CN1690163A - Luminous microsphere and its production method and water dispersion system - Google Patents
Luminous microsphere and its production method and water dispersion system Download PDFInfo
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Abstract
The invention provides a method for produing fluorescent microsphere, which contains: mixing thermo-sensitive polymer microspheres with water-soluble inorganic fluorescent nanometer particles with function group on the surface; evoking phase change of the composite; separating the phase-changed composite to prepare fluorescent microsphere. And it also provides the fluorescent microsphere and its water disperse system prepared by the method. The invention is of mild reaction condition, simple preparing process and convenient operation, which is suitable for scaled and commercial production, especially for preparing fluorescent marking microsphere for biomedicine check. The prepared fluorescent microsphere is in the nanometer dimensional range; grain size and appearance is homogeneous; luminous intensity is high; luminous purity is nice, dispersion is steady in water and have fine biocompatibility.
Description
Technical field:
The present invention relates to a kind of fluorescent microsphere preparation method, fluorescent microsphere and aqueous dispersion thereof, more particularly, but relate to a kind of in water stable dispersion, have simultaneously biocompatibility polymer/inorganic nanometer particulate composite fluorescence microballoon the preparation method and utilize the fluorescent microsphere and the aqueous dispersion thereof of the preparation of this method.
Background technology:
Compare with traditional organic dye, the photoluminescent property of semiconductor nano particulate has plurality of advantages, as: wide excitation spectrum, fluorescence are absorbed with big stokes (Stokes) displacement, symmetric fluorescent emission feature, high fluorescent stability and fluorescent emission to dependency of particle size etc., these unique optical properties of fluorescence semiconductor nanoparticle make it embody great application prospect as the biological fluorescent labelling material in biomedical sector, especially in high-throughout bioanalysis and detecting.With the photoluminescent property of inorganic nano-particle be used for the biomedical a kind of typical method that detects be with fluorescent nano particles be compound to size between tens and the hundreds of nanometer between other material in form fluorescent microsphere.The advantage of this method be on the one hand by with the compound chemical environment adaptability that can improve microparticle fluorescence effectively of other material; On the other hand, the fluorescent nano particles of different size is integrated into the fluorescent microsphere that can also easily obtain having different fluorescent characteristicss in the same microballoon, this has just simplified the preparation process of the fluorescent microsphere that can be used as fluorescence labeling material widely.Up to now, roughly can be divided into fluorescent nano particles and the compound method for preparing fluorescent microsphere of other material following several: 1, by the method for hydrolysis organo-siloxane, in situ the water soluble fluorescence nanoparticle is compound in the silicon-dioxide, obtain fluorescent microsphere.A.L. (Chem.Mater. such as Rogach, 2000,12,2676) reported and be compounded with CdTe and CdSe/CdS nanoparticle, the silicon dioxide microsphere of size between the 40-80 nanometer, but the preparation process of above-mentioned microballoon often causes the reduction of the fluorescence efficiency of nanoparticle.2, fluorescent nano particles is compound in the formed micellar structure of the surfactant molecule with reactive behavior, the further reaction by the micella molecule is fixed on fluorescent nano particles and forms fluorescent microsphere in the micellar structure then.(NanoLetter such as Y.F.Chen, 2002,2,1299) utilize the quaternary surfactant molecule that has organic siloxane head base in water, to form micella, oil-soluble CdSe nanoparticle is coated in the micella, and the hydrolysis organo-siloxane forms thin layer of silicon dioxide with the stable fluorescent nano particles micella that is compounded with at micellar surface then.The fluorescent glue beam diameter of this method preparation is between 50 nanometer to 130 nanometers.The shortcoming that this obviously method exists is that the hydrolysis of organo-siloxane is wayward, and the condensation between the silanol key can very large distribution of sizes on the adjacent micella in the hydrolytic process, and the shape of resulting fluorescence micellar structure is also irregular simultaneously.3, utilize the preparation of stratiform static self-assembling method to be compounded with the fluorescent microsphere of fluorescent nano particles.H.Moehwald (Adv.Mater.2001,13 (22), 1684) and his study group have reported the preparation method of this fluorescent microsphere the earliest.This method mainly utilizes inorganic or organic colloidal spheres as the film forming template, by in its surperficial electrostatic adhesion, inorganic fluorescent nano particles can be assembled film forming with alternative mode and different types of polyelectrolyte.But it is various to utilize this method to prepare the fluorescent microsphere step, and the process complexity is unfavorable for large-scale production.4, recently, (NanoLetter such as Y.F.Chen, 2003,3,581) reported a kind of preparation of glycan glycosides fluorescent nanometer