CN101608020A - Magnetic Fe prepared by hydrothermal method3O4Polymer submicron sphere and application - Google Patents
Magnetic Fe prepared by hydrothermal method3O4Polymer submicron sphere and application Download PDFInfo
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- CN101608020A CN101608020A CNA2008101152966A CN200810115296A CN101608020A CN 101608020 A CN101608020 A CN 101608020A CN A2008101152966 A CNA2008101152966 A CN A2008101152966A CN 200810115296 A CN200810115296 A CN 200810115296A CN 101608020 A CN101608020 A CN 101608020A
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- 230000005291 magnetic effect Effects 0.000 title claims abstract description 192
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 184
- 229920000642 polymer Polymers 0.000 claims abstract description 68
- 229920001503 Glucan Polymers 0.000 claims abstract description 35
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 33
- 239000004584 polyacrylic acid Substances 0.000 claims abstract description 31
- 238000002360 preparation method Methods 0.000 claims abstract description 27
- 229920001661 Chitosan Polymers 0.000 claims abstract description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 32
- 239000000463 material Substances 0.000 claims description 27
- 229920002307 Dextran Polymers 0.000 claims description 20
- 150000004676 glycans Chemical class 0.000 claims description 17
- 230000008878 coupling Effects 0.000 claims description 15
- 238000010168 coupling process Methods 0.000 claims description 15
- 238000005859 coupling reaction Methods 0.000 claims description 15
- 238000003384 imaging method Methods 0.000 claims description 15
- 239000002245 particle Substances 0.000 claims description 15
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 12
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 238000012637 gene transfection Methods 0.000 claims description 6
- 150000002505 iron Chemical class 0.000 claims description 6
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 claims description 5
- 239000002096 quantum dot Substances 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 101710153593 Albumin A Proteins 0.000 claims description 3
- 241000191967 Staphylococcus aureus Species 0.000 claims description 3
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 claims description 3
- PVFSDGKDKFSOTB-UHFFFAOYSA-K iron(3+);triacetate Chemical compound [Fe+3].CC([O-])=O.CC([O-])=O.CC([O-])=O PVFSDGKDKFSOTB-UHFFFAOYSA-K 0.000 claims description 3
- 229910000360 iron(III) sulfate Inorganic materials 0.000 claims description 3
- 230000006798 recombination Effects 0.000 claims description 3
- 238000005215 recombination Methods 0.000 claims description 3
- 238000001476 gene delivery Methods 0.000 claims description 2
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 abstract description 17
- 239000002086 nanomaterial Substances 0.000 abstract description 8
- 238000001027 hydrothermal synthesis Methods 0.000 abstract description 5
- 239000004094 surface-active agent Substances 0.000 abstract description 5
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 229910052742 iron Inorganic materials 0.000 abstract description 2
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 abstract 2
- 150000003839 salts Chemical class 0.000 abstract 1
- 239000011805 ball Substances 0.000 description 42
- 210000004027 cell Anatomy 0.000 description 32
- 239000000696 magnetic material Substances 0.000 description 21
- 108090000623 proteins and genes Proteins 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 10
- 239000001963 growth medium Substances 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 239000008363 phosphate buffer Substances 0.000 description 9
- 238000000799 fluorescence microscopy Methods 0.000 description 8
- 238000011091 antibody purification Methods 0.000 description 7
- 210000003712 lysosome Anatomy 0.000 description 7
- 230000001868 lysosomic effect Effects 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 230000005540 biological transmission Effects 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 238000007306 functionalization reaction Methods 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000004132 cross linking Methods 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000000975 dye Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 206010003445 Ascites Diseases 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000007720 emulsion polymerization reaction Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 235000014413 iron hydroxide Nutrition 0.000 description 2
- MVFCKEFYUDZOCX-UHFFFAOYSA-N iron(2+);dinitrate Chemical compound [Fe+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MVFCKEFYUDZOCX-UHFFFAOYSA-N 0.000 description 2
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 2
- 230000002132 lysosomal effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229910008051 Si-OH Inorganic materials 0.000 description 1
- 229910006358 Si—OH Inorganic materials 0.000 description 1
- 101000582398 Staphylococcus aureus Replication initiation protein Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- UHYPYGJEEGLRJD-UHFFFAOYSA-N cadmium(2+);selenium(2-) Chemical compound [Se-2].[Cd+2] UHYPYGJEEGLRJD-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
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- 229910001447 ferric ion Inorganic materials 0.000 description 1
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- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
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- 239000003292 glue Substances 0.000 description 1
- 229960001269 glycine hydrochloride Drugs 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
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- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- -1 polyoxyethylene Polymers 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the technical field of controllable preparation and application of nano materials, and particularly relates to magnetic Fe prepared by a hydrothermal method3O4Polymer submicron spheres and magnetic Fe3O4Use of polymer submicrospheres. The invention takes ferric salt as an iron source, takes polymer glucan, chitosan or polyacrylic acid as a surfactant, and can obtain magnetic Fe in one step by a hydrothermal method3O4Magnetic Fe with glucan coated on surface of ball3O4Polymer submicron sphere and magnetic Fe with chitosan coated surface3O4Polymer submicron sphere or magnetic Fe with polyacrylic acid coated on surface3O4Polymer submicron spheres. According to the difference of functional groups carried by the polymers, different functional molecules can be combined to realize different biological applications. The three polymers are magnetic Fe3O4The size, uniformity and monodispersity of the submicron spheres can be well controlled by reaction conditions, and the sphere size is 200-1000 nm.
