CN101168597B - Hollow polymer sub-micron sphere coated with gold case and preparation method - Google Patents
Hollow polymer sub-micron sphere coated with gold case and preparation method Download PDFInfo
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- CN101168597B CN101168597B CN2006101140419A CN200610114041A CN101168597B CN 101168597 B CN101168597 B CN 101168597B CN 2006101140419 A CN2006101140419 A CN 2006101140419A CN 200610114041 A CN200610114041 A CN 200610114041A CN 101168597 B CN101168597 B CN 101168597B
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Abstract
The invention belongs to the nanometer material technical field, in particular to gold shell coated hollow polymer sub micrometer sphere, and the preparation method and the purpose thereof. The invention takes the polymer sub micrometer sphere as a template, and takes multi-layer coated polyelectrolyte as functional material, and the surface is uniformly coated with gold shells. The dimension of the hollow gold shell sub micrometer sphere and the thickness of the gold shell of the invention can be uniformly controlled. At the same time, according to the Mie scatting theory, the gold shell coated hollow polymer sub micrometer sphere can adjust the absorption in the near infrared region, can convert the optical energy of near infrared laser into the peripheral heat energy, can be applicable for the heat sensitive material of cancer treatment, and can be applicalbe for killing malignant tumor cells. The material of the invention can combine a thermotherapy with the slow release of anti-tumor drug to be used for the cancer treatment.
Description
Technical field
The invention belongs to technical field of nano material, hollow polymer sub-micron ball that particularly a kind of golden shell coats and its production and use.
Background technology
Famous Nobel laureate Feyneman is in the sixties of prophesy just: if in addition certain control of the arrangement on the small scale to object, object just can obtain a large amount of thundering characteristics.His said material is exactly present nano material.Nano material becomes a focus of present Materials science research because of its unique physicochemical property.Research is the peculiar performance and the mechanism of applying nano materials also, has become the core content of nanometer science and technology.
Metal nanoparticle shows the not available superior character of many block materials, can be used for catalysis, photochemical catalysis, fuel cell, chemical sensitisation, nonlinear optics, information storage etc.And the optical property of the uniqueness that metal nanoparticle possessed---(Surface Plasma Resonance, SPR) character is studied one of focus to surface plasma resonance especially.The frequency that surface plasma absorbs is relevant with the size and dimension of metallic particles with width, and is also relevant with the specific inductivity of the specific inductivity of metal itself and surrounding medium.By size, pattern and the structure of control metal nanoparticle, can regulate its plasma resonance peak position.As the Halas group optical property of the metal and dielectric structure of golden shell coated silica comparatively systematic research (Oldenburg, S.J. have been carried out; Averitt, R.D.; Westcott, S.L.; Halas, N.J.Chem.Phys.Lett., 1998,288 (2-4): 243).In recent years, metal casing hollow nano structure has caused people's extensive concern, because its specific surface area height, density are low, structure hollow etc., thereby have many new purposes, can be widely used in fields such as catalysis, optics, biosensor, biological medicine.
Template is adopted in the preparation of hollow metal structure more, prepare golden shell silica nuclear nanoparticle as van Blaaderen (Graf C, vanBlaaderen A.Langmuir, 2002,18:524～534) after, with HF with SiO
2Corrosion is prepared hollow gold shell particle step of going forward side by side and has been carried out the arrangement of photonic crystal.People such as Liang are that template has prepared the adjustable hollow gold shell structure (Liang H P, WanL J, Bai C L, et al.J.Phys.Chem.B, 2005,109:7795～7800) of optical property with Co.In these methods, the optical property of many its metal hollow material of research, and metal hollow structure nano material is not appeared in the newspapers in medicine loading and controlling slow release and the application that combines aspect metal plasma resonance, the present invention is template with the polymer drops, the hollow gold shell sub-micron ball of preparation not only can accurately be regulated the position at its plasma resonance peak, can carry out medicine simultaneously and load, the slow release of control medicine is having broad application prospects aspect the treatment of malignant tumour especially.
Summary of the invention
The hollow polymer sub-micron ball that the object of the present invention is to provide a kind of golden shell to coat, the narrow diameter distribution of this sub-micron ball, outer casing thickness, particle diameter are controlled.
Another object of the present invention is to provide the preparation method of the hollow polymer sub-micron ball that golden shell coats, this method is template with the polymer sub-micron sphere, and the polyelectrolyte that coats with multilayer is the functionalization material, can be used for medicament slow release.Simultaneously, according to the Mie scattering theory, this hollow gold shell structure can be regulated its absorption in the near-infrared region, and the heat energy around the luminous energy of near-infrared laser can being converted into is used to kill malignant cell.This material preparation process is simple, does not need specific installation, and cost is low, and the preparation process gentleness is with short production cycle.
A further object of the present invention is to provide the purposes of the hollow polymer sub-micron ball that golden shell coats, and this material can combine thermotherapy with the slow controlled release of antitumor drug, be used for the cancer therapy aspect.
The objective of the invention is to realize by following technical scheme:
Adopt seed mediated growth method to combine, earlier employing sodium borohydride (NaBH with the method for coating layer by layer
4) prepare Radioactive colloidal gold for reductive agent; Polymer sub-micron sphere adopts poly-positive ionogen and poly-cloudy ionogen alternately to coat several layers as template, and outermost layer adopts poly-positive ionogen functionalization; Polymer sub-micron sphere after the functionalization (as polystyrene (PS) ball) mixes stirring with colloid gold particle, the Radioactive colloidal gold electrostatic adhesion is to polymer sub-micron sphere (as polystyrene spheres), as the seed of further reduction growth.With the gold kind is epipole, by further reduction, can obtain the polymer sub-micron sphere (as polystyrene spheres) of the golden shell coating of controllable thickness.Adopt organic solvent with polymer sub-micron sphere (as polystyrene spheres) dissolving, can obtain the hollow polymer sub-micron ball that golden shell coats.The particle diameter of this material can accurately be controlled by polymer sub-micron sphere (as polystyrene spheres) template, and the golden thickness of the shell that coats also can be by control hydrochloro-auric acid (HAuCl
4) regulate with the ratio of polymer sub-micron sphere (as polystyrene spheres).
The hollow polymer sub-micron ball that golden shell of the present invention coats is spherical, be coated with the polyelectrolyte multilayer film of polycation and polyanion at the shell of this hollow polymer sub-micron ball, and the outermost tunic is the polycation film, is coated with golden shell at the polycation film.The hollow polymer sub-micron ball uniform particle diameter that this gold shell coats, its particle size range are between 50～1000nm, and the golden thickness of the shell of the hollow polymer sub-micron ball that this gold shell coats is between 10～100nm, and thickness is even.
The polyelectrolyte multilayer film of described polycation and polyanion is the sequence layer that is made of polycation and polyanion alternating deposit.
The Preparation method and use of the hollow polymer sub-micron ball that golden shell of the present invention coats may further comprise the steps:
(1) preparation Radioactive colloidal gold, in the aqueous solution, HAuCl
4Concentration range is 10
-7～10
-4Mol/L, the sodium citrate concentration scope is 10
-7～10
-4Mol/L adds a certain amount of sodium borohydride (NaBH
4) the back dispersed with stirring, make NaBH
4The ultimate density scope be 10
-6～10
-3Mol/L makes colloidal gold solution.