microsphere, microballoon is to utilize that electrostatic interaction forms between the polysaccharide molecule of fluorescent nano particles with CdSe/ZnS nucleocapsid structure and polyelectrolyte and functionalization, concrete steps are as follows: at first, prepare oil-soluble CdSe/ZnS nanoparticle by the TOP/TOPO method, promptly adopt trialkyl phosphorous oxides (as TOPO, trioctylphosphine oxide) as stablizer with nucleocapsid structure, trialkyl phosphorus is (as TOP, trioctyphosphine) as solvent synthetic fluorescence CdSe/ZnS nanoparticle under high temperature (~ 300 ℃).Utilize the TOP/TOPO method to prepare fluorescent nano particles, severe reaction conditions, experimental implementation have very high danger, and especially the organometallics as the cadmium source has very large toxicity; Secondly, utilizing the process need of method for preparing fluorescent microsphere further to utilize sulfhydryl compound (as Thiovanic acid) that the TOPO of CdSe/ZnS microparticle surfaces is replaced makes microparticle surfaces have electronegativity, it is high water-soluble that microsome is revealed, although Thiovanic acid itself can not influence the fluorescence efficiency of fluorescent nano particles, the rapid treating processes of this multistep certainly will cause fluorescence efficiency to reduce.In addition, the particle diameter of microballoon is inhomogeneous in this report.5, utilize adsorption method that fluorescent nano particles is compound to SiO
2In the porous microsphere.Adopt the hydrophobicity long chain alkyl compound to modify SiO
2The duct inwall of porous material, TOPO by being modified at CdSe/ZnS fluorescent nano particles surface and the hydrophobic interaction between the surface, duct, SiO rapidly and accurately packs fluorescent particle into
2Form microballoon J.Phys.Chem.B such as (, 2003,107,11575) S.M.Nie of high fluorescent brightness in the porous duct.Though this method is simple and convenient, selected porous SiO with high-specific surface area
2Body material may produce non-specific adsorption to biomolecules, and therefore, the fluorescent microsphere of formation may face a lot of problems in bio-medical applications.6, S.M.Nie etc. (NatureBiotech., 2001,19,631) reported adopt above-mentioned TOP/TOPO method synthetic oil soluble fluorescent nano particles with by swelling polystyrene microsphere in organic solvent, be compounded to form the method for fluorescent microsphere.Utilize this method can be respectively the CdSe/ZnS nanoparticle of different fluorescence colors to be integrated into the composite fluorescence microballoon that obtains high brightness in the polystyrene microsphere, developed composite fluorescence microballoon multiplex fluorescence coding techniques based on fluorescent nano particles.Though also there is a lot problems in the TOP/TOPO method aspect the preparation fluorescent nano particles a lot of advantages being arranged, and mainly is the preparation process more complicated of TOP/TOPO method, and preparation condition is required harsh.In addition, resulting fluorescent nano particles only is dissolved in organic solvent, and this has limited the purposes of above-mentioned fluorescent particle to a certain extent.If want the oil solubility nanometer particulate of TOP/TOPO method preparation is changed into water miscible nanoparticle, also need very complicated process.Prepare with regard to microballoon, though the polystyrene microsphere swelling method of Nie invention is simple, resulting microballoon does not have biocompatibility.
Summary of the invention
But an object of the present invention is to provide a kind of in water stable dispersion, have the preparation method of the polymer/inorganic nanometer particulate composite fluorescence microballoon of biocompatibility simultaneously, this method is simple, resulting microballoon has excellent biological compatibility.
A further object of the present invention provides a kind of polymer/inorganic nanometer particulate compound fluorescent microsphere with excellent biological compatibility.
Another object of the present invention provides the aqueous dispersion of above-mentioned fluorescent microsphere.
To achieve these goals, the present inventor has carried out a large amount of intensive researchs, found that, selection has thermo-sensitive property, biocompatibility, the polymkeric substance of good water-dispersion performance, preferred poly N-isopropyl acrylamide (pNIPAM) hydrogel, matrix as microballoon, finishing can there be the inorganic fluorescent nano particles of functional group to be adsorbed onto the inside of ball by simple mixing, be securely fixed in polymeric matrix inside by induced transformation then, thereby formed polymer/inorganic nanometer particulate compound fluorescent microsphere with excellent biological compatibility.
Therefore, a first aspect of the present invention provides a kind of preparation method of fluorescent microsphere, comprising:
Make thermosensitive polymer microballoon and finishing have the water-soluble inorganic fluorescent nano particles of functional group to carry out compound;
The gained mixture is carried out induced transformation;
To separate through the mixture of induced transformation, obtain fluorescent microsphere.
A second aspect of the present invention provides a kind of fluorescent microsphere, comprises that thermosensitive polymer microballoon and finishing have the mixture of the water-soluble inorganic fluorescent nano particles of functional group, and described inorganic fluorescent nano particles is fixed on microballoon inside by induced transformation.
