CN101954085A - Method for preparing magnetic-targeted thermochemotherapy gold shell nano-drug delivery system - Google Patents
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Abstract
The invention discloses a method for preparing a magnetic-targeted thermochemotherapy gold shell nano-drug delivery system, which comprises the following steps: preparing Fe3O4 magnetic nano-nucleus by using FeCl3 @6H2O and FeCl2 @ 4H2O as raw materials through a chemical precipitation process; and then plating a layer of gold shell on the surface of magnetic nanoparticles by using a self-assembly-electroless plating method, washing the prepared particles, and dissolving the prepared particles with pure water, then mixing the prepared particles with NIPAM and AA, and forming a temperature sensitive and controllable macromolecule polymer layer on the surface of the gold shell by using ammonium persulfate as initiator and under ultrasonic conditions. The diameter of a PNIPAM @ Au Fe3O4 particle prepared by using the method of the invention is 230 to 250nm, and the magnetic saturation strength thereof is 12.5 to 17emu/g, and the PNIPAM @ Au Fe3O4 particle shows super-paramagnetism. The particles prepared by using the method of the invention can load anti-neoplastic drugs into PNIPAM, and transfer near infrared radiation into thermal energy by using the gold shell layer, thereby realizing the function of releasing the drugs, and finally treating cancers through the principle of thermal ablation and chemotherapy.
Description
Technical field
The invention belongs to the nano-medicament carrier field, particularly a kind of preparation of magnetic targeting thermochemotherapy gold shell nano medicament carrying system.
Background material
The targeted of medicine is the research focus of modern biomedical.Nano-medicament carrier is to realize one of effective means that drug targeting is carried.
Although the method for treatment of cancer is varied, as drug alone treatment or cooperation operation, radiotherapy or biotherapy etc., but the cancer therapy drug of clinical use utilizes the high toxicity cell killing mostly, in cell killing, also grievous injury normal cell, and be easy to generate drug resistance.Target administration, improved the drug level of diseased region on the one hand, strengthened curative effect, reduced the drug distribution of non-target site on the other hand, alleviated the toxicity of medicine, this chemotherapy for the Drug therapy of disease especially tumor is significant, makes more patient can bear heavy dose of chemotherapy.Nano-medicament carrier has its unique advantage in the targeted therapy of tumor.Tumor vessel has higher permeability to nano-particle, and therefore available nano-carrier carries drug targeting and acts on tumor tissues.Medicine delivered to accurately method can be that antibody, part are combined on the carrier in the tumor cell,, reach the targeting of specific tumour by the specificity combination of Ag-Ab, receptor-ligand.The specificity of this targeting process has determined that antibody target tropism nanometer can only be at the tumor cell with corresponding antigens, and still general TCSA has complexity, is not that all cancerous cell all have corresponding antigen to express.At present, the magnetic targeting that utilizes magnetic Nano is to use wider a kind of targeting principle at present, and magnetic Nano mainly is with Fe
3O
4Be the magnetic raw material, also the someone uses Fe
2O
3, but Fe
2O
3Magnetic a little less than, thereby the principle of magnetic Nano is to utilize externally-applied magnetic field guiding nano-carrier at rich long-pending its targeting of realizing of diseased region.
The gold nanoshell spheroid is a kind of spherical stratified nano-complex particle, and the Halas by U.S. RICE university teaches at first
[1]Invention, it is a kind of nanometer of nucleocapsid structure, kernel is by insulator nuclear (SiO
2) constitute, outer golden shell for approaching, its plasmon resonance frequency systematically changes with the variation of nuclear and shell relative size.According to the Mie scattering theory, by regulating the nucleocapsid ratio of gold layer and dielectric hollow ball, the plasma resonance delustring peak that can make a part of composite is to be absorbed as the master, regulate its absorption in the near infrared region, with the Conversion of energy of near infrared light is heat energy on every side, reach the purpose of kill tumor cell, and chemotherapeutics can be loaded in this composite.Develop thus and a kind of special tumor therapeuticing method-Re and melt treatment (Thermal ablative therapy)
[2]In recent years, the research of relevant gold nanoshell spheroid report is more and more, and the structure of golden shell nanometer also had very big variation, as magnetic gold shell nanometer, hollow golden shell nanometer, Fe
3O
4@SiO
2@Au multilayered shell nanoparticle, Au@Au
2S nanometer etc.
