CN100469854C - Nanometer magnetic fluorescent microsphere and its prepn and application - Google Patents
Nanometer magnetic fluorescent microsphere and its prepn and application Download PDFInfo
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- CN100469854C CN100469854C CNB2006100291996A CN200610029199A CN100469854C CN 100469854 C CN100469854 C CN 100469854C CN B2006100291996 A CNB2006100291996 A CN B2006100291996A CN 200610029199 A CN200610029199 A CN 200610029199A CN 100469854 C CN100469854 C CN 100469854C
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- fluorescent microsphere
- nanometer magnetic
- magnetic fluorescent
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Abstract
The present invention relates to nanometer magnetic fluorescent microsphere and its preparation process and application. The nanometer magnetic fluorescent microsphere is one core-shell including core of Eu3+Y-Fe2O3 compound, shell of SiO2 coated fluorescent material and surface modifying organic functional group. It is prepared through reverse micro emulsion process to synthesize nanometer particle, and the subsequent surface chemical modification to become magnetic nanometer particle capable of combining with probe. The nanometer magnetic fluorescent microsphere is used as biological research tool with integrated fluorescent indication and magnetic separation, and may have important application in biomicromolecule detection, medical diagnosis and other fields.
Description
Technical field
The invention belongs to technical field of nano material, more specifically, relate to a kind ofly can be used for biological nano material.
Background technology
Forward position, intercrossing new branch of science field that nanosecond science and technology are late 1980s, the beginning of the nineties, development came.It is the technology of on 0.1-100nm yardstick motion of matter rule or its characteristic being studied, because the target of this technology is to make the mankind handle microcosm and to make him serve the mankind according to the wish of oneself, so be considered to the generation and the development of a series of new and high technologies of 21 century one of popular subject that has material impact is arranged, the fast development of nano material relates to human lives's all respects especially.
Nano material claims nanoparticle (nanoparticles) again, has some unique effect, shows characteristics such as special light, heat, power and magnetics.And magnetic nanometer particles is except having the characteristic of high molecular particle, as chemical reactions such as copolymerization, surface modification microsphere surface introduce multiple reactive functional group (as-OH ,-COOH ,-CHO ,-NH
2Deng) outside, can also pass through the covalent bonding biologically active substance; The more important thing is,, can under the effect of externally-applied magnetic field, separate the target material easily because of it has magnetic.It has brought revolutionary development for the target organism product separation, and because it can fast enriching at magnetic field environment, therefore may for realizing that the target administration provides.
At present numerous about the nano material product in, function all is single, or has magnetic, or has fluorescence, the two specific character persons of having concurrently, used fluorescence metal europium and Y-Fe in the application's patent in other words
2O
3Through handling the Eu that forms
3+Y-Fe
2O
3The nanometer magnetic fluorescent microsphere of mixture yet there are no report.
From the related data result for retrieval, the report of existing more magnetic nano-particle also has the making method of fluorescent particles, but yet there are no report with the also magnetic difunctional nanometer magnetic fluorescent microsphere of existing fluorescence that metal europium and iron are mixed and made into.More not with the surface active of nanoparticle, or claim " surface biological functionalization ", make the surface can connect nucleic acid, protein, Nucleotide, amino acid, antibody, polypeptide, animal and plant cells, subcellular structure, virus, bacterium or the like biomacromolecule Research on ability.
Summary of the invention
Technical problem to be solved
The technical issues that need to address of the present invention provide a kind of nanometer magnetic fluorescent microsphere and its production and application, lack the also magnetic difunctional nanometer magnetic fluorescent microsphere of existing fluorescence, the defective that can't come the spike magnetic Nano material by fluorescent substance in the prior art to overcome.
Technical scheme
One of content of the present invention provides a kind of nanometer magnetic fluorescent microsphere, possesses the hud typed structure of kernel and shell, and its composition comprises: interior nuclear composition is Eu
3+Y-Fe
2O
3Mixture; Outer shell is SiO
2
A kind of preferred version of above-mentioned nanometer magnetic fluorescent microsphere is that said microballoon outer shell surface is the decorative layer of amino or sulfydryl.
The another kind of preferred version of above-mentioned nanometer magnetic fluorescent microsphere is that said microspherulite diameter is 50-100nm.Most preferably being said microsphere average grain diameter is 97.5nm.
