts of Triton X-100, 4 parts of octanol and 60 parts of cyclohexane are mixed and stirred until the solution is clear and transparent, then 5 parts of ammonia water are dripped into the system within 20min, and the mixture is stirred until the solution is clear and transparent, so that the C microemulsion is obtained.
4. The method of claim 1, wherein in step S12, G-mesoporous SiO is used as the carrier2The specific preparation method of the ball is as follows:
s121: preparing the mesoporous SiO prepared in the step S112Adding the ball and the gold nanorod into methanol acidified by hydrochloric acid, and stirring and mixing uniformly;
s122: heating the mixed solution prepared in the step S121 at 60 ℃ for 8 hours under reflux, centrifuging to obtain a precipitate, and washing with methanol and deionized water to obtain a product;
s123: adding the product prepared in the step S122 and ammonia water into a CTAB micelle system, dropwise adding TEOS at 45 ℃, mixing and reacting for 40min, centrifuging to obtain a precipitate, washing with methanol and deionized water to obtain G-mesoporous SiO2A ball.
5. The method for preparing a magnetic carrier for a targeted drug according to claim 1, wherein the step S2 is to prepare magnetic particles by the following steps:
s21: preparation of sodium glutamate-Fe3O4Magnetic particles:
s211: calculated by mol components, 1-6 parts of sodium glutamate, 5 parts of NaOH and 20 parts of NaNO3Mixing;
s212: mixing 1 part of the mixture prepared in step S211 with 1 part of deionized water, and heating to 100 ℃;
s213: mixing 1 part of the mixed solution prepared in step S212 with 1 part of FeSO4Mixing the solutions, reacting at 100 ℃ for 1h, and then cooling to room temperature;
s214: separating the solution prepared in step S123 by magnetic separation method, and washing the separated precipitate with deionized water to obtain sodium glutamate-Fe3O4Magnetic particles;
s22: preparation of PEG 6000-sodium glutamate-Fe3O4Magnetic particles:
sodium glutamate-Fe prepared in step S2143O4Adding the magnetic particles into PEG6000 solution with mass concentration of 0.1g/mL, stirring and mixing uniformly, and drying to obtain PEG 6000-sodium glutamate-Fe3O4And (4) magnetic particles.
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