CN1219303C - Method for preparing magnetic nano microparticles with biological compatibility - Google Patents
Method for preparing magnetic nano microparticles with biological compatibility Download PDFInfo
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- CN1219303C CN1219303C CN 03136273 CN03136273A CN1219303C CN 1219303 C CN1219303 C CN 1219303C CN 03136273 CN03136273 CN 03136273 CN 03136273 A CN03136273 A CN 03136273A CN 1219303 C CN1219303 C CN 1219303C
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-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y25/00—Nanomagnetism, e.g. magnetoimpedance, anisotropic magnetoresistance, giant magnetoresistance or tunneling magnetoresistance
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
- H01F1/01—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials
- H01F1/03—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity
- H01F1/12—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity of soft-magnetic materials
- H01F1/34—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties of inorganic materials characterised by their coercivity of soft-magnetic materials non-metallic substances, e.g. ferrites
- H01F1/342—Oxides
- H01F1/344—Ferrites, e.g. having a cubic spinel structure (X2+O)(Y23+O3), e.g. magnetite Fe3O4
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F1/00—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties
- H01F1/0036—Magnets or magnetic bodies characterised by the magnetic materials therefor; Selection of materials for their magnetic properties showing low dimensional magnetism, i.e. spin rearrangements due to a restriction of dimensions, e.g. showing giant magnetoresistivity
- H01F1/0045—Zero dimensional, e.g. nanoparticles, soft nanoparticles for medical/biological use
- H01F1/0054—Coated nanoparticles, e.g. nanoparticles coated with organic surfactant
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- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Crystallography & Structural Chemistry (AREA)
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Abstract
The present invention relates to a method for preparing magnetic nanometer micro-particles with biological compatibility, which comprises the following steps: metal organic iron compounds are heated and decomposed in polar solvent of high boiling point under the condition that molecules with biological compatibility exist; then, magnetic nanometer micro-particles with biological compatibility are obtained through settling and separation; the molecules with biological compatibility containing a double-function base (such as double-function base polyethylene glycol and derivatives thereof, double-function base amino acid) are adopted and are embellished to obtain the magnetic nanometer micro-particles of which the surface is provided with different function bases; different iron materials are adopted to obtain the magnetic nanometer micro-particles with biological compatibility of different types of (Fe, gamma-Fe#-[2]O#-[3], Fe#-[3]O#-[4]); the magnetic nanometer micro-particles of different sizes, different crystallinity degree and different magnetic properties can be obtained by controlling reaction conditions. The magnetic nanometer micro-particle obtained by the preparation of the method has the characteristics of uniform particle diameter, high crystallization degree, strong magnetic response property, good water solubility and excellent biological compatibility, and the present invention has wide application perspective and market perspective.
Description
Technical field:
The present invention relates to prepare the method for magnetic nanometer particles with biocompatibility.
Background technology:
Iron and oxide magnetic nanoparticle thereof are widely used for biomedical every field, as magnetic resonance contrast agent (MRI), cell marking and separate, DNA separates, Clinics and Practices of tumour, target medicine carrier etc.Yet the size of particulate, magnetic responsiveness and biocompatibility thereof are restricting the application of magnetic nanometer particles in above-mentioned various fields always.Coprecipitation is the conventional method of preparation magnetic nanometer particles, but gained particle size distribution broad, and the size of particulate and the stable pH value that depends on system consumingly.For overcoming this shortcoming, numerous scholars adopt micella (reverse micelle) legal system to be equipped with magnetic nanometer particles, although the relative homogeneous of this method gained particle size, the degree of crystallinity of particulate is low, a little less than the magnetic responsiveness.In recent years, high-temperature decomposition has been successfully used to prepare the oil-soluble magnetic nanometer particles of single dispersion, high-crystallinity, strong magnetic responsiveness.Yet, how the synthetic uniform particle diameter of one-step method, magnetic responsiveness is strong and magnetic nanometer particles with biocompatibility is scientific circles' outstanding question always.