A third aspect of the present invention provides a kind of aqueous dispersion of fluorescent microsphere, comprises the described fluorescent microsphere of the second aspect that stably is dispersed in the water.
Among the present invention, except as otherwise noted, term " thermosensitive polymer " is meant the polymkeric substance that has tangible volume phase transition through certain temperature range.
Except as otherwise noted, term " induced transformation " is meant the polyalcohol hydrogel microballoon is heated to it more than transformation temperature, makes it to produce volume phase transition.
Term " nanoparticle " is meant that median size is the inorganic semiconductor fluorescent nano particles of 2-10nm.
The accompanying drawing summary
Fig. 1 is the fluorescent microscope photo for preparing the pNIPAM-CdTe535 of embodiment 1 preparation according to fluorescent microsphere;
Fig. 2 is the fluorescent microscope photo for preparing the pNIPAM-CdTe560 of embodiment 1 preparation according to fluorescent microsphere;
Fig. 3 is the fluorescent microscope photo for preparing the pNIPAM-CdTe610 of embodiment 1 preparation according to fluorescent microsphere;
Fig. 4 is the fluorescence spectrum of pNIPAM-CdTe microballoon (pNIPAM-CdTe535, pNIPAM-CdTe560, pNIPAM-CdTe610) for preparing three kinds of different single fluorescence colors of embodiment 1 preparation according to fluorescent microsphere; With
Fig. 5 is the fluorescence spectrum of pNIPAM-CdTe microballoon for preparing compound two kinds of color particulates of embodiment 1 preparation according to fluorescent microsphere.
Embodiment
The invention provides a kind of preparation method of fluorescent microsphere, comprising:
Make thermosensitive polymer microballoon and finishing have the water-soluble inorganic fluorescent nano particles of functional group to carry out compound;
The gained mixture is carried out induced transformation;
To separate through the mixture of induced transformation, obtain fluorescent microsphere.
Be applicable to that it is the polymer materials of matrix that thermosensitive polymer of the present invention includes but not limited to the N-N-isopropylacrylamide; The homopolymer of preferred N-N-isopropylacrylamide and N-N-isopropylacrylamide and the monomeric multipolymer of other free radical, wherein said other free radical monomer includes but not limited to acrylamide, vinylformic acid, methacrylic acid, N, N '-methylene-bisacrylamide or two or more mixture in them.
Be applicable to that thermosensitive polymer microballoon of the present invention is preferably hydrogel microsphere, its median size is not particularly limited, but preferred 50-800.The median size of the thermosensitive polymer microballoon that uses as raw material is the 50-800 nanometer, preferred 100-600 nanometer.
The thermosensitive polymer microballoon can be by conventional method preparation.For example, Langmuir 2003,19, disclosed method in the 5212-5216 document.
According to a preferred embodiment of the present invention, can by the monomeric homopolymerization of N-N-isopropylacrylamide (NIPAM) or with the monomeric copolymerization uniform particle diameter of other free radical can be in water dispersive pNIPAM hydrogel (microgel) microballoon, other free radical monomer is respectively vinylformic acid, methacrylic acid, acrylamide, N-DMAA etc.Utilize intramolecularly and the intermolecular interaction of hydrogen bond of pNIPAM, obtain spherical hydrogel sphere.
Be example with poly N-isopropyl acrylamide (pNIPAM) microballoon below, be described in more detail the preparation method of thermosensitive polymer microballoon, but should be appreciated that the present invention is not limited to the thermosensitive polymer microballoon that obtains with this method:
N-N-isopropylacrylamide (NIPAM) monomer is dissolved in secondary deionized water, and to be made into weight percent be the 1.0%-5.0% aqueous solution, according to N-N-isopropylacrylamide (NIPAM) weight percent monomer be that the ratio of 0%-10% (preferred 0%-3%) adds N, N '-methylene-bisacrylamide is as linking agent, feed nitrogen and remove oxygen in the system, heat temperature raising to 70 ℃ formation solution I (mixed monomer solution); The preparation weight percent is 0.1%-5% Potassium Persulphate (KPS) aqueous solution, feeds nitrogen and forms solution II (initiator solution); Under nitrogen atmosphere, solution II is added solution I and in 3-8 hour (preferred 4.5 hours) of 70 ℃ of reactions, makes the pNIPAM hydrogel microsphere.
In the preparation process of above-mentioned microballoon, can add the free radical monomer of other kind such as vinylformic acid, methacrylic acid, acrylamide, N-DMAA etc. in right amount, thereby the structure and morphology of pNIPAM hydrogel microsphere is finely tuned.