(2) functionalization of polymer sub-micron sphere
(i) be that 0.1～5% acetum mixes with water or mass concentration respectively with polycation and polyanion, be mixed with said polycation solution A and polyanion solution B respectively; The polycation in said polycation solution A or the polyanion solution B or the concentration of polyanion are 1～10
-3Mol/L;
The effect of acetic acid is to dissolve the molten polycation of some shipwreck in this step, and acetic acid does not participate in next step reaction, and the acetic acid of trace does not influence next step reaction yet and carries out in the system.
(ii) polymer sub-micron sphere is dispersed in deionized water or the acidic buffer solution, the concentration of the polymer sub-micron sphere in deionized water or the acidic buffer solution is 10
-1～10
2Mg/ml; Add the said polycation solution A that a certain amount of step (i) obtains, polycation concentration is 10 in the system
-2～10
-5Mol/L, whip attachment is 5 minutes～3 hours under the room temperature; The centrifugation product is removed supernatant liquid afterwards, precipitates about 3～5 times with acidic buffer solution or deionized water wash, does not adsorb polycation in the system fully to remove, and obtains the polymer sub-micron sphere that polycation coats;
(iii) the polymer sub-micron sphere that coats of the polycation that step is obtained in (ii) is dispersed in deionized water or the acidic buffer solution again, and the concentration of the polymer sub-micron sphere in deionized water or the acidic buffer solution is 10
-1～10
2Mg/ml; Add the polyanion solution B that a certain amount of step (i) obtains, polyanion concentration is 10 in the system
-2～10
-5Mol/L, whip attachment is 5 minutes～3 hours under the room temperature; The centrifugation product is removed supernatant liquid afterwards, precipitates about 3～5 times with acidic buffer solution or deionized water wash, does not adsorb polyanion in the system fully to remove, and obtains the polymer sub-micron sphere that polyanion coats;
(iv) alternately repeating step (ii) (iii) coats polycation and polyanion step with step, until reaching the desirable polycation and the polyanion sequence number of plies of coating;
(v) outermost layer ionogen repeating step (ii) coats the polycation step, obtains the polymer sub-micron sphere that polycation coats.
(3) gold is planted adsorpting polymerization thing ball
In the colloidal gold solution that step (1) prepares, add citric acid/sodium citrate acidic buffer solution (pH is 4～6) with volume, the polymer sub-micron sphere that adds the functional poly positively charged ion coating for preparing in the step (2) afterwards, stir, make that polymer sub-micron sphere concentration is 10 in the solution
-1～10
2Mg/ml, churning time is 1～12 hour.
(4) formation of golden shell
In concentration is 10
-4～10
-1Salt of wormwood (the K of mol/L
2CO
3) in the solution, add certain amount of H AuCl
4, HAuCl in solution
4Concentration be 10
-8～10
-5Mol/L, this solution stirring added the gold kind adsorpting polymerization thing ball for preparing in a certain amount of step (3) after 1～24 hour, and making gold plant the concentration of adsorpting polymerization thing ball in solution is 10
-2～10
2Mg/ml adds a certain amount of oxammonium hydrochloride solution afterwards, and making the concentration of oxammonium hydrochloride in solution is 10
-8～10
-5Mol/L stirred 2 minutes～12 hours, prepared the polymer sub-micron sphere that golden shell coats for about 3～5 times with washed with de-ionized water.
(5) hollow of golden shell sub-micron ball is handled
In organic solvent, be 10 with concentration
-2～10
2The polymer sub-micron sphere that the golden shell for preparing in the step of mg/mL (4) coats stirred 10 minutes～12 hours, and eccentric cleaning obtains the hollow polymer sub-micron ball that golden shell coats for about 3～5 times afterwards.
Described polymer sub-micron sphere comprises polystyrene microsphere (PS), polymethylmethacrylate (PMMA) microballoon or polystyrene and polymethylmethacrylate (PS/PMMA) compound ball.
The particle size range of the hollow polymer sub-micron ball that described golden shell coats is between 50～1000nm, and the golden thickness of the shell of this sub-micron ball is between 10～100nm, and thickness is even.
Acidic buffer described in the step (2) be pH be 3.6 or pH be acetic acid/sodium-acetate standard buffer solution of 3.8, pH be 3.6 or pH be the physiological buffer that Sodium phosphate dibasic/citric acid of 3.8 is formed.
Described polyelectrolyte multilayer film is the sequence layer that is made of polycation and polyanion alternating deposit, and its sequence number of plies is unrestricted.ABABAB for example ..., wherein A is a polycation, B is a polyanion.Polycation can be selected polymine (polyethyleneimine for use, PEI), diallyl dimethyl ammoniumchloride (poly (diallyldimethylammonium chloride), PDDA), the PAH hydrochloride (poly (allylamine hydrochloride), PAH), one or more the mixture in polylysin (polylysine), chitosan (chitosan), gelatin (gelatin) etc.; Polyanion can be selected poly-4-styrene sulfonate (poly (styrenesulfonate) for use, PSS), polyvinyl sulfuric acid salt (poly (vinylsulfate), PVS), polyacrylic acid (poly (acrylic acid), PAA), one or more the mixture in dextran vitriol (dextran sulfate), sodiun alginate (sodium alginate), Vitrum AB (heparin), DNA etc.
Described organic solvent is toluene or tetrahydrofuran (THF) etc.
The hollow polymer sub-micron ball that golden shell of the present invention coats can be used as sustained and controlled release carrier material as the capsule that loads treatment human body diseases medicine, especially can be used as the carrier of antitumor drug.Material of the present invention can combine thermotherapy with the slowly-releasing of antitumor drug, be used for the cancer therapy aspect.
Described curative drug is selected from Cephradine, Zorubicin, Ibuprofen BP/EP, taxol, the mixture of one or more in Docetaxel, 5-fluor-uracil, Rheumatrex, mitoxantrone, dactinomycin, cis-platinum and the cis-platinum derivative etc.
Described malignant tumour comprises SK-BR-3 mammary cancer and Lewis lung cancer.
The vitro drug release performance test: water soluble drug is made into the aqueous solution, and concentration is unrestricted, and peak concentration is a medicine saturated aqueous solution concentration.Or fat-soluble medicine is made into organic solvent solution, and concentration is unrestricted, and peak concentration is the saturated organic reagent strength of solution of medicine.In drug solution, make medicine fully enter the cavity of golden shell hollow sub-micron ball in stirring at room 24h～1 week golden shell hollow sub-micron ball dry powder ultra-sonic dispersion.The centrifugal medicine carrying microballoons that obtains, centrifugal water or acetone are washed 3～10 times and are removed the drug molecule of surface adsorption.60 degree oven dryings obtain medicine carrying gold shell hollow sub-micron ball dry powder.
The above-mentioned compound year Cephradine microballoon for preparing of 10mg placed dialysis tubing, and add the neutral standard phosphoric acid sustained-release liquid (pH=7.4) of 2ml.Dialysis tubing seals and is placed on 20ml corresponding in the sustained-release liquid in the band of dialysing, stirring at room, thus in specified time interval, adopt the uv-spectrophotometric instrument to measure the definite drug level of the absorption intensity of medium under specific wavelength outside the dialysis tubing.The microballoon drug loading that this composite drug-loaded system is carried is about 20%～40%, (drug quality/medicine carrying microballoons quality).
In the malignant tumour experimentation on animals of Balb/c mouse, having two groups of experimental mouse forms, one group is the administration group, one group is the control group of no any injection, every group all has 7 experimental mouse, the tumor average volume of two groups of experimental mouse of contrast after one month, the tumour inhibiting rate that obtains golden shell hollow submicron medicine carrying ball is 40%～60%.