Description
Technical field
The invention belongs to controlled preparation and the applied technical field of nano material, particularly with the standby multifunction magnetic Fe that obtains of hydro-thermal legal system
3O
4Polymer sub-micron sphere and magnetic Fe
3O
4The purposes of polymer sub-micron sphere.
Background technology
Magnetic Nano material has huge application potential because of having ferromagnetism and low cytotoxicity on biomedicine, all be widely used as the aspects such as delivery, immunodetection and nuclear magnetic resonance at purifying, medicine or the gene of antibody and fusion rotein.But, the application of simple magnetic Nano material on biomedicine exists serious defective, therefore, the multifunction of magnetic Nano material is because of thinking novelty and the research focus that becomes of many uses in recent years, and it has the advantage that integrates active target, imaging, low cytotoxicity and treatment etc.There are good dispersion, size and the pattern advantages on controllability such as easily control and homogeneity be good in inorganic material, organic material has that toxicity is little, degradable in vivo and be easy to the advantage on application such as multifunction, therefore makes up new multifunction magnetic material in conjunction with both strong point and will remedy mutual deficiency and expand application on biomedicine.
For the preparation of general nano particle, it is bigger that multifunctional polymer magnetic nano-balls particulate prepares difficulty, often need comparatively loaded down with trivial details preparation flow, make material surface be with the functional group amount fewer, influence the purpose of material multifunction, and then weaken the application of material on biomedicine.At present, the preparation multifunction polymer magnetic nanometer ball particulate method of having reported mainly contains: emulsion polymerization technology, heat cross-linking technology etc.As emulsion polymerization technology, exist uniform particle diameter, size to be difficult to control in these methods, the shortcoming of bad dispersibility, and complicated operation, flow process is loaded down with trivial details.Zhou etc. prepare have fluorescence, the multi-functional nanometer material of magnetic and targeted cells, magnetic Nano material, CdSe/ZnS and multipolymer are prepared into the compound nanometer ball, under the effect of glutaraldehyde, synthesize multi-functional fluorescence magnetic nano material [Hai-Yan Xie again with amidized polyoxyethylene glycol (PEG) and folate conjugate, Dai-Wen PangWuzong Zhou.Small, 2005,506～509].Hyeon etc. are with Fe
3O
4, adriamycin and PLA/ethanol copolymer (PLGA) method by microemulsion, according to Fe
3O
4The size of magnetic material synthesizes the multifunctional nanoparticles [Jaeyun Kim, Ji Eun Lee, TaeGhwan Park.Advanced Materials, 2007,478] with different sizes.The heat cross-linking technology exists monodispersity poor too, complicated operation, and flow process is more loaded down with trivial details.Jon etc. utilize the magnetic Nano material of the synthetic excess of export paramagnetic of method of heat cross-linking, with the synthetic multipolymer that contains Si-OH of heat cross-linking, under 80 ℃ condition, multipolymer glue is connected in the surface of magneticsubstance again, synthesize surface band carboxyl function group super paramagnetic material, the material surface carboxyl is through after being modified into amino, after dyestuff Cy5.5 coupling, realize multifunction [Haerim Lee, YongYeon Jeong, the Sangyong Jon.J.Am.Chem.Soc. of material, 2007,12739].
From above progress as can be seen, current multifunction polymer magnetic nanometer ball exists preparation loaded down with trivial details, purposes is single, the shortcoming of aspect such as monodispersity and poor controllability, therefore explore a kind of simple to operate, it is necessary having good magneticsubstance dispersed and the controlled preparation of energy, also becomes current difficult point and the hot issue that presses for solution both at home and abroad.
Summary of the invention
The object of the present invention is to provide a kind of with the standby multifunction magnetic Fe that obtains of hydro-thermal legal system
3O
4Polymer sub-micron sphere, this multifunction magnetic Fe
3O
4The preparation of polymer sub-micron sphere is reacted after only needing a step to add reactant, can realize multifunction magnetic Fe
3O
4The controlled preparation of polymer sub-micron sphere, have simple to operate, the characteristics such as cost is low, and is with short production cycle.
A further object of the present invention is to provide multifunction magnetic Fe
3O
4The purposes of polymer sub-micron sphere
The present invention has prepared multifunction magnetic Fe by one step hydro thermal method
3O
4Polymer sub-micron sphere, this multifunction magnetic Fe
3O
4The preparation of polymer sub-micron sphere can obtain glucan, the shitosan of amino or the polyacrylic multifunction magnetic Fe of carboxyl that the surface coats hydroxyl only by adding glucan, shitosan or polyacrylic acid
3O
4Polymer sub-micron sphere, resulting three kinds of multifunction magnetic Fe
3O
4The monodispersity of polymer sub-micron sphere particle is good, and size is more even, and particle diameter can better be controlled by demand.Resulting three kinds of multifunction magnetic Fe
3O
4Polymer sub-micron sphere can be assembled with the functionalization material, realizes different biologic applications.