Poly N-isopropyl acrylamide (pNIPAM) by the preparation of free radical method is a kind of typical thermo-sensitivity high molecular polymer, and its critical volume transformation temperature is between 32-35 ℃.When system temperature subcritical temperature, pNIPAM shows highly hydrophilic, and formed microballoon is expanded by water-soluble easily; When system temperature was higher than critical temperature, pNIPAM became hydrophobicity by wetting ability, and the result causes the contraction of microsphere volume.The result of volumetric shrinkage can be securely fixed in microballoon inside with fluorescent nano particles very much, thereby forms the fluorescence complex microsphere.In addition, excellent biological compatibility has made the pNIPAM microballoon embody important use in biological field and has been worth, and for example: it can be used to the immobilization of enzyme; The cell thermal induction separates; Aspects such as medicine sustained release and gene therapy.Nearest white mouse cell toxicity test result shows that there is bio-toxicity hardly in (Bioconjugate Chem. such as D.Cube, 2002,13,685) poly N-isopropyl acrylamide.
Prepare the important feature that fluorescent microsphere is a preferred embodiment of the present invention with poly N-isopropyl acrylamide (pNIPAM) hydrogel as composite fluorescence particulate body material.
Be applicable to that inorganic fluorescent nano particles of the present invention includes but not limited to the inorganic semiconductor fluorescent nano particles.Preferred II-VI family semi-conductor, more preferably CdTe nanoparticle.The median size of described inorganic fluorescent nano particles is preferably 2-5nm.Preferably, the fluorescent emission center peak position of described CdTe fluorescent nano particles is between the 510-650 nanometer.
The functional group of being modified on the inorganic fluorescent nano particles surface includes but not limited to various sulfhydryl compounds, on the preferred sulfhydryl compound.At least a or two in hydroxyl, amido and the carboxyl.Described functional group preferably by carrier band on sulfhydryl compound.
According to a preferred embodiment of the invention a, water-soluble CdTe fluorescent nano particles surface is modified with sulfhydryl compound that contains hydroxyl and the sulfhydryl compound that contains carboxyl simultaneously.More preferably, described sulfhydryl compound selected from mercapto glycerine, the mercaptoethanol that contains hydroxyl, described sulfhydryl compound selected from mercapto acetate, thiohydracrylic acid, the Thioctic Acid that contains carboxyl.
Be applicable to that inorganic fluorescent nano particles of the present invention can adopt various known method preparations.But,, the condition easily angle consideration of control simple from preparation technology, preferably direct reaction prepares fluorescent nano particles in the aqueous solution.More preferably utilize the sulfhydryl compound used as stabilizers through single step reaction synthetic water-soluble CdTe nanoparticle.But method set forth in the present invention is equally applicable to utilize the fluorescent nano particles of TOP/TOPO method preparation, but particulate must be the water miscible particulate that obtains through surface replacement.
A kind of preparation method of fluorescent nano particles is disclosed in M.Y.Gao etc., and J.Phys.Chem. is in 1998,102,8360 (being incorporated herein by reference in full).
Preferably, can be according to M.Y.Gao etc., J.Phys.Chem., disclosed method in 1998,102,8360, adopt following condition to prepare fluorescent nano particles:
In order to realize effectively compound with pNIPAM, the main stablizer that adopts comprises mercapto glycerol (or mercaptoethanol) and Thiovanic acid (or Thioctic Acid, thiohydracrylic acid etc.), its molar ratio is an example with mercapto glycerol and Thiovanic acid, mercapto glycerol: Thiovanic acid=10: 10～10: 1 (preferred 10: 2.5), the center emission peak position of the fluorescence emission spectrum of resulting CdTe nanoparticle can be between the 510-650 nanometer.Realize effectively regulating by the control to particle size, the peak width at half height of resulting fluorescent nano particles is about 50 nanometers.CdTe concentration is between 10mM-20mM in resulting fluorescent particle solution.
Among the present invention, the compound the whole bag of tricks that can adopt of thermosensitive polymer microballoon and inorganic fluorescent nano particles carries out.The compositely proportional of thermosensitive polymer microballoon and inorganic fluorescent nano particles is not particularly limited, and can suitably be adjusted according to actual needs.But, be preferably 1-15% (weight ratio), more preferably 3.0-9.0%.For example, a kind of preferred manufacturing procedure can be described below: is that 1: 0.01～1: 1 ratio is mixed with pNIPAM hydrogel microsphere and CdTe nanoparticle in the liquor capacity ratio.Detailed process is as follows: at first, the pH of pNIPAM hydrogel sphere is transferred to 6.5-10.0 (preferred pH transfers to 7.0-8.0), stirred 30 minutes, add sulfhydryl compound then and stablize the CdTe nanoparticle aqueous solution, pH with system transfers to 9.0-13.0 (preferred pH transfers to 9.0-10.0) again, and at room temperature continue to stir 2-72 hour (preferred 2-24 hour), obtain pNIPAM-CdTe fluorescence hydrogel microsphere.
