CN100502948C - Magnetic high polymer nanometer micro-balls type medicine carrying system, and its preparation method - Google Patents
Magnetic high polymer nanometer micro-balls type medicine carrying system, and its preparation method Download PDFInfo
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- CN100502948C CN100502948C CNB200310108097XA CN200310108097A CN100502948C CN 100502948 C CN100502948 C CN 100502948C CN B200310108097X A CNB200310108097X A CN B200310108097XA CN 200310108097 A CN200310108097 A CN 200310108097A CN 100502948 C CN100502948 C CN 100502948C
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Abstract
A magenetic high-molecular nano-ball medicine-carrying system is prepared through the polymerizing reaction on oil-water interface between magnetic inorganic nanoparticles (Fe3O4), liposoluble medicine and alpha-alkyl cyanoacrylate to obtain the medicine-carried nano-spheres which has magnetic responsibility and controllable diameter and encapsulated rate of medicine.
Description
Technical field
The invention belongs to technical field of polymer materials, be specifically related to magnetic high-molecular Nano microsphere drug-loading system that has magnetic responsiveness and preparation method thereof.
Technical background
The stimulating responsive polymer microsphere is the very interested a kind of functional polymer microsphere of people in recent years, they can respond to the stimulation of outside such as temperature, pH, ionic strength, pressure, electric field, magnetic field etc., and physicochemical properties, colloidal nature of making himself etc. change.The response to outside stimulus of polymer microsphere makes it still in application great value be arranged all in the basic research field.Magnetic macromolecular microsphere belongs to a kind of in the polymer microsphere, be that organic polymer combines the microsphere with magnetic and special construction that forms with the inorganic magnetic material, because magnetic macromolecular microsphere has the numerous characteristics and the distinctive magnetic responsiveness of polymer microsphere, not only can make its surface have various functional groups by methods such as copolymerization and surface modifications, as-OH ,-COOH ,-NH
2,-SH etc. can also utilize externally-applied magnetic field that it is separated from various media rapidly.Above-mentioned characteristic makes magnetic macromolecular microsphere in a lot of fields, particularly in biomedicine, as clinical diagnosis, enzyme mark, target administration etc., bioengineering field, as cell culture medium, cell marking, cell separation, immunoassay and enzyme immobilization etc., have a wide range of applications.
At present, the research of relevant magnetic high-molecular ball can be divided three classes by its structure: the one, and nuclear is inorganic magnetic material (mainly being iron oxides), shell is the nucleocapsid structure of polymer (synthesized polymer material or natural macromolecular material); Second class is that nuclear is polymer, and shell is the nucleocapsid structure of magnetic material; The 3rd class is a sandwich structure, and promptly the innner and outer layer is polymer, and the intermediate layer is a magnetic material.About preparation method mainly comprises: investment, monomer polymerization method and in-situ method.Investment is class methods the earliest of preparation magnetic macromolecular microsphere.Be to be nuclear, be scattered in the macromolecular solution,, obtain magnetic macromolecular microsphere (Gupta PK, Hong CT, Lam CF, et al.Int J Pharm, 1998 through atomizing, deposition, evaporation etc. by Van der Waals force, hydrogen bond or covalent bond with the magnetic particle; 43:161) Yen etc. is at FeCl
3, and FeCl
2Acidic aqueous solution in dissolve chitosan, then by control pH value obtain chitosan magnetic micro-sphere (Landel RF.USP 4,285,819,1981 for Yen SDS, Rembanm A).Monomer polymerization method wherein mainly contains suspension polymerization, dispersion copolymerization method and emulsion polymerization (comprising emulsifier-free emulsion polymerization, seeding polymerization) etc.Monomer polymerization method is under magnetic particle and organic monomer existence condition, adds materials such as initiator, surfactant, stabilizing agent according to different polymerization methods, and monomer directly forms microsphere at the surface aggregate of magnetic particle.People such as Margel have prepared particle size range in the presence of oil-soluble initiator, suspension stabilizer and inorganic magnetic particle be the magnetic polypropylene aldehydes microsphere (Margel S, Beitler U.USP4,783,336,1988) of 0.03um-80um.It is the hydrophobic magnetic polymer microsphere (Daniel J C, Schuppsier J L.USP 4,358,388.1982) of 0.03um-5um that employing microsuspension polymerizations such as Daniel have obtained particle size range.The microspherulite diameter of suspension polymerization is bigger, the particle size distribution