Polyethylene glycol and derivative thereof have been widely used in various fields such as medicine, health, food, chemical industry.Polyethylene glycol has excellent biocompatibility, can be dissolved in the in-vivo tissue liquid and can be got rid of external rapidly by body and do not produce any toxic side effects.Therefore, polyethylene glycol is used as excipient substance with the dispersiveness of improving medicine, film forming, lubrification, slow release etc. in pharmaceutical industries, and in various bio-medical new materials (as PLA, polyaminoacid etc.), polyethylene glycol is given new function of material and characteristic, as hydrophily, flexibility, anticoagulant property, anti-macrophage phagocytic etc.Amino acid is the raw material of synthetic protein, polypeptide, therefore also has excellent biocompatibility and is widely used in medicine and biomedical every field.In addition, polyethylene glycol and amino acid are at high temperature comparatively stable, are difficult for taking place degraded and decomposition.Although polyethylene glycol (and derivative) and amino acid all are widely used in biomedical aspect, and use it for the also rarely seen report in magnetic nanometer particles modification aspect.
Summary of the invention:
The object of the present invention is to provide a kind of preparation to have the method for the magnetic nanometer particles of biocompatibility, the diameter of particle homogeneous, the magnetic responsiveness that make are strong, and have excellent biological compatibility.This method is particularly suitable for preparing the magnetic nanometer particles that finishing has amino acid and other biocompatiblity molecules to temperature stabilization (as polyethylene glycol and derivative thereof), and the magnetic nanometer particles among the present invention mainly is iron and oxide thereof.
Between 1 nanometer-100 nanometer, in water and intensive polar solvent, have dispersibility or dissolubility according to the magnetic nanometer particles diameter of the biocompatibility of method of the present invention preparation, can be distributed to once more in these media, form stable magnetic fluid.This magnetic nanometer particles is Fe, γ-Fe
2O
3, or Fe
3O
4Magnetic nanometer particles.
The invention provides a kind of preparation method of biological compatibility magnetic nanoparticle, being included in biocompatiblity molecules exists down, heating and decomposition metal organoiron compound in high bp polar solvent is through obtaining the biological compatibility magnetic nanoparticle after precipitation, the separation.
The present invention is the method that the one-step method preparation has the biological compatibility magnetic nanoparticle, and its main contents have following 2 points: 1) decompose the organic metal iron compound and prepare uniform particle diameter, ferromagnetic magnetic nanometer particles in high bp polar solvent.The high bp polar solvent that is adopted among the present invention mainly comprises alpha-pyrrolidone and derivative (N-N-methyl-2-2-pyrrolidone N-, N-ethyl-2-pyrrolidone etc.) thereof, N, N-dimethyl-2-imidazolone, gamma-butyrolacton and derivative thereof, hexamethyl phosphoramide, low-molecular-weight (M≤5000) polyethylene glycol and derivative thereof, the molecular formula See Figure of various high bp polar solvent:
(alpha-pyrrolidone) (N-N-methyl-2-2-pyrrolidone N-) (N-ethyl-2-pyrrolidone) (N, N-dimethyl-2-imidazolone)
(hexamethyl phosphoramide) (gamma-butyrolacton) (4-methyl butyrolactone)
The organic metal iron compound that is adopted mainly contains iron pentacarbonyl (Fe (CO)
5), iron octoate, praseodynium iron (Fe (acac)
3), diacetyl acetone iron (Fe (acac)
2), the complex compound of cupferron and molysite is (as FeCup
3, Cup:N-nitroso N-Phenylhydroxylamine), ferric oxalate (Fe
2(C
2O
4)
35H
2O, FeC
2O
42H
2O) etc.; 2) adopt biocompatiblity molecules to modify the gained magnetic nanometer particles.The biocompatiblity molecules that is adopted among the present invention mainly is amino acid such as glycine, alanine, aspartic acid, asparagine, glutamic acid, glutamine, serine, threonine, lysine, arginine, histidine, cysteine, methionine, valine, leucine, isoleucine, proline, phenylalanine, the network propylhomoserin, the natural amino acid of 20 kinds of needed by human body of tryptophan, polyethylene glycol (PEG) and derivative thereof, as single functional group such as hydroxyl, carboxyl, amido, sulfydryl, aldehyde radical, the ester group polyethylene glycol, with the distant pawl polyethylene glycol of (different) dual-functional group, polyethylene glycol and acrylic copolymer (PEG-PAA), polyethylene glycol and polymethyl acid copolymer (PEG-PMA), polyethylene glycol and polyvinylamine copolymer (PEG-PEI), with in polyethylene glycol and the copolymer of poly lactic acid (PEG-PLA) one or more, the molecular weight of wherein said polyethylene glycol is 200～20000.Various biocompatiblity molecules structural formulas are as follows:
Biocompatiblity molecules: (1) polyethylene glycol and derivative thereof
-CH
2CH
2SH，-CH
2CH
2NH
2，-CH
2COOCH
3
n＝10-500
(2) contain the copolymer of polyethylene glycol
(3) amino acids
R＝-H，-CH
3，-CH
2OH，-CH
2COOH，
-CH
2CONH
2，-CH
2CH
2SCH
3，-(CH
2)
4NH
2，
-CH
2CH
2CONH
2，
-CH
2CH
2COOH，-CH
2CH(CH
3)
2，-CH(CH
3)
2，
-CH
2SH，-CH(CH
3)CH
2CH
3，-CH(OH)CH
3，
Biocompatiblity molecules of the present invention obtains the magnetic nanometer particles that finishing has the difference in functionality group if adopt with the distant pawl polyethylene glycol of dual-functional group, the distant pawl polyethylene glycol of isodigeranyl functional group or have the amino acid of difunctional such as serine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, network propylhomoserin, arginine.