Above-mentioned mixture is carried out induced transformation.The condition of described induced transformation is not particularly limited, but needs the temperature of the hierarchy of control.For instance, above-mentioned composite aquogel microballoon can be heated to certain temperature (for example 40-80 ℃) and carry out induced transformation, make inorganic fluorescent nano particles to be securely fixed in the thermosensitive polymer.The time length of induced transformation is not particularly limited, but preferred 0.5-24 hour, more preferably 1-5 hour, most preferably 1-3 can be securely fixed in the thermosensitive polymer to guarantee inorganic fluorescent nano particles.
Can also can pass through centrifugation directly as the dispersion system of fluorescent microsphere through the compound system behind the induced transformation, and randomly precipitate and wash, thereby obtain fluorescent microsphere.Fluorescent microsphere of the present invention can be dispersed in the water.Therefore, also the fluorescent microsphere that obtains can be scattered in an amount of secondary deionized water again, thereby obtain the aqueous dispersion of fluorescent microsphere.
According to a preferred embodiment of the invention, the pNIPAM-CdTe fluorescent microsphere particle diameter that makes can be controlled between the 200-800 nanometer, the even particle size distribution of microballoon, its photoluminescent property is by being determined by the compound fluorescent particle, the content of fluorescence CdTe nanoparticle in microballoon can carry out controllable adjustment usually between 1.0%-15% (weight percent, preferred 3.0%-9.0%).
From the recombination process of above-mentioned fluorescent microsphere, it is more simpler than the preparation method of the fluorescent microsphere that has existed, and has overcome many technical shortcomings such as the step that exists in the above-mentioned preparation process is various.
In a word, based on thermosensitive polymer for example pNIPAM as the fluorescent microsphere of matrix, no matter be aspect the preparation method, still in the characteristics and the advantage that all embody highly significant aspect the selection of compound fluorescent particle, therefore, the fluorescent microsphere with this method preparation should embody more wide application prospect and good market outlook in biomedicine detects.
Be bound by any theory although be reluctant, but it is believed that, the compound fluorescent microsphere that obtains with pNIPAM and CdTe fluorescent nano particles is an example, preparation principle is: by the modification group and the pNIPAM segmental interaction of hydrogen bond of nano-particle surface, make the CdTe fluorescent nano particles after overheated phase transformation, be compounded in the pNIPAM microballoon, form the fluorescence complex microsphere at pNIPAM.Main preparation process is as follows: 1) by the monomeric homopolymerization of N-N-isopropylacrylamide (NIPAM) or with the monomeric copolymerization uniform particle diameter of other free radical can be in water dispersive pNIPAM hydrogel (microgel) microballoon, other free radical monomer is respectively vinylformic acid, methacrylic acid, acrylamide, N-DMAA etc.Utilize intramolecularly and the intermolecular interaction of hydrogen bond of pNIPAM, obtain spherical hydrogel sphere.2) according to and improve literature method and utilize the single step reaction method to synthesize the CdTe fluorescent nano particles in aqueous systems, by selecting suitable sulfhydryl compound as stablizer, can make microparticle surfaces be modified with different functional groups, as: carboxyl and hydroxyl etc., this can strengthen nanoparticle with the intersegmental interaction of hydrogen bond of pNIPAM chain.3) mix above-mentioned pNIPAM hydrogel sphere and water soluble fluorescence nanoparticle, by inducing the phase transformation of pNIPAM microballoon, make the fluorescent microsphere that is compounded with the CdTe nanoparticle.The complex microsphere diameter that utilizes method for preparing is between 50 nanometer to 800 nanometers, and the monochromaticity of fluorescence and color depend on the fluorescent characteristics of institute's compound fluorescent particle.If compound CdTe fluorescence nanocrystalline, resulting microballoon fluorescence color can be regulated arbitrarily between green (the fluorescence centre peak position is 510 nanometers) and red (the fluorescence centre peak position is 650 nanometers).Also the CdTe nanoparticle of different size can be integrated into and prepare the fluorescent microsphere that is compounded with multiple fluorescence color particulate in the same pNIPAM microballoon.