broad.Emulsion polymerisation is the more method for preparing magnetic polymer microsphere of using at present, Furusawa etc. deposit to magnetic-particle on the high molecular emulsion particle that has functional group, adopt seeded emulsion polymerization to make magnetic microsphere (the Furusawa K of sandwich structure then, Nagashima K, Anzai C, ColloidPolym.Sci, 1994,272:1104).Sun Zonghua etc. with magnetic fluid as nuclear, adopt improved emulsion polymerization prepared particle size range be magnetic polystyrene microsphere (Qiu Guangming, Sun Zonghua, chemical reagent, 1993,15 (4): 324) of 0.06um-10um.It is the microsphere of PNIPAM for the polystyrene shell that the method for employing emulsifier-free emulsion polymerizations such as Sauzedde has prepared nuclear, then at its surface adsorption ferriferrous oxide particles, nuclear/shell microsphere with the surface adsorption ferriferrous oxide particles is a seed, repolymerization one deck PNIPAM makes magnetic microsphere (the Sauzedde F of submicron, Elaissari A, Pichot C, ColloidPolym.Sci, 1999,277; 846).The original position rule at first makes monodispersed densification or porous polymer microsphere, and described microsphere contains the group that can form coordinate bond or ionic bond with iron salt according to different needs, as N group, epoxy radicals ,-OH ,-COOH ,-SO
3H etc. can have the difference in functionality base according to polymer microballoon subsequently and prepare magnetic microsphere with diverse ways.Ugelstad etc. have reported that in-situ method prepares the monodisperse magnetic polymer microsphere, its characteristics are to prepare porous polystyrene microsphere with two step swelling methods earlier, in the duct of polystyrene microsphere, use the alkali precipitation iron salt then, make monodispersed magnetic polystyrene microsphere (Ugelstad J, Mork P C, Schmid R, et al, Polym.Int, 1993,30:15.).The defective that in-situ method exists is that the particle diameter of polymer microballoon is big, is not suitable as pharmaceutical carrier, generally is used for cell separation etc. more.
The magnetic macromolecular microsphere of method for preparing has magnetic responsiveness, but is not suitable for being used for research of target medicine carrier microsphere and application.Do not see the pertinent literature report of magnetic high-molecular Nano microsphere drug-loading system up to now with magnetic response performance.
Summary of the invention
The object of the present invention is to provide a kind of magnetic high-molecular Nano microsphere drug-loading system and preparation method thereof with magnetic responsiveness.
Magnetic high-molecular Nano microsphere drug-loading system of the present invention, being to be that the polymer that monomer polymerization produces is an integument with a-alkyl cyanoacrylate (a-Tisuacryl or ethyl ester, isobutyl ester etc.), is the polymer microballoon of nuclear with ferriferrous oxide nano microgranule and fat-soluble medicine dispersion.Described polymer microballoon is synthetic by the method for interfacial polymerization, its particle diameter is 200-300 nanometers in the time of 20 ℃, magnetic saturation intensity is 3.0-40.0emu/g, and has superparamagnetism, since its by organic polymer and inorganic material form, size is nanoscale, and have the magnetic response performance, carrying drug ratio and envelop rate height are so also be referred to as magnetic high-molecular Nano microsphere drug-loading system.
The polymer integument of above-mentioned microsphere is a-alkyl cyanoacrylate copolymer, can be a-Tisuacryl or ethyl ester or isobutyl ester.
The kernel of above-mentioned microsphere is ferriferrous oxide nano microgranule and fat-soluble medicine dispersion.
The above-mentioned magnetic high-molecular Nano microsphere drug-loading system with magnetic responsiveness that the present invention proposes adopts interfacial polymerization method synthetic.Concrete preparation process is as follows:
1, chemical precipitation method prepares ferroferric oxide nano granules: the bivalence and the trivalent iron salt that will be 1:0.5-4.0 with the mol ratio are dissolved in certain deionization water clock, logical nitrogen 5-100 minutes, under mechanical agitation, slowly drip aqueous slkali, reaction temperature is 10-30 ℃, after dripping end, continue to stir 0.3-2.0 hours.Be warming up to 60-90 ℃ and heated 1.0-3.0 hours when stirring, course of reaction need be led to nitrogen.After heating finishes, make product be cooled to room temperature under stirring, separate, collect product and use deionized water wash with Magnet then.Again product is dispersed in the acid solution subsequently, stirred 5-20 minutes, with Magnet separated and collected product.Products therefrom alternately washs with acetone and deionized water.At last iron oxides is scattered in the sodium citrate aqueous solution, is heated to 60-95 ℃, stirred 10-60 minutes, getting concentration is the iron oxides aqueous dispersions of 1-10%wt.