Those of ordinary skill in the art need not special experiment and can understand, and prepares said outer shell composition except SiO
2Can also be outward other inorganic integument, for example aminosilane, hydrosulphonyl silane also can be organic integument, for example glucosides, protein etc.Preferably, selecting outer shell component for use is silicon-dioxide.
Two of content of the present invention provides a kind of preparation method of nanometer magnetic fluorescent microsphere, in turn includes the following steps:
(1) ferrous ion is mixed with metal europium ion solution, agitation and dropping NaOH solution, wherein the mol ratio of iron ion, europium ion and NaOH is 3:2:5, gained precipitates through ageing, filtration, washing, drying, grinding, obtains Eu
3+Y-Fe
2O
3Mixture;
(2) Triton X-100, n-hexyl alcohol and hexanaphthene mix in 1:1:4 mole number ratio, and supersound process becomes homogeneous transparent stable microemulsion liquid, add Eu
3+Y-Fe
2O
3Mixture, after the supersound process in supernatant successively dropping ammonia, add positive silicic acid fat, stirring reaction 12 hours leaves standstill, the sedimentary particle of gained is calcined through cleaning the back repeatedly, promptly gets nanometer magnetic fluorescent microsphere;
A kind of preferred version of the preparation method of above-mentioned nanometer magnetic fluorescent microsphere is that said step also comprises:
(1) nanometer magnetic fluorescent microsphere that claim 5 is made adds in the alcoholic solution, supersound process;
(2) N-(2-amine ethyl)-3-aminopropyl trimethyl silane is added in the mixed solution supersound process reaction;
(3) will react the particle that obtains washs, is drying to obtain.
The preparation method's of above-mentioned nanometer magnetic fluorescent microsphere another kind of preferred version is that said step also comprises:
(1) nanometer magnetic fluorescent microsphere that claim 5 is made joins in acetate and the alcoholic acid damping fluid, supersound process;
(2) 3-sulfydryl glyceryl methoxy silane is joined in the mixed solution mixing reaction;
(3) will react the particle that obtains washs, is drying to obtain.
Another preferred version of the preparation method of above-mentioned nanometer magnetic fluorescent microsphere is, said ferrous ion is ferrous sulfate or iron protochloride or both combinations, and europium ion is an Europium trichloride.Preferred said ferrous ion is FeSO
4.7H
2O and FeCl
2.6H
2O.
Those of ordinary skill in the art need not special experiment and can understand, and said modifier is the silicane modifier, but is not limited to above-mentioned several.For selected outer shell component, those skilled in the art can select suitable shell layer forming agent for use according to prior art.For example when outer shell component is silicon-dioxide, can select tetraethoxy or other suitable shell layer forming agent for use.
Three of content of the present invention provide a kind of above-mentioned nanometer magnetic fluorescent microsphere biomaterial detect and separation and purification in the application of the above-mentioned nanometer magnetic fluorescent microsphere of application.
Preferably said carboxyl or sulfydryl are combined with nucleic acid, protein, Nucleotide, amino acid or its derivative by chemical bond, the preparation namo fluorescence probe carries out spike, and utilizes the magnetic of this probe to carry out the separation and purification of biomolecules.
The another kind of above-mentioned nanometer magnetic fluorescent microsphere is applied as, said amino or sulfydryl and animal and plant cells or subcellular structure or virion combine, the preparation namo fluorescence probe carries out spike, and utilizes the magnetic of this probe to carry out the separation and purification of cell or subcellular structure.
Beneficial effect
1, the present invention passes through at magnetic cup nanometer ball (magnetic fluorescence nanometerbeads, MFNB) finishing connect some chemically reactive group (-OH ,-COOH ,-CHO ,-NH2 etc.), bonding bioactive molecules (antibody, nucleic acid etc.), target arrival target site by these bioactive molecules, play the effect of probe, by the foreign field effect, target substance can be separated then.So the advantage of MFNB is collection indication and the biological study instrument that is separated into one.In actual application, determine to have or not in the biomaterial required material with fluorescent characteristic earlier, separated the target material with externally-applied magnetic field again, and then further investigation.
2, nanometer magnetic fluorescent microsphere of the present invention is compared with fluorescent tracing material in the prior art, can make material not only possess fluorescent mark can indicate easily, also possesses over paramagnetism, combine with nucleic acid, protein, Nucleotide, amino acid or its derivative by amino or sulfydryl chemical bond, and even combine with animal and plant cells or subcellular structure or virion, its biologic applications function is expanded greatly.