Compare with traditional preparation method, the present invention has the following advantages: 1) prepare the fluorescent microsphere particle diameter of gained and pattern homogeneous, luminous intensity height (luminosity is enhanced about more than once than the fluorescent particle of same concentrations), luminous high color purity (peak width at half height near or less than 50nm), fluorescent microsphere stably dispersing and have excellent biological compatibility in water by this method, therefore, this method is particularly suitable for preparing the fluorescence labeling material that is used for biomedical detection.2) fluorescent particle that this method synthetic microballoon not only can compound single size obtains the microballoon of single fluorescence color, compound different size fluorescent nano particles simultaneously, thus realize fluorescence-encoded to microballoon.3) the microballoon matrix and the fluorescent particle that use of the inventive method is all synthetic in aqueous systems, and preparation process is simple, and is easy to operate, is suitable for mass-producing and commercially produces, and this will further accelerate and widen the application of inorganic fluorescent nano material in biomedical sector.
Embodiment
Adopted three kinds of representative fluorescent nano particles among the following embodiment of the present invention, its fluorescence emission peak central position wavelength is respectively 535 nanometers, 560 nanometers, 610 nanometers (being designated as CdTe535, CdTe560, CdTe610 respectively).The pNIPAM-CdTe composite fluorescence hydrogel microsphere that adopts CdTe535, CdTe560, CdTe610 particulate to obtain is designated as pNIPAM-CdTe535, pNIPAM-CdTe560, pNIPAM-CdTe610 respectively.Adopt CdTe535, CdTe610 particulate to be compound to the composite fluorescence hydrogel microsphere that obtains in the pNIPAM microballoon simultaneously and to be expressed as pNIPAM-CdTe535-CdTe610.
Following examples are used to further specify the concrete preparation process of fluorescent microsphere, do not limit the preparation process condition of fluorescent microsphere among the present invention.
The embodiment of pNIPAM microballoon preparation:
The thermosensitive polymer microballoon prepares embodiment 1:
The preparation of N-N-isopropylacrylamide homopolymer (pNIPAM) microballoon.Take by weighing 1.53gN-N-isopropylacrylamide (NIPAM) monomer and be dissolved in the 125ml secondary deionized water, feed high purity nitrogen deoxygenation 30 minutes, heated solution is warming up to 70 ℃ and forms solution I; Take by weighing 0.076g Potassium Persulphate (KPS) and be dissolved in the 25ml secondary deionized water, feed high purity nitrogen and formed solution II in 30 minutes; Solution II is added solution I, and under nitrogen protection, under 70 ℃, mixed solution 4.5 hours, obtain the pNIPAM microballoon.
The thermosensitive polymer microballoon prepares embodiment 2:
The preparation of N-N-isopropylacrylamide and linking agent copolymer microsphere, the linking agent that is adopted are N, N '-methylene-bisacrylamide.Detailed process is as follows, takes by weighing 1.50g N-N-isopropylacrylamide (NIPAM) and 0.013gN, and N '-methylene-bisacrylamide is dissolved in the 125ml secondary deionized water, logical high purity nitrogen deoxygenation 30 minutes, heating systems to 70 ℃ formation solution I; It is identical that the preparation condition of initiator solution and microballoon polymerizing condition and microballoon prepare embodiment 1, obtains the pNIPAM microballoon.
The thermosensitive polymer microballoon prepares embodiment 3:
The preparation of N-N-isopropylacrylamide, linking agent, methacrylic acid ter-polymer microballoon.Concrete preparation process is as follows, get 1.40g N-N-isopropylacrylamide (NIPAM), methacrylic acid 10 μ l and 0.013g N, N '-methylene-bisacrylamide, it is dissolved in the 125ml secondary water, obtain solution I through high purity nitrogen deoxygenation, it is identical that the preparation condition of initiator solution and microballoon polymerizing condition and microballoon prepare embodiment 1, obtains the pNIPAM microballoon.
The thermosensitive polymer microballoon prepares embodiment 4:
The preparation of N-N-isopropylacrylamide, linking agent, N-DMAA terpolymer microballoon.Concrete preparation process is as follows, get 1.40g N-N-isopropylacrylamide, 0.013g N, N '-methylene-bisacrylamide and 0.10g N-DMAA, it is dissolved in the 125ml water, obtain solution I through high purity nitrogen deoxygenation, it is identical that the preparation condition of initiator solution and microballoon polymerizing condition and microballoon prepare embodiment 1, obtains the pNIPAM microballoon.