The warm transformation experiment of near-infrared laser: in the experimentation on animals of Balb/c mouse malignant tumour, having two groups of experimental mouse forms, one group for using the irradiation group of laser radiation behind the hollow polymer sub-micron ball of injecting golden shell coating, one group is control group, every group all has 7 experimental mouse, the irradiation group is injected and adopted wavelength behind the hollow polymer sub-micron ball that golden shell coats is 808nm, and power is 4w/cm
2Laser radiation 10min, irradiation frequency be at interval irradiation in 3 days once.Control group is not injected the hollow polymer sub-micron ball that golden shell coats, and only adopting wavelength is 808nm, and power is 4w/cm
2Laser radiation 10min, irradiation frequency be at interval irradiation in 3 days once.The tumor average volume of two groups of experimental mouse of contrast after one month, the tumour inhibiting rate that obtains the hollow polymer sub-micron ball of golden shell coating is 40%～60%.
The hollow polymer sub-micron ball that golden shell of the present invention coats has following characteristics: (1) is with the container of golden shell sub-micron ball as drug loading, because the template of the golden shell sub-micron ball of preparation is the monodisperse polymer micro-sphere of controllable size, hollow ball big or small single controlled.Medicine can be controlled drug loading by diffusing into the inner chamber of hollow ball by the size and the drug concentrations of control inner chamber; (2) by changing the polyelectrolyte kind and the sequence number of plies, can realize the controlled of drug release rate, simultaneously, the polyelectrolyte multilayer film perviousness can change with envrionment conditions such as pH value or ionic strength etc., thereby realizes that the selectivity of drug molecule under different physiological environments discharges.(3) Biao Mian polyelectrolyte has stronger functional and biocompatibility, and can be easy to connect various biologically active substances such as antibody, antigen, enzyme, protein or nucleic acid etc., thereby can realize the biological targeting function simultaneously.(4) because the plasma resonance peak of the hollow polymer sub-micron ball that golden shell coats can be adjusted to near-infrared wavelength easily, this material can with the laser combination, heat energy around the luminous energy of near-infrared laser can being converted into, the thermo-sensitive material that can be used for cancer therapy is used to kill malignant cell.(5) the hollow polymer sub-micron ball of the golden shell coating of above-mentioned preparation not only can be used for the targeting sustained and controlled release of general medicine, be particularly useful for carrier as antitumor drug, can combine with the physicals of self, reach the purpose of a material, many means treatment cancer.
The hollow polymer sub-micron ball that golden shell of the present invention coats has sustained drug release effect preferably as the slow-released carrier of curative drug.Drug loading is to adopt the method for soaking diffusion to make drug loading arrive golden shell sub-micron ball cavity, by the perviousness of pH value or ionic strength control polyelectrolyte multilayer film, thereby realizes that the selectivity of drug molecule under different physiological environments discharges.The drug loading of the hollow polymer sub-micron ball that golden shell of the present invention coats reaches 20～40% of sub-micron ball quality, and medicament slow release can reach a couple of days.Described curative drug can be Cephradine, Zorubicin, Ibuprofen BP/EP, taxol, Docetaxel, 5-fluor-uracil, Rheumatrex, mitoxantrone, dactinomycin, cis-platinum and cis-platinum derivative etc.
The hollow polymer sub-micron ball that golden shell of the present invention coats is particularly useful for the carrier as antitumor drug, can combine with the physicals of self, the slow controlled release of chemotherapeutics and the thermotherapy of warm conversion therapy can be combined, reach the purpose of a material, many means treatment cancer.
Description of drawings
Fig. 1 is the transmission electron microscope photo of the polystyrene sub-micron ball that coats of the golden shell of the embodiment of the invention 1 gained.
Fig. 2 is the transmission electron microscope photo of the hollow polystyrene sub-micron ball that coats of the golden shell of the embodiment of the invention 1 gained.
Fig. 3 is the medicament slow release figure to paclitaxel solution of the hollow polystyrene sub-micron ball that coats of the golden shell of the embodiment of the invention 1 gained.
Embodiment
Embodiment 1.
(1) preparation Radioactive colloidal gold, in a certain amount of aqueous solution, HAuCl
4Concentration range is 10
-7Mol/L, sodium citrate concentration are 10
-7Mol/L adds a certain amount of sodium borohydride (NaBH
4) the back dispersed with stirring, NaBH
4Concentration be 10
-6Mol/L.
(2) functionalization of polymer drops
I) preparation polyelectrolyte solution, it is wiring solution-forming A in 0.1% the acetic acid that chitosan is dissolved in mass concentration, chitosan concentration is 10
-2Mol/L is with 10
-2The mol/L polyacrylic acid aqueous solution is as solution B.
Ii) be that the concentration of the polymer sub-micron sphere in the buffered soln is 100mg/ml in the buffered soln of the polystyrene sub-micron ball of 50nm acetic acid/sodium-acetate of being dispersed in pH=3.6 with particle diameter; Add a certain amount of said polycation solution A, make that chitosan concentration reaches 10 in the system
-4Mol/L, whip attachment under the room temperature; Acetic acid/sodium acetate buffer solution centrifugal with pH=3.8 cleans 3 times afterwards, uses washed with de-ionized water again 3 times, obtains the polymer sub-micron sphere that chitosan coats;
Iii) with step I i) in the polystyrene sub-micron ball that coats of chitosan be dispersed in again in acetic acid/sodium acetate buffer solution of pH=3.6, the concentration of polystyrene sub-micron ball is 100mg/ml, adds a certain amount of PAA solution, makes that PAA concentration reaches 10 in the system
-4Mol/L, whip attachment 5min under the room temperature, the acetic acid/sodium acetate buffer solution centrifugal with pH=3.8 cleans 3 times afterwards, uses washed with de-ionized water again 3 times, obtains the polystyrene sub-micron ball that PAA coats;
Iv) replace repeating step i) and ii), obtain the polystyrene sub-micron ball that 4 double-deck polyelectrolyte multilayer films coat at last;
V) outermost layer ionogen repeating step ii) obtains the polystyrene sub-micron ball that the surface coats for chitosan.
(3) gold is planted adsorpting polymerization thing ball
In the colloidal gold solution of step (1) preparation, add citric acid/sodium citrate buffered soln with the pH=4 of volume, the polystyrene sub-micron ball that adds the functional shell glycan coating of preparation in the step (2) afterwards stirs, polymer drops concentration is 5mg/mL, and churning time is 6hr.
(4) formation of golden shell
In concentration is 2 * 10
-3Salt of wormwood (the K of mol/L
2CO
3) in the solution, add certain amount of H AuCl
4, HAuCl in solution
4Concentration be 8 * 10
-7Mol/L behind this solution stirring 2hr, adds the gold kind adsorpting polymerization thing ball of preparation in a certain amount of step (3), and making its concentration in solution is 5mg/mL, adds a certain amount of oxammonium hydrochloride solution afterwards, and making its concentration in solution is 7 * 10
-7Mol/L stirs 4min, prepares the polystyrene sub-micron ball that golden shell coats for 3 times with washed with de-ionized water.As shown in Figure 1.
(5) hollow of golden shell sub-micron ball is handled
In toluene solution, strength of solution is that the polystyrene sub-micron ball that the golden shell of the middle preparation of step (4) of 20mg/mL coats stirs 2hr, and eccentric cleaning obtains the hollow polystyrene sub-micron ball that golden shell coats for 3 times afterwards.As shown in Figure 2.