Three kinds of multifunction magnetic Fe
3O
4Polymer sub-micron sphere is respectively in magnetic Fe
3O
4The multifunction magnetic Fe of the surperficial dextran-coated of ball
3O
4The multifunction magnetic Fe of polymer sub-micron sphere, surperficial encasement glycan
3O
4Polymer sub-micron sphere, and the surface coats polyacrylic multifunction magnetic Fe
3O
4Polymer sub-micron sphere.
The glucan material can carry fluorescent material, in magnetic Fe
3O
4The magnetic Fe of the surperficial dextran-coated of ball
3O
4Polymer sub-micron sphere and fluorescent material assembling are used for the research of cell imaging aspect, and described fluorescent material can be fluorescein isothiocynate (FITC) or quantum dot etc.
Chitosan material can carry dna molecular or fluorescent material, described dna molecular is all plasmids that can express in eukaryotic, described fluorescent material can be fluorescein isothiocynate (FITC) or quantum dot etc. (fluorescent material can be some with fluorescent material such as 6-Fluoresceincarboxylic acid or the tetrachloro-6-Fluoresceincarboxylic acid etc. of carboxyl).In magnetic Fe
3O
4The magnetic Fe of the surperficial encasement glycan of ball
3O
4Polymer sub-micron sphere and the dna molecular assembling that can express in eukaryotic are used thereby can carry out the aspects such as gene transfection, gene delivery; Or in magnetic Fe
3O
4The magnetic Fe of the surperficial encasement glycan of ball
3O
4Polymer sub-micron sphere and fluorescent material assembling are used for carrying out the application of cell imaging aspect.
Polyacrylic acid can coupling recombination staphylococcus aureus albumin A (protein A), in magnetic Fe
3O
4The surface of ball coats polyacrylic magnetic Fe
3O
4Polymer sub-micron sphere and recombination staphylococcus aureus albumin A (protein A) coupling can be used for the purifying of all antibody.
The present invention adopts hydro-thermal method, take trivalent iron salt as source of iron, in pure system, obtains respectively different multifunction magnetic Fe with glucan, shitosan or polyacrylic acid as surfactant
3O
4Polymer sub-micron sphere.By changing consumption and the reaction time of glucan, shitosan or acrylic acid polymer, three kinds of multifunction magnetic Fe of control gained
3O
4The particle diameter of polymer sub-micron sphere is distributed in 200～1000nm.Can obtain the surface with the multifunction magnetic Fe of hydroxyl by glucan as surfactant
3O
4The polymer sub-micron sphere magnetic material can obtain the surface with the multifunction magnetic Fe of amino by shitosan as surfactant
3O
4The polymer sub-micron sphere magnetic material can obtain the surface with the multifunction magnetic Fe of carboxyl by polyacrylic acid as surfactant
3O
4The polymer sub-micron sphere magnetic material according to the character of material group, again in conjunction with different functional moleculars, obtains the magnetic material of difference in functionality, realizes different biologic applications.
The present invention is with the standby multifunction magnetic Fe that obtains of hydro-thermal legal system
3O
4Polymer sub-micron sphere is prepared by following methods:
1) ethylene glycol solution of preparation trivalent iron salt, concentration is 0.01～0.5mol/L, preferred concentration is 0.05～0.3mol/L;
2) obtain adding sodium acetate, anhydrous in the solution to step 1), the final concentration that makes sodium acetate, anhydrous is 0.05～10mol/L, and preferred concentration is 0.5～5mol/L;
3) to step 2) obtain adding dextran, chitosan or polyacrylic acid in the solution, making dextran, chitosan or polyacrylic final concentration is 0.05～100mg/ml; Wherein the preferred concentration of dextran is 1～50mg/ml, and the preferred concentration of chitosan is 2～50mg/ml, and polyacrylic preferred concentration is 0.5～30mg/ml;
4) with step 3) mixture that obtains places airtight reactor, reacts under 100～250 ℃, and the reaction time is 5～50 hours; Obtain in magnetic Fe
3O
4The multifunction magnetic Fe of the surperficial dextran-coated of ball
3O
4The multifunction magnetic Fe of polymer sub-micron sphere, surperficial encasement glycan
3O
4Polymer sub-micron sphere, or the surface coats polyacrylic multifunction magnetic Fe
3O
4Polymer sub-micron sphere.
Described multifunction magnetic Fe
3O
4Polymer sub-micron sphere is solid, and particle diameter is distributed in 200～1000nm.
Described trivalent iron salt is FeCl
36H
2O, iron nitrate, ferric sulfate or iron acetate.
Three kinds of multifunction magnetic Fe of the present invention
3O
4The polymer sub-micron sphere magnetic material, according to they with the character of group, assemble by the means such as electrostatic attraction, covalent coupling and some functionalization materials, and then be implemented in some application on the biomedical sector.