3, its outer shell of nanometer magnetic fluorescent microsphere of the present invention adopts this nontoxic, as to have biocompatibility material of silicon-dioxide, makes to be applied to biochemical field and to become possibility.
4, preparation method of the present invention adopts organic fluorescent substance with low cost, shell to form agent etc., makes practical large-scale production have feasibility.
5, adopt nano particle parcel fluorescent substance and modification carboxyl or sulfydryl, can effectively bring into play the surface-area advantage of nano material, improve biological respinse efficient, accelerate the reaction times, reduce the total amount of reaction system simultaneously, make carry out trace detection and micro-reaction simple and easy to do.
6, nanometer magnetic fluorescent microsphere of the present invention provides the foundation for the research of the physico-chemical property of the biomaterial on the nanometer level, and the possibility of broadened application further is provided simultaneously.
7, on nanoparticle of the present invention, connect nucleic acid, protein, Nucleotide, amino acid, antibody, polypeptide, animal and plant cells, subcellular structure, virus, bacterium or the like, have the prospect of the spike treatment of the detection that is applied to each quasi-molecule and disease.
Description of drawings
Fig. 1 is that scanning electronic microscope is amplified 30,000 times MFNB
Fig. 2 is that scanning electronic microscope is amplified 20,000 times MFNB
Fig. 3 is that scanning electronic microscope is amplified 30,000 times and recorded the MFNB size
Fig. 4 is that scanning electronic microscope is amplified 40,000 times and recorded the MFNB size.The MFB median size of surveying from scanning electron microscope is 97.5.The nanometer magnetic fluorescent microsphere particle diameter that the used in embodiments coprecipitation method of prompting the application is made has reached the nano level of standard of comparison.
Fig. 5 is the separating effect graphic representation of MFNB-NH2 to bovine serum albumin, and ordinate is a light absorption value, and abscissa is a MFNB-NH2 concentration.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, as the Chemicals handbook, or the condition of advising according to manufacturer.All inorganic chemical reagents and organic solvent are available from Shanghai chemical reagent factory, RE
2O
3(〉 99.95%) available from Yaolong Non-ferrous Metal Co. Ltd., Shanghai, N-(2-amine ethyl)-3-aminopropyl trimethyl silane (AEAPS), 3-sulfydryl glyceryl methoxy silane (MPTS) are available from Sigma company.
Eu
3+Y-Fe
2O
3Preparation preparation:
0.2mol/L FeSO
4.7H
2O, 0.2mol/L FeCl
2.6H
2O and 0.2mol/L EuCl
2.6H
2The mixing solutions of O, (final concentration is FeCl to the NaOH solution that wherein drips 2.5mol/L while stirring
2: FeSO
4.:EuCl
2: NaOH=1:2:2:5).Gained is deposited in 65 ℃ of following ageing 2.5h.Filter and use repeatedly ddH
2The O washing, 65 ℃ of following dry 24h place agate mortar to grind, and products therefrom is Eu
3+Y-Fe
2O
3Mixture.
SiO2 wraps up Eu
3+Y-Fe
2O
3:
Triton X-100, n-hexyl alcohol, hexanaphthene are pressed the 1:1:4 mixed, and supersound process becomes homogeneous transparent stable microemulsion liquid, adds the Eu of 0.1g
3+Y-Fe
2O
3Mixture behind the ultrasonic 30min, is got supernatant liquor and is put in the Erlenmeyer flask, places 25 ℃ water bath with thermostatic control to stir 30min. successively to the ammoniacal liquor 1ml of system dropping 28%, stirs 30min, adds positive silicic acid fat 1ml, stirring reaction 12h, standing over night.After cleaning repeatedly with ethanol in the sedimentary particle outside magnetic field of gained, 650 ℃ of calcinings 2 hours.This product be the magnetic cup Nano microsphere (magnetic fluorescence nanometer beads, MFNB).
Modify amino (MFNB-NH at the magnetic cup microsphere surface
2Preparation):
Get the magnetic cup Nano microsphere of 20mg silicon-dioxide parcel, join in the mixed solution of the methyl alcohol of 30ml and 20ml glycerol, supersound process 40min, get 1.5ml AEAPS[N-(2-amine ethyl)-3-aminopropyl trimethyl silane again] add in the mixed solution, supersound process 40min mixes solution.Reaction is 4 hours under 90 ℃ reaction conditions.Take out particle then and use methyl alcohol and water washing respectively 3-4 time, vacuum-drying is about 2 hours under 150 degree, collects particle and it is formulated as the suspension of 2 μ g/ml.