The embodiment of CdTe fluorescent nano particles preparation:
The preparation embodiment 1 of inorganic fluorescent nano particles:
The preparation of the CdTe nanoparticle of mercapto glycerol one Thiovanic acid finishing.Get the 150ml secondary deionized water, feed the deoxygenation more than 0.5 hour of high purity nitrogen, take by weighing 1.405g cadmium perchlorate (Cd (ClO
4)
26H
2O) join in the above-mentioned secondary deionized water, add 0.56ml mercapto glycerol and 0.12ml Thiovanic acid stablizer (mol ratio is 8: 2) subsequently, the NaOH aqueous solution with 5M transfers to 11.2 with its pH value again, forms the solution that contains sulfhydryl compound and cadmium ion.On the other hand, configuration 0.5M sulphuric acid soln, and feed nitrogen deoxygenation 0.5 hour.Then, getting this sulphuric acid soln of 30ml is injected into and fills 0.39g tellurium aluminium (Al
2Te
3) flask in react the H that will reaction generates
2Te directly feeds in the above-mentioned cadmium solution, under agitation react 15 minutes after, this solution of reflux obtains the stable CdTe fluorescent nano particles aqueous solution of mercapto glycerol one Thiovanic acid then.By the control return time, obtain the stable CdTe fluorescent nano particles of mercapto glycerol one Thiovanic acid of different size, its fluorescent emission center peak position is any modulation between 510 nanometer to 650 nanometers.
The embodiment of fluorescent microsphere preparation:
The preparation embodiment 1 of fluorescent microsphere:
The preparation of pNIPAM-CdTe solid color composite fluorescence microballoon.Get above-mentioned pNIPAM and prepare the pNIPAM hydrogel microsphere 100ml for preparing among the embodiment, with the 2M NaOH aqueous solution its pH value is transferred to 7.5, add the CdTe nanoparticle aqueous solution (the arbitrary fluorescence color of launching centre peak position between 510nm to 610nm) that 10ml mercapto glycerol-Thiovanic acid (8: 2) is modified then, the pH to 9.5 of regulation system, at room temperature continue to stir 24 hours, then, mixed solution was kept 2 hours down at 45 ℃, pass through centrifugation then, washing and disperse to obtain the composite fluorescence microballoon again, its fluorescence photo is seen accompanying drawing 1,2 and 3, fluorescence spectrum is seen Fig. 4.
The preparation embodiment 2 of fluorescent microsphere:
The preparation of pNIPAM-CdTe solid color composite fluorescence microballoon.Get above-mentioned pNIPAM and prepare the pNIPAM hydrogel microsphere 10ml for preparing among the embodiment, its pH value is transferred to 7.0 with the 2M NaOH aqueous solution; The CdTe nanoparticle aqueous solution of mercapto glycerol-Thiovanic acid (8: 2) being modified in 5: 1 ratios concentrates, add the above-mentioned spissated CdTe nanoparticle aqueous solution of 2ml (the arbitrary fluorescence color of launching centre peak position between 510nm to 610nm) then, the pH to 9.0 of regulation system, at room temperature continue to stir 48 hours, then, mixed solution 70 ℃ of following maintenances 1 hour, is passed through centrifugation, washing and disperses to obtain the composite fluorescence microballoon again.
The preparation embodiment 3 of fluorescent microsphere:
Be compounded with the preparation of the pNIPAM-CdTe fluorescent microsphere of two kinds of color fluorescent particles.Used pNIPAM hydrogel microsphere is identical with the preparation embodiment 1 of fluorescent microsphere with the CdTe nanoparticle aqueous solution and concrete preparation process, just add the CdTe535 nanoparticle aqueous solution of 5ml mercapto glycerol-Thiovanic acid (8: 2) modification and the CdTe610 nanoparticle aqueous solution (adding the two kind fluorescence colors of launching centre peak position between 510nm to 610nm on demand) that 5ml mercapto glycerol-Thiovanic acid (8: 2) is modified in proportion simultaneously, all the other processes are identical with the preparation embodiment 1 of fluorescent microsphere, obtain being compounded with the fluorescent microsphere of the CdTe particulate of two kinds of different fluorescence colors.Its fluorescence emission spectrum is seen Fig. 5.
The preparation embodiment 4 of fluorescent microsphere:
Be compounded with the preparation of the pNIPAM-CdTe fluorescent microsphere of three kinds of color fluorescent particles.Used pNIPAM hydrogel microsphere is identical with the preparation embodiment 1 of fluorescent microsphere with the CdTe nanoparticle aqueous solution and concrete preparation process, just add the CdTe535 nanoparticle aqueous solution that 4ml mercapto glycerol-Thiovanic acid (8: 2) is modified simultaneously in 4: 4: 2 ratios, the 4ml CdTe580 nanoparticle aqueous solution, the 2ml CdTe580 nanoparticle aqueous solution (adding the three kind fluorescence color particulates of launching centre peak position between 510nm to 610nm on demand), all the other processes are identical with the preparation embodiment 1 of fluorescent microsphere, obtain being compounded with the fluorescent microsphere of the CdTe particulate of three kinds of different fluorescence colors.