Concrete steps are as follows:
With organic metal iron compound and biocompatiblity molecules (1: 0 ~ 1: 100 by a certain percentage, between preferred 1: 0 ~ 1: 50) be dissolved in the high bp polar solvent, be mixed with 0.001 ~ 2mol/L, solution between preferred 0.01 ~ 0.5mol/L, then at 100 ~ 350 ℃, preferred 180 ~ 280 ℃ of heating reflux reactions 10 minutes ~ 10 hours are between preferred 10 minutes ~ 5 hours.With the gained nanoparticle with a large amount of organic solvent deposits after, oven dry just can obtain being easy to the magnetic nanometer particles dry powder storing and transport after the centrifugation, can be made into the stable magnetic fluid of variable concentrations as required.
Compare with traditional preparation method, the present invention has the following advantages: 1) by this legal system be equipped with that the magnetic nanometer particles uniform particle diameter of gained is controlled, degree of crystallinity and crystalline texture is adjustable, magnetic property also scalable, water-soluble and good dispersion, have excellent biocompatibility; 2) amino acid (as serine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine etc.) that adopt different biocompatiblity molecules such as the distant pawl polyethylene glycol of two carboxyl, telechelic polyglycol with different terminal group, contains dual-functional group can obtain the magnetic nanometer particles that the surface has difference in functionality group (hydroxyl, amido, carboxyl, sulfydryl etc.) when modifying.This provides huge convenience for magnetic nanometer particles and biomolecule coupling connection; 3) this synthetic magnetic nanometer particles with biocompatibility of one step of method does not need particulate is carried out finishing or coating once more; 4) the magnetic nanometer particles dry powder by this method gained has good solubility or dispersibility, can form magnetic fluid steady in a long-term, and this provides huge convenience for storing and transport magnetic nanometer particles.In a word, the inventive method is easy and simple to handle, and gained particulate advantage is outstanding, is suitable for scale and commercially produces, and this will further accelerate and widen the application of magnetic nanometer particles in various fields.
Description of drawings:
Accompanying drawing 1: transmission electron microscope (TEM) photo of pressing the resulting biological compatibility magnetic nanoparticle of preparation method of embodiment 1-6.
Accompanying drawing 2: X-ray diffraction (XRD) figure that presses the resulting biological compatibility magnetic nanoparticle of preparation method of embodiment 1-4.
Accompanying drawing 3: the schematic diagram behind biological compatibility magnetic nanoparticle dry powder water-soluble formation the stablizing magnetic fluid under the outside magnetic field effect.
Embodiment 1:
Take by weighing the two hydroxyl polyethylene glycol (HO-PEG-OH of 0.32g iron octoate and 0.72g, M=4000) be dissolved in the 50ml alpha-pyrrolidone, 240 ℃ of heating reflux reactions 40 minutes, be chilled to room temperature, with a large amount of methanol extraction reaction gained solution, after centrifugation, oven dry, can obtain being easy to the magnetic nanometer particles dry powder of storing and transporting.Accompanying drawing 1 (A) is transmission electron microscope (TEM) photo of gained particulate, and the average diameter of particulate is 4nm as seen from the figure, narrow particle size distribution.Accompanying drawing 2 (A) is X-ray diffraction (XRD) figure of gained particulate, and the gained particulate is γ-Fe as seen from the figure
2O
3, but the degree of crystallinity of particulate is lower.
Embodiment 2:
Take by weighing 0.30g ferric oxalate and 0.42g arginine and be dissolved in the 80ml N-N-methyl-2-2-pyrrolidone N-, 210 ℃ of heating reflux reactions 50 minutes, all the other were operated all with embodiment 1.Accompanying drawing 1 (B) is transmission electron microscope (TEM) photo of gained particulate, and the average diameter of particulate is 6nm as seen from the figure, narrow particle size distribution.Accompanying drawing 2 (B) is X-ray diffraction (XRD) figure of gained particulate, and the gained particulate is γ-Fe as seen from the figure
2O
3, but the degree of crystallinity of particulate is lower.
Embodiment 3:
Take by weighing 0.32g ferric acetyl acetonade and 0.32g aspartic acid and be dissolved in the 90ml alpha-pyrrolidone, 230 ℃ of heating reflux reactions 30 minutes, be chilled to room temperature with a large amount of acetone precipitations, all the other are operated all with embodiment 1.Accompanying drawing 1 (C) is transmission electron microscope (TEM) photo of gained particulate, and the average diameter of particulate is 8nm as seen from the figure, narrow particle size distribution.Accompanying drawing 2 (C) is X-ray diffraction (XRD) figure of gained particulate, and the gained particulate is Fe as seen from the figure
3O
4, the degree of crystallinity of particulate is higher.
Embodiment 4:
Take by weighing the cupferron complex compound (FeCup of 0.40g molysite
3) and the two carboxy polyethylene glycol of 0.76g (HOOC-PEG-COOH M=4000) is dissolved in 100ml poly glycol monomethyl ether (M=200), and 280 ℃ of heating reflux reactions 60 minutes, all the other were operated all with embodiment 1.Accompanying drawing 1 (D) is transmission electron microscope (TEM) photo of gained particulate, and the average diameter of particulate is 11nm as seen from the figure, narrow particle size distribution.Accompanying drawing 2 (D) is X-ray diffraction (XRD) figure of gained particulate, and the gained particulate is Fe as seen from the figure
3O
4, the degree of crystallinity of particulate is higher.
Embodiment 5:
Measure 0.31g iron pentacarbonyl (Fe (CO)
5) and the 0.58g glycine be dissolved in 60ml N, in N-dimethyl-2-imidazolone, added thermal response 60 minutes at 100 ℃, all the other are operated all with embodiment 1.Accompanying drawing 1 (E) is transmission electron microscope (TEM) photo of gained particulate, and the average diameter of particulate is 6nm as seen from the figure, narrow particle size distribution.X-ray diffraction shows that the gained particulate is the Fe nanoparticle, and the degree of crystallinity of particulate is higher.
Embodiment 6:
Take by weighing 0.36g ferric acetyl acetonade and 0.76g end carboxy polyethylene glycol monomethyl ether (CH
3O-PEG-COOH M=1100) is dissolved in the 20ml alpha-pyrrolidone, 250 ℃ of heating reflux reactions 30 minutes, is chilled to room temperature with a large amount of acetone precipitations, and all the other are operated all with embodiment 1.Accompanying drawing 1 (F) is transmission electron microscope (TEM) photo of gained particulate, and the average diameter of particulate is 20nm as seen from the figure, narrow particle size distribution.X-ray diffraction (XRD) the analysis showed that the gained particulate is Fe
3O
4, the degree of crystallinity of particulate is higher.
Claims (24)
1. the preparation method of a biological compatibility magnetic nanoparticle, be included under the biocompatiblity molecules existence condition, heating and decomposition metal organoiron compound in high bp polar solvent is then through obtaining the biological compatibility magnetic nanoparticle after precipitation, the separation.
2. according to the preparation method of claim 1, wherein said biocompatiblity molecules is the natural amino acid of needed by human body.
3. according to the preparation method of claim 2, wherein said natural amino acid is glycine, alanine, aspartic acid, asparagine, glutamic acid, glutamine, serine, threonine, lysine, arginine, histidine, cysteine, methionine, valine, leucine, isoleucine, proline, phenylalanine, network propylhomoserin, tryptophan.
4. according to the preparation method of claim 1, wherein said biocompatiblity molecules is selected from one or more in polyethylene glycol and derivative, polyethylene glycol and acrylic copolymer, polyethylene glycol and polymethyl acid copolymer, polyethylene glycol and polyvinylamine copolymer and polyethylene glycol and the copolymer of poly lactic acid.
5. according to the preparation method of claim 4, the molecular weight of wherein said polyethylene glycol is 200～20000.
6. according to the preparation method of claim 4, wherein said polyethyleneglycol derivative is single functional group polyethylene glycol, with distant pawl polyethylene glycol of dual-functional group or the distant pawl polyethylene glycol of isodigeranyl functional group.
7. according to the preparation method of claim 6, wherein said single functional group is hydroxyl, carboxyl, amido, sulfydryl, aldehyde radical or ester group.