Modify sulfydryl (preparation of MFB-SH) at the magnetic cup microsphere surface:
In the acetate that the MFNB of 20mg is joined and the damping fluid (pH=4.5) of ethanol (1:1), the supersound process mixing, the 3-sulfydryl glyceryl methoxy silane (MPTS) of getting 1ml again joins mixing in 1:1 acetate and the ethanol damping fluid.Above-mentioned two kinds of mixed solutions are combined into 1 body, at 22 ℃ of reaction 1.5h, take out particle, after acetate and ethanol buffer solution for cleaning three times, 150 ℃ of vacuum-drying 2h. collect the MFNB that the surface has been added with sulfydryl.
Embodiment 2
Implementation result
The Eu that several steps is handled among the process embodiment 1
3+Y-Fe
2O
3Mixture, through sem observation, the particle diameter of measuring magnetic fluorescent nanosphere is even relatively, and particle surface is bright and clean.Can be used as carrier and probe and be used for research.See Fig. 1-4.
Embodiment 3
Amido modified fluorescent nano particles is applied to separate nucleic acid
Get the nanometer magnetic fluorescent microsphere of the finishing amino of 1～3mg such as embodiment 1 preparation, join pH and be in 7.0～8.0 the phosphate buffer, adding consumption is 50～200 μ L linking agents such as glutaraldehyde or the like, forms mixing solutions.Described mixing solutions is used ultrasonication 10～30 minutes.Under suitable temperature condition, reacted 4～6 hours.After supernatant is removed in centrifugation, use phosphate buffered saline buffer supersound washing 2～3 times then after, again particle is scattered in phosphate buffer solution.
Get a certain amount of Oligo (dT), carry out crosslinking reaction according to ordinary method and above-mentioned microballoon.Magnetic resolution is removed supernatant liquor, and with phosphate buffer solution washing 1～2 time, the nanometer magnetic fluorescent microsphere that obtains being connected with Oligo (dT) at last is standby.
With above-mentioned Nano microsphere, join in the normal human subject write cell lysis buffer, in the presence of RNase, carry out the hybridization of conventional Oligo (dT) and mRNA.Thorough washing behind the stopped reaction utilizes magnetic resolution to have the Nano microsphere of mRNA, with nucleic acid staining agent dyeing, observes separating effect under fluorescent microscope.And utilize RT-PCR to detect the magnetic decontamination effect of mRNA.
The result shows that microscopically fluorescence and nucleic acid staining agent position consistency show the mRNA good separation; RT-PCR detects mRNA result and shows nucleic acid purity behind the purifying greater than 80%, and purification effect reaches expection.
Embodiment 4
MFNB-NH
2Separating effect to bovine serum albumin
The bovine serum albumin of same concentration (20 μ g/ml) is added in the separator tube of MFNB of different concns (10 μ g/ml, 20 μ g/ml, 30 μ g/ml, 40 μ g/ml), after reacting 15min in 37 ℃ of temperature incubators, under the effect of outside magnetic field, with PBS washing 3 times, survey the absorption value (seeing accompanying drawing 5) of 280nm on the microplate reader.Experimental result prompting, the absorbance value of A280nm is with what of the proteic amount of Niu Qingbai of MFNB absorption, and the A value is also in continuous increase, and the two presents proportional relation.Through correlation analysis, has significant correlation (r=0.996, p＜0.001).In order to get rid of the interference of MFNB, establish the MFNB experimental group in addition as a means of contrast in this experiment to the protein separation effect.From accompanying drawing 5 as can be known, MFNB truly has certain uv-absorbing effect at the 280nm place, but does not influence MFNB to proteinic separation function.
Claims (10)
1. nanometer magnetic fluorescent microsphere possesses the hud typed structure of kernel and shell, and its composition comprises: interior nuclear composition is Eu
3+Y-Fe
2O
3Mixture; Outer shell is SiO
2
2. nanometer magnetic fluorescent microsphere according to claim 1 is characterized in that, said microballoon outer shell surface is the decorative layer of amino or sulfydryl.
3. nanometer magnetic fluorescent microsphere according to claim 1 and 2 is characterized in that, said microspherulite diameter is 50-100nm.
4. nanometer magnetic fluorescent microsphere according to claim 2 is characterized in that, said microsphere average grain diameter is 97.5nm.