Claims (16)
1. the preparation method of a fluorescent microsphere comprises:
Make thermosensitive polymer microballoon and finishing have the water-soluble inorganic fluorescent nano particles of functional group to carry out compound;
The gained mixture is carried out induced transformation;
To separate through the mixture of induced transformation, obtain fluorescent microsphere.
2. according to the process of claim 1 wherein that described thermosensitive polymer is the homopolymer of N-N-isopropylacrylamide, and/or, N-N-isopropylacrylamide and the monomeric multipolymer of other free radical.
3. according to the method for claim 2, wherein said other free radical monomer is for being selected from acrylamide, vinylformic acid, methacrylic acid, N, at least a in N '-methylene-bisacrylamide.
4. according to the process of claim 1 wherein that described thermosensitive polymer microballoon is that median size is the hydrogel microsphere of 50-800 nanometer.
5. according to the process of claim 1 wherein that described inorganic fluorescent nano particles is the water-soluble CdTe nanoparticle.
6. according to the method for claim 5, wherein said finishing functional group is a sulfhydryl compound.
7. at least a according to the process of claim 1 wherein that described functional group is selected from the sulfhydryl compound that contains hydroxyl, amido and carboxyl.
8. according to the method for claim 6, wherein said functional group is selected from least a in hydroxyl, amido and the carboxyl.
9. method according to Claim 8, wherein said water-soluble CdTe fluorescent nano particles surface are modified with sulfhydryl compound that contains hydroxyl and the sulfhydryl compound that contains carboxyl simultaneously.
10. according to the method for claim 9, wherein said sulfhydryl compound selected from mercapto glycerine, mercaptoethanol and their mixture that contains hydroxyl.
11. according to the method for claim 9, the wherein said sulfhydryl compound selected from mercapto acetate that contains carboxyl, thiohydracrylic acid, Thioctic Acid and two or more mixture in them.
12. according to the method for claim 5, the fluorescent emission center peak position of wherein said CdTe fluorescent nano particles is between the 510-650 nanometer.
13. according to the process of claim 1 wherein that described inorganic fluorescent nano particles has multiple size is multiple fluorescence color.
14. a fluorescent microsphere comprises that thermosensitive polymer microballoon and finishing have the mixture of the water-soluble inorganic fluorescent nano particles of functional group, described inorganic fluorescent nano particles is fixed on microballoon inside by induced transformation.
15. according to the fluorescent microsphere of claim 14, its photoluminescent property depends on the value volume and range of product of institute's compound fluorescent particle.
16. the aqueous dispersion of a fluorescent microsphere comprises the described fluorescent microsphere of the claim 14 that stably is dispersed in the water.
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| CN101775112B (en) * | 2010-02-05 | 2012-01-11 | 苏州大学 | Preparation method of magnetic fluorescence dual functional thermo-sensitive nano particle |
| CN103361067A (en) * | 2013-07-16 | 2013-10-23 | 天津大学 | Water-soluble quantum dot fluorescent nanosphere and preparation method thereof |
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| US4774189A (en) * | 1984-12-24 | 1988-09-27 | Flow Cytometry Standards Corp. | Fluorescent calibration microbeads simulating stained cells |
| FR2800384B1 (en) * | 1999-10-28 | 2003-01-10 | Cypher Science | COMPOSITION FOR MARKING A SOLID OR LIQUID PRODUCT AND PROCESS FOR PRODUCING SUCH A COMPOSITION |
| CN1278534A (en) * | 2000-06-13 | 2001-01-03 | 复旦大学 | Polymer microball with fluorescent mark and its preparation |
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| CN101775112B (en) * | 2010-02-05 | 2012-01-11 | 苏州大学 | Preparation method of magnetic fluorescence dual functional thermo-sensitive nano particle |
| CN103361067A (en) * | 2013-07-16 | 2013-10-23 | 天津大学 | Water-soluble quantum dot fluorescent nanosphere and preparation method thereof |
| CN108743564A (en) * | 2018-08-30 | 2018-11-06 | 东南大学 | A kind of combination drug carrier and its application based on metal nanoparticle and microgel |
| CN109405996A (en) * | 2018-10-17 | 2019-03-01 | 京东方科技集团股份有限公司 | A kind of thermometer and its control method |
| CN109540331A (en) * | 2018-11-08 | 2019-03-29 | 中国科学院理化技术研究所 | Cocktail-type nano assembly-based wide-range fluorescent nano thermometer and preparation method thereof |
| WO2022063337A1 (en) * | 2020-09-27 | 2022-03-31 | 上海交通大学 | Fluorescent encoding microspheres and array and preparation method |
| CN118652366A (en) * | 2024-08-16 | 2024-09-17 | 纳晶科技股份有限公司 | Quantum dot functional microsphere and preparation method and application thereof |
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