[3-5]Owing to have monodispersity, biocompatibility, photo-thermal conversion etc. a lot of good characteristics arranged, golden shell nanometer in the application of biomedical sector more and more widely, especially at aspects such as immunoassay, oncotherapy, antimicrobial agent treatment and medicine controlled releasings.
[6-11]
Poly-(N-N-isopropylacrylamide) be temperature sensitive controllability polymeric material (PNIPAM), and (Lower Critical Solubility Temperature sharply variation often takes place near LCST) at lower critical solution temperature.When solution temperature changes near LCST, many character such as hydrophilic, particle diameter, hole, electrophoretic mobility and the rheological equationm of state of microgranule all change, utilize these character of PNIPAM microgranule, make it many fields such as separate and have tempting application prospect at drug release, bio-sensing and biomacromolecule.Golden shell nanometer and temperature sensitive controllability polymeric material are combined, and under near infrared irradiation, golden shell absorbs luminous energy and changes into heat energy, when temperature surpasses LCST, and PNIPAM polymer layer generation collapse, thus reach the ability that discharges medicine.
The photo-thermal that has the research report of customs gold unit shell nanometer mainly to concentrate on golden shell nanometer at present melts the aspect, the irradiation of the near infrared light by penetrable tissue, utilize the different distributions of golden shell nanometer, send the therapeutic dose of required heat, finally reach the purpose of kill tumor cell at deep skin.Customs gold unit shell nanometer heating ablation principle is arranged, and experiment has in vitro and in vivo all obtained confirmation, especially golden shell nanometer has been applied in the treatment of breast carcinoma
[12-13]Human epidermal growth prime factor receptor-2 (HER-2) is the expressed specific antigen of most of breast cancer cell, will resist HER-2 antibody to be connected with golden shell nanometer, makes it have the breast carcinoma targeting
[14]The magnetic targeting gold shell nano medicament carrying system of this research invention preparation will, with the heating ablation effect of golden shell nanometer with load the antitumor drug associating, finally reach the order ground of therapeutic alliance breast carcinoma.
Summary of the invention
In order to reduce taxol drug to patient's side effect, increase patient's compliance, unite the heating ablation effect of golden shell nanometer and the chemotherapy effect of cancer therapy drug, the invention provides a kind of preparation method of magnetic targeting thermochemotherapy gold shell nano medicament carrying system.
The present invention is by gold nanoshell spheroid paclitaxel loaded class medicine, utilizes PINPAM@Au@Fe
3O
4The magnetic of the good dispersion of carrier and body-internal-circulation characteristic and nano-carrier, under the effect of externally-applied magnetic field, medicament-carried nano is directed to the cancerous cell zone, utilize the gold nanoshell spheroid under near infrared light photo-thermal effect and the cytotoxic effect of cancer therapy drug kill breast cancer cell.The preparation method of a kind of magnetic targeting of the present invention chemotherapy nano medicament carrying system hot in nature may further comprise the steps:
(1) Fe
3O
4Preparation: take by weighing 0.6～1.2g FeCl
2@4H
2O, 1.80～2.2g FeCl
3@6H
2O is dissolved under the guarantor of nitrogen in 80～120mL deoxidation distilled water, adds 0.5～1.5mL triton x-100, stirs accelerate dissolution.Heating in water bath to 70～90 ℃, and be that the ammonia of 0.75～1.25mol/L slowly is added drop-wise in the above-mentioned solution with 70～120mL concentration, vigorous stirring and continue to feed nitrogen generates black Fe simultaneously
3O
4Precipitation; After dripping, stop logical nitrogen, be cooled to room temperature, stop to stir, magnetic separates, after difference water, the washing with alcohol, and vacuum lyophilization, standby;
(2) Fe
3O
4Surperficial is amido modified: the Fe that gets preparation in (1) step
3O
4Particle 50～150mg adds 80～120mL, 95% ethanol, the ultrasonic 20～40min of 60KHz, add 1～3mL γ-aminopropyl diethoxy silane and be abbreviated as APTES, room temperature stirs 6～12h down, and placement is spent the night, magnetic separates, and after 95% washing with alcohol, is made into the 10mg/mL dispersion liquid with dehydrated alcohol;
(3) Fe
3O
4The preparation of @Au compound particle: get the above-mentioned Fe of 90～150 μ L
3O
4-APTES 10mg/mL dispersion liquid adds 90～95mL distilled water, and 5～10mL concentration is the HAuCl of 1mM
4, behind the ultrasonic 10～30min of 60KHz, add oleyl amine, in 70～90 ℃, 60KHz ultrasonic reaction 2～4h to solution by the light yellow atropurpureus that becomes.Magnetic separates, and is neutral until solution several times with distilled water wash;
(4) Fe
3O
4The preparation of @Au@PNIPAM: with 60 μ L, the above-mentioned Fe of 10mg/mL
3O
4The @Au particle dispersion, 0.02～0.03g N-isopropylacrylic acid amine is abbreviated as NIPAM, 0.002～0.003g N, N '-methylene-bisacrylamide is abbreviated as MBA, and 2.0～3.0 μ L acrylic acid are abbreviated as AA and are dissolved in 20～30 mL H
2Among the O, feed N
2, being warming up to 70～90 ℃, the Ammonium persulfate. that adds 0.020～0.030g is abbreviated as APS, 60KHz ultrasonic reaction 5～8h; Magnetic separates, and is washed to neutrality, promptly obtains Fe
3O
4The temperature sensitive medicament-carried nano of @Au@PNIPAM, after the vacuum lyophilization, 4 ℃ of preservations;
Nano inner core described in the present invention is Fe
3O
4Magnetic Nano is at Fe
3O
4Skin is one deck gold shell, and thickness is 20nm; Described magnetic targeting gold shell nano medicament carrying system Fe
3O
4The particle diameter of @Au@PNIPAM is less than 250nm, and the size of its outer field temperature sensitive high molecular polymerization layer is 120～180nm, and all types of particles are by infrared spectrum analysis and transmission electron microscope scanning, and its result is as figure-2 and scheme shown in-3;
The method that the targeting of magnetic described in the present invention thermochemotherapy gold shell nano medicament carrying system loads cancer therapy drug is characterized in that, gets 10mg Fe
3O
4The @Au@PNIPAM nanometer powder is distributed to the distilled water of 100mL, and temperature is controlled at 25～35 ℃, adds antitumor drug taxotere 1～3mg, and pH is controlled at 6.5～7.5, ultrasonic 0.5～2h, and 3000r/min is centrifugal, removes supernatant, distilled water wash.
Antitumor drug of the present invention is a taxotere.
The medicament-carried nano of this Experiment Preparation has the following advantages: 1. synthetic Fe
3O
4The @Au@PNIPAM particle has magnetic and 2. temperature sensitive property double-response ability uses triton x-100 as stabilizing agent, the Fe of preparation
3O
4Nanometer particle size is the 3. temperature sensitive PNIPAM layer of homogeneous more, can realize the loading of medicine and controlled release process 4. nanoparticle have multi-layer core-shell structure 5. the particle diameter of nanoparticle be stable, size is below 250nm.
Description of drawings
Figure the-1st, Fe
3O
4The sketch map of @Au@PNIPAM compound particle preparation process.
Figure the-2nd, the Fe that oleyl amine is stable
3O
4@Au particle x-ray photoelectron power spectrum follow according to x-ray photoelectron to show by spectrogram that contain Fe, O, Au, C and N element in this particle structure, wherein C and N element are the composition of oleyl amine, and the existence of Fe, O, Au element has proved that also nanometer constitutes Fe substantially
3O
4@Au.
Figure the-3rd, the transmission electron microscope picture of nanoparticle, the lower left corner is scale.(a) be Fe
3O
4The Electronic Speculum figure of particle, Fe
3O
4Particle is easily reunited, but the profile of nanometer as seen, and particle diameter is about 20nm.(b) be Fe
3O
4@Au, its monodispersity is better, and nanometer particle size compares Fe
3O
4Particle is big.(c) Fe
3O
4@Au@PNIPAM particle, nanometer particle size are about 250nm, and particle inner electron density is higher, and outer-shell electron density is very low and scope is very big.
Figure the-4th, PNIPAM and Fe
3O
4The hysteresis curve figure of @Au@PNIPAM particle can find that from figure two kinds of particles all have super magnetized character, and under the situation of no externally-applied magnetic field, particle magnetic disappears.And the particle magnetizability that is enclosed with the PNIPAM layer is than independent Fe
3O
4A little less than the @Au particle.
Figure-5 is the release in vitro curve of taxotere medicine carrying gold shell nanometer, the number of times of abscissa for discharging, and vertical coordinate is a release rate.The figure illustrates near infrared ray irradiation group and without the release rate curve of irradiation group, two groups of release rate obvious differences may ultimately reach 90% through the release rate of irradiation group, and are 30% without the irradiation group.
The specific embodiment
Below be the example of the preparation of magnetic targeting medicine carrying gold shell nanosystems, but this preparation method is not limit therewith.
Example 1.
(1) Fe
3O
4Preparation: take by weighing 0.6g FeCl
2@4H
2O, 1.8g FeCl
3@6H
2O is dissolved under the guarantor of nitrogen in the 100mL deoxidation distilled water, adds the 0.5mL triton x-100 as surfactant, uses the motor stirrer stirring and dissolving.Heating in water bath to 80 ℃, and 70mL 1M ammonia slowly is added drop-wise in the above-mentioned solution, vigorous stirring and continue to feed nitrogen generates black Fe simultaneously
3O
4Precipitation.After dripping, stop logical nitrogen, be cooled to room temperature, stop to stir.Magnetic separates, after difference water, the washing with alcohol, and vacuum lyophilization, standby;
(2) Fe
3O
4Surperficial is amido modified: get 75mg Fe
3O
4Particle adds 98mL 95% ethanol, and the ultrasonic 20min of 60KHz adds 1mL APTES, and room temperature stirs 6h down, and placement is spent the night, and magnetic separates, and after 95% washing with alcohol, is made into the 10mg/mL dispersion liquid with dehydrated alcohol;
(3) Fe
3O
4The preparation of @Au compound particle: get the above-mentioned Fe of 90 μ L
3O
4-APTES 10mg/mL dispersion liquid adds the 91mL distilled water, and 5mL concentration is the HAuCl of 1mM
4, behind the ultrasonic 10min of 60KHz, add 5 μ L oleyl amines, in 70 ℃ of ultrasonic reaction 2h to solution by the light yellow atropurpureus that becomes.Magnetic separates, and uses distilled water wash 3 times;
(4) Fe
3O
4The preparation of @Au@PNIPAM: get above-mentioned 60 μ L, 10mg/mLFe
3O
4The @Au particle dispersion, 0.02g NIPAM, 0.002g MBA, 2.0 μ L AA are dissolved in 25mL H
2Among the O, logical N
230min is warming up to more than 70 ℃, adds 0.020gAPS, 60KHz ultrasonic reaction 6h.Magnetic separates, wash 3 times after, promptly obtain water white Fe
3O
4The temperature sensitive medicament-carried nano of @Au@PNIPAM, vacuum lyophilization, 4 ℃ of preservations.
(5) loading of cancer therapy drug: get 10mg Fe
3O
4The @Au@PNIPAM nanometer powder is distributed to the distilled water of 100mL, and temperature is controlled at 25 ℃, adds the 3mg taxotere, and pH is controlled at 7, ultrasonic 0.5h.3000r/min is centrifugal, collects supernatant, adopts ultraviolet spectrophotometer to detect in the 227nm place, measures absorbance, according to the standard curve of taxotere, calculates the content of taxotere in the supernatant.The taxotere magnetic gold shell nanometer of this example preparation is calculated after testing, and its envelop rate is 80.0%, and drug loading is 19.4%.
(6) release in vitro of taxotere magnetic gold shell nano medicament carrying system is measured: with PBS (pH=7.0) is release medium, near infrared ray with 802nm shines to control the release of taxotere nano medicament carrying system, and the matched group nano medicament carrying system does not carry out the near-infrared irradiation.The each irradiation time of experimental group and matched group is respectively 5min, 10min and 15min, and be 2 hours blanking time, after having discharged, with the centrifugal 10min of solution 3000r/min, gets supernatant, detects the content of taxotere in the solution.According to the content that records after discharging in this example, the release rate that calculates six samples is shown in figure-5.The figure illustrates near infrared ray irradiation group and without the release rate curve of irradiation group, the obvious difference of its release rate may ultimately reach 90% through the release rate of irradiation group, and is 30% without the irradiation group.Irradiation 5min, 10min, three groups of 15min, the general trend of its drug release is similar, and the release rate that finally reaches is all about 90%, in the release experiment afterwards, time of irradiation is controlled at 10min.
Example 2.
(1) Fe
3O
4Preparation: take by weighing 1.0g FeCl
2@4H
2O, 2.0g FeCl
3@6H
2O is dissolved under the guarantor of nitrogen in the 100mL deoxidation distilled water, adds the 0.8mL triton x-100 as surfactant, uses the motor stirrer stirring and dissolving.Heating in water bath to 80 ℃, and 90mL 1M ammonia slowly is added drop-wise in the above-mentioned solution, vigorous stirring and continue to feed nitrogen generates black Fe simultaneously
3O
4Precipitation.After dripping, stop logical nitrogen, be cooled to room temperature, stop to stir.Magnetic separates, after difference water, the washing with alcohol, and vacuum lyophilization, standby;
(2) Fe
3O
4Surperficial is amido modified: get 100mg Fe
3O
4Particle adds 98mL 95% ethanol, and the ultrasonic 20min of 60KHz adds 2mL APTES, and room temperature stirs 10h down, and placement is spent the night, and magnetic separates, and after 95% washing with alcohol, is made into the 10mg/mL dispersion liquid with dehydrated alcohol;
(3) Fe
3O
4The preparation of @Au compound particle: get the above-mentioned Fe of 120 μ L
3O
4-APTES 10mg/mL dispersion liquid adds the 91mL distilled water, and 9mL concentration is the HAuCl of 1mM
4, behind the ultrasonic 10min of 60KHz, add 10 μ L oleyl amines, in 70 ℃ of ultrasonic reaction 2.5h to solution by the light yellow atropurpureus that becomes.Magnetic separates, and uses distilled water wash 3 times;
(4) Fe
3O
4The preparation of @Au@PNIPAM: get 60 μ L, the above-mentioned Fe of 10mg/mL
3O
4The @Au particle dispersion, 0.025g NIPAM, 0.0025g MBA, 2.0 μ L AA are dissolved in 25mL H
2Among the O, logical N
230min is warming up to 80 ℃, adds 0.02g APS, 60KHz ultrasonic reaction 6h.Magnetic separates, wash 3 times after, promptly obtain Fe
3O
4The temperature sensitive medicament-carried nano of @Au@PNIPAM.
(5) loading of cancer therapy drug: get 10mgFe
3O
4The @Au@PNIPAM nanometer powder is distributed to the distilled water of 100mL, and temperature is controlled at 35 ℃, adds the 1mg taxotere, and pH is controlled at 7, ultrasonic 1.5h.3000r/min is centrifugal, gets supernatant, and by detecting the content of taxotere in the supernatant, calculating envelop rate is 71.0%, and drug loading is 6.6%.
Example 3.
(1) Fe
3O
4Preparation: take by weighing 0.8g FeCl
2@4H
2O, 2.08g FeCl
3@6H
2O is dissolved under the guarantor of nitrogen in the 100mL deoxidation distilled water, adds the 0.8mL triton x-100 as surfactant, the motor stirrer stirring and dissolving.Heating in water bath to 80 ℃, and 80mL 1M ammonia slowly is added drop-wise in the above-mentioned solution, vigorous stirring and continue to feed nitrogen generates black Fe simultaneously
3O
4Precipitation.After dripping, stop logical nitrogen, be cooled to room temperature, stop to stir.Magnetic separates, after difference water, the washing with alcohol, and right vacuum lyophilization, standby;
(2) Fe
3O
4Surperficial is amido modified: get 100mg Fe
3O
4Particle adds 98mL 95% ethanol, and ultrasonic 30min adds 2mL APTES, and room temperature stirs 8h down, and placement is spent the night, and magnetic separates, and after 95% washing with alcohol, is made into the 10mg/mL dispersion liquid with dehydrated alcohol;
(3) Fe
3O
4The preparation of @Au compound particle: get the above-mentioned Fe of 120 μ L
3O
4-APTES 10mg/mL dispersion liquid adds the 91mL distilled water, and 9mL concentration is the HAuCl of 1mM
4, behind the ultrasonic 10min of 60KHz, add 1 μ L oleyl amine, in 70 ℃ of ultrasonic reaction 2.5h to solution by the light yellow atropurpureus that becomes.Magnetic separates, and uses distilled water wash 3 times;
(4) Fe
3O
4The preparation of @Au@PNIPAM: get 60 μ L, the above-mentioned Fe of 10mg/mL
3O
4The @Au particle dispersion, 0.025g NIPAM, 0.0025g MBA, 2.0 μ L AA are dissolved in 25mL H
2Among the O, logical N
230min is warming up to 70 ℃, adds 0.025g APS, 60KHz ultrasonic reaction 6h.Magnetic separates, wash 3 times after, promptly obtain water white Fe
3O
4The temperature sensitive magnetic gold of @Au@PNIPAM shell nanometer.
(5) loading of cancer therapy drug: get 10mgFe
3O
4The @Au@PNIPAM nanometer powder is distributed to the distilled water of 100mL, and temperature is controlled at 37 ℃, adds the 1.5mg taxotere, and pH is controlled at 7.5, ultrasonic 1.5h.3000r/min is centrifugal, gets supernatant, and by detecting the content of taxotere in the supernatant, calculating envelop rate is 82.0%, and drug loading is 11.0%.
Example 4.
(1) Fe
3O
4Preparation: take by weighing 1.2g FeCl
2@4H
2O, 2.2g FeCl
3@6H
2O is dissolved under the guarantor of nitrogen in the 100mL deoxidation distilled water, adds the 1mL triton x-100 as surfactant, and motor stirrer stirs and makes sample dissolution.Heating in water bath to 80 ℃, and 100mL 1.25M ammonia slowly is added drop-wise in the above-mentioned solution, vigorous stirring and continue to feed nitrogen generates black Fe simultaneously
3O
4Precipitation.After dripping, stop logical nitrogen, be cooled to room temperature, stop to stir.Magnetic separates, after difference water, the washing with alcohol, and vacuum lyophilization, standby;
(2) Fe
3O
4Surperficial is amido modified: get 150mg Fe
3O
4Particle adds 98mL 95% ethanol, and the ultrasonic 30min of 60KHz adds 3mL APTES, and room temperature stirs 12h down, and placement is spent the night, and magnetic separates, and after 95% washing with alcohol, is made into the 10mg/mL dispersion liquid with dehydrated alcohol;
(3) Fe
3O
4The preparation of @Au compound particle: get the above-mentioned Fe of 150 μ L
3O
4-APTES 10mg/mL dispersion liquid adds the 90mL distilled water, and 10mL concentration is the HAuCl of 1mM
4, behind the ultrasonic 30min of 60KHz, add 10 μ L oleyl amines, in 90 ℃ of ultrasonic reaction 4h to solution by the light yellow atropurpureus that becomes.Magnetic separates, and uses distilled water wash 3 times;
(4) Fe
3O
4The preparation of @Au@PNIPAM: get 60 μ L, the above-mentioned Fe of 10mg/mL
3O
4The @Au particle dispersion, 0.03g NIPAM, 0.003g MBA, 3.0 μ L AA are dissolved in 25mL H
2Among the O, logical N
230min is warming up to more than 70 ℃, adds 0.030gAPS, 60KHz ultrasonic reaction 8h.Magnetic separates, wash 3 times after, promptly obtain water white Fe
3O
4The temperature sensitive medicament-carried nano of @Au@PNIPAM.
(5) loading of cancer therapy drug: get 10mgFe
3O
4The @Au@PNIPAM nanometer powder is distributed to the distilled water of 100mL, and temperature is controlled at 40 ℃, adds the 2mg taxotere, and pH is controlled at 7, ultrasonic 2h.3000r/min is centrifugal, gets supernatant, and by detecting the content of taxotere in the supernatant, calculating envelop rate is 88.0%, and drug loading is 15.0%.
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Claims (5)
1. the preparation method of a magnetic targeting thermochemotherapy gold shell nano medicament carrying system is characterized in that, may further comprise the steps:
(1) Fe
3O
4Preparation: take by weighing 0.6～1.2g FeCl
2@4H
2O, 1.80～2.2g FeCl
3@6H
2O is dissolved under the guarantor of nitrogen in 80～120mL deoxidation distilled water, adds 0.5～1.5mL triton x-100, stirs accelerate dissolution.Heating in water bath to 70～90 ℃, and be that the ammonia of 0.75～1.25mol/L slowly is added drop-wise in the above-mentioned solution with 70～120mL concentration, vigorous stirring and continue to feed nitrogen generates black Fe simultaneously
3O
4Precipitation; After dripping, stop logical nitrogen, be cooled to room temperature, stop to stir, magnetic separates, after difference water, the washing with alcohol, and vacuum lyophilization, standby;
(2) Fe
3O
4Surperficial is amido modified: the Fe that gets preparation in (1) step
3O
4Particle 50～150mg adds 80～120mL, 95% ethanol, the ultrasonic 20～40min of 60KHz, add 1～3mL γ-aminopropyl diethoxy silane and be abbreviated as APTES, room temperature stirs 6～12h down, and placement is spent the night, magnetic separates, and after 95% washing with alcohol, is made into the 10mg/mL dispersion liquid with dehydrated alcohol;
(3) Fe
3O
4The preparation of @Au compound particle: get the above-mentioned Fe of 90～150 μ L
3O
4-APTES 10mg/mL dispersion liquid adds 90～95mL distilled water, and 5～10mL concentration is the HAuCl of 1mM
4, behind the ultrasonic 10～30min of 60KHz, add oleyl amine, in 70～90 ℃, 60KHz ultrasonic reaction 2～4h to solution by the light yellow atropurpureus that becomes.Magnetic separates, and is neutral until solution several times with distilled water wash;
(4) Fe
3O
4The preparation of @Au@PNIPAM: with 60 μ L, the above-mentioned Fe of 10mg/mL
3O
4The @Au particle dispersion, 0.02～0.03g N-isopropylacrylic acid amine is abbreviated as NIPAM, 0.002～0.003g N, N '-methylene-bisacrylamide is abbreviated as MBA, and 2.0～3.0 μ L acrylic acid are abbreviated as AA and are dissolved in 20～30mL H
2Among the O, feed N
2, being warming up to 70～90 ℃, the Ammonium persulfate. that adds 0.020～0.030g is abbreviated as APS, 60KHz ultrasonic reaction 5～8h; Magnetic separates, and is washed to neutrality, promptly obtains Fe
3O
4The temperature sensitive medicament-carried nano of @Au@PNIPAM, after the vacuum lyophilization, 4 ℃ of preservations.
2. the preparation method of a kind of magnetic targeting thermochemotherapy gold shell nano medicament carrying system according to claim 1 is characterized in that, at Fe
3O
4Skin is one deck gold shell, and golden shell thickness is 20nm.
3. the preparation method of a kind of magnetic targeting thermochemotherapy gold shell nano medicament carrying system according to claim 1 is characterized in that: the magnetic targeting gold shell nano medicament carrying system Fe of preparation
3O
4The particle diameter of @Au@PNIPAM is less than 250nm, and the size of its outer field temperature sensitive high molecular polymerization layer is 120～180nm.
4. a method of loading cancer therapy drug by the described magnetic targeting of claim 1 thermochemotherapy gold shell nano medicament carrying system is characterized in that, gets 10mgFe
3O
4The @Au@PNIPAM nanometer powder is distributed to the distilled water of 100mL, and temperature is controlled at 25～35 ℃, adds antitumor drug 1～3mg, and pH is controlled at neutrality, ultrasonic 0.5～2h, and 3000r/min is centrifugal, removes supernatant, uses distilled water wash.
5. the preparation method of a kind of magnetic targeting thermochemotherapy gold shell nano medicament carrying system according to claim 4, it is characterized in that: described antitumor drug is a taxotere.
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| CN102699321A (en) * | 2012-06-11 | 2012-10-03 | 华东理工大学 | Plasma coupling structure microsphere for surface-enhanced Raman scattering (SERS) and manufacturing method thereof |
| CN103240120A (en) * | 2013-05-22 | 2013-08-14 | 天津工业大学 | Temperature switch type catalyst based on magnetic artificial cells |
| CN103251558A (en) * | 2012-12-25 | 2013-08-21 | 苏州大学 | Preparation of multifunctional nano-medicine with high medicine-loading rate and combined treatment effect |
| CN106334190A (en) * | 2016-08-25 | 2017-01-18 | 北京科技大学 | Compound drug carrier for multi-response mechanism and preparation method thereof |
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| CN101323022A (en) * | 2008-07-11 | 2008-12-17 | 中山大学 | Method for preparing gold magnetic core-shell nano-particle |
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| CN102699321A (en) * | 2012-06-11 | 2012-10-03 | 华东理工大学 | Plasma coupling structure microsphere for surface-enhanced Raman scattering (SERS) and manufacturing method thereof |
| CN102699321B (en) * | 2012-06-11 | 2014-07-23 | 华东理工大学 | Plasma coupling structure microsphere for surface-enhanced Raman scattering (SERS) and manufacturing method thereof |
| CN103251558A (en) * | 2012-12-25 | 2013-08-21 | 苏州大学 | Preparation of multifunctional nano-medicine with high medicine-loading rate and combined treatment effect |
| CN103251558B (en) * | 2012-12-25 | 2014-12-24 | 苏州大学 | Preparation of multifunctional nano-medicine with high medicine-loading rate and combined treatment effect |
| CN103240120A (en) * | 2013-05-22 | 2013-08-14 | 天津工业大学 | Temperature switch type catalyst based on magnetic artificial cells |
| CN103240120B (en) * | 2013-05-22 | 2015-05-13 | 天津工业大学 | Temperature switch type catalyst based on magnetic artificial cells |
| CN106334190A (en) * | 2016-08-25 | 2017-01-18 | 北京科技大学 | Compound drug carrier for multi-response mechanism and preparation method thereof |
| CN106334190B (en) * | 2016-08-25 | 2019-09-24 | 北京科技大学 | A kind of multiple response mechanism compound pharmaceutical carrier and preparation method thereof |
| CN107551271A (en) * | 2017-08-28 | 2018-01-09 | 上海长海医院 | A kind of dual intelligent targeted nano granules of magnetic ROS and preparation method thereof |
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