Three kinds of magnetic Fe that the present invention obtains
3O
4Polymer sub-micron sphere reaches at surface coated polymer and realizes by the one-step synthesis strategy, and in airtight reactor, ferric ion generates iron hydroxide in conjunction with hydroxyl earlier, and afterwards iron hydroxide generation decomposition generates monodispersed magnetic Fe
3O
4Crystal, magnetic Fe
3O
4Crystal is grown along with the prolongation in reaction time, namely slowly grow up into sub-micron ball by a little monocrystal ball, polymer is coated on the surface of crystal ball in the process of crystal growth, mainly play a part dispersion, can prevent from mutually assembling in growth course between crystal and crystal merging.
Three kinds of multifunction magnetic Fe that the present invention obtains
3O
4Polymer sub-micron sphere as shown in Figure 1.The present invention obtains multifunction magnetic Fe by one step hydro thermal method
3O
4The polymer sub-micron sphere magnetic material owing to have dispersiveness good in water, is adapted at the application on the biology.Have simple to operately, cost is low, and is with short production cycle, is easy to promote, and has substantive distinguishing features and marked improvement.By selecting different polymer, can obtain the surface with the magnetic material of different functional groups, according to the characteristic of these functional groups, can obtain different multifunction magnetic materials in conjunction with the molecule of some functionalization, thereby can realize different biologic applications.Therefore, can select different polymkeric substance, realize the multifunction of material again in conjunction with some functionalization molecules according to the needs of using.
The multifunction magnetic Fe that the present invention obtains
3O
4What polymer sub-micron sphere was significantly different from the past preparation method is, same reaction system, same reaction condition, thereby only obtain with not isoplastic magnetic material by the difference of adding polymer, realize different biologic applications, this method of what is more important also is suitable for other polymer.
Description of drawings
Figure 1A. the embodiment of the invention 1 is resulting in magnetic Fe
3O
4The glucan magnetic Fe of the surperficial dextran-coated of ball
3O
4The transmission electron microscope of polymer sub-micron sphere.
Figure 1B. the embodiment of the invention 1 is resulting in magnetic Fe
3O
4The glucan magnetic Fe of the surperficial dextran-coated of ball
3O
4The stereoscan photograph of polymer sub-micron sphere.
Fig. 1 C. embodiment of the invention 3 is resulting in magnetic Fe
3O
4The shitosan magnetic Fe of the surperficial encasement glycan of ball
3O
4The transmission electron microscope of polymer sub-micron sphere.
Fig. 1 D. embodiment of the invention 3 is resulting in magnetic Fe
3O
4The shitosan magnetic Fe of the surperficial encasement glycan of ball
3O
4The stereoscan photograph of polymer sub-micron sphere.
Fig. 1 E. embodiment of the invention 6 is resulting in magnetic Fe
3O
4The surface of ball coats polyacrylic polyacrylic acid magnetic Fe
3O
4The transmission electron microscope of polymer sub-micron sphere.
Fig. 1 F. embodiment of the invention 6 is resulting in magnetic Fe
3O
4The surface of ball coats polyacrylic polyacrylic acid magnetic Fe
3O
4The stereoscan photograph of polymer sub-micron sphere.
Fig. 2. the glucan magnetic Fe of the embodiment of the invention 1 gained
3O
4The application of polymer sub-micron sphere magnetic material on the A375 tumour cell; Wherein, Fig. 2 A is shown as the glucan magnetic Fe
3O
4Polymer sub-micron sphere takes place significantly to assemble in cell; Fig. 2 B shows the glucan magnetic Fe
3O
4The polymer sub-micron sphere magnetic material is at intracellular fluorescence imaging; Fig. 2 C is shown as cell and fluorescent co-location imaging; Fig. 2 B, the white edge inner cell among Fig. 2 C is the glucan magnetic Fe
3O
4The enlarged drawing of polymer sub-micron sphere magnetic material imaging in cell.
The shitosan magnetic Fe of Fig. 3 A, 3B, 3C, 3D, 3E, the 3F. embodiment of the invention 3, embodiment 4 and embodiment 5 gained
3O
4The application of polymer sub-micron sphere magnetic material in gene transfection; Wherein: Fig. 3 A is shown as the lysosome imaging of cell; Fig. 3 B is shown as shitosan magnetic Fe
3O
4The polymer sub-micron sphere magnetic material is at intracellular fluorescence imaging; Fig. 3 C is shown as shitosan magnetic Fe
3O
4The polymer sub-micron sphere magnetic material in cell with lysosomal altogether positioning and imaging; Fig. 3 D is shown as cell imaging; Fig. 3 E is shown as gene with shitosan magnetic Fe
3O
4The polymer sub-micron sphere magnetic material is that carrier is transfected into can well express in the cell and obtains yellow fluorescence protein (GFP); Fig. 3 F is shown as cell and yellow fluorescence protein (GFP) is total to positioning and imaging.
Fig. 4. the polyacrylic acid magnetic Fe of the embodiment of the invention 6 gained
3O
4The application of polymer sub-micron sphere magnetic material on antibody purification; Wherein: Fig. 4 A is shown as the polyacrylic acid magnetic Fe
3O
4The polymer sub-micron sphere magnetic material is analyzed as the acrylamide gel electrophoresis (SDS-PAGE) that carrier of separating carries out behind the antibody purification, and 1 is shown as the antibody behind the purifying, and 2 are shown as and pass liquid, and 3 are shown as not purified mouse ascites; Fig. 4 B is shown as the polyacrylic acid magnetic Fe
3O
4The polymer sub-micron sphere magnetic material is as the analysis of the activity of carrier of separating antagonist, and 1 is shown as antibody has in conjunction with active, and 2 are shown as contrast.
