CN102580642B - Method for preparing high-magnetization chitosan nanospheres - Google Patents
Method for preparing high-magnetization chitosan nanospheres Download PDFInfo
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- CN102580642B CN102580642B CN201210060861.XA CN201210060861A CN102580642B CN 102580642 B CN102580642 B CN 102580642B CN 201210060861 A CN201210060861 A CN 201210060861A CN 102580642 B CN102580642 B CN 102580642B
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Abstract
The invention provides a method for preparing high-magnetization chitosan nanospheres. according to the invention, an improved ultrasonic emulsification pre-crosslinking technique is adopted, namely, a chitosan solution in which superparamagnetic nanoparticles are dispersed is taken as a water phase, and liquid paraffin is taken as an oil phase, a high-magnetization and particle-size-controlled chitosan nanosphere is obtained through adjusting the composition of the oil and water phases and carrying out mixing, ultrasonic dispersion and ultrasonic pre-crosslinking,. The preparation method provided by the invention is simple, high in efficiency and low in cost; the highest saturation magnetization of the obtained chitosan nanosphere can be more than 45 emu/g; and the method has great application potentials in the fields of biological medicines, enzyme engineering and magnetic separation.
Description
Technical field
The invention belongs to nano meter biomaterial and field of pharmaceutical preparations, specifically adopt the method for the chitosan nano ball of the standby parcel of ultrasonic emulsification precrosslink legal system superparamagnetic nano particle.
Background technology
Magnetic macromolecular microsphere has important application prospect in fields such as cell separation purifying, enzyme immobilization, drug delivery, biological detection, is subject in recent years extensive concern (Adv Drug Deliv Rev, 2008,60:1252-1265; Biomateria, 2005,26:3995-4021).The magnetic nano-particles such as tri-iron tetroxide are easily assembled due to attraction between particle dipole, have limited its actual application value.In order to improve biocompatibility and the dispersion stabilization of superparamagnetic nanoparticle, conventionally adopt surfactant or macromolecular material to modify it.By the different magnetic macromolecular microspheres of structure, be divided into: 1. shell/core formula, outer shell is macromolecular material, inner nuclear layer is magnetic material; 2. core/shell-type, outer shell is magnetic material, inner nuclear layer is macromolecular material; 3. shell/core/shell-type, outer and internal layer is macromolecular material, intermediate layer is magnetic material.Wherein with first kind shell/core formula polymer microsphere, study and apply more.Conventional macromolecular material comprises synthetic material (as polyethylene glycol, polystyrene, polymethyl methacrylate etc.) and natural macromolecular material (as shitosan, cellulose, starch etc.).Natural macromolecular material is because its biocompatibility fortunately biomedicine field is widely used, and wherein shitosan is paid attention in recent years widely because its good biocompatibility, hypotoxicity, biodegradability and output are abundant.
The preparation method of shell/core formula magnetic macromolecular microsphere mainly contains three kinds at present: investment, monomer polymerization method and in-situ method.Monomer polymerization comprise again suspension polymerisation, emulsion polymerisation, dispersin polymerization (Progress in Biochemistry and Biophysics, 2010,37:433-440).Magnetic particle wider distribution prepared by investment, out-of-shape and be difficult to control, in-situ polymerization is complicated, and the magnetic microsphere magnetic content obtaining is lower.Monomer polymerization method is a kind of common method of preparing magnetic macromolecular microsphere, suspension polymerisation is generally used for prepares micron order microballoon, dispersin polymerization is general adopts artificial synthetic macromolecule to prepare micron order to nanoscale microballoon, but manually synthetic macromolecule is poor aspect biocompatibility, limited the biologic applications of magnetic nano-balls.The people such as Shen (Colloids Surf B:Biointerfaces, 2009,68:1-6) reported a kind of shitosan magnetic nanosphere that adopts emulsion polymerization to prepare load 5-fluorouracil, particle diameter 100 ± 20nm, but the specific saturation magnetization of this nanosphere only has 3.4emu/g, there is in actual applications the not strong problem of magnetic responsiveness.
The present invention adopts a kind of improved ultrasonic emulsification cross-linking method, with tri-iron tetroxide (Fe
3o
4) nano particle is core, shitosan is shell, and by changing reaction condition, to obtain a kind of magnetic content high, and the shitosan magnetic nanosphere of particle size range controlled (100-1000nm), has potential using value at technical field of bioengineering.
Summary of the invention
The present invention is intended to overcome prior art deficiency, provides a kind of simple to operate, the preparation method of the shitosan magnetic nanosphere that the scale that is easy to is amplified, and the nanosphere particle diameter that the method obtains is controlled, and good biocompatibility can be widely used in biotechnology and field of medicaments.
The technology path that the present invention takes is:
1. by chemical coprecipitation, prepare superparamagnetism Fe
3o
4nano particle, further adopts natrium citricum to modify and makes water-based magnetic fluid.
2. get water-based magnetic fluid in appropriate step 1 and mix as water with chitosan-acetic acid solution, slowly inject the oil phase that is added with surfactant after ultrasonic 10 minutes, under given pace, mechanical agitation is more than 15 minutes.
The emulsion obtaining in step 2 is further ultrasonic in ultrasonic cell disruption instrument 3., in ultrasonic, drip crosslinking agent precrosslink, after a period of time, stop ultrasonic.Gained emulsion is continued to stir after a period of time at a certain temperature, use successively benzinum, isopropyl alcohol, second alcohol and water centrifuge washing, obtain target product.For the ease of storing, also can adopt freeze-drying to obtain chitosan magnetic nanosphere powder.
The present invention is applicable to prepare nanoscale (100-1000nm) magnetic microsphere.Macromolecular material used is shitosan, but is not limited to shitosan, can also be that other natural polysaccharides are as glucan, starch, cellulose etc.
Superparamagnetism Fe in step 1 of the present invention
3o
4nano particle is self-control, particle size range 9.6-22.4nm.But be not limited to Fe
3o
4, can also be MnFe
2o
4, γ-Fe
2o
3etc. superparamagnetic nano particle.
Fe in step 2 of the present invention
3o
4nano particle with chitosan mass than scope 1; 1～1; 4, chitosan molecule weight range is 5000-1,000,000 ten thousand, and oil phase used can be atoleine, castor oil, olive oil, soybean wet goods, or the mixture of they and benzinum.Optimum condition is Fe
3o
4nano particle with chitosan mass than 1; 1, chitosan molecule amount 5000, oil phase is atoleine.
Ultrasonic cell disruption instrument ultrasonic power scope 100w-800W in step 3 of the present invention, cross-linking reaction temperature range 25-50 ℃, cross-linking reaction time 6-24 hour.Optimum condition is: ultrasonic power 500W, 40 ℃ of cross-linking reaction temperature, cross-linking reaction time 12 hours.
Technology path 3 in the present invention is committed steps, its feature is to add crosslinking agent in ultrasonic dispersion process, make nanosphere first carry out precrosslink, precrosslink time range 10min-60min, contribute to like this to keep sphericity and the high magnetic content of chitosan nano ball, avoided the poor or not balling-up of conventional method chitosan sphere degree, the shortcoming that coated magnetic nanoparticle is few.Again through being further cross-linked and just can obtaining the good nanosphere of sphericity in later stage whipping process.
The technique effect that the present invention produces:
The invention provides a kind of crosslinked method of preparing chitosan magnetic nanosphere of ultrasonic emulsification.Fe
3o
4nano particle both can have been bought also and can make by oneself in laboratory, and the particle diameter of nanosphere can be controlled by changing the conditions such as ultrasonic power, chitosan molecule amount and oil phase viscosity, and reproducible, preparation method is simple, and efficiency is high, and cost is low.More than the saturation magnetization of gained shitosan magnetic nanosphere reaches as high as 45emu/g.At biological medicine, enzyme engineering, magnetic separation field, having very greatly should be potential.
Accompanying drawing explanation
Fig. 1 is transmission electron microscope (TEM) photo of the shitosan magnetic nanosphere of embodiment 1 preparation
The specific embodiment
Embodiment mono-
2% shitosan, (Mw 5,000) the nano ferriferrous oxide particle aqueous solution 1ml of acetum 1ml and 10mg/ml mixes, ultrasonic 30 minutes, then under certain stir speed (S.S.), above-mentioned solution is slowly added drop-wise in the atoleine that contains 4%Span80, continue to stir 15 minutes.By the colostric fluid obtaining in ultrasonic cell disruption instrument ultrasonic 30 minutes, power 500W, dripped 4ml glutaraldehyde solution after ultrasonic 15 minutes, and chitosan nano ball is tentatively cross-linked.After ultrasonic end, tentatively crosslinked emulsion is transferred in there-necked flask, under agitation continued 40 ℃ of temperature crosslinked 12 hours.After reaction finishes, use successively benzinum, isopropyl alcohol, ethanol and pure water centrifuge washing, obtain wrapping up Fe
3o
4magnetic chitosan nanoparticles, average grain diameter 174nm (figure mono-).
Embodiment bis-
2% shitosan, (Mw 50,000) the nano ferriferrous oxide particle aqueous solution 1ml of acetum 1ml and 20mg/ml mixes, ultrasonic 30 minutes, then under certain stir speed (S.S.), above-mentioned solution is slowly added drop-wise in the atoleine that contains 4%Span80, continue to stir 15 minutes.By the colostric fluid obtaining in ultrasonic cell disruption instrument ultrasonic 30 minutes, power 400W, dripped 4ml glutaraldehyde solution after ultrasonic 15 minutes, and chitosan nano ball is tentatively cross-linked.After ultrasonic end, tentatively crosslinked emulsion is transferred in there-necked flask, under agitation continued temperature 50 C crosslinked 12 hours.After reaction finishes, use successively benzinum, isopropyl alcohol, ethanol and pure water centrifuge washing, obtain magnetic chitosan nanoparticles, average grain diameter 360nm.
Embodiment tri-
2% shitosan, (Mw 200,000) the nano ferriferrous oxide particle aqueous solution 1ml of acetum 1ml and 15mg/ml mixes, ultrasonic 30 minutes, then under certain stir speed (S.S.), above-mentioned solution is slowly added drop-wise in the olive oil/benzinum (volume ratio 8/2) that contains 4%Span80, continues to stir 15 minutes.By the colostric fluid obtaining in ultrasonic cell disruption instrument ultrasonic 30 minutes, power 500W, dripped 4ml glutaraldehyde solution after ultrasonic 15 minutes, and chitosan nano ball is tentatively cross-linked.After ultrasonic end, tentatively crosslinked emulsion is transferred in there-necked flask, under agitation continued 40 ℃ of temperature crosslinked 24 hours.After reaction finishes, use successively benzinum, isopropyl alcohol, ethanol and pure water centrifuge washing, obtain magnetic chitosan nanoparticles, average grain diameter 870nm.
Claims (7)
1. a method of preparing high-magnetization chitosan nanospheres, it is characterized in that, the chitosan solution that is dispersed with superparamagnetic nano particle of take is water, adopt a kind of improved ultrasonic emulsification cross-linking method, by regulating profit phase composition, by stirring and ultrasonic dispersion, be aided with ultrasonic precrosslink, obtain the chitosan nano ball that a kind of magnetic content is high, particle diameter is controlled, the step of described method comprises:
1) by chemical coprecipitation, prepare superparamagnetism Fe
3o
4nano particle, further adopts natrium citricum to modify and makes
Water-based magnetic fluid;
2) getting water-based magnetic fluid in appropriate step 1 mixes as water with chitosan-acetic acid solution, after ultrasonic 10 minutes, slowly inject the oil phase that is added with surfactant, mechanical agitation is more than 15 minutes, oil phase is not limited to atoleine, can also be the mixture of olive oil, soybean oil, castor oil and they and benzinum;
3) emulsion obtaining in step 2 is further ultrasonic in ultrasonic cell disruption instrument, in ultrasonic, drip crosslinking agent precrosslink, after a period of time, stop ultrasonic, gained emulsion is continued to stir after a period of time at a certain temperature, use successively benzinum, isopropyl alcohol, second alcohol and water centrifuge washing, obtain target product.
2. method according to claim 1, is characterized in that, described magnetic nano-particle has superparamagnetism, and composition can be Fe
3o
4, MnFe
2o
4, γ-Fe
2o
3, particle diameter is less than 30nm.
3. method according to claim 1, is characterized in that, described chitosan molecule weight range is 5k-1000k.
4. method according to claim 1, is characterized in that, profit phase volume ratio scope is 100:1-20:1.
5. method according to claim 1, is characterized in that, the power bracket of ultrasonic cell disruption instrument is 100W-800W; Mechanical agitation speed range is 100-2000rpm.
6. method according to claim 1, is characterized in that, ultrasonic precrosslink time range 10-120 minute.
7. method according to claim 1, is characterized in that, crosslinking temperature scope 25-50 ℃ after mechanical agitation, rear crosslinking time 6-24 hour.
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| CN104258822B (en) * | 2014-10-22 | 2016-05-11 | 天津工业大学 | Shitosan and chitosan quaternary ammonium salt composite magnetic microballoon and preparation method |
| CN104622845A (en) * | 2015-01-02 | 2015-05-20 | 吉林大学 | Preparation method of chitosan microcapsules containing magnetic nano particles inside |
| CN105294908A (en) * | 2015-11-20 | 2016-02-03 | 云南健牛生物科技有限公司 | Synthesis method and applications of magnetic nano high-molecular polymer |
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Effective date of registration: 20221025 Address after: 255214 Liangzhuang Sanquan mountain, Chengdong sub district office, Boshan District, Zibo City, Shandong Province Patentee after: ZIBO KANGBEI MEDICAL DEVICES Co.,Ltd. Address before: 266580 No. 66 Changjiang West Road, Qingdao economic and Technological Development Zone, Shandong Patentee before: CHINA University OF PETROLEUM (EAST CHINA) |
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