2, emulsion polymerization prepares ferroso-ferric oxide and fat-soluble medicine decentralized photo: fat-soluble medicine is dissolved in the aqueous solution that is dispersed with ferroso-ferric oxide, regulate pH value to 1.0-4.0, stir, aqueous dispersion is added drop-wise in the oil phase that is dissolved with emulsifying agent, continues stirring and made system present even emulsus in 0.5-2.0 hour.
3, interfacial polymerization prepares magnetic high-molecular Nano microsphere drug-loading system: under the room temperature, under stirring a-alkyl cyanoacrylate monomer slowly is added drop-wise in the emulsive system, reacted 4.0-8.0 hour.The gained suspension is placed on the Magnet, remove supernatant,, gained pitchy jelly is dispersed in the methanol, place again on the Magnet, remove supernatant comprising free fat-soluble medicine and blank polyalkylcyanoacrylanano nano microcapsule.Repeat above-mentioned steps, inflated with nitrogen gets magnetic PBCA nano drug-carrying microgranule.
Magnetic nanoparticle of the present invention accounts for the 0.1-5.0% of whole system weight, and oil phase and water volume ratio are 10-45:1, Fe
3O
4The suitable proportion of content and content of monomer is 0.5-2.0:1.
The magnetic high-molecular Nano microsphere drug-loading system of the inventive method preparation can separate under the Magnet effect and wash with water.Described microsphere has the inorganic magnetic kernel, has magnetic responsiveness, can be used as pharmaceutical carrier, under the effect of outside magnetic field, and the targeted therapy effect of performance medicine.
Among the present invention, used magnetic nanoparticle can be wherein a kind of of ferroso-ferric oxide, r-iron sesquioxide.
Among the present invention, used oil phase is a normal hexane.
Among the present invention, used emulsifying agent is the span80/tween80 compound emulsifying agent.
Among the present invention, adopt the interfacial polymerization preparation to have the magnetic high-molecular Nano microsphere drug-loading system of magnetic responsiveness, mixing speed is advisable with 600-1000 rev/min.
The magnetic high-molecular Nano microsphere drug-loading system with magnetic responsiveness of the present invention's preparation, its particle diameter is 200-300 nanometers in the time of 20 ℃.Can control the size of microsphere by the consumption of control monomer consumption, oil phase and water volume ratio, solution pH value, emulsifying agent.In the certain limit, the monomer consumption increases, and microspherulite diameter increases; The oil phase ratio increases, and microspherulite diameter increases.The emulsifying agent consumption increases, and particle diameter reduces.
The magnetic high-molecular Nano microsphere drug-loading system with magnetic responsiveness of the present invention's preparation, its carrying drug ratio and envelop rate can be controlled by the consumption of adjusting monomer consumption, oil phase and water volume ratio, solution pH value, emulsifying agent.
The magnetic high-molecular Nano microsphere drug-loading system with magnetic responsiveness of the present invention's preparation, its magnetic saturation intensity is 3.0-40.0emu/g, and has superparamagnetism.
The present invention is in the above-mentioned scope that feeds intake, and the microsphere of the polymer of preparation parcel inorganic magnetic material is a kind of magnetic high-molecular Nano microsphere drug-loading system with magnetic responsiveness.Its particle diameter is 200-300 nanometers in the time of 20 ℃, and magnetic saturation intensity is 3.0-40.0emu/g, and has superparamagnetism, carrying drug ratio and envelop rate height.
At present, the research of medicine carrying microballoons mainly biases toward simple medicine carrying effect in the world, comparatively speaking, the present invention has following characteristics by the magnetic high-molecular nano drug-carrying microsphere that makes at interfacial polymerization: (1) has magnetic, response performance, targeting administration in the practicable body.(2) size is at nanoscale, and size is adjustable.(3) carrying drug ratio of microsphere and envelop rate can be controlled by the consumption that changes comonomer, oil phase and emulsifying agent.(4) preparation method is simple to operate, and stability is high.
The specific embodiment
Embodiment 1
Get the aqueous dispersion (solid content contains 1.0wt% approximately) of 2.0g ferroso-ferric oxide, add the Aclacnomycin A hydrochloric acid solution of 0.35mg, in the ultrasonic aqueous dispersion that is dispersed in ferroso-ferric oxide, and regulate pH value to 2.0.0.50g span80 and 0.10g tween80 are dissolved in the 50mL normal hexane, and change 500mL three neck round-bottomed flasks over to.Under high-speed stirred (about 600 revolutions per seconds) stirs, aqueous dispersion is added drop-wise in the oil phase that is dissolved with emulsifying agent, continue to stir 0.5h and make system present even emulsus.Under stirring a-Tisuacryl monomer 1.0g slowly is added drop-wise in the good system of emulsifying, reacts 6h under the room temperature again.The gained suspension is placed on the Magnet, remove supernatant (comprising free aklavine and blank PBCA nano-microcapsule).Gained pitchy jelly is scattered in the methanol, places again on the Magnet, remove supernatant.Repeat 5 times, inflated with nitrogen gets magnetic aklavine PBCA nanoparticle.Prepared microspherulite diameter is at 20 ℃ of (D
20 ℃) be 210nm, carrying drug ratio is 10.0%, envelop rate is 36.0%.
Embodiment 2
Get the aqueous dispersion (solid content contains 1.0wt% approximately) of 2.0g ferroso-ferric oxide, add the Aclacnomycin A hydrochloric acid solution of 0.35mg, in the ultrasonic aqueous dispersion that is dispersed in ferroso-ferric oxide, and regulate pH value to 2.0.0.50g span80 and 0.10g tween80 are dissolved in the 50mL normal hexane, change 500mL three neck round-bottomed flasks over to.High-speed stirred (about 600 revolutions per seconds) is added drop-wise to aqueous dispersion in the oil phase that is dissolved with emulsifying agent, continues to stir 0.5h and makes system present even emulsus.At last, under agitation a-Tisuacryl monomer 2.0g slowly is added drop-wise in the good system of emulsifying, reacts 6h after dripping off again.Entire reaction is at room temperature carried out.The gained suspension is placed on the Magnet, remove supernatant (comprising free aklavine and blank PBCA nano-microcapsule).Gained pitchy jelly is dispersed in a certain amount of methanol, and then places on the Magnet, remove supernatant.So repeat 5 times, inflated with nitrogen promptly gets magnetic aklavine PBCA nanoparticle.
The microspherulite diameter that makes is at 20 ℃ of (D
20 ℃) be 256nm, carrying drug ratio is 5.8%, envelop rate is 41.4%.
Embodiment 3:
Get the aqueous dispersion (solid content contains 1.0wt% approximately) of 2.0g ferroso-ferric oxide, add the Aclacnomycin A hydrochloric acid solution of 0.35mg, in the ultrasonic aqueous dispersion that is dispersed in ferroso-ferric oxide, and regulate pH value to 2.0.0.50g span80 and 0.10g tween80 are dissolved in the 20mL normal hexane, and change 500mL three neck round-bottomed flasks over to.Under high-speed stirred (about 600 revolutions per seconds) stirs, aqueous dispersion is added drop-wise in the oil phase that is dissolved with emulsifying agent then, drips off back continuation stirring 0.5h and make system present even emulsus.At last, under agitation a-Tisuacryl monomer 1.0g slowly is added drop-wise in the good system of emulsifying, reacts 6h under the room temperature again.The gained suspension is placed on the Magnet, remove supernatant (comprising free aklavine and blank PBCA nano-microcapsule).Gained pitchy jelly is dispersed in a certain amount of methanol, and then places on the Magnet, remove supernatant.So repeat 5 times, inflated with nitrogen promptly gets magnetic aklavine PBCA nanoparticle.
The microspherulite diameter that makes is at 20 ℃ of (D
20c) be 412nm, carrying drug ratio is 6.2%, envelop rate is 21.4%.
Embodiment 4
Get the aqueous dispersion (solid content contains 1.0wt% approximately) of 2.0g ferroso-ferric oxide, add the Aclacnomycin A hydrochloric acid solution of .35mg, in the ultrasonic aqueous dispersion that is dispersed in ferroso-ferric oxide, and regulate pH value to 4.0.0.50g span80 and 0.10g tween80 are dissolved in the 50mL normal hexane, and change 500mL three neck round-bottomed flasks over to.Under high-speed stirred (about 600 revolutions per seconds) stirs, aqueous dispersion is added drop-wise in the oil phase that is dissolved with emulsifying agent then, drips off back continuation stirring 0.5h and make system present even emulsus.At last, under agitation a-Tisuacryl monomer 1.0g slowly is added drop-wise in the good system of emulsifying, reacts 6h after dripping off again.Entire reaction is at room temperature carried out.The gained suspension is placed on the Magnet, remove supernatant (comprising free aklavine and blank PBCA nano-microcapsule).Gained pitchy jelly is dispersed in a certain amount of methanol, and then places on the Magnet, remove supernatant.So repeat 5 times, inflated with nitrogen promptly gets magnetic aklavine PBCA nanoparticle.
The microspherulite diameter that makes is at 20 ℃ of (D
20 ℃) be 308nm, carrying drug ratio is 7.3%, envelop rate is 24.8%.
Claims (1)
1, a kind of magnetic high-molecular nano drug-carrying microgranule is characterized in that with inorganic magnetic material and Aclacnomycin A be nuclear, is that the polymer that monomer copolymerization produces is a shell with a-Tisuacryl, and following preparation method preparation gets according to concrete steps:
(1) chemical precipitation method prepares ferroferric oxide nano granules: the bivalence and the trivalent iron salt that will be 1:0.5-4.0 with the mol ratio are dissolved in deionized water, logical nitrogen 5-100 minutes, mechanical agitation drips aqueous slkali, reaction temperature is 10-30 ℃, continue to stir 0.3-2.0 hours, 60-90 ℃ were heated 1.0-3.0 hours, and course of reaction is led to nitrogen, after the heating, separate, collect product and washing, product is scattered in acid solution, stirred 5-20 minutes, behind the Magnet separated and collected product, iron oxides is dispersed in the sodium citrate aqueous solution, heat 60-95 ℃, stirred 10-60 minutes, getting concentration is the iron oxides aqueous dispersions of 1-10%wt;
(2) emulsion polymerization prepares ferroso-ferric oxide and Aclacnomycin A decentralized photo: Aclacnomycin A is dissolved in the aqueous solution that is dispersed with ferroso-ferric oxide, regulate pH value to 1.0-4.0, stir down, aqueous dispersion is added drop-wise in the oil phase that is dissolved with emulsifying agent, continues stirring and made system present even emulsus in 0.5-2.0 hour; With
(3) interfacial polymerization prepares magnetic high-molecular Nano microsphere drug-loading system: stir with a-Tisuacryl monomer dropping in emulsive system, reacted again 4.0-8.0 hour, remove supernatant, with the repeating dispersion of gained pitchy jelly in methanol, remove supernatant, inflated with nitrogen promptly gets magnetic PBCA nano drug-carrying microgranule.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100344277C (en) * | 2005-03-30 | 2007-10-24 | 深圳市人民医院 | Nano-magnetic medicinal microglobule, its preparation method and application |
| CN100336857C (en) * | 2005-08-26 | 2007-09-12 | 浙江大学 | Method for preparing ordered ferriferrous oxide/chitosan nanometre composite material |
| CN101164621B (en) * | 2006-10-19 | 2010-05-12 | 陕西西大北美基因股份有限公司 | Super-paramagnetic composite particle drug-loaded body and preparation method thereof |
| CN100532436C (en) * | 2007-08-03 | 2009-08-26 | 中国科学院广州化学研究所 | Water dispersible magnetic polymer microsphere, preparing method and application of the same |
| CN104922702A (en) * | 2015-05-19 | 2015-09-23 | 中国科学院过程工程研究所 | Superparamagnetic nano-particle and preparation method and application thereof |
| CN114573038A (en) * | 2022-03-21 | 2022-06-03 | 同济大学 | Granular magnetic drive micro motor and magnetic control preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5427767A (en) * | 1991-05-28 | 1995-06-27 | Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin | Nanocrystalline magnetic iron oxide particles-method for preparation and use in medical diagnostics and therapy |
| CN1399958A (en) * | 2001-07-27 | 2003-03-05 | 潘君琦 | Taxol nano magnetic target preparation and its preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5427767A (en) * | 1991-05-28 | 1995-06-27 | Institut Fur Diagnostikforschung Gmbh An Der Freien Universitat Berlin | Nanocrystalline magnetic iron oxide particles-method for preparation and use in medical diagnostics and therapy |
| CN1399958A (en) * | 2001-07-27 | 2003-03-05 | 潘君琦 | Taxol nano magnetic target preparation and its preparation method |
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