Embodiment
Embodiment 1.
Step 1): controlled preparation is in magnetic Fe
3O
4The glucan magnetic Fe of the surperficial dextran-coated of ball
3O
4Polymer sub-micron sphere.
Preparation 0.1mol/L FeCl
36H
2The ethylene glycol solution of O adds sodium acetate, anhydrous, and making its final concentration is 0.05mol/L, adds molecular weight again and be 10000 dextran, and making its final concentration is 0.05mg/ml.Said mixture is placed airtight reactor, and 100 ℃ of lower reactions 25 hours obtain solid in magnetic Fe
3O
4The glucan magnetic Fe of the surperficial dextran-coated of ball
3O
4Polymer sub-micron sphere.
Step 2): step 1 the glucan magnetic Fe that) obtains
3O
4Polymer sub-micron sphere carries FITC and realizes multifunction and the application on cell imaging.
With 20mg step 1) the glucan magnetic Fe that obtains
3O
4Polymer sub-micron sphere joins among the green fluorescence dyestuff FITC of 1mg/ml, and stirring at room reaction 12 hours is collected the glucan magnetic Fe with magnet
3O
4Polymer sub-micron sphere, and with their washings three times, freeze drying is for subsequent use.The glucan magnetic Fe of carrying FITC of 1mg
3O
4Polymer sub-micron sphere changes liquid and removes glucan magnetic Fe in the DMEM culture medium with the A375 tumour cell is hatched 4 hours in DMEM culture medium (Beijing sunlight Si Te company) after
3O
4Polymer sub-micron sphere continues to cultivate 8 hours, with fluorescence imaging in laser confocal microscope (confocol, the Leca company) observation of cell.
Figure 1A and Figure 1B are resulting in magnetic Fe
3O
4The glucan magnetic Fe of the surperficial dextran-coated of ball
3O
4The transmission electron microscope of polymer sub-micron sphere and stereoscan photograph, as seen from the figure prepared in magnetic Fe
3O
4The glucan magnetic Fe of the surperficial dextran-coated of ball
3O
4The polymer sub-micron sphere particle diameter is more even, and particle diameter is 360nm, has preferably monodispersity.Fig. 2 is the glucan magnetic Fe
3O
4Polymer sub-micron sphere is in intracellular fluorescence imaging situation, as can be seen from the figure, (Fig. 2 A) can take place significantly to assemble in material in cell, there is obvious green fluorescence to have (Fig. 2 B) in the whole cell, shows that material can enter cell and can penetrate lysosome and enter in the kytoplasm.Fig. 2 C is cell and fluorescent co-location imaging, and the glucan magnetic Fe is described
3O
4Polymer sub-micron sphere can be good at entering in the cell.
Step 1): controlled preparation is in magnetic Fe
3O
4The glucan magnetic Fe of the dextran-coated of ball
3O
4Sub-micron ball.
The ethylene glycol solution of preparation 0.25mol/L iron nitrate adds sodium acetate, anhydrous, and making its final concentration is 1mol/L, adds molecular weight again and be 10000 dextran, and making its final concentration is 100mg/ml.Said mixture is placed airtight reactor, and 200 ℃ of lower reactions 5 hours obtain solid in magnetic Fe
3O
4The glucan magnetic Fe of the surperficial dextran-coated of ball
3O
4Polymer sub-micron sphere.
Step 2): step 1 the glucan magnetic Fe that) obtains
3O
4Polymer sub-micron sphere carries FITC and realizes multifunction and the application on cell imaging.
With 20mg step 1) the glucan magnetic sub-micron ball that obtains joins in the quantum dot of 1mg/ml, and stirring at room reaction 12 hours is collected the glucan magnetic Fe with magnet
3O
4Polymer sub-micron sphere, and with their washings three times, freeze drying is for subsequent use.The glucan magnetic Fe of carrying FITC with 1mg
3O
4Polymer sub-micron sphere changes liquid after hatching 4 hours together in DMEM culture medium (Beijing sunlight Si Te company) and removes glucan magnetic Fe in the DMEM culture medium in the A375 tumour cell
3O
4Polymer sub-micron sphere continues to cultivate 8 hours, with fluorescence imaging in laser confocal microscope (confocol, the Leca company) observation of cell.
The glucan magnetic Fe of resultant coating hydroxyl
3O
4The sign of polymer sub-micron sphere is similar with embodiment 1, and particle diameter is 760nm, has preferably monodispersity.The surface coats the glucan magnetic Fe of hydroxyl
3O
4Polymer sub-micron sphere carries fluorescein isothiocynate (FITC) can realize multifunction, and the application on cell detection and phenomenon are similar with embodiment 1.
Step 1): controlled preparation is in magnetic Fe
3O
4The shitosan magnetic Fe of the encasement glycan of ball
3O
4Sub-micron ball.
