CN1994469A - Biodegradable magnetic nanoparticle, preparation method and application thereof - Google Patents
Biodegradable magnetic nanoparticle, preparation method and application thereof Download PDFInfo
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- CN1994469A CN1994469A CN 200610031077 CN200610031077A CN1994469A CN 1994469 A CN1994469 A CN 1994469A CN 200610031077 CN200610031077 CN 200610031077 CN 200610031077 A CN200610031077 A CN 200610031077A CN 1994469 A CN1994469 A CN 1994469A
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Abstract
The invention relates to a method for producing biological degradable magnetic nanometer particles, wherein said particle has corn and frame; the corn layer is magnetic ferric oxide; the frame is natural macromolecule materials as liposome, blood albumin, dope, starch, or chitose; its diameter is 1-100nm; the nanometer particles is prepared by reverse-phase micro emulsion method. The inventive particle has wide application.
Description
Technical field
The invention belongs to field of nanometer material technology, particularly be applied to the nano material of biotechnology.
Background technology
The ultimate principle of cell separation technology is to have different physicss, chemistry, biology and immunophenotype characteristic according to different cell masses, selects corresponding one or more methods that specific target cell group is separated from blended cell mass or tissue.The main method of initial separation enrichment of cell promptly is to have different specific weight according to cell, adopt to comprise that technology such as speed centrifugation, density gradient centrifugation separate, but the time is long, weak effect.The appearance of the seventies middle and late stage flow cytometry and sorting technology and monoclonal antibody technique and development make cell separation technology qualitative leap occur.Fluorescence-activated cell sorting (the Fluorescence-activated cellsorting that the using monoclonal antibody fluorescence staining combines with the fluidic cell sorting, FACS) technology has greatly improved the efficient of cell separation purification, makes the few cell mass of some content of efficient fast separating and purifying become possibility.But after fluorescent labeling, cell activity has been subjected to influence to a certain degree, and this has produced obstruction to follow-up study work.Magnetic bead separates can overcome above shortcoming, it is based on the specific recognition of antibody pair cell surface antigen, to be coupled at marked by magnetic bead on the antibody on cell, be issued to the purpose of isolated cell at the action of a magnetic field, can in a few minutes, from the cell mixture of complexity, isolate highly purified target cell.Magnetic bead is the key of cell sorting.Magnetic bead should be that the material of superparamagnetism, ferromagnetism or ferrimagnetism constitutes, and has the characteristics of good magnetic response, low-coercivity and low remanent magnetism, magnetic materials such as the most widely-used at present ferrum simple substance, iron oxides.Because these materials are reunited seriously after forming particle, chemical property is active, therefore, in application, usually they are wrapped up modification, form the particle of the nucleocapsid structure of " magnetic nuclear "-" coating ", to address these problems.But present inorganic substances in order to parcel can't be degraded in vivo and pair cell still has certain influence.Therefore, need to select a kind of Nantural non-toxic material that can be degraded to wrap up.
The condition that must satisfy as coating layer material has: have excellent biological compatibility and antigenicity, and biodegradable in vivo, metabolite is nontoxic, and excretes within a certain period of time; Have the ability of parcel a certain amount of " magnetic nuclear ", certain mechanical strength is arranged.Natural macromolecular material is better because of its biological characteristics and film property (or balling-up), thereby extremely research worker is paid close attention to.As liposome, the albumin that gathers the natural amino acid class, gelatin, fibroin albumen etc.; The starch of poly-polysaccharide, chitosan etc.
Liposome (Liposomes) is to be formed for film material enclose by phospholipid cholesterol etc.Can form the multilamellar microcapsule when phospholipid is dispersed in the water, and every layer be lipid bilayer, separated by water between each layer, this microcapsule is exactly a liposome.Liposome is having potentiality as pharmaceutical carrier aspect the target administration treatment of malignant tumor.Liposome is undesirable as the targeting distribution of carrier in order to overcome, the shortcoming of less stable, has developed some novel lipides in recent years, as responsive to temperature type, PL responsive type, immunity, polymerized liposome.
Chitosan is a kind of natural polysaecharides cellulose, extensively be present in insecticide, in Crustacean shell and the fungal cell wall, be called soluble chitin again, have a cationic edible cellulose but be that occurring in nature is unique, chitosan has nontoxic, good biocompatibility, advantages such as degradable, also have antibiotic, antitumor, anticoagulant, antiacid, the antiulcer isoreactivity, can stop or weaken the zest of medicine to stomach, and have under sour environment and form hydrogel, characteristic with mucosa, these biological activitys have determined chitosan to be widely used at field of medicaments, and by chitosan is carried out modification, enlarge its range of application medically, now become one of focus of macromolecular material research.
Fibroin albumen derives from silkworm silk, is made up of 18 seed amino acids.It does not have immunoreation, has good blood, histocompatibility and anticoagulant property.When load and release medicine, have to a certain degree pH value response and enzyme decomposability.More than these characteristics for it provides condition as controlled (or slow release) framework material.Present research mainly concentrates on release membranes material aspect, and as the report of microsphere wall material seldom.
Chitosan magnetic micro-sphere, be meant hud typed structure particles with chitosan parcel " magnetic nuclear ", can introduce multiple reactive functional group (as hydroxyl, carboxyl, aldehyde radical, amino etc.) by chemical reaction at microsphere surface, also can fix bioactive substances such as enzyme, cell, antibody by covalent bond, therefore at immobilized enzyme, cell separation, immunologic diagnosis and neoplasm targeted therapy, aspects such as the separation of protein, DNA and purification are widely used.
Immunocyte separates the specific recognition that is based on antibody pair cell surface antigen, to be coupled at marked by magnetic bead on the antibody on cell, be issued to the purpose of isolated cell at the action of a magnetic field, can in a few minutes, from the cell mixture of complexity, isolate highly purified cell.
Immune magnetic cytopheresis (Immunomagnetic cell separation methods) more and more becomes the focus that experts and scholars pay close attention in cytobiology.The immune magnetic cell separation relies on two kinds of mechanism to realize that target cell separates.Direct method is exactly by being connected to affinity ligand (being antibody) on the magnetic microsphere, form immune magnetic microsphere (the immunomagnetic microspheres of surface combination monoclonal antibody, IMMS), this microsphere can combine and make it to have magnetic responsiveness specifically with target cell, under the outside magnetic field effect, target cell is separated with other impurity.Indirect method is exactly earlier antibody to be added in the cell suspension, does not have the cell of binding antibody to be washed off after the hatching, and antibody-target cell complex is then by being marked with the immune magnetic microsphere enrichment of another aglucon (promptly two is anti-).With the immune magnetic microsphere of inorganic matter as integument, can't degradation in vivo, after finishing, it must be removed from being labeled cell cell sorting.But promptly use macromolecule to wrap up, the size of magnetic-particle also can have very big influence by pair cell.If granular size and cell are approaching, then particle must be removed at after separating; If particle diameter is in 100nm, particle can directly be degraded by organism, and the pair cell activity influence is less, need not after the separation to remove, and the cell that obtains can be directly used in the research that cells in vivo is transplanted.
In addition, immobilized enzyme is meant and utilizes physical absorption or chemical bond method that free enzyme is fixed on the carrier, with operational stability that improves enzyme and the technology of recycling enzyme repeatedly.Enzyme fixing means commonly used has: absorption method, investment, covalent bond method and cross-linking method.Magnetic microsphere also of no use as the carrier of immobilized enzyme so that the simple research of the separation of immobilized enzyme.
In addition, often not fully up to expectations with chemotherapy treatment malignant tumor, this mainly is not enough because of the medicine that is sent to tumor locus.Do not pass through with Preparation of Chitosan microsphere a kind of magnetic guiding, that pair cell is harmless as the immobilized cancer therapy drug of carrier and still have at present, utilize cation in its structure in conjunction with the cell in the sugared sincere polysaccharide (GAG) of negative charge, heparin, the cerebrovascular, reach the purpose of target administration, slow release control medicine, thereby improve utilization ratio of drug and the report of tumor treatment effect.
Summary of the invention
Technical problem to be solved
The technical issues that need to address of the present invention provide a kind of Biodegradable magnetic nanoparticle and method for making and application, can't biodegrade to overcome magnetic nanoparticle in the prior art, the cell that is contacted had a defective of adverse effect.
Technical scheme
One of content of the present invention provides a kind of Biodegradable magnetic nanoparticle, possesses the hud typed structure of kernel and shell, it is characterized in that: inner nuclear layer is a magnetic oxide, and outer shell is a natural macromolecular material; And particle diameter is 1-100nm.
One of preferred version of above-mentioned Biodegradable magnetic nanoparticle is that said natural macromolecular material is selected from liposome, blood albumin, gelatin, fibroin albumen, starch or chitosan, perhaps its combination.Preferred said natural macromolecular material is a chitosan.
Another preferred version of above-mentioned Biodegradable magnetic nanoparticle is that said nano particle diameter is 25-50nm.
The another preferred version of above-mentioned Biodegradable magnetic nanoparticle is that said magnetic oxygenated ferrous components is γ-Fe
2O
3
Those of ordinary skill in the art need not special experiment and can understand, and preparing said outer shell composition can be different types of biodegradable natural macromolecular material, such as: liposome, blood albumin, gelatin, starch or chitosan; Also can be the combination of these compositions, such as: form gelatin outside chitosan at interior double casing or blood albumin at interior starch double casing outside; Can also be the uniform mixing shell of starch and liposome or the uniform mixing shell of chitosan and gelatin.Preferably, its outer shell component adopts gelatin, blood albumin, chitosan or its combination; Best, described outer shell component is a chitosan.Why saying that these outer shell components all can adopt, is because it is all relatively good on biodegradability, and good with the compatibility of cell, does not have cytotoxicity.It is also fairly simple on raw material provides and prepares, only need on the basis of chitosan magnetic nanometer grain preparation method of the present invention, to change a little, can obtain liposome magnetic nanoparticle, blood albumin magnetic nanoparticle, gelatin magnetic nanoparticle or starch magnetic nanoparticle.
Two of content of the present invention provides a kind of method for preparing said Biodegradable magnetic nanoparticle, and its steps in sequence is as follows:
(1) chitosan is joined in the acid solution dissolves, add γ-Fe
2O
3Particle is uniformly dispersed, as water;
(2) get paraffin and mix, get homogeneous system, as oil phase with surfactant, cosurfactant;
(3) water is joined in the oil phase, stir, obtain the water-in-oil type reverse micro emulsion;
(4) add cross-linking agent in system, 25～40 ℃ are stirred down;
(5) the washing particle is removed particle surface activating agent and Organic substance, vacuum drying.
One of preferred version of the preparation method of above-mentioned Biodegradable magnetic nanoparticle is that the deacetylation of said chitosan is 80～95%.
Two of the preferred version of the preparation method of above-mentioned Biodegradable magnetic nanoparticle is that said cross-linking agent is a glutaraldehyde.
Three of the preferred version of the preparation method of above-mentioned Biodegradable magnetic nanoparticle is, surfactant is class of department, and said cosurfactant is a tween.
Those of ordinary skill in the art need not special experiment and can understand, for selected outer shell component, as liposome, blood albumin, gelatin, starch or chitosan or the like, those skilled in the art can select suitable shell for use according to prior art---the kernel cross-linking agent.For example be raw material with the soluble starch, epoxychloropropane is a cross-linking agent, and Span 60 is an emulsifying agent, and the mixture of toluene and Oleum Ricini is an oil phase, adopts anti-phase suspension cross-linked polymeric method synthetic starch microsphere.
Three of content of the present invention provides the described Biodegradable magnetic nanoparticle of a kind of claim 1 and separates the application of neutralization as bioabsorbable carrier material or pharmaceutical carrier at biomaterial.
A kind of mode of said application is, utilizes Biodegradable magnetic nanoparticle to prepare immune magnetic microsphere with immune antibody or antigen, utilizes the corresponding cell of specific immune response separation and concentration.
The another kind of mode of said application is, utilizes Biodegradable magnetic nanoparticle with physical absorption or chemical bond method free enzyme to be fixed on the granule, makes immobilized enzyme, utilizes the Magnetic Isolation immobilized enzyme, and it is used repeatedly.
Another mode of said application is, utilizes Biodegradable magnetic nanoparticle as the immobilized cancer therapy drug of carrier, carries out target administration, slow release control medicine.
Those of ordinary skill in the art need not special experiment and can understand, because said Biodegradable magnetic nanoparticle is not limited to chitosan magnetic, also have liposome magnetic nanoparticle, blood albumin magnetic nanoparticle, gelatin magnetic nanoparticle or starch magnetic nanoparticle, and the magnetic nanoparticle that combines of several natural polymers, so utilize the different in kind of different sheathing materials, carry the characteristic of medicine, enter the characteristic of cell easily such as: liposome itself, can make good cancer therapy drug magnetic nano-carrier; Utilize the compatibility of blood albumin and peripheral blood and progressively metabolic characteristic to prepare the hepatic disease medicine, compensatory and slowly continuingly act on diseased tissue with the nutrition of keeping liver, form dual support of medicine and nutrition or the like.
Beneficial effect
1. its outer shell of Biodegradable magnetic nanoparticle of the present invention adopts the material that liposome, blood albumin, gelatin, starch or chitosan etc. are nontoxic, have biocompatibility, and making it be applied to biochemical field becomes possibility.
2. because its biodegradation character, Biodegradable magnetic nanoparticle of the present invention is compared with the magnetic nano-particle of biologically inert in the prior art, can make nano-particle not only possess general magnetic nano-particle, also have the biological function of using in the body in external separating power to nucleic acid, protein, animal and plant cells.
3. the present invention prepares the method for Biodegradable magnetic nanoparticle such as chitosan magnetic nano composite material, the particle diameter of gained is that 1-100nm is controlled, such as preferred target grain size is about 40nm, can pass through the conditioned reaction condition, obtain size evenly, favorable dispersibility, magnetic response is good, and the nano-particle of narrow diameter distribution, technology is simple, favorable reproducibility.
4. experiment of the present invention shows, Biodegradable magnetic nanoparticle is used for the CD34 of enrichment
+Cell, purity reach about 80%, are a kind of good detection nano materials.
5. adopt nano-particle to connect biocompatible material, can effectively bring into play the surface area advantage of nano material, improve biological respinse efficient, accelerate the response time, reduce the total amount of reaction system simultaneously, make carry out trace detection and micro-reaction simple and easy to do.
6. Biodegradable magnetic nanoparticle provided by the invention particularly chitosan magnetic is proteinic good biological adsorbent.To proteinic separation and purification, can reach the purpose to resource recycling by chitosan magnetic micro-sphere, and be easy to be separated by eluting through the protein of absorption, activity of proteins also can improve greatly.
7. chitosan magnetic micro-sphere of the present invention can make the separation of immobilized enzyme simple as the carrier of immobilized enzyme.
8. utilize chitosan magnetic micro-sphere of the present invention as the immobilized cancer therapy drug of carrier, utilize cation in its structure in conjunction with the cell in the sugared sincere polysaccharide (GAG) of negative charge, heparin, the cerebrovascular, can reach the purpose of target administration, slow release control medicine, improve utilization ratio of drug and the tumor treatment effect.
9. preparation method of the present invention adopts natural organic high-molecular with low cost, shell cross-linking agent etc., makes practical large-scale production have feasibility.
10. biodegradable magnetic nanoparticle provides the foundation for the research of the physicochemical property of the biomaterial on the nanometer level, and the expansion possibility of its application further is provided simultaneously.
11. on nanoparticle of the present invention, connect nucleic acid, protein, nucleotide, aminoacid, antibody, polypeptide, animal and plant cells, subcellular structure, virus, antibacterial or the like, can be widely used in the interior spike treatment of body of the vitro detection and the disease of each quasi-molecule.
Description of drawings
Fig. 1 is chitosan (a), chitosan magnetic material (b), Fe
2O
3(c) infrared spectrum.The 2882cm of a in the drawings
-1Absworption peak be the stretching vibration peak of the C-H of methyl on the chitosan residual sugar base or methine, b is at 2920cm among the figure
-1And 2845cm
-1Place's absworption peak, this is in the glutaraldehyde-CH
2Stretching vibration peak; At 1729cm
-1New absworption peak appears in the place, the absworption peak of the suspension aldehyde radical that this generates when being the preparation nanoparticle; At 1665cm
-1The stretching vibration absworption peak of schiff base reaction product C=N has appearred in the place; 572cm has also appearred in c simultaneously in the drawings
-1And 632cm
-1Absworption peak be γ-Fe
2O
3Two characteristic peaks.
Fig. 2 is the atomic force microscope figure (a) and the corresponding magnetic scanning figure (b) of chitosan magnetic nano composite material.Zhi Bei magnetic Nano material particle diameter is about 40nm as can see from Figure 1, and size evenly good dispersibility is arranged, and the magnetic response performance of particle is very good.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, as the chemical products handbook, or the condition of advising according to manufacturer.All inorganic chemical reagents and organic solvent are available from Shanghai chemical reagent factory, γ-Fe
2O
3Available from Sigma company.
Embodiment 1
The present invention takes the method for reverse micro emulsion, and preparation chitosan magnetic nano composite material obtains size and be the nano spherical particle about 40nm, and specific implementation method is as follows:
1. take by weighing 1～100mg deacetylation and be respectively 80 ~ 95% chitosan powder and join in 1～10mL, 1% acetum, ultrasonic dissolution adds 5～25mg γ-Fe
2O
3Particle is uniformly dispersed, as water;
2. get 5～50g paraffin, add class of 5～10g department, 5～10g tween stirs, and gets homogeneous system, as oil phase;
3. water is joined in the oil phase, stir, obtain transparent brown water-in-oil type (w/o type) reverse micro emulsion;
4. in system, add 1～3mL glutaraldehyde as cross-linking agent, 25～40 ℃ of waters bath with thermostatic control of water bath with thermostatic control, mechanical agitation, the washed with isopropyl alcohol particle is used in the reaction back, removes particle surface activating agent, Organic substance, dries in 60 ℃ of vacuum drying ovens;
5. with infrared spectrometer, atomic force microscope, instruments such as transmission electron microscope characterize prepared sample.
Fig. 1,2 result show that microsphere is chitosan and γ-Fe
2O
3Composite.
Embodiment 2
Adopt classical reverse phase evaporation to prepare magnetic liposome.An amount of soybean phospholipid, cholesterol (mol ratio is 2: 1) are dissolved in methanol one chloroform (1: the 1) mixed solvent, and rotary evaporation forms the transparent and homogeneous adipose membrane, behind an amount of ether dissolution adipose membrane, adds an amount of γ-Fe
2O
3The particle suspension carries out the rotary evaporation second time after the ultrasonic emulsification, then carry out ultrasonic homogenize, and the microporous filter membrane that at last the liposome suspension is pressed through 450nm promptly gets magnetic liposome, logical nitrogen protection in the operating process.
Liposome has the class cellularity, enters the autoimmune function that is mainly activated body in the body by reticuloendothelial system phagocytic, and changes interior distribution of body of encapsulated medicine.Liposome is stable in lymph, enters lymph node by engulfing of macrophage, is then destroyed by lysosome.
Embodiment 3
Take the method for the reverse micro emulsion identical with embodiment 1, preparation magnetic blood albumin nano composite material obtains size and is the nano spherical particle about 50nm.Under receptor-mediated, can be absorbed when albumin is electronegative by lymph, and infiltration rate with negative charge relevant.The negative charge albumin can arrive around the embryo center and follicle of lymph node, and not only itself is to the inhibitory action of having duplicated of HIV (human immunodeficiency virus) (Human Immunodeficiency Virus), but also can be used as the carrier of anti-acquired immunodeficiency syndrome drug.
Embodiment 4
Take the method for the reverse micro emulsion identical with embodiment 1, preparation magnetic gelatine nano composite material obtains size and is the nano spherical particle about 100nm.Gelatin easily carries out cross-linking reaction with formaldehyde or glutaraldehyde, forms that to have the post bake layer that the three-dimensional network knot draws be the basis of its slow releasing function, consistency, thickness and the fastness of control formation network.
Embodiment 5
Take the method for the reverse micro emulsion identical with embodiment 1, preparation magnetic starch nano composite material obtains the nano spherical particle that size is 50～370nm.The spherex cost is low, stable storage, nontoxic, can not cause immunoreation, itself has microcellular structure, easily adsorbs medicine; Have certain deformability in vivo, can change the shape of oneself according to the microenvironment of vascular plexus; When enzymatic degradation, its medicine carrying ability can keep the long duration before the skeleton disintegrate of microsphere, thereby can effectively prolong the release time of contained medicine, improves the curative effect of medicine.
Embodiment 6
CD34
+Cell enrichment
1.CD34 the preparation of immune magnetic microsphere
The chitosan magnetic Dispersion of Particles that makes in 2mLPBS solution, behind the ultra-sonic dispersion, is added the glutaraldehyde solution of 5mL 5%, and room temperature vibration 12 hours with the washing of PBS buffer solution, adds people CD34 monoclonal antibody, antibody the has been labelling anti-CD34 monoclonal antibody of phycoerythrin.4 ℃ were reacted 12 hours.With CD34 immune magnetic microsphere Magnetic Isolation, 4 ℃ are kept in the PBS buffer solution, standby.
2.CD34
+Cell enrichment
Through the dilution of PBS buffer solution, the lymphocyte separation medium gradient density centrifugal is told mononuclearcell (MNC), washs standby with cell suspension.The CD34 immune magnetic microsphere that adds preparation carries out Magnetic Isolation.
3. cell purity is measured
Detect the CD34 of enrichment through flow cytometer
+Cell purity is for reaching 80%～87%, separates the CD34+ cell that obtains in the umbilical blood of back and accounts for 1.29% ± 0.31% of MNC sum in the umbilical blood sample.
Embodiment 7
The immobilization of cellulase
Take by weighing a certain amount of magnetic gelatine microgranule, add an amount of cellulase, room temperature vibration 8h, the redistilled water thorough washing washes out until no pheron, promptly gets magnetic immobilized cellulase (MIE).Adopt Folin2 phenol method to measure, make standard with bovine serum albumin.And enzymatic activity measured.The maximum carrying capacity of cellulase reaches 138mg/g, and activity recovery can reach 77%.
Embodiment 8
Targeted anticancer medicine
Adopt emulsion-chemical crosslink technique to prepare magnetic-fluorouracil-chitosan microball, magnetic fluorouracil chitosan microball has over paramagnetism, particle size distribution 100nm, γ-Fe
2O
3Mass fraction is 4.5% ~ 11.5%, and entrapment efficiency is 40% ~ 85%.The vitro drug release experiment shows that obvious to the slow releasing function of fluorouracil, deenergized period is long, γ-Fe
2O
3Particle and content are not obvious to the rate of releasing drug influence of microsphere; Drug release is controlled by flooding mechanism mainly, and medicament contg is big more, and the speed that medicine discharges from microsphere is fast more, can be used as ideal magnetic target medicine control delivery.
Claims (10)
1. Biodegradable magnetic nanoparticle possesses the hud typed structure of kernel and shell, and it is characterized in that: inner nuclear layer is a magnetic oxide, and outer shell is a natural macromolecular material; And particle diameter is 1-100nm.
2. Biodegradable magnetic nanoparticle according to claim 1 is characterized in that said natural macromolecular material is selected from liposome, blood albumin, gelatin, starch or chitosan, perhaps its combination.
3. Biodegradable magnetic nanoparticle according to claim 2 is characterized in that, said natural macromolecular material is a chitosan.
4. Biodegradable magnetic nanoparticle according to claim 1 is characterized in that, said nano particle diameter is 25-50nm.
5. Biodegradable magnetic nanoparticle according to claim 4 is characterized in that, said magnetic oxygenated ferrous components is γ-Fe
2O
3
6. the preparation method of the described Biodegradable magnetic nanoparticle of claim 1, its steps in sequence is as follows:
(1) chitosan is joined in the acid solution dissolves, add γ-Fe
2O
3Particle is uniformly dispersed, as water;
(2) get paraffin and mix, get homogeneous system as oil phase with surfactant, cosurfactant;
(3) water is joined in the oil phase, stir, obtain the water-in-oil type reverse micro emulsion;
(4) add cross-linking agent in system, 25～40 ℃ are stirred down;
(5) the washing particle is removed particle surface activating agent and Organic substance, vacuum drying.
7. the preparation method of Biodegradable magnetic nanoparticle according to claim 6 is characterized in that, the deacetylation of said chitosan is 80 ~ 95%.
8. the preparation method of Biodegradable magnetic nanoparticle according to claim 6 is characterized in that, said cross-linking agent is a glutaraldehyde.
9. the preparation method of Biodegradable magnetic nanoparticle according to claim 1 is characterized in that, said surfactant is class of department, and said cosurfactant is a tween.
10. the described Biodegradable magnetic nanoparticle of claim 1 separates the application of neutralization as bioabsorbable carrier material or pharmaceutical carrier at biomaterial.
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