5. the preparation method of a nanometer magnetic fluorescent microsphere in turn includes the following steps:
(1) ferrous ion is mixed with metal europium ion solution, agitation and dropping NaOH solution, wherein the mol ratio of iron ion, europium ion and NaOH is 3:2:5, gained precipitates through ageing, filtration, washing, drying, grinding, obtains Eu
3+Y-Fe
2O
3Mixture;
(2) triton x-100, n-hexyl alcohol and hexanaphthene mix in 1:1:4 mole number ratio, and supersound process becomes homogeneous transparent stable microemulsion liquid, add Eu
3+Y-Fe
2O
3Mixture, after the supersound process in supernatant liquor successively dropping ammonia, add the own ester of positive silicic acid, stirring reaction 12 hours leaves standstill, the sedimentary particle of gained is calcined through cleaning the back repeatedly, promptly gets nanometer magnetic fluorescent microsphere.
6. the preparation method of nanometer magnetic fluorescent microsphere according to claim 5 is characterized in that, said step also comprises:
(1) nanometer magnetic fluorescent microsphere that claim 5 is made adds in the alcoholic solution, supersound process;
(2) N-(2-aminoethyl)-3-aminopropyl trimethyl silane is added in the mixed solution supersound process reaction;
(3) will react the particle that obtains and wash, be drying to obtain nanometer magnetic fluorescent microsphere.
7. the preparation method of nanometer magnetic fluorescent microsphere according to claim 5 is characterized in that, said step also comprises:
(1) nanometer magnetic fluorescent microsphere that claim 5 is made joins in acetate and the alcoholic acid damping fluid, supersound process;
(2) 3-sulfydryl glyceryl methoxy silane is joined in the mixed solution mixing reaction;
(3) will react the particle that obtains and wash, be drying to obtain nanometer magnetic fluorescent microsphere.
8. the preparation method of nanometer magnetic fluorescent microsphere according to claim 5 is characterized in that, said ferrous ion is from ferrous sulfate or iron protochloride or both combinations, and europium ion is from Europium trichloride.
9. the preparation method of nanometer magnetic fluorescent microsphere according to claim 5 is characterized in that, said ferrous ion is from FeSO
4.7H
2O and FeCl
2.6H
2O.
Claim 1 or 2 described nanometer magnetic fluorescent microspheres biomaterial detect and separation and purification in application.
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| CN100469854C true CN100469854C (en) | 2009-03-18 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101858908B (en) * | 2010-05-21 | 2013-05-29 | 上海师范大学 | Method by utilizing magnetic fluorescent nanometer particle to mark housefly nerve cell |
| CN102085380B (en) * | 2010-12-30 | 2012-09-05 | 成都西南交大科技园管理有限责任公司 | Preparation method of nano magnetic particles for detection and treatment of coronary heart diseases |
| CN102500291B (en) * | 2011-09-30 | 2015-04-08 | 深圳市易瑞生物技术有限公司 | Preparation method and application of magnetic fluorescent nanoparticle with shell-core structure |
| CN105445465A (en) * | 2015-11-16 | 2016-03-30 | 珠海国际旅行卫生保健中心 | Fluorescent nano-immunochromatography kit for quickly detecting vibrio parahaemolyticus and preparation method |
| CN106905968B (en) * | 2017-02-24 | 2019-05-24 | 温州医科大学 | The preparation method of magnetic fluorescence material |
| CN107603592B (en) * | 2017-08-30 | 2019-12-13 | 河南理工大学 | Preparation method of magnetic fluorescent nano material and fluorescence detection method thereof |
| CN112980806B (en) * | 2021-02-08 | 2022-09-13 | 厦门大学 | Virus single particle separation method based on nano-micro composite sphere |
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Non-Patent Citations (4)
| Title |
|---|
| "Effects of rare earth ...... Fe2O3 magnetic powder". Zeng Huan-Xing,Ren Fu-Min.Journal of Rare Earths,Vol.12 No.3. 1994 |
| "Effects of rare earth ...... Fe2O3 magnetic powder". Zeng Huan-Xing,Ren Fu-Min.Journal of Rare Earths,Vol.12 No.3. 1994 * |
| "Synthesis and characterization of ......bio-affinity properties". Huachang Lu,et al.Journal of Materials Chemistry,Vol.14 . 2004 |
| "Synthesis and characterization of ......bio-affinity properties". Huachang Lu,et al.Journal of Materials Chemistry,Vol.14 . 2004 * |
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