8. according to the preparation method of claim 1, wherein said metal organoiron compound is selected from complex compound, iron octoate, the ferric oxalate of iron pentacarbonyl, diacetyl acetone iron, praseodynium iron, cupferron and molysite.
9. according to the preparation method of claim 8, the complex compound of wherein said cupferron and molysite is FeCup
3, Cup:N-nitroso N-Phenylhydroxylamine.
10. according to the preparation method of claim 1, wherein said high bp polar solvent is selected from down one or more in the group: N, the polyethylene glycol and the derivative thereof of N-dimethyl-2-imidazolone, alpha-pyrrolidone and derivative, gamma-butyrolacton and derivative thereof, hexamethyl phosphoramide, molecular weight≤5000.
11. according to the preparation method of claim 10, wherein said alpha-pyrrolidone derivative is N-N-methyl-2-2-pyrrolidone N-or N-ethyl-2-pyrrolidone.
12. preparation method according to claim 1, it is characterized in that adopting with the distant pawl polyethylene glycol of dual-functional group, the distant pawl polyethylene glycol of isodigeranyl functional group or to have the amino acid whose biocompatiblity molecules of difunctional particles coated, obtain the magnetic nanometer particles that the surface has the difference in functionality group.
13. according to the preparation method of claim 12, wherein said functional group is hydroxyl, carboxyl, amido, sulfydryl, aldehyde radical or ester group.
14. according to the preparation method of claim 12, wherein said difunctional amino acid is selected from serine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine.
15. according to the preparation method of claim 1, reaction temperature wherein is controlled between 100～350 ℃.
16. according to the preparation method of claim 15, reaction temperature wherein is controlled between 180～280 ℃.
17. according to the preparation method of claim 1, wherein the weight ratio of organic metal iron compound and biocompatiblity molecules is between 1: 0～1: 100.
18. according to the preparation method of claim 17, wherein the weight ratio of organic metal iron compound and biocompatiblity molecules is between 1: 0～1: 50.
19. according to the preparation method of claim 1, wherein reactant concentration is controlled between 0.001～2mol/L.
20. according to the preparation method of claim 19, wherein reactant concentration is controlled between 0.01～0.5mol/L.
21. according to the preparation method of claim 1, wherein the reaction time was controlled at 10 minutes～10 hours.
22. according to the preparation method of claim 21, wherein the reaction time is controlled between 10 minutes～5 hours.
23. according to the preparation method of claim 1, wherein said magnetic nanometer particles is Fe, Fe
2O
3, or Fe
3O
4Magnetic nanometer particles.
24. according to the preparation method of claim 1, the described magnetic nanometer particles that wherein obtains can dissolve or be distributed in the water once more, forms stable magnetic fluid.
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| CN101046472A (en) * | 2006-03-31 | 2007-10-03 | 成都夸常医学工业有限公司 | Biochip and its prepn process and the rit therewith |
| CN101178961B (en) * | 2006-11-10 | 2011-02-09 | 北京万德高科技发展有限公司 | Water soluble magnetic nanometer crystal with high dissolvability and method of producing the same |
| CN101241788B (en) * | 2007-01-15 | 2012-02-22 | 北京万德高科技发展有限公司 | Biological compatibility magnetic nano crystal for high dissolving and stable distribution in physiologicalbuffer liquid and its making method |
| CN101099931B (en) * | 2007-05-23 | 2010-05-19 | 江苏天一超细金属粉末有限公司 | Nanometer iron-series catalyst and preparation method and device thereof |
| EP2350651B1 (en) * | 2008-11-10 | 2015-01-14 | Luminex Corporation | Method for manufacture of macroporous beads |
| CN101819838B (en) * | 2010-03-02 | 2012-10-03 | 中国科学院上海应用物理研究所 | Alkynyl-modified magnetic nano-particle module, amino acid compound-modified magnetic nano-particles, preparation method and application thereof |
| CN102881398B (en) * | 2012-09-14 | 2015-10-14 | 北京化工大学 | Nanometer magnetofluid composite material that a kind of polyamino acid is coated and preparation method thereof |
| CN104388076B (en) * | 2013-12-26 | 2016-06-22 | 华东理工大学 | A kind of water soluble fluorescence magnetic corpusculum and preparation method thereof |
| CN110211758A (en) * | 2019-06-14 | 2019-09-06 | 南宁师范大学 | Ferroso-ferric oxide/gold nano composite particles preparation method |
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