(6) ethanolic soln of preparation 20mg/ml Docetaxel.The hollow polystyrene sub-micron ball dry powder ultra-sonic dispersion that 0.2g gold shell is coated is in the ethanolic soln of this Docetaxel, and stirring at room is after a couple of days, the centrifugal medicine carrying microballoons that obtains, and centrifugal washing is removed the drug molecule of surface adsorption 3 times.60 degree oven dryings get medicine carrying hollow gold shell submicron dry powder.
Vitro drug release performance test: the above-mentioned compound carrying docetaxel microballoon for preparing of 10mg is placed dialysis tubing, and add the neutral standard phosphoric acid sustained-release liquid (pH=7.4) of 2ml.Dialysis tubing seals and is placed on 20ml corresponding in the sustained-release liquid in the band of dialysing, stirring at room, thus in specified time interval, adopt the uv-spectrophotometric instrument to measure the definite drug level of the absorption intensity of medium under specific wavelength outside the dialysis tubing.The result as shown in Figure 3, under neutral environment, drug release rate can reach about 80% in 80 hours.The microballoon drug loading of this composite drug-loaded system carrying docetaxel is 42% (drug quality/medicine carrying microballoons quality).As shown in Figure 3.
(7) in the experimentation on animals of the SK-BR-3 of Balb/c mouse mammary cancer, having two groups of experimental mouse forms, one group is the administration group of paclitaxel loaded, one group is control group, every group all has 7 experimental mouse, the tumor average volume of two groups of experimental mouse of contrast after one month, the tumour inhibiting rate that draws the hollow polystyrene submicron medicine carrying ball of this gold shell coating is 47%.
Embodiment 2.
(1) preparation Radioactive colloidal gold, in a certain amount of aqueous solution, HAuCl
4Concentration range is 10
-4Mol/L, the concentration of Trisodium Citrate is 10
-4Mol/L adds a certain amount of sodium borohydride (NaBH
4) the back dispersed with stirring, NaBH
4Concentration be 10
-3Mol/L.
(2) functionalization of polymer drops
I) preparation polyelectrolyte solution, (poly (allylaminehydrochloride) PAH) is dissolved in wiring solution-forming A in the water, and PAH concentration is 1mol/L with the PAH hydrochloride.(poly (styrenesulfonate) PSS) is mixed with aqueous solution wiring solution-forming B (1mol/L) with same concentrations will to gather the 4-styrene sulfonate.
Ii) be that the concentration of the polymer sub-micron sphere in the buffered soln is 10mg/ml in the buffered soln formed of Sodium phosphate dibasic/citric acid that the polystyrene sub-micron ball of 1000nm is dispersed in pH=3.6 with particle diameter; Add a certain amount of said polycation solution A, make that polycation concentration reaches 10 in the system
-2Mol/L, whip attachment 3hr under the room temperature; Use washed with de-ionized water afterwards 3 times, obtain the polymkeric substance micron ball that the PAH hydrochloride coats;
Iii) with step I i) in the polymkeric substance micron ball that coats of PAH hydrochloride be dispersed in again in the buffered soln that Sodium phosphate dibasic/citric acid of pH=3.6 forms, the concentration of polymkeric substance micron ball is 10mg/ml, add a certain amount of PSS solution, make that PSS concentration reaches 10 in the system
-2Mol/L, whip attachment 3hr under the room temperature uses washed with de-ionized water 3 times afterwards, obtains the polystyrene sub-micron ball that poly-4-styrene sulfonate coats;
Iv) replace repeating step i) and ii).Obtain the polymer sub-micron sphere that 4 double-deck polyelectrolyte multilayer films coat at last.
V) outermost layer ionogen repeating step ii) obtains the polymer sub-micron sphere that the surface coats for the PAH hydrochloride.
(3) gold is planted adsorpting polymerization thing ball
In the colloidal gold solution of step (1) preparation, add citric acid/sodium citrate buffered soln with the pH=5 of volume, the polymer sub-micron sphere that adds the functional poly allyl group amine hydrochlorate coating of preparation in the step (2) afterwards stirs, polymer drops concentration is 10mg/mL, and churning time is 2hr.
(4) formation of golden shell
In concentration is 10
-2Salt of wormwood (the K of mol/L
2CO
3) in the solution, add certain amount of H AuCl
4, HAuCl in solution
4Concentration be 10
-6Mol/L behind this solution stirring 24hr, adds the gold kind adsorpting polymerization thing ball of preparation in a certain amount of step (3), and making its concentration in solution is 30mg/mL, adds a certain amount of oxammonium hydrochloride solution afterwards, and making its concentration in solution is 10
-6Mol/L stirs 1hr, prepares the polystyrene sub-micron ball that golden shell coats for 3 times with washed with de-ionized water.
(5) hollow of golden shell sub-micron ball is handled
In toluene solution, strength of solution is that the polystyrene sub-micron ball that the golden shell of the middle preparation of step (4) of 30mg/mL coats stirs 4hr, and eccentric cleaning obtains the hollow polystyrene sub-micron ball that golden shell coats for 3 times afterwards.
(6) the medicine-releasing performance evaluation method is with embodiment 1, with the Docetaxel aqueous solution in 2.5mg/ml cis-platinum normal saline solution replacement embodiment 1 step 6).The result shows that drug release rate can reach about 80% in 140 hours, and the cis-platinum drug loading of the hollow polystyrene sub-micron ball that this gold shell coats is 35%.
(7) the malignant tumour animal experiment method replaces the experimentation on animals of embodiment 1 step (7) SK-BR-3 mammary cancer with embodiment 1 with the Lewis lung cancer experimentation on animals, and the tumour inhibiting rate of the hollow polystyrene sub-micron ball that this gold shell coats is 43%.
Embodiment 3.
(1) preparation Radioactive colloidal gold, in a certain amount of aqueous solution, HAuCl
4Concentration range is 2 * 10
-5Mol/L, the concentration of Trisodium Citrate is 5 * 10
-5Mol/L adds a certain amount of sodium borohydride (NaBH
4) the back dispersed with stirring, NaBH
4Concentration be 2 * 10
-4Mol/L.
(2) functionalization of polymer drops
I) preparation polyelectrolyte solution, it is wiring solution-forming A in 5% the acetic acid that chitosan is dissolved in mass concentration, chitosan concentration is 10
-3Mol/L is with 10
-3The sodium alginate aqueous solution of mol/L is as solution B.
Polymethylmethacrylate (PMMA) sub-micron ball that ii) with particle diameter is 300nm is dispersed in acetic acid/sodium acetate buffer solution of pH=3.6, and the concentration of the polymer sub-micron sphere in the buffered soln is 1mg/ml; Add a certain amount of said polycation solution A, make that polycation concentration reaches 10 in the system
-5Mol/L, whip attachment 2hr under the room temperature; Acetic acid/sodium acetate buffer solution with pH=3.8 cleans 3 times afterwards, obtains the polymkeric substance micron ball that chitosan coats;
Iii) with step I i) in the polymkeric substance micron ball that coats of chitosan be dispersed in again in acetic acid/sodium acetate buffer solution of pH=3.6, the concentration of polymkeric substance micron ball is 1mg/ml, adds a certain amount of polyanion solution B, makes that polyanion concentration reaches 10 in the system
-5Mol/L, whip attachment 2hr under the room temperature, the acetic acid/sodium acetate buffer solution with pH=3.8 cleans 3 times afterwards, obtains the polymethylmethacrylate sub-micron ball that sodium alginate coats;
Iv) replace repeating step i) and ii).Obtain the polymer sub-micron sphere that 4 double-deck polyelectrolyte multilayer films coat at last.
V) outermost layer ionogen repeating step ii) obtains the polymethylmethacrylate sub-micron ball that the surface coats for chitosan.
(3) gold is planted adsorpting polymerization thing ball
In the colloidal gold solution of step (1) preparation, add citric acid/sodium citrate buffered soln with the pH=6 of volume, the polymer sub-micron sphere that adds the functional shell glycan coating of preparation in the step (2) afterwards stirs, polymer drops concentration is 20mg/mL, and churning time is 10hr.
(4) formation of golden shell
In concentration is 6 * 10
-3Salt of wormwood (the K of mol/L
2CO
3) in the solution, add certain amount of H AuCl
4, HAuCl in solution
4Concentration be 10
-8Mol/L behind this solution stirring 12hr, adds the gold kind absorption PMMA sub-micron ball of preparation in a certain amount of step (3), and making its concentration in solution is 10mg/mL, adds a certain amount of oxammonium hydrochloride solution afterwards, and making its concentration in solution is 3 * 10
-7Mol/L stirs 10min, prepares the PMMA sub-micron ball that golden shell coats for 3 times with washed with de-ionized water.
(5) hollow of golden shell sub-micron ball is handled
In tetrahydrofuran (THF) (THF) solution, concentration is that the polymer sub-micron sphere that the golden shell of the middle preparation of step (4) of 10mg/mL coats stirs 10min, and eccentric cleaning obtains the hollow polymethylmethacrylate sub-micron ball that golden shell coats for 3 times afterwards.
(6) the medicine-releasing performance evaluation method is with embodiment 1, with the Docetaxel aqueous solution in 15mg/ml Cephradine aqueous solution replacement embodiment 1 step 6).The result shows that drug release rate can reach about 80% in 200 hours, and the Cephradine drug loading of the hollow polymethylmethacrylate sub-micron ball that this gold shell coats is 20%.
Embodiment 4.
(1) preparation Radioactive colloidal gold, in a certain amount of aqueous solution, HAuCl
4Concentration range is 4 * 10
-6Mol/L, the concentration of Trisodium Citrate is 8 * 10
-6Mol/L adds a certain amount of sodium borohydride (NaBH
4) the back dispersed with stirring, NaBH
4Concentration be 6 * 10
-5Mol/L.
(2) functionalization of polymer drops
I) preparation polyelectrolyte solution, it is wiring solution-forming A in 2% the acetic acid that chitosan is dissolved in mass concentration, chitosan concentration is 2 * 10
-2Mol/L is with 2 * 10
-2The PAA aqueous solution of mol/L is as solution B.
The PS/PMMA compound ball that ii) with particle diameter is 200nm is dispersed in acetic acid/sodium acetate buffer solution of pH=3.6, and the concentration of the polymer sub-micron sphere in the buffered soln is 5mg/ml; Add a certain amount of said polycation solution A, make that polycation concentration reaches 4 * 10 in the system
-4Mol/L, whip attachment 0.5hr under the room temperature; Acetic acid/sodium acetate buffer solution with pH=3.8 cleans 3 times afterwards, obtains the polymkeric substance micron ball that chitosan coats;
Iii) with step I i) in the polymkeric substance micron ball that coats of chitosan be dispersed in again in acetic acid/sodium acetate buffer solution of pH=3.6, the concentration of polymkeric substance micron ball is 5mg/ml, add a certain amount of polyanion solution B, make that polyanion concentration reaches 4 * 10 in the system
-4Mol/L, whip attachment 0.5hr under the room temperature uses washed with de-ionized water 3 times afterwards, obtains the compound sub-micron ball of PS/PMMA that PAA coats;
Iv) replace repeating step i) and ii).Obtain the polymer sub-micron sphere that 2 double-deck polyelectrolyte multilayer films coat at last.
V) outermost layer ionogen repeating step ii) obtains the polymer sub-micron sphere that the surface coats for chitosan.
(3) gold is planted adsorpting polymerization thing ball
In the colloidal gold solution of (1) preparation, add buffered soln with the pH=4.5 citric acid/sodium citrate of volume, the polymer sub-micron sphere that adds the functional shell glycan coating of preparation in the step (2) afterwards stirs, polymer drops concentration is 0.5mg/mL, and churning time is 12hr.
(4) formation of golden shell
In concentration is 8 * 10
-3Salt of wormwood (the K of mol/L
2CO
3) in the solution, add certain amount of H AuCl
4, HAuCl in solution
4Concentration be 2 * 10
-7Mol/L behind this solution stirring 20hr, adds the gold kind adsorpting polymerization thing ball of preparation in a certain amount of step (3), and making its concentration in solution is 20mg/mL, adds a certain amount of oxammonium hydrochloride solution afterwards, and making its concentration in solution is 6 * 10
-7Mol/L stirs 0.5hr, prepares the compound sub-micron ball of PS/PMMA that golden shell coats for 3 times with washed with de-ionized water.
(5) hollow of golden shell sub-micron ball is handled
In tetrahydrofuran solution, strength of solution is that the compound sub-micron ball of PS/PMMA that the golden shell of the middle preparation of step (4) of 10mg/mL coats stirs 3hr, and eccentric cleaning obtains the hollow PS/PMMA sub-micron ball that golden shell coats for 3 times afterwards.
(6) the medicine-releasing performance evaluation method is with embodiment 1.The result shows that drug release rate can reach about 80% in 78 hours, and the cis-platinum drug loading of the hollow PS/PMMA submicron that this gold shell coats is 45%.
(7) the malignant tumour animal experiment method replaces the experimentation on animals of embodiment 1 step (7) SK-BR-3 mammary cancer with embodiment 1 with the Lewis lung cancer experimentation on animals, and the tumour inhibiting rate of the hollow PS/PMMA submicron medicine carrying ball that this gold shell coats is 60%.
Embodiment 5.
(1) preparation Radioactive colloidal gold, in the 20ml aqueous solution, HAuCl
4Concentration range is 3 * 10
-4Mol/L, the concentration of Trisodium Citrate is 5 * 10
-4Mol/L adds a certain amount of sodium borohydride (NaBH
4) the back dispersed with stirring, NaBH
4Concentration be 2 * 10
-6Mol/L.
(2) functionalization of polymer drops
I) preparation polyelectrolyte solution, with diallyl dimethyl ammoniumchloride (poly (diallyldimethylammonium chloride), PDDA) be dissolved in wiring solution-forming A in the water, the concentration of diallyl dimethyl ammoniumchloride is 0.1mol/L, with the sodium alginate aqueous solution of 0.1mol/L as solution B.
The polystyrene sub-micron ball that ii) with particle diameter is 500nm is dispersed in acetic acid/sodium acetate buffer solution of pH=3.6, and the concentration of the polymer sub-micron sphere in the buffered soln is 0.1mg/ml; Add a certain amount of said polycation solution A, make that polycation concentration reaches 10 in the system
-3Mol/L, whip attachment 1hr under the room temperature; Use washed with de-ionized water afterwards 3 times, obtain the polymkeric substance micron ball that diallyl dimethyl ammoniumchloride coats;
Iii) with step I i) in the polymkeric substance micron ball that coats of diallyl dimethyl ammoniumchloride be dispersed in again in the buffered soln of acetic acid/sodium-acetate of pH=3.6, the concentration of polymkeric substance micron ball is 0.1mg/ml, add a certain amount of polyanion solution B, make that polyanion concentration reaches 10 in the system
-3Mol/L, whip attachment 1hr under the room temperature, the acetic acid/sodium acetate buffer solution with pH=3.8 cleans 3 times afterwards, obtains the polystyrene sub-micron ball that sodium alginate coats;
Iv) replace repeating step i) and ii).Obtain the polymer sub-micron sphere that 8 double-deck polyelectrolyte multilayer films coat at last.
V) outermost layer ionogen repeating step ii) obtains the polymer sub-micron sphere that the surface coats for diallyl dimethyl ammoniumchloride.
(3) gold is planted adsorpting polymerization thing ball
In the colloidal gold solution of step (1) preparation, add citric acid/sodium citrate buffered soln with the pH=5.5 of volume, the polymer sub-micron sphere that adds the functional poly diallyldimethylammonium chloride coating of preparation in the step (2) afterwards stirs, polymer drops concentration is 15mg/mL, and churning time is 8hr.
(4) formation of golden shell
In concentration is 4 * 10
-3Salt of wormwood (the K of mol/L
2CO
3) in the solution, add certain amount of H AuCl
4, HAuCl in solution
4Concentration be 6 * 10
-7Mol/L behind this solution stirring 10hr, adds the gold kind adsorpting polymerization thing ball of preparation in a certain amount of step (3), and making its concentration in solution is 15mg/mL, adds a certain amount of oxammonium hydrochloride solution afterwards, and making its concentration in solution is 5 * 10
-7Mol/L stirs 3hr, prepares the polystyrene sub-micron ball that golden shell coats for 3 times with washed with de-ionized water.
(5) hollow of golden shell sub-micron ball is handled
In toluene solution, strength of solution is that the polystyrene sub-micron ball that the golden shell of the middle preparation of step (4) of 20mg/mL coats stirs 3hr, and eccentric cleaning obtains the hollow polystyrene sub-micron ball that golden shell coats for 3 times afterwards.
(6) the medicine-releasing performance evaluation method is with embodiment 1, with the Docetaxel aqueous solution in 2.5mg/ml cis-platinum normal saline solution replacement embodiment 1 step 6).The result shows that drug release rate can reach about 80% in 150 hours, and the cis-platinum drug loading of the hollow polystyrene sub-micron ball that this gold shell coats is 30%.
(7) the malignant tumour animal experiment method is with embodiment 1, and the tumour inhibiting rate of the hollow polystyrene submicron medicine carrying ball that this gold shell coats is 40%.
Embodiment 6.
(1) preparation Radioactive colloidal gold, in a certain amount of aqueous solution, HAuCl
4Concentration range is 7 * 10
-6Mol/L, the concentration of Trisodium Citrate is 3 * 10
-5Mol/L adds a certain amount of sodium borohydride (NaBH
4) the back dispersed with stirring, NaBH
4Concentration be 5 * 10
-4Mol/L.
(2) functionalization of polymer drops
I) preparation polyelectrolyte solution, (polyethyleneimine PEI) is dissolved in wiring solution-forming A in the water, and PEI concentration is 1mg/mL with polymine.(poly (styrenesulfonate) PSS) is mixed with aqueous solution B (1mg/mL) with same concentrations will to gather the 4-styrene sulfonate
The PMMA sub-micro ball that ii) with particle diameter is 700nm is dispersed in acetic acid/sodium acetate buffer solution of pH=3.6, and the concentration of the polymer sub-micron sphere in the buffered soln is 0.1mg/ml; Add a certain amount of said polycation solution A, make that polycation concentration reaches 10 in the system
-2Mol/L, whip attachment 2hr under the room temperature; Use washed with de-ionized water afterwards 3 times, obtain the polymkeric substance micron ball that polymine coats;
Iii) with step I i) in the polymkeric substance micron ball that coats of polymine be dispersed in again in the buffered soln of acetic acid/sodium-acetate of pH=3.6, the concentration of polymkeric substance micron ball is 0.1mg/ml, add a certain amount of polyanion solution B, make that polyanion concentration reaches 10 in the system
-2Mol/L, whip attachment 2hr under the room temperature, the acetic acid/sodium acetate buffer solution with pH=3.8 cleans 3 times afterwards, obtains the polystyrene sub-micron ball that poly-4-styrene sulfonate coats;
Iv) replace repeating step i) and ii).Obtain the polymer sub-micron sphere that 5 double-deck polyelectrolyte multilayer films coat at last.
V) outermost layer ionogen repeating step ii) obtains the PMMA sub-micro ball sub-micron ball that the surface coats for poly-4-styrene sulfonate.
(3) gold is planted adsorpting polymerization thing ball
Add the citric acid/sodium citrate buffered soln with the pH=4.5 of volume in the colloidal gold solution of step (1) preparation, the functionalized polymer sub-micron ball that adds preparation in (2) afterwards stirs, and polymer drops concentration is 25mg/mL, and churning time is 4hr.
(4) formation of golden shell
In concentration is 10
-3Salt of wormwood (the K of mol/L
2CO
3) in the solution, add certain amount of H AuCl
4, HAuCl in solution
4Concentration be 2 * 10
-8Mol/L behind this solution stirring 6hr, adds the gold kind adsorpting polymerization thing ball of preparation in a certain amount of step (3), and making its concentration in solution is 25mg/mL, adds a certain amount of oxammonium hydrochloride solution afterwards, and making its concentration in solution is 2 * 10
-7Mol/L stirs 3hr, prepares the polystyrene sub-micron ball that golden shell coats for 3 times with washed with de-ionized water.
(5) hollow of golden shell sub-micron ball is handled
In tetrahydrofuran solution, strength of solution is that the golden shell for preparing in the step (4) of 15mg/mL coats polystyrene sub-micron ball stirring 4hr, and eccentric cleaning obtains hollow gold shell PMMA sub-micron ball for 3 times afterwards.
(6) the medicine-releasing performance evaluation method is with embodiment 1, with the Docetaxel aqueous solution in 15mg/ml Cephradine aqueous solution replacement embodiment 1 step 6).The result shows that drug release rate can reach about 80% in 190 hours, and the Cephradine drug loading of this gold shell hollow microsphere is 25%.
Embodiment 7.
1) preparation Radioactive colloidal gold, in a certain amount of aqueous solution, HAuCl
4Concentration range is 10
-6Mol/L, sodium citrate concentration are 10
-6Mol/L adds a certain amount of sodium borohydride (NaBH
4) the back dispersed with stirring, NaBH
4Concentration be 10
-5Mol/L.
(2) functionalization of polymer drops
I) preparation polyelectrolyte solution, it is wiring solution-forming A in 1% the acetic acid that chitosan is dissolved in mass concentration, chitosan concentration is 10
-2Mol/L is with 10
-2The mol/L polyacrylic acid aqueous solution is as solution B.
Ii) be that the concentration of the polymer sub-micron sphere in the buffered soln is 50mg/ml in the buffered soln of the polystyrene sub-micron ball of 100nm acetic acid/sodium-acetate of being dispersed in pH=3.6 with particle diameter; Add a certain amount of said polycation solution A, make that chitosan concentration reaches 10 in the system
-4Mol/L, whip attachment under the room temperature; Acetic acid/sodium acetate buffer solution centrifugal with pH=3.8 cleans 3 times afterwards, uses washed with de-ionized water again 3 times, obtains the polymer sub-micron sphere that chitosan coats;
Iii) with step I i) in the polystyrene sub-micron ball that coats of chitosan be dispersed in again in acetic acid/sodium acetate buffer solution of pH=3.6, the concentration of polystyrene sub-micron ball is 50mg/ml, adds a certain amount of PAA solution, makes that PAA concentration reaches 10 in the system
-4Mol/L, whip attachment 5min under the room temperature, the acetic acid/sodium acetate buffer solution centrifugal with pH=3.8 cleans 3 times afterwards, uses washed with de-ionized water again 3 times, obtains the polystyrene sub-micron ball that PAA coats;
Iv) replace repeating step i) and ii), obtain the polystyrene sub-micron ball that 4 double-deck polyelectrolyte multilayer films coat at last;
V) outermost layer ionogen repeating step ii) obtains the polystyrene sub-micron ball that the surface coats for chitosan.
(3) gold is planted adsorpting polymerization thing ball
In the colloidal gold solution of step (1) preparation, add citric acid/sodium citrate buffered soln with the pH=4 of volume, the polystyrene sub-micron ball that adds the functional shell glycan coating of preparation in the step (2) afterwards stirs, polymer drops concentration is 5mg/mL, and churning time is 6hr.
(4) formation of golden shell
In concentration is 2 * 10
-3Salt of wormwood (the K of mol/L
2CO
3) in the solution, add certain amount of H AuCl
4, HAuCl in solution
4Concentration be 8 * 10
-7Mol/L behind this solution stirring 2hr, adds the gold kind adsorpting polymerization thing ball of preparation in a certain amount of step (3), and making its concentration in solution is 5mg/mL, adds a certain amount of oxammonium hydrochloride solution afterwards, and making its concentration in solution is 7 * 10
-7Mol/L stirs 4min, prepares the polystyrene sub-micron ball that golden shell coats for 3 times with washed with de-ionized water.
(5) hollow of golden shell sub-micron ball is handled
In toluene solution, strength of solution is that the polystyrene sub-micron ball that the golden shell of the middle preparation of step (4) of 20mg/mL coats stirs 2hr, and eccentric cleaning obtains the hollow polystyrene sub-micron ball that golden shell coats for 3 times afterwards.
(6) the warm transformation experiment of near-infrared laser: in the experimentation on animals of the SK-BR-3 of Balb/c mouse mammary cancer, having two groups of experimental mouse forms, one group of irradiation group for usefulness laser radiation behind the hollow polystyrene sub-micron ball of the golden shell coating of injection, one group is control group, every group all has 7 experimental mouse.The irradiation group is injected and adopted wavelength behind the hollow polystyrene sub-micron ball that golden shell coats is 808nm, and power is 4w/cm
2Laser radiation 10min, irradiation frequency be at interval irradiation in 3 days once.Control group is not injected the hollow polystyrene sub-micron ball that golden shell coats, and only adopting wavelength is 808nm, and power is 4w/cm
2Laser radiation 10min, irradiation frequency be at interval irradiation in 3 days once.The tumor average volume of two groups of experimental mouse of contrast after one month, the tumour inhibiting rate that obtains the hollow polystyrene sub-micron ball of golden shell coating is 40%.
Embodiment 8.
1) preparation Radioactive colloidal gold, in a certain amount of aqueous solution, HAuCl
4Concentration range is 7 * 10
-5Mol/L, the concentration of Trisodium Citrate is 3 * 10
-4Mol/L adds a certain amount of sodium borohydride (NaBH
4) the back dispersed with stirring, NaBH
4Concentration be 5 * 10
-3Mol/L.
(2) functionalization of polymer drops
I) preparation polyelectrolyte solution, (polyethyleneimine PEI) is dissolved in wiring solution-forming A in the water, and PEI concentration is 1mg/mL with polymine.(poly (styrenesulfonate) PSS) is mixed with aqueous solution B with same concentrations, and concentration is 2mg/mL will to gather the 4-styrene sulfonate.
The PMMA sub-micro ball that ii) with particle diameter is 700nm is dispersed in acetic acid/sodium acetate buffer solution of pH=3.6, and the concentration of the polymer sub-micron sphere in the buffered soln is 1mg/ml; Add a certain amount of said polycation solution A, make that polycation concentration reaches 10 in the system
-2Mol/L, whip attachment 3hr under the room temperature; Use washed with de-ionized water afterwards 3 times, obtain the polymkeric substance micron ball that polymine coats;
Iii) with step I i) in the polymkeric substance micron ball that coats of polymine be dispersed in again in the buffered soln of acetic acid/sodium-acetate of pH=3.6, the concentration of polymkeric substance micron ball is 1mg/ml, add a certain amount of polyanion solution B, make that polyanion concentration reaches 10 in the system
-2Mol/L, whip attachment 3hr under the room temperature, the acetic acid/sodium acetate buffer solution with pH=3.8 cleans 3 times afterwards, obtains the polystyrene sub-micron ball that poly-4-styrene sulfonate coats;
Iv) replace repeating step i) and ii).Obtain the polymer sub-micron sphere that 4 double-deck polyelectrolyte multilayer films coat at last.
V) outermost layer ionogen repeating step ii) obtains the PMMA sub-micro ball sub-micron ball that the surface coats for poly-4-styrene sulfonate.
(3) gold is planted adsorpting polymerization thing ball
Add the citric acid/sodium citrate buffered soln with the pH=5.5 of volume in the colloidal gold solution of step (1) preparation, the functionalized polymer sub-micron ball that adds preparation in (2) afterwards stirs, and polymer drops concentration is 25mg/mL, and churning time is 4hr.
(4) formation of golden shell
In concentration is 10
-3Salt of wormwood (the K of mol/L
2CO
3) in the solution, add certain amount of H AuCl
4, HAuCl in solution
4Concentration be 2 * 10
-8Mol/L behind this solution stirring 6hr, adds the gold kind adsorpting polymerization thing ball of preparation in a certain amount of step (3), and making its concentration in solution is 25mg/mL, adds a certain amount of oxammonium hydrochloride solution afterwards, and making its concentration in solution is 2 * 10
-7Mol/L stirs 3hr, prepares the polystyrene sub-micron ball that golden shell coats for 3 times with washed with de-ionized water.
(5) hollow of golden shell sub-micron ball is handled
In tetrahydrofuran solution, strength of solution is that the golden shell for preparing in the step (4) of 15mg/mL coats polystyrene sub-micron ball stirring 4hr, and eccentric cleaning obtains hollow gold shell PMMA sub-micron ball for 3 times afterwards.
(6) the warm transformation experiment of near-infrared laser
Replace the SK-BR-3 mammary cancer mouse of embodiment 7 step 6) with the lotus knurl Balb/c mouse of Lewis lung cancer, the tumour inhibiting rate that obtains golden shell hollow sub-micron ball is 60%.
Because malignant cell is all responsive to high temperature with respect to normal cell, the near-infrared laser thermotherapy among the embodiment is tackled most of malignant cells and all is suitable for.
Claims (5)
1. the preparation method of the hollow polymer sub-micron ball that coats of a golden shell is characterized in that:
(1) preparation Radioactive colloidal gold, in the aqueous solution, HAuCl
4Concentration range is 10
-7～10
-4Mol/L, the sodium citrate concentration scope is 10
-7～10
-4Mol/L, dispersed with stirring behind the adding sodium borohydride, the ultimate density scope that makes sodium borohydride is 10
-6～10
-3Mol/L makes colloidal gold solution;
(2) functionalization of polymer sub-micron sphere
(i) be that 0.1～5% acetum mixes with water or mass concentration respectively with polycation and polyanion, be mixed with said polycation solution A and polyanion solution B respectively; The polycation in said polycation solution A or the polyanion solution B or the concentration of polyanion are 1～10
-3Mol/L;
(ii) polymer sub-micron sphere is dispersed in deionized water or the acidic buffer solution, the concentration of the polymer sub-micron sphere in deionized water or the acidic buffer solution is 10
-1～10
2Mg/ml; Add the said polycation solution A that step (i) obtains, polycation concentration is 10 in the system
-2～10
-5Mol/L, whip attachment under the room temperature; The centrifugation product is removed supernatant liquid afterwards, with acidic buffer solution or deionized water wash precipitation, does not adsorb polycation in the system fully to remove, and obtains the polymer sub-micron sphere that polycation coats;
(iii) the polymer sub-micron sphere that coats of the polycation that step is obtained in (ii) is dispersed in deionized water or the acidic buffer solution again, and the concentration of the polymer sub-micron sphere in deionized water or the acidic buffer solution is 10
-1～10
2Mg/ml; Add the polyanion solution B that step (i) obtains, polyanion concentration is 10 in the system
-2～10
-5Mol/L, whip attachment under the room temperature; The centrifugation product is removed supernatant liquid afterwards, with acidic buffer solution or deionized water wash precipitation, does not adsorb polyanion in the system fully to remove, and obtains the polymer sub-micron sphere that polyanion coats;
(iv) alternately repeating step (ii) (iii) coats polycation and polyanion step with step, until reaching the desirable polycation and the polyanion sequence number of plies of coating;
(v) outermost layer ionogen repeating step (ii) coats the polycation step, obtains the polymer sub-micron sphere that polycation coats;
(3) gold is planted adsorpting polymerization thing ball
In the colloidal gold solution that step (1) prepares, add pH with volume and be 4～6 citric acid/sodium citrate acidic buffer solution, the polymer sub-micron sphere that adds the functional poly positively charged ion coating for preparing in the step (2) afterwards, stir, make that polymer sub-micron sphere concentration is 10 in the solution
-1～10
2Mg/ml stirs;
(4) formation of golden shell
In concentration is 10
-4～10
-1In the solution of potassium carbonate of mol/L, add HAuCl
4, HAuCl in solution
4Concentration be 10
-8～10
-5Mol/L stirs, and adds the gold kind adsorpting polymerization thing ball for preparing in the step (3), and making gold plant the concentration of adsorpting polymerization thing ball in solution is 10
-2～10
2Mg/ml adds oxammonium hydrochloride solution afterwards, and making the concentration of oxammonium hydrochloride in solution is 10
-8～10
-5Mol/L stirs, and uses washed with de-ionized water, prepares the polymer sub-micron sphere that golden shell coats;
(5) hollow of golden shell sub-micron ball is handled
In organic solvent, be 10 with concentration
-2～10
2The polymer sub-micron sphere that the golden shell for preparing in the step of mg/mL (4) coats stirs, and eccentric cleaning obtains the hollow polymer sub-micron ball that golden shell coats afterwards;
The hollow polymer sub-micron ball that described golden shell coats is spherical, be coated with the polyelectrolyte multilayer film of polycation and polyanion at the shell of this hollow polymer sub-micron ball, and the outermost tunic is the polycation film, is coated with golden shell at the polycation film;
The particle size range of the hollow polymer sub-micron ball that described golden shell coats is between 50～1000nm, and golden thickness of the shell is between 10～100nm;
Described polymer sub-micron sphere is polystyrene microsphere, poly (methyl methacrylate) micro-sphere or polystyrene and polymethylmethacrylate compound ball;
Described polycation is selected from more than one in polymine, diallyl dimethyl ammoniumchloride, PAH hydrochloride, polylysin, chitosan, the gelatin; Polyanion is selected from more than one among poly-4-styrene sulfonate, polyvinyl sulfuric acid salt, polyacrylic acid, dextran vitriol, sodiun alginate, Vitrum AB, the DNA;
Acidic buffer described in the step (2) be pH be 3.6 or pH be acetic acid/sodium-acetate standard buffer solution of 3.8, pH be 3.6 or pH be the physiological buffer that Sodium phosphate dibasic/citric acid of 3.8 is formed.
2. method according to claim 1 is characterized in that: the polyelectrolyte multilayer film of described polycation and polyanion is the sequence layer that is made of polycation and polyanion alternating deposit.
3. the purposes of a hollow polymer sub-micron ball that coats according to the golden shell of each described method preparation of claim 1～2, it is characterized in that: the hollow polymer sub-micron ball that described golden shell coats can be as the sustained and controlled release carrier material that loads treatment human body diseases medicine.
4. purposes according to claim 3 is characterized in that: described treatment human body diseases medicine is selected from more than one in Cephradine, Zorubicin, Ibuprofen BP/EP, taxol, Docetaxel, 5-fluor-uracil, Rheumatrex, mitoxantrone, dactinomycin, cis-platinum and the cis-platinum derivative.
5. the purposes of a hollow polymer sub-micron ball that coats according to the golden shell of each described method preparation of claim 1～2, it is characterized in that: the hollow polymer sub-micron ball that described golden shell coats can be regulated its absorption in the near-infrared region, heat energy around the luminous energy of near-infrared laser can being converted into is used to kill the thermo-sensitive material of the cancer therapy of malignant cell.
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| CN101953797B (en) * | 2010-09-06 | 2012-05-23 | 中华人民共和国卫生部肝胆肠外科研究中心 | Method for preparing medicament carrying controlled-release nanometer material and application |
| CN102552157B (en) * | 2010-12-17 | 2013-06-12 | 南京大学 | Chitosan-polyacrylic acid composite nanometer micro-sphere covered with precious metal on surface as well as preparation method and application thereof |
| CN102805870B (en) * | 2012-05-25 | 2014-04-30 | 天津大学 | Gold nano-spherical shell carrier with procedural gene drug release property and preparation method |
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| WO2016046847A1 (en) | 2014-09-23 | 2016-03-31 | Council Of Scientific & Industrial Research | Metal embedded hydrophilic polymer for drug delivery applications |
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| CN108579633B (en) * | 2018-03-29 | 2020-09-22 | 山东大学 | Preparation method of rare earth nano particle/polystyrene composite microsphere |
| CN109249018B (en) * | 2018-10-15 | 2019-09-06 | 华中科技大学 | A kind of self-assembling method of nanogold particle foam covering polystyrene microsphere |
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| US6479146B1 (en) * | 1998-03-19 | 2002-11-12 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften, E.V. | Fabrication of multilayer-coated particles and hollow shells via electrostatic self-assembly of nanocomposite multilayers on decomposable colloidal templates |
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2006
- 2006-10-25 CN CN2006101140419A patent/CN101168597B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6479146B1 (en) * | 1998-03-19 | 2002-11-12 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften, E.V. | Fabrication of multilayer-coated particles and hollow shells via electrostatic self-assembly of nanocomposite multilayers on decomposable colloidal templates |
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| CN101168597A (en) | 2008-04-30 |
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