Preparation 0.01mol/L FeCl
36H
2The ethylene glycol solution of O adds sodium acetate, anhydrous, and making its final concentration is 10mol/L, adds molecular weight again and be 50000～800000 chitosan, and making its final concentration is 20mg/ml.Said mixture is placed airtight reactor, and 150 ℃ of lower reactions 18 hours obtain solid in magnetic Fe
3O
4The shitosan magnetic Fe of the surperficial encasement glycan of ball
3O
4Polymer sub-micron sphere.
Step 2): step 1 the shitosan magnetic Fe that) obtains
3O
4Realize multifunction and the research of locating altogether with lysosome after polymer sub-micron sphere and the FITC coupling.
Locate altogether with lysosome: shitosan magnetic Fe
3O
4Behind the polymer sub-micron sphere covalent coupling FITC, get the shitosan magnetic Fe behind the 1mg covalent coupling FITC
3O
4Polymer sub-micron sphere joins in the A375 cell, cultivates in DMEM culture medium (Beijing sunlight Si Te company) together after 6 hours, adds the lysosome dyestuff, cultivates 30 minutes, changes liquid and removes shitosan magnetic Fe in the DMEM culture medium
3O
4Behind the polymer sub-micron sphere, with fluorescence imaging in laser confocal microscope (confocol, the Leca company) observation of cell.
Fig. 1 C and Fig. 1 D are the shitosan magnetic Fe of resulting surperficial encasement glycan
3O
4The transmission electron microscope of polymer sub-micron sphere and stereoscan photograph, as seen from the figure prepared shitosan magnetic Fe
3O
4The polymer sub-micron sphere particle diameter is more even, and particle diameter is 230nm, has good monodispersity.Fig. 3 A, B and C are shitosan magnetic Fe
3O
4Polymer sub-micron sphere (Fig. 3 B) in cell is total to the imaging situation of locating (Fig. 3 C) with lysosome (Fig. 3 A), can find out shitosan magnetic Fe
3O
4Polymer sub-micron sphere and lysosome can be located basically altogether, but shitosan magnetic Fe
3O
4Polymer sub-micron sphere has been distributed in the whole cell (shown in the arrow), shows shitosan magnetic Fe
3O
4Polymer sub-micron sphere can be escaped lysosomal constraint and enter kytoplasm, for it realizes that gene transfection lays the foundation.
Embodiment 4.
Step 1): controlled preparation is in magnetic Fe
3O
4The shitosan magnetic Fe of the encasement glycan of ball
3O
4Sub-micron ball.
The ethylene glycol solution of preparation 0.25mol/L ferric sulfate adds sodium acetate, anhydrous, and making its final concentration is 0.05mol/L, adds molecular weight again and be 50000～800000 chitosan, and making its final concentration is 0.05mg/ml.Said mixture is placed airtight reactor, and 200 ℃ of lower reactions 30 hours obtain solid in magnetic Fe
3O
4The shitosan magnetic Fe of the surperficial encasement glycan of ball
3O
4Polymer sub-micron sphere.
Step 2): step 1 the shitosan magnetic Fe that) obtains
3O
4Realize multifunction and the application on cell transfecting after polymer sub-micron sphere and the FITC coupling.
Gene transfection: with 1mg shitosan magnetic Fe
3O
4Polymer sub-micron sphere joins in the phosphate buffer (PBS) of pH6.0, adds the plasmid pYFP of 10 μ g, stirring at room reaction 1 hour, and magnet is collected shitosan magnetic Fe
3O
4Polymer sub-micron sphere, and wash three times with phosphate buffer (PBS), place phosphate buffer (PBS), now with the current.Get the shitosan magnetic Fe of 100 μ g
3O
4Polymer sub-micron sphere joins in the A375 tumour cell, cultivates in DMEM culture medium (Beijing sunlight Si Te company) after 48 hours together, changes liquid and removes shitosan magnetic Fe in the DMEM culture medium
3O
4Behind the polymer sub-micron sphere, with fluorescence imaging in laser confocal microscope (confocol, the Leca company) observation of cell.
The sign of the chitosan magnetic sub-micron ball that resulting coating is amino is similar with embodiment 3.Fig. 3 D, Fig. 3 E and Fig. 3 F are shitosan magnetic Fe
3O
4The entrained gene of polymer sub-micron sphere is at the expression of A375 tumour cell, as can be seen from the figure, and shitosan magnetic Fe
3O
4Polymer sub-micron sphere can carry DNA and well express in cell, and transfection efficiency is 8.9%.
Embodiment 5.
Step 1): controlled preparation is in magnetic Fe
3O
4The shitosan magnetic Fe of the encasement glycan of ball
3O
4Sub-micron ball.
Preparation 0.2mol/L FeCl
36H
2The ethylene glycol solution of O adds sodium acetate, anhydrous, and making its final concentration is 4mol/L, adds molecular weight again and be 50000～800000 chitosan, and making its final concentration is 100mg/ml.Said mixture is placed airtight reactor, and 180 ℃ of lower reactions 50 hours obtain solid in magnetic Fe
3O
4The shitosan magnetic Fe of the surperficial encasement glycan of ball
3O
4Polymer sub-micron sphere.
Step 2): step 1 the shitosan magnetic Fe that) obtains
3O
4Realize multifunction and the application on cell transfecting after polymer sub-micron sphere and the FITC coupling.
Gene transfection: with 1mg shitosan magnetic Fe
3O
4Polymer sub-micron sphere joins in the phosphate buffer (PBS) of pH6.0, adds the plasmid pYFP of 10 μ g, stirring at room reaction 1 hour, and magnet is collected shitosan magnetic Fe
3O
4Polymer sub-micron sphere, and wash three times with PBS, place PBS, now with the current.Get the shitosan magnetic Fe of 100 μ g
3O
4Polymer sub-micron sphere joins in the A375 tumour cell, cultivates in DMEM culture medium (Beijing sunlight Si Te company) after 48 hours together, changes liquid and removes shitosan magnetic Fe in the DMEM culture medium
3O
4Behind the polymer sub-micron sphere, with fluorescence imaging in laser confocal microscope (confocol, the Leca company) observation of cell.
The shitosan magnetic Fe of resulting surperficial encasement glycan
3O
4The sign of polymer sub-micron sphere is similar with embodiment 3, and particle diameter is 840nm, has good monodispersity.Shitosan magnetic Fe
3O
4The entrained gene of polymer sub-micron sphere is at the expression of A375 tumour cell, shitosan magnetic Fe
3O
4Polymer sub-micron sphere can carry DNA and well express in cell, and expression is similar with Fig. 3 D among the embodiment 4, figure E and figure F, and expression efficiency is 7.6%.
Embodiment 6.
Step 1): controlled preparation is in magnetic Fe
3O
4The polyacrylic polyacrylic acid magnetic Fe of the coating of ball
3O
4Sub-micron ball.
Preparation 0.1mol/L FeCl
36H
2The ethylene glycol solution of O adds sodium acetate, anhydrous, and making its final concentration is 1mol/L, adds molecular weight again and be 1800 polyacrylic acid, and making its final concentration is 100mg/ml.Said mixture is placed airtight reactor, and 250 ℃ of lower reactions 10 hours obtain solid in magnetic Fe
3O
4The surface of ball coats polyacrylic polyacrylic acid magnetic Fe
3O
4Polymer sub-micron sphere.
Step 2): step 1 the polyacrylic acid magnetic Fe that) obtains
3O
4Polymer sub-micron sphere with protein A coupling after realize multifunction and the application on antibody purification.
With 10mg polyacrylic acid magnetic Fe
3O
4Polymer sub-micron sphere joins in the carbodiimide (EDC) and 2.5mg/ml succinimide (NHS) mixed liquor of 2.5mg/ml, stirring at room reaction 30 minutes, and magnet is collected the polyacrylic acid magnetic Fe
3O
4Polymer sub-micron sphere, and wash with water 3 times, with the polyacrylic acid magnetic Fe of upper functionalization
3O
4Polymer sub-micron sphere joins in staphylococcus aureus protein A (protein A) sodium-acetate buffer of 0.1mg/ml (pH6.0,0.2mol/L), 4 ℃ of lower reactions 2 hours, and magnet is collected the polyacrylic acid magnetic Fe
3O
4Polymer sub-micron sphere, and wash three times with the phosphate buffer (PBS) of pH7.0 added in the Tris solution (pH7.5,50m mol/L) incubated at room 30 minutes, was scattered in the phosphate buffer (PBS) for subsequent use.The mouse ascites of 20 μ l joins and disperses the polyacrylic acid magnetic Fe
3O
4In the 1ml phosphate buffer (PBS) of polymer sub-micron sphere, 4 ℃, stirring reaction 2 hours, magnet is collected the polyacrylic acid magnetic Fe
3O
4Polymer sub-micron sphere, and wash 2 times with phosphate buffer (PBS), with glycine-hydrochloride buffer (100 μ l, pH3.0,50m mol/L) wash-out, phosphate buffer (PBS) dialysis three times, carbopol gel electrophoresis (SDS-PAGE) is analyzed with Western blotting (Western blot).
Fig. 1 E and Fig. 1 F are that resulting surface coats polyacrylic polyacrylic acid magnetic Fe
3O
4The transmission electron microscope of polymer sub-micron sphere and stereoscan photograph, as seen from the figure prepared polyacrylic acid magnetic Fe
3O
4The polymer sub-micron sphere particle diameter is more even, and particle diameter is 400nm, has preferably monodispersity.Figure 4 shows that activity analysis behind antibody purification and the purifying, as can be seen from Figure, the polyacrylic acid magnetic Fe of coupling protein A
3O
4Polymer sub-micron sphere can be realized the purifying (Fig. 4 A) of antibody, and active few of impact of antagonist (Fig. 4 B), its simplified control the purifying of antibody.
Embodiment 7.
Step 1): controlled preparation is in magnetic Fe
3O
4The polyacrylic polyacrylic acid magnetic Fe of the coating of ball
3O
4Sub-micron ball.
