CN103239410B - Preparation method of fluorescence and heat/pH sensitive organic-inorganic composite microsphere carrier - Google Patents
Preparation method of fluorescence and heat/pH sensitive organic-inorganic composite microsphere carrier Download PDFInfo
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Abstract
The invention relates to a preparation method of a fluorescence and heat/pH sensitive organic-inorganic composite microsphere carrier. A porous silicon nano particle is crosslinked inside the carrier by using a poly (N-isopropylacrylamide) grafted carboxymethyl chitosan microsphere as a body and encapsulated with an inorganic quantum dot to form a composite microsphere carrier using a porous silicon nano particle loaded with the quantum dot as a core and poly (N-isopropylacrylamide) grafted carboxymethyl chitosan as a shell. The carrier is capable of loading an anti-cancer drug in a polymer shell gel network and orderly releasing drugs at a specific temperature and pH. Compared with the prior art, the fluorescence and heat/pH sensitive organic-inorganic composite microsphere carrier has hydrophilcity and biocompatibility, is capable of realizing controllable encapsulation and release of the anti-cancer drugs, has a fluorescent tracing function, and has important application values in the fields such as biology, medicine and functional materials of sustained-release materials, drug carriers, catalyst carriers and separating mediums.
Description
Technical field
The invention belongs to drug carrier material field, be specifically related to the preparation method of the organic-inorganic composite microballoons carrier of a kind of novel fluorescence and heat/pH sensitivity.
Background technology
Cancer is one of first cause of current human death, about has more than 1,000 ten thousand newly-increased patients to suffer its evil every year.Cancer treatment method mainly comprises excision, radiotherapy and chemotherapy etc., wherein chemotherapy (i.e. chemotherapy) is the Main Means for the treatment of tumor and immune disease, and existing 100 Treated with Chemotherapeutic Drugs things are ratified Clinical practice by FDA (Food and Drug Adminstration) (FDA).Due to water solublity and the less stable of most of antitumor drug, cause the bioavailability of medicine low, occur administration difficulty, capillary embolism, the remarkable and effective medicine concentration of whole body of patient individual difference is difficult to the problems such as maintenance.In addition, nearly all Effective Anti cancer drug all has larger toxicity, lacks selectivity to tumor and normal structure, and is easy to infiltrate tumor and healthy cell simultaneously, thus produces larger side effect to human body.In order to solve Problems existing in chemotherapeutics, drug delivery system is used to be the most effective approach.Based on this; a kind of antitumor drug transmission system efficiently of design; solubilising and protective effect can be provided for medicine; reduce medicine effective dose and toxic and side effects; conduct drugs to target tumor tissue, realize efficient intracellular delivery, drug controlled release with effectively treat; and can not normal cell be affected, this drug delivery system (i.e. pharmaceutical carrier) is extremely important for oncotherapy.
In order to effectively treat tumor, researcher has carried out a large amount of scientific researches, and achieves a series of progress, and especially in multi-functional drug carriers, achievement is remarkable.Multi-functional drug carriers refers to and passes through ingehious design, multiple functional material is integrated in single and stable system, to reach specific purpose, as extended blood circulation time, targeting, Physiological sensitivity, drug controlled release, load therapeutic agent, developer or contrast agent etc.Multi-functional drug carriers can be used as the active platform that multi-medicament transmits, by the release that the surface signal and medicine that identify targeted cells uniqueness are controlled in order, make medicine play synergistic function, and significantly reduce the toxic and side effects of medicine, this has unique advantage to oncotherapy.
In recent years, about the research report of multi-functional drug carriers presents increasing trend, particularly there is the pharmaceutical carrier of targeting or tracking function, significantly abnormal in the using value of biomedicine field.The present invention is intended to design one and has fluorescent tracing function, and has the drug controlled release behavior of heat and pH sensitivity and the anti-cancer medicament carrier of biocompatibility.Selection Crosslinked Carboxymethyl Chitosan Resin is main carriers, and grafting NIPA, encloses the porous silicon nanoparticle of quantum dot load, form a kind of novel multi-functional drug carriers.This carrier can load cancer therapy drug (as amycin) discharging in order at specific temperature and pH, can realize the targeting of tumor and control administration, and the therapeutic purposes of original position spike or imaging.
