CN1473558A - Compound function supermicro magnetic carrier particle and its preparing method - Google Patents
Compound function supermicro magnetic carrier particle and its preparing method Download PDFInfo
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- CN1473558A CN1473558A CNA031302696A CN03130269A CN1473558A CN 1473558 A CN1473558 A CN 1473558A CN A031302696 A CNA031302696 A CN A031302696A CN 03130269 A CN03130269 A CN 03130269A CN 1473558 A CN1473558 A CN 1473558A
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Abstract
The present invention relates to superfine magnetic carrier particle with compound function and its preparation process. It is a kind of complex with three-layered core-shell structure including the first layer of ferric oxide, the second layer of polymer carrier material and the third layer of bioactive functional preparation. It has the compound functions of magnetic positioning, biological targeting positioning and controlled medicine release. The preparation process includes the following steps: preparing of super-paramagnetic superfine particle, covering the superfine carrier particle with bioactive functional preparation via physical coagulation and chemical linkage. The preparation process can prepare superfine magnetic carrier particle with compound function in 40-80 nm size and with narrow size distribution, good targeting property, controlled medicine release and thus important application foreground in local medicinal treatment and diagnosis carrier preparation.
Description
Technical field
The invention belongs to technical field of polymer materials, be specifically related to complex function ultramicro magnetic carrier particle and preparation method thereof.
Background technology
Magnetic material is a kind of functional material with good targeting locating features, especially the magnetic material of ultra micron sub level is at magnetic property, all be different from common magnetic material on hot property and the chemical property, utilize these special performances, as far back as eighties of last century sixties just the someone begin the preparation and the application of ultramicro magnetic particle are studied, it is widely used at biomedical sector, as be used as the carrier material of topical medications or diagnosis, and the carrying gene, polypeptide fragments or other biological active ingredient etc.Along with the development of nanoparticle research in recent years, magnetic material has also entered the conceptual phase of nanoparticle.
Existing ultramicro magnetic particle preparation technology roughly has several classes such as hydro-thermal method, plasma method, coprecipitation, sol-gel process.Wherein, coprecipitation is to use the most extensive, the classical way that preparation process is the easiest.Yet existing chemical coprecipitation technique technology is outmoded, and the magnetic particle particle size distribution for preparing is wide, and function singleness is difficult to have superparamagnetism, and adaptive surface is narrow.
Summary of the invention
The purpose of this invention is to provide a kind of magnetic orientation that has concurrently, the ultra-micro carrier particle and the preparation method of biological targeting location and medicine controlled releasing complex function.
The preparation method of this ultramicro magnetic carrier material is improved on the basis of existing chemical coprecipitation technique, concentration control particle size distribution by the conditioned reaction polymer-matrix, produce superparamagnetism with rational heating-up time and speed, and add the bioactive functions preparation with the form of chemical bonding and physical connection at the different application field of ultramicro magnetic particle, made multicomponent, narrow diameter distribution, be generally 40～80 nanometers, have stable superparamagnetism, and have the ultramicro magnetic carrier particle of magnetic orientation, biological targeting location and drug controlled-releasing function concurrently.
The present invention is realized by following technical scheme:
Complex function ultramicro magnetic carrier particle is the three-layer nuclear shell structure complex.Ground floor is an iron oxides, and the second layer is a polymer carrier, and the 3rd layer is the bioactive functions preparation.
Ground floor and second layer particle diameter are the super paramagnetic ultramicron of 20～40 nanometers.
The particle diameter that the surface coats the super paramagnetic ultra-micro carrier of trilaminar bioactive functions preparation is 40～80 nanometers.
Wherein the iron oxides of ground floor 1 is Fe as shown in Figure 1
3O
4, γ-Fe
2O
3Deng one of ferromagnetic material.
The polymer carrier of the second layer 2 is polysaccharide and derivant thereof, is that 10,000～100,000 glucosan, molecular weight are that 50,000～100,000 O-carboxymethyl chitosan and molecular weight are 3,000～10,000 water soluble oligo-chitosan as molecular weight; And molecular weight is a kind of of 2,000～7,000 Polyethylene Glycol carrier materials such as (PEG).
The 3rd layer 3 bioactive functions preparation mainly comprises three major types:
1) targeting preparation comprises antibody and segment thereof, as M
4G
3Human breast carcinoma monoclonal antibody, goat-anti rabbit lgGF (ab ')
2Segment etc.; Cytokine and receptor, transferrins etc.
2) various kinds of drug, as indometacin, aklavine, erythromycin, and various antitumor drug such as amycin, epirubicin, methotrexate, fluorouracil, cisplatin, cytosine arabinoside, bleomycin and all kinds of genetic stews etc.
3) other active function preparations, as have polypeptides matter, pathological diagnosis class material, stem cell etc. such as the higher TAT that strides membrane property.
In concrete enforcement, the bioactive functions ghe layer can be a kind of material, also can be being used of several materials, and main fit system is as follows:
In topical medications, the bioactive functions preparation can be a kind of medicine, also can be targeting preparation, various kinds of drug and has higher combination of striding the polypeptides matters such as TAT of membrane property, gets final product the intensifier target tropism like this and strides film, reduce side effect, strengthened drug effect simultaneously again.For example, in the malignant tumor topical therapeutic, antibody and segment, antitumor drug and TAT polypeptide small molecule can be used.
In local stem-cell therapy, the bioactive functions preparation is being used of targeting preparation and stem cell.
In local pathological diagnosis, the bioactive functions preparation is mainly being used of targeting preparation and other active function preparations, to improve the accuracy of diagnosis.
The present invention provides a kind of method for preparing complex function ultramicro magnetic carrier material simultaneously, and concrete preparation process is as follows:
(1) preparation of super paramagnetic ultramicron;
(2) utilize physical condensation method and chemical bonding at ultra-micro carrier particle surface coated biologically active function preparation.The concrete grammar of step is as follows:
(1) preparation of super paramagnetic ultramicron
The preparation of X solution:
With polymer carrier: iron salt: the weight ratio ratio of deionized water=1: 1.5～2.3: 8～15 (what do not specify among the present invention all is weight ratios) obtain solution, and in ice-water bath, be cooled to 0～15 ℃, stand-by;
Wherein iron salt is FeCl
3, Fe
2(SO
4)
3Deng.
The preparation of Y solution:
With ferrous salt: the ratio obtain solution of deionized water=1: 0.2～4, in ice bath, be cooled to 0～15 ℃, stand-by;
Wherein ferrous salt is FeCl
2, FeSO
4Deng.
X solution is placed ice-water bath, Y solution is dropwise added to mix stir.The heating ice-water bath, the control temperature progressively rose to 50～100 ℃ in 10～60 minutes, keep under this temperature 0.1～0.8 volumetric concentration is that 1～4 mole every milliliter aqueous alkali joins in the XY mixed solution, continued to mix solution 30～60 minutes, obtain the super paramagnetic ultramicron colloid solution of pitchy, obtain the super paramagnetic ultramicron that particle diameter is 20～40 nanometers through common post processing.
The method that post processing can be adopted is: with the colloid solution that obtains through dialysis, magnetic separation, high speed centrifugation, lyophilization etc.(2) utilize physical condensation method and chemical bonding at ultra-micro carrier particle surface coated biologically active function preparation
Super paramagnetic ultramicron by step (1) preparation is dissolved in rare bioactive functions preparation aqueous solution,, is connected with biologically active agents in conjunction with the low frequency ultrasound bath by physical condensation method and chemical bonding; The colloid solution that obtains obtains the super paramagnetic ultra-micro carrier that particle diameter is the surperficial coated biologically active function preparation of 40～80 nanometers through common post processing.
The concrete grammar of step (2) can adopt many kinds, is described below several here:
Super paramagnetic ultramicron by step (1) preparation is dissolved in rare bioactive functions preparation aqueous solution, be warmed up to 45～75 ℃, add buffer solution again and regulate Ph value 4.5～7.5, low frequency ultrasound obtains the super paramagnetic ultra-micro carrier particle of surperficial coated biologically active function preparation by physical condensation;
Maybe can utilize strong oxidizer, as NalO
4Will be by the super paramagnetic ultramicron hydroformylation of step (1) preparation, again by the super paramagnetic ultramicron of hydroformylation: the bioactive functions preparation: the mixed of buffer solution=1: 0.1～0.8: 15, room temperature reacted 18～36 hours down, mixture through common post processing, is obtained the super paramagnetic ultra-micro carrier of surperficial coated biologically active function preparation.
Also can be by super paramagnetic ultramicron: bioactive functions preparation: cross-linking agent: the mixed of deionized water=1: 0.1～0.8: 0.25～2: 15, with diluted acid adjust pH 4～7.5, in 10～40 ℃ of reactions 10～48 hours.The colloid solution that obtains is fully dialysed after Magnetic Isolation, high speed centrifugation, lyophilization, and obtaining particle diameter is the super paramagnetic ultra-micro carrier of the surperficial coated biologically active function preparation of 40～80 nanometers.
By the ultramicro magnetic carrier particle of the present invention preparation because the adding of polymer carrier and bioactive functions preparation, formed the nucleocapsid system of polymer and ferrum oxygen particle, make the carrier particle of preparation have two kinds of locate modes of magnetic orientation and biological targeting location concurrently, but at treatment and diagnostic procedure Chinese medicine controlled release.Especially this carrier particle has reduced side effect to lesion tissue targeting locating features accurately, strengthens drug effect, has improved patient's life quality.
The ultramicro magnetic carrier particle of this law preparation is with the obvious advantage aspect the medicine topical therapeutic.At first, the dual positioning function of magnetic targeting and biological targeting has determined that medicine only in the lesions position gathering, has reduced medicine to Normocellular toxic and side effects; Secondly, the polymer carrier of one of component can connect different medicines, as antineoplastic agent and genomic medicine etc.; And can also connect some micromolecule polypeptide, and as TAT etc., increase the ability that this carrier system passes cell membrane and crosses over blood brain barrier, make the ultra-micro carrier of this complex function have versatility widely.In addition, this carrier system also can reach the effect that some disease is positioned diagnosis and stem cell reparation by in conjunction with material and stem cell with pathological diagnosis characteristic.
The present invention is simple to operate, raw material economics, and the operating process cleaning has vast potential for future development in the preparation of medicine topical therapeutic and diagnosis carrier system.
Description of drawings:
Fig. 1 is the ultramicro magnetic carrier particle nucleocapsid structure sketch map of the present invention's preparation;
Fig. 2 is the pattern of the ultramicro magnetic carrier particle of 35nm for the mean diameter of the present invention's preparation;
Fig. 3 is the transmission electron microscope photo of complex function ultramicro magnetic carrier particle;
Fig. 4 is the particle size distribution figure of the complex function ultramicro magnetic carrier particle of the present invention's preparation;
Fig. 5 is the infrared spectrum of the complex function ultramicro magnetic carrier particle of the present invention's preparation;
Fig. 6 returns curve (M-H curve) for the complex function ultramicro magnetic carrier particle of the present invention's preparation by the measured magnetic hysteresis of VSM LDJ9600-1.
The specific embodiment
Embodiment 1:
Polymer carrier is glucosan (MW=40,000) in this example, and the bioactive functions preparation is an epirubicin.
The preparation of X solution:
With glucosan: FeCl
3: the ratio obtain solution of deionized water=1: 1.5: 8, and in ice-water bath, be cooled to 0 ℃, stand-by;
The preparation of Y solution:
With FeCl
2: the ratio obtain solution of deionized water=1: 0.2, in ice bath, be cooled to 15 ℃, stand-by;
X solution is placed 4 ℃ of ice-water baths, Y solution is added to mix stir.The heating ice-water bath, be controlled at and progressively be warming up to 50 ℃ in 10 minutes, keep that 4 moles every milliliter NaOH solution 0.1 times of volume joins in the XY mixed solution under this temperature, continued to mix solution 30 minutes, obtain the super paramagnetic ultramicron of the glucosan colloid solution of pitchy; The colloid solution that obtains is fully dialysed, and again through Magnetic Isolation, high speed centrifugation, lyophilization, obtaining mean diameter is the super paramagnetic ultramicron of glucosan of 35nm, as shown in Figure 2.
Take by weighing the super paramagnetic ultramicron of glucosan that 6mg the present invention prepares and put into test tube, add the deionized water dissolving of 15 times of volumes.The sodium metaperiodate that in pipe, adds 0.5% (W/V) again, lucifuge reaction is 1 hour under the room temperature, and purification and lyophilizing obtain the super paramagnetic ultramicron of glucosan of hydroformylation.
The super paramagnetic ultramicron of glucosan with hydroformylation: epirubicin: the mixed of PBS buffer=1: 0.1: 15, room temperature reaction 24 hours.Reactant mixture is again through sodium borohydride reduction, and fully dialysis, lyophilizing, and promptly getting mean diameter is the super paramagnetic ultra-micro carrier of the epirubicin-glucosan particle of 60nm.
Product such as Fig. 3 of example of the present invention 1 preparation, Fig. 3 is the transmission electron microscope photo of the product that obtains with the JEM-100CXII of NEC Optical Co., Ltd type transmission electron microscope.
Obtain the particle size distribution of the super paramagnetic ultramicron of epirubicin-glucosan by image analysis software, as see shown in Figure 4, the super paramagnetic ultramicron of epirubicin-glucosan particle diameter with this method preparation is a nanoscale, and mean diameter is 45 nanometers, and particle size distribution is narrower.
The super paramagnetic ultramicron of freeze dried epirubicin-glucosan is obtained a slick magnetic hysteresis by VSM LDJ9600-1 magnetic property analyser return curve as shown in Figure 5, can judge that thus the super paramagnetic ultramicron of epirubicin-glucosan with this method preparation has superparamagnetism.
By infrared absorption spectroscopy, as shown in Figure 6, detect the glucosan that is complexed to ferrum oxygen particle top layer.
Embodiment 2:
Polymer carrier is O-carboxymethyl chitosan (MW=100,000) in this example, and the bioactive functions preparation is a doxorubicin hydrochloride.
The preparation of X solution:
With O-carboxymethyl chitosan: Fe
2(SO
4)
3: the ratio obtain solution of deionized water=1: 2.3: 15, and in ice-water bath, be cooled to below the room temperature, stand-by;
The preparation of Y solution:
With FeSO
4: the ratio obtain solution of deionized water=1: 4, in ice bath, be cooled to 4 ℃, stand-by;
X mixed with Y solution and place ice-water bath.The heating ice-water bath makes its temperature progressively rise to 80 ℃ at 30 minutes, keeps temperature, 1 mole every milliliter NH of 0.5 times of volume
4OH joins in the XY mixed solution, continues reaction 50 minutes, obtains the super paramagnetic ultramicron of cervine O-carboxymethyl chitosan colloid solution; With colloid solution purification and lyophilization, obtaining mean diameter is the super paramagnetic ultramicron of O-carboxymethyl chitosan of 40nm.
Press the super paramagnetic ultramicron of O-carboxymethyl chitosan: doxorubicin hydrochloride: EDC: deionized water=1: 0.1: 0.25: 15 mixed, with hydrochloric acid adjust pH 5.5, in 16 ℃ of reactions 24 hours.Product is fully dialysed and purification, and obtaining mean diameter is the doxorubicin hydrochloride-super paramagnetic ultra-micro carrier of O-carboxymethyl chitosan particle of 60nm.Embodiment 3:
Identical with the step among the embodiment 1, different is
Polymer carrier is water soluble oligo-chitosan (MW=3,000) in this example, and the bioactive functions preparation is a bleomycin.
By the super paramagnetic ultramicron of oligo-chitosan of hydroformylation: bleomycin: the mixed of PBS buffer=1: 0.4: 15, the room temperature lucifuge was reacted 24 hours.Reactant mixture is again through sodium borohydride reduction, and subsequent purificn and lyophilizing promptly get the super paramagnetic ultra-micro carrier of the bleomycin-chitosan particle of mean diameter 70nm.
Embodiment 4:
Identical with the step among the embodiment 1, different is
Polymer carrier is Polyethylene Glycol (MW=7,000) in this example, and the bioactive functions preparation is a methotrexate.
The super paramagnetic ultramicron of Polyethylene Glycol with hydroformylation: methotrexate: the mixed of PBS buffer=1: 0.8: 15, room temperature lucifuge reaction 24 hours.Reactant mixture is through sodium borohydride reduction, and fully dialysis, lyophilizing, and promptly getting mean diameter is the super paramagnetic ultra-micro carrier of the methotrexate-Polyethylene Glycol particle of 75nm.
Embodiment 5:
Identical with the step among the embodiment 2, different is
Polymer carrier is water soluble oligo-chitosan (MW=10,000) in this example, and the bioactive functions preparation is an epirubicin
By the super paramagnetic ultramicron of oligo-chitosan of hydroformylation: epirubicin: the mixed of PBS buffer=1: 0.5: 15, the room temperature lucifuge was reacted 24 hours.Reactant mixture is again through sodium borohydride reduction, subsequent purificn and lyophilizing, and obtaining mean diameter is the super paramagnetic ultra-micro carrier of the epirubicin-oligo-chitosan particle of 70nm.
Embodiment 6:
Identical with the step among the embodiment 1, different is
Polymer carrier is Polyethylene Glycol (MW=4,000) in this example, and the bioactive functions preparation is a cytosine arabinoside.
By the super paramagnetic ultramicron of Polyethylene Glycol of hydroformylation: cytosine arabinoside: the mixed of PBS buffer=1: 0.3: 15, the room temperature lucifuge was reacted 24 hours.Reactant mixture is again through sodium borohydride reduction, and subsequent purificn and lyophilizing promptly get the super paramagnetic ultra-micro carrier of the cytosine arabinoside-Polyethylene Glycol particle of mean diameter 80nm.
Embodiment 7:
Identical with the step among the embodiment 2, different is
Polymer carrier is O-carboxymethyl chitosan (MW=50,000) in this example, and the bioactive functions preparation is ferrum saturation type transferrins (MW=80,000).
The super paramagnetic ultramicron of O-carboxymethyl chitosan of 1mg the present invention preparation is dissolved in the ferrum saturation type transferrins aqueous solution of 5ml 1% (W/V), and in water-bath, is warming up to 60 ℃.Acetic acid-sodium acetate buffer solution is added in the above-mentioned aqueous solution fast, regulate pH value 5.5, sonic oscillation.Purified processing of the colloid solution that obtains and lyophilization, obtaining mean diameter is the super paramagnetic ultra-micro carrier of O-carboxymethyl chitosan of the surface coating ferrum saturation type transferrins of 80nm.
Embodiment 8:
Identical with the step among the embodiment 1, different is
Polymer carrier is glucosan (MW=10,000) in this example, and the bioactive functions preparation is M
4G
3Human breast carcinoma monoclonal antibody and doxorubicin hydrochloride.
Press the super paramagnetic ultra-micro carrier of doxorubicin hydrochloride-glucosan particle: M
4G
3Human breast carcinoma monoclonal antibody: the mixed of PBS buffer=1: 0.4: 15, low-temp reaction 24 hours.Reactant mixture is again through sodium borohydride reduction, and is centrifugal, gets supernatant, and the Sephacry-300 gel filtration is collected first peak, and lyophilization promptly gets the super paramagnetic ultra-micro carrier of the doxorubicin hydrochloride immunity complex function particle of purification.Detect through ELISA, the antibody activity on the ultra-micro carrier particle keeps more than 80%.
This carrier particle is in the extracorporeal anti-tumor test cell line, and inhibition rate of tumor cell reaches more than 80%.In the animal body in later stage in the targeting positioning experiment, carrier particle is injected by the rabbit one edge vein of picking up the ears, and successfully is enriched in the rabbit offside ear magnetic region at external magnetic field place, and by the ECT detection of dynamic enrichment process of carrier particle.
Embodiment 9:
Identical with the step among the embodiment 1, different is
Polymer carrier is glucosan (MW=100,000) in this example, and the bioactive functions preparation is goat-anti rabbit lgGF (ab ')
2Segment and methotrexate.
Press the super paramagnetic ultra-micro carrier of methotrexate-glucosan particle: goat-anti rabbit lgGF (ab ')
2: the mixed of PBS buffer=1: 0.35: 15, lucifuge low-temp reaction 24 hours.Reactant mixture is again through sodium borohydride reduction, and is centrifugal, gets supernatant, and the Sephacry-300 gel filtration is collected first peak, and lyophilization promptly gets the super paramagnetic ultra-micro carrier of the methotrexate immunity complex function particle of purification.Detect through ELISA, the antibody activity on the ultra-micro carrier particle keeps 80%.
The present invention open and the preparation method and the product that propose, those skilled in the art can be by using for reference this paper content, and links such as appropriate change raw material, technological parameter, structural design realize.Method of the present invention and product are described by preferred embodiment, person skilled obviously can be in not breaking away from content of the present invention, spirit and scope to method as herein described with product is changed or suitably change and combination, realize the technology of the present invention.Special needs to be pointed out is, the replacement that all are similar and change apparent to those skilled in the artly, they are regarded as being included in spirit of the present invention, scope and the content.
Claims (10)
1. complex function ultra-micro carrier particle, it is the three-layer nuclear shell structure complex; It is characterized in that ground floor is an iron oxides, the second layer is a polymer carrier, and the 3rd layer is the bioactive functions preparation.
2. a kind of complex function ultra-micro carrier particle as claimed in claim 1, it is characterized in that described ground floor and second layer particle diameter are the super paramagnetic ultramicron of 20～40 nanometers, the particle diameter that the surface coats the super paramagnetic ultra-micro carrier of trilaminar bioactive functions preparation is 40～80 nanometers.
3. a kind of complex function ultra-micro carrier particle as claimed in claim 1 is characterized in that described ground floor iron oxides is Fe
3O
4Or γ-Fe
2O
3The polymer carrier of the second layer is polysaccharide and derivant and Polyethylene Glycol (PEG); Trilaminar biologically active agents mainly comprises three major types:
1) targeting preparation comprises antibody and segment thereof, as M
4G
3Human breast carcinoma monoclonal antibody, goat-anti rabbit lgGF (ab ')
2And cytokine and receptor, transferrins;
2) various kinds of drug, as indometacin, aklavine, erythromycin, and amycin, epirubicin, methotrexate, fluorouracil, cisplatin, the various antitumor drug of cytosine arabinoside and all kinds of genetic stew;
3) other active function preparations, as have higher TAT polypeptides matter, pathological diagnosis class material, the stem cell that strides membrane property.
4. a kind of complex function ultra-micro carrier particle as claimed in claim 3, it is characterized in that described polysaccharide and derivant thereof are that molecular weight is 10,000～100,000 glucosan, molecular weight are 50,000～100,000 O-carboxymethyl chitosan and molecular weight are 3,000～10,000 water soluble oligo-chitosan, the molecular weight of described PEG are 2,000～7,000.
5. preparation method for preparing complex function ultramicro magnetic carrier material, concrete preparation process is as follows:
(1) preparation of super paramagnetic ultramicron;
(2) utilize physical condensation method and chemical bonding at ultra-micro carrier particle surface coated biologically active function preparation.
6. a kind of method for preparing complex function ultramicro magnetic carrier material as claimed in claim 5,
(1) preparation of super paramagnetic ultramicron
The preparation of X solution:
With polymer carrier: iron salt: the weight ratio ratio obtain solution of deionized water=1: 1.5～2.3: 8～15 (what do not specify among the present invention all is weight ratios), and in ice-water bath, be cooled to 3～25 ℃, stand-by;
The preparation of Y solution:
With ferrous salt: the ratio obtain solution of deionized water=1: 0.2～4, in ice bath, be cooled to below 3～25 ℃, stand-by;
Y solution is added the X solution that places ice-water bath mix stirring; The heating ice-water bath, make its temperature in 10～60 minutes, progressively rise to 50～100 ℃, keeping following 0.1～0.8 times of volumetric concentration of this temperature is that 1～4 mole/milliliter aqueous alkali joins in the XY mixed solution, continue to mix solution fast 30～60 minutes, obtain the super paramagnetic ultramicron colloid solution of pitchy, obtain the super paramagnetic ultramicron that particle diameter is 20～40 nanometers through common post processing;
(2) utilize physical condensation method and chemical bonding at ultra-micro carrier particle surface coated biologically active function preparation:
Super paramagnetic ultramicron by step (1) preparation is dissolved in rare bioactive functions preparation aqueous solution,, is connected with biologically active agents in conjunction with the low frequency ultrasound bath by physical condensation method and chemical bonding; The colloid solution that obtains obtains the super paramagnetic ultra-micro carrier that particle diameter is the surperficial coated biologically active function preparation of 40～80 nanometers through common post processing.
7. a kind of method for preparing complex function ultramicro magnetic carrier material as claimed in claim 6 is characterized in that described step (2) is:
Super paramagnetic ultramicron by step (1) preparation is dissolved in rare bioactive functions preparation aqueous solution, be warmed up to 45～75 ℃, add buffer solution again and regulate Ph value 6.5～8.5, low frequency ultrasound obtains the super paramagnetic ultra-micro carrier particle of surperficial coated biologically active function preparation by physical condensation;
Or utilize strong oxidizer, will be by the super paramagnetic ultramicron hydroformylation of step (1) preparation, again by the super paramagnetic ultramicron of hydroformylation: the bioactive functions preparation: the reaction 18～36 hours down of the mixed of buffer solution=1: 0.1～0.8: 15, room temperature; Mixture through common post processing, is obtained the super paramagnetic ultra-micro carrier of surperficial coated biologically active function preparation;
Or by super paramagnetic ultramicron: bioactive functions preparation: cross-linking agent: the mixed of deionized water=1: 0.1～0.8: 0.25～2: 15, with diluted acid adjust pH 4～7.5, reacted 10～48 hours at 10～40; The colloid solution that obtains is fully dialysed after Magnetic Isolation, high speed centrifugation, lyophilization, obtains the super paramagnetic ultra-micro carrier of surperficial coated biologically active function preparation.
8. a kind of method for preparing complex function ultramicro magnetic carrier material as claimed in claim 6, it is characterized in that the preparation of described X, Y solution after, be 4～7 ℃ with the cold temperature of ice bath.
9. a kind of method for preparing complex function ultramicro magnetic carrier material as claimed in claim 6 is characterized in that described X, Y solution mix the back and was warming up to 70～85 ℃ at 20～30 minutes.
10. a kind of method for preparing complex function ultramicro magnetic carrier material as claimed in claim 6 is characterized in that described aqueous alkali is NaOH or NH
4OH solution; Is 0.5～0.7 times of volumetric concentration that 2.5～4 moles/milliliter aqueous alkali joins in the XY mixed solution.
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| CN1973832B (en) * | 2006-10-24 | 2010-05-12 | 中山大学 | Biodegradable nanometer medicine capsule with CT trace effect and its preparation process |
| CN1943565B (en) * | 2006-10-24 | 2010-05-26 | 中山大学 | Biological degradable nano medicinal capsule with MRI tracer effect and its preparing method |
| CN102218150A (en) * | 2010-08-17 | 2011-10-19 | 扬州大学 | Novel liver-targeting nanometer Fe3O4MRI (Magnetic Resonance Imaging) contrast medium and preparation method |
| CN105102979A (en) * | 2013-01-29 | 2015-11-25 | 生物辐射海法有限公司 | Hand maneuverable laser welding gun |
| CN105412951A (en) * | 2015-11-17 | 2016-03-23 | 浙江大学 | Super-paramagnetic iron oxide nanoparticle compound as well as preparation method and application thereof |
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