The ethylene glycol solution of preparation 0.5mol/L iron acetate adds sodium acetate, anhydrous, and making its final concentration is 3mol/L, adds molecular weight again and be 1800 polyacrylic acid, and making its final concentration is 0.05mg/ml.Said mixture is placed airtight reactor, and 150 ℃ of lower reactions 20 hours obtain solid in magnetic Fe
3O
4The surface of ball coats polyacrylic polyacrylic acid magnetic Fe
3O
4Polymer sub-micron sphere.
Step 2): step 1 the polyacrylic acid magnetic Fe that) obtains
3O
4Realize multifunction and the application on antibody purification after polymer sub-micron sphere and the protein A coupling.
Realize after the protein A coupling that multifunction and the application test flow process on antibody purification are identical with embodiment 6.
Resulting surface coats polyacrylic polyacrylic acid magnetic Fe
3O
4The sign of polymer sub-micron sphere is similar with embodiment 6, and particle diameter is 960nm, has preferably monodispersity.Basically identical with embodiment 6 with realization multifunction after the protein A coupling and the applicable cases on antibody purification.
Claims (10)
1. one kind with the standby magnetic Fe that obtains of hydro-thermal legal system
3O
4Polymer sub-micron sphere is characterized in that, this magnetic Fe
3O
4Polymer sub-micron sphere is prepared by following methods:
1) ethylene glycol solution of preparation trivalent iron salt, concentration is 0.01～0.5mol/L;
2) obtain adding sodium acetate, anhydrous in the solution to step 1), the final concentration that makes sodium acetate, anhydrous is 0.05～10mol/L;
3) to step 2) obtain adding dextran, chitosan or polyacrylic acid in the solution, making dextran, chitosan or polyacrylic final concentration is 0.05～100mg/ml;
4) with step 3) mixture that obtains places airtight reactor, reacts under 100～250 ℃, and the reaction time is 5～50 hours; Obtain in magnetic Fe
3O
4The magnetic Fe of the surperficial dextran-coated of ball
3O
4The magnetic Fe of polymer sub-micron sphere, surperficial encasement glycan
3O
4Polymer sub-micron sphere, or the surface coats polyacrylic magnetic Fe
3O
4Polymer sub-micron sphere.
2. magnetic Fe according to claim 1
3O
4Polymer sub-micron sphere is characterized in that: described magnetic Fe
3O
4Polymer sub-micron sphere is solid.
3. magnetic Fe according to claim 1 and 2
3O
4Polymer sub-micron sphere is characterized in that: described magnetic Fe
3O
4The particle diameter of polymer sub-micron sphere is distributed in 200～1000nm.
4. magnetic Fe according to claim 1
3O
4Polymer sub-micron sphere is characterized in that: the concentration of the ethylene glycol solution of described trivalent iron salt is 0.05～0.3mol/L.
5. according to claim 1 or 4 described magnetic Fe
3O
4Polymer sub-micron sphere is characterized in that: described trivalent iron salt is FeCl
36H
2O, ferric nitrate, ferric sulfate or ferric acetate.
6. magnetic Fe according to claim 1
3O
4Polymer sub-micron sphere is characterized in that: the final concentration of described anhydrous sodium acetate is 0.5～5mol/L.
7. magnetic Fe according to claim 1
3O
4Polymer sub-micron sphere is characterized in that: the final concentration of described glucan is 1～50mg/ml; The final concentration of shitosan is 2～50mg/ml, and polyacrylic final concentration is 0.5～30mg/ml.
A claim 1～7 each with the standby magnetic Fe that obtains of hydro-thermal legal system
3O
4The purposes of polymer sub-micron sphere is characterized in that: in magnetic Fe
3O
4The magnetic Fe of the surperficial dextran-coated of ball
3O
4Polymer sub-micron sphere and fluorescent material assembling are used for the research of cell imaging aspect; Described fluorescent material is fluorescein isothiocynate or quantum dot.
A claim 1～7 each with the standby magnetic Fe that obtains of hydro-thermal legal system
3O
4The purposes of polymer sub-micron sphere is characterized in that: in magnetic Fe
3O
4The magnetic Fe of the surperficial encasement glycan of ball
3O
4Polymer sub-micron sphere and the dna molecular assembling that can express in eukaryotic are used for carrying out the application of gene transfection, gene delivery aspect;
In magnetic Fe
3O
4The magnetic Fe of the surperficial encasement glycan of ball
3O
4Polymer sub-micron sphere and fluorescent material assembling are used for carrying out the application of cell imaging aspect;
Described fluorescent material is fluorescein isothiocynate or quantum dot.
A claim 1～7 each with the standby magnetic Fe that obtains of hydro-thermal legal system
3O
4The purposes of polymer sub-micron sphere is characterized in that: in magnetic Fe
3O
4The surface of ball coats polyacrylic magnetic Fe
3O
4Polymer sub-micron sphere and the coupling of recombination staphylococcus aureus albumin A are used for the purifying of antibody.
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| CNA2008101152966A CN101608020A (en) | 2008-06-20 | 2008-06-20 | Magnetic Fe prepared by hydrothermal method3O4Polymer submicron sphere and application |
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| CNA2008101152966A CN101608020A (en) | 2008-06-20 | 2008-06-20 | Magnetic Fe prepared by hydrothermal method3O4Polymer submicron sphere and application |
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