Through retrieving domestic and international patent documentation, extensively consulting domestic and international public publication, up to now, there is not yet the identical technical method with the present invention.In addition, the beneficial effect of the present invention in treatment tumor, makes the present invention have practicality widely.
Summary of the invention
Object of the present invention is exactly the preparation method providing a kind of reasonable in design, fluorescence of feasible process, easy control of reaction and the organic-inorganic composite microballoons carrier of heat/pH sensitivity in order to overcome defect that above-mentioned prior art exists.
Object of the present invention can be achieved through the following technical solutions: the preparation method of the organic-inorganic composite microballoons carrier of fluorescence and heat/pH sensitivity, and it is characterized in that, the method specifically comprises the following steps:
(1) at N
2protection, in magnetic agitation and alkaline aqueous solution, tellurium powder and sodium borohydride react, and prepare sodium hydrogen telluride presoma, then join in the mixed aqueous solution being dissolved with Caddy (Cleary) and mercaptopropionic acid, react in the basic conditions, prepare cadmium telluride quantum dot;
(2) cadmium telluride quantum dot is dispersed in the water containing chloroform and surfactant (I), then rotary evaporation removing chloroform and water, obtain the quantum dot that surfactant (I) is stable, then add in the aqueous solution containing sodium hydroxide, ethyl acetate and alkyl silicon (I), react under certain reaction temperature and magnetic agitation, carry out centrifugal after end, wash with ethanol/water mixed solvent;
(3) step (2) gained sample is added in the ethanol being dissolved with alkyl silicon (II), react under certain reaction temperature and magnetic agitation, then add ammonium nitrate and continue reaction a period of time, product carries out centrifugal, with ethanol/water mixed solvent washing, obtain the porous silicon nanoparticle of load quantum dot;
(4) to being dissolved with NIPA, the porous silicon nanoparticle that step (3) is obtained is added in the aqueous solution of carboxymethyl chitosan and cross-linking agent, at uniform temperature and N
2protection lower magnetic force stirring reaction, then add initiator and surfactant (II) continuation reaction, terminate afterproduct and carry out centrifugal, dialysis, obtain target product;
(5) added in the target product after dialysis by amycin aqueous solution and hatch, then dialysis is to remove the amycin be not loaded into, and is adjusted to different pH value, with determined by ultraviolet spectrophotometry amycin release profiles at different temperatures with phosphate buffer solution.
Alkaline aqueous solution described in step (1) refers to sodium hydrate aqueous solution, and pH value is 9 ~ 11; Described tellurium powder and sodium borohydride molar concentration ratio (1: 4) carry out reacting obtained sodium hydrogen telluride presoma.
Hydrogen telluride described in step (1) is received, Caddy (Cleary) and TGA molar concentration rate are 1: 5: 8 ~ 1: 10: 15, and reaction temperature is 60 ~ 90 DEG C, and system pH is 9 ~ 11.
Surfactant (I) described in step (2) is bromohexadecane base trimethylamine; Described alkyl silicon (1) is ethyl orthosilicate; The mass ratio of described cadmium telluride quantum dot and surfactant (I) and chloroform is (5 ~ 10): (50 ~ 100): (5000 ~ 10000); The volume ratio of described sodium hydroxide, ethyl acetate and alkyl silicon (I) consumption is (1 ~ 5): (5 ~ 10): (0.5 ~ 1); Described cadmium telluride quantum dot and the mass volume ratio of sodium hydroxide are (5 ~ 10) mg/ (1 ~ 5) ml; Described reaction temperature is 25 ~ 60 DEG C, and the response time is 5 ~ 10h, and the stir speed (S.S.) of magnetic agitation is 100 ~ 300rpm.
Alkyl silicon (II) described in step (3) is 3-(trimethoxysilyl) propyl acrylate, and the consumption volume ratio of the consumption of alkyl silicon (II) and the consumption of ammonium nitrate and alkyl silicon (I) is (0.05 ~ 0.1): (1 ~ 5): (10 ~ 50); Described reaction temperature is 20 ~ 40 DEG C, and the response time is 6 ~ 12h.
NIPA described in step (4), the mass ratio of carboxymethyl chitosan, cross-linking agent, porous silicon nanoparticle, surfactant (II), initiator is (0.1 ~ 1): (0.1 ~ 0.2): (0.005 ~ 0.02): (0.5 ~ 1): (0.005 ~ 0.010): (0.005 ~ 0.02), described reaction temperature is 20 ~ 40 DEG C, and the response time is 6 ~ 12h.
Described cross-linking agent is N,N methylene bis acrylamide, and described surfactant (II) is sodium lauryl sulphate, and described initiator is potassium peroxydisulfate.
The pH value that phosphate buffer solution described in step (5) regulates is 6 ~ 8, and release temperature is 20 ~ 42 DEG C, and the consumption of target product and amycin is 1 ~ 5wt%.
Compared with prior art, first quantum dot is encapsulated in porous silicon by the present invention, forms fluorescence porous silicon nanoparticle, then at the carboxymethyl chitosan gel shell of its surface settlement polymerization temperature sensitive polymer grafting, to prepare organic-inorganic composite microballoons, can be used as multi-functional drug carriers.Compared with prior art, the advantages such as the present invention is reasonable in design, feasible process, easy control of reaction, and prepare product there is the responsive and biocompatibility of fluorescence, heat/pH, show wide application prospect in fields such as medicine controlled releasing, bio-sensing, Chemical Decompositions.
Accompanying drawing explanation
Fig. 1 is the preparation of complex microsphere pharmaceutical carrier and drug loading and release schematic diagram;
Fig. 2 is the transmission electron microscope photo of complex microsphere pharmaceutical carrier;
Fig. 3 is uv-visible absorption spectra and the fluorescence emission spectrum of complex microsphere pharmaceutical carrier;
Fig. 4 is that the hydrodynamic size of complex microsphere pharmaceutical carrier raises and the curve of reduction with temperature;
Fig. 5 is that the absorptance of complex microsphere pharmaceutical carrier raises and the curve of increase with pH;
Fig. 6 be complex microsphere pharmaceutical carrier at different temperatures Temporal Evolution discharge the curve of amycin.
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, the present invention is described in detail.
Embodiment 1
The preparation of the organic-inorganic composite microballoons carrier of a kind of fluorescence and heat/pH sensitivity and drug loading and release schematic diagram are see Fig. 1, and detailed preparation process is as follows: at N
2atmosphere, in magnetic agitation and alkaline aqueous solution (pH9.0), add tellurium powder/sodium borohydride that mol ratio is 1/2, peony supernatant liquid is obtained react 0.5h at 80 DEG C after, be sodium hydrogen telluride presoma, then getting part adds in the mixed aqueous solution of Caddy (Cleary) and mercaptopropionic acid fast, and sodium hydrogen telluride/Caddy (Cleary)/glutathion mol ratio is wherein 1/5/8, reacts 4h to prepare cadmium telluride quantum dot at 90 DEG C.Take in the 9mL deionized water that 5mg cadmium telluride quantum dot is dispersed in containing 1mL chloroform and 50mg Cetyltrimethyl Ammonium Bromide, homogeneous solution is formed under ultrasonication, then at 65 DEG C, rotate evaporative removal chloroform and water, obtain the quantum dot that Cetyltrimethyl Ammonium Bromide is coated.Add in the 45mL deionized water containing 1mL ethyl orthosilicate, 5mL (2M) sodium hydroxide, 0.5mL ethyl acetate wherein, under 50 DEG C and 100rpm, react 6h.Head product is centrifugal, ethanol/water mixed solvent washs 3 times, add in the 50mL dehydrated alcohol being dissolved with 50 μ L3-(trimethoxysilyl) propyl acrylate again, in 25 DEG C of lower magnetic force stirring reaction 10h, then add 10mL (10mg/mL) ammonium nitrate and continue reaction 6h.Product is centrifugal washs 3 times with ethanol/water mixed solvent, obtains the porous silicon nanoparticle of load quantum dot.Take 0.5g porous silicon nanoparticle suspension (1wt%), add in the 45mL deionized water being dissolved with 0.5g NIPA, 0.1g chitosan, 10mg N,N methylene bis acrylamide, at N
2react 0.5h under atmosphere, 70 DEG C and 300rpm, then add and be dissolved with in the 4mL deionized water of 10mg potassium peroxydisulfate and 5mg sodium lauryl sulphate, continue reaction 6h, head product is centrifugal, dialysis, obtain target product.The reaction mixture of configuration 1wt%, adding the amycin of 1wt%, regulate pH to be 5.0 with phosphate buffer, then dialysing to remove the amycin into being loaded into, at 25 DEG C, adopt determined by ultraviolet spectrophotometry doxorubicin content, draw Temporal Evolution and discharge the curve of amycin.
Adopt pattern and the size of transmission electron microscope observation target product, in regular core/shell ball-shape, average-size is 220nm (see Fig. 2); Uv-visible absorption spectra and fluorescence emission spectrum is adopted to measure the photoluminescent property of target product, maximal ultraviolet absorption peak is at 480nm, maximum fluorescence emission peak is 535nm (see Fig. 3), adopt dynamic light scattering to measure the hydrodynamic size of target product and the relation of temperature, the size with temperature between 29 ~ 36 DEG C raises and significantly reduces (see Fig. 4); Adopt ultraviolet visible spectrophotometry to measure the relation of target product light absorption value and system pH, the light absorption value between pH4 ~ 7 raises with pH and enlarges markedly (see Fig. 5); Target product Temporal Evolution and discharge the curve of amycin 25 DEG C time, raising accumulation release amount of medicine with temperature enlarges markedly, and accumulation release amount of medicine at the same temperature reduces with pH and increases (see Fig. 6).
Embodiment 2
The preparation of cadmium telluride quantum dot is with embodiment 1.Take in the 9mL deionized water that 7.5mg quantum dot is dispersed in containing 1mL chloroform and 75mg Cetyltrimethyl Ammonium Bromide, homogeneous solution is formed under ultrasonication, then at 65 DEG C, rotate evaporative removal chloroform and water, obtain the quantum dot that Cetyltrimethyl Ammonium Bromide is coated.Add in the 45mL deionized water containing 2.5mL ethyl orthosilicate, 7.5mL (2M) sodium hydroxide, 0.75mL ethyl acetate wherein, under 55 DEG C and 200rpm, react 8h.Head product is centrifugal, ethanol/water mixed solvent washs 3 times, add in the 50mL dehydrated alcohol being dissolved with 75 μ L3-(trimethoxysilyl) propyl acrylate again, in 30 DEG C of lower magnetic force stirring reaction 8h, then add 20mL (10mg/mL) ammonium nitrate and continue reaction 6h.Product is centrifugal washs 3 times with ethanol/water mixed solvent, obtains the porous silicon nanoparticle of load quantum dot.Take 0.75g porous silicon nanoparticle suspension (1wt%), add in the 45mL deionized water being dissolved with 0.25g NIPA, 0.05g chitosan, 10mg N,N methylene bis acrylamide, at N
2react 0.5h under atmosphere, 70 DEG C and 300rpm, then add and be dissolved with in the 4mL deionized water of 15mg potassium peroxydisulfate and 10mg sodium lauryl sulphate, continue reaction 8h, head product is centrifugal, dialysis, obtain target product.The reaction mixture of configuration 2wt%, adding the amycin of 2wt%, regulate pH to be 6.5 with phosphate buffer, then dialysing to remove the amycin into being loaded into, at 37 DEG C, adopt determined by ultraviolet spectrophotometry doxorubicin content, draw Temporal Evolution and discharge the curve of amycin.Target product performance characterization is with embodiment 1.
Embodiment 3
The preparation of cadmium telluride quantum dot is with embodiment 1.Take in the 9mL deionized water that 10mg quantum dot is dispersed in containing 1mL chloroform and 100mg Cetyltrimethyl Ammonium Bromide, homogeneous solution is formed under ultrasonication, then at 65 DEG C, rotate evaporative removal chloroform and water, obtain the quantum dot that Cetyltrimethyl Ammonium Bromide is coated.Add in the 45mL deionized water containing 5mL ethyl orthosilicate, 10mL (2M) sodium hydroxide, 1mL ethyl acetate wherein, under 60 DEG C and 300rpm, react 10h.Head product is centrifugal, ethanol/water mixed solvent washs 3 times, add in the 50mL dehydrated alcohol being dissolved with 100 μ L3-(trimethoxysilyl) propyl acrylate again, in 40 DEG C of lower magnetic force stirring reaction 12h, then add 20mL (10mg/mL) ammonium nitrate and continue reaction 6h.Product is centrifugal washs 3 times with ethanol/water mixed solvent, obtains the porous silicon nanoparticle of load quantum dot.Take 1g porous silicon nanoparticle suspension (1wt%), add in the 45mL deionized water being dissolved with 0.75g NIPA, 0.15g chitosan, 10mgN, N-methylene-bisacrylamide, at N
2react 0.5h under atmosphere, 70 DEG C and 300rpm, then add and be dissolved with in the 4mL deionized water of 15mg potassium peroxydisulfate and 10mg sodium lauryl sulphate, continue reaction 10h, head product is centrifugal, dialysis, obtain target product.The reaction mixture of configuration 3wt%, adding the amycin of 3wt%, regulate pH to be 7.4 with phosphate buffer, then dialysing to remove the amycin into being loaded into, at 40 DEG C, adopt determined by ultraviolet spectrophotometry doxorubicin content, draw Temporal Evolution and discharge the curve of amycin.Target product performance characterization is with embodiment 1.
Embodiment 4
The preparation method of the organic-inorganic composite microballoons carrier of fluorescence and heat/pH sensitivity, the method specifically comprises the following steps:
(1) at N
2protection, magnetic agitation and pH value are in the sodium hydrate aqueous solution of 9, tellurium powder reacts with sodium borohydride molar concentration ratio (1: 4), prepare sodium hydrogen telluride presoma, then join in the mixed aqueous solution being dissolved with Caddy (Cleary) and mercaptopropionic acid, hydrogen telluride is received, Caddy (Cleary) and TGA molar concentration rate are 1: 5: 8, is to react 60 DEG C under the alkali condition of 9 at pH, prepares cadmium telluride quantum dot;
(2) cadmium telluride quantum dot is dispersed in the water containing chloroform and surfactant (I), then rotary evaporation removing chloroform and water, obtain the quantum dot that surfactant (I) is stable, then add in the aqueous solution containing sodium hydroxide, ethyl acetate and alkyl silicon (I), react under certain reaction temperature and magnetic agitation, carry out centrifugal after end, wash with ethanol/water mixed solvent; Surfactant (I) described in step (2) is bromohexadecane base trimethylamine; Described alkyl silicon (I) is ethyl orthosilicate; The mass ratio of described cadmium telluride quantum dot and surfactant (I) and chloroform is 5: 50: 5000; The volume ratio of described sodium hydroxide, ethyl acetate and alkyl silicon (I) consumption is 1: 5: 0.5; Described cadmium telluride quantum dot and the mass volume ratio of sodium hydroxide are 5mg/1ml; Described reaction temperature is 25 DEG C, and the response time is 10h, and the stir speed (S.S.) of magnetic agitation is 100rpm.
(3) step (2) gained sample is added in the ethanol being dissolved with alkyl silicon (II), react under certain reaction temperature and magnetic agitation, then add ammonium nitrate and continue reaction a period of time, product carries out centrifugal, with ethanol/water mixed solvent washing, obtain the porous silicon nanoparticle of load quantum dot; Alkyl silicon (II) described in step (3) is 3-(trimethoxysilyl) propyl acrylate, and the consumption volume ratio of the consumption of alkyl silicon (II) and the consumption of ammonium nitrate and alkyl silicon (I) is 0.05: 1: 10; Described reaction temperature is 20 DEG C, and the response time is 12h.
(4) to being dissolved with NIPA, the porous silicon nanoparticle that step (3) is obtained is added in the aqueous solution of carboxymethyl chitosan and cross-linking agent, at uniform temperature and N
2protection lower magnetic force stirring reaction, then add initiator and surfactant (II) continuation reaction, terminate afterproduct and carry out centrifugal, dialysis, obtain target product; NIPA described in step (4), the mass ratio of carboxymethyl chitosan, cross-linking agent, porous silicon nanoparticle, surfactant (II), initiator is 0.1: 0.1: 0.005: 0.5: 0.005: 0.005, described reaction temperature is 20 DEG C, and the response time is 12h.Described cross-linking agent is N,N methylene bis acrylamide, and described surfactant (II) is sodium lauryl sulphate, and described initiator is potassium peroxydisulfate.
(5) amycin aqueous solution is added in the target product after dialysis hatch, then dialysis is to remove the amycin be not loaded into, in the scope that pH value is 6 ~ 8, different pH value is adjusted to, with determined by ultraviolet spectrophotometry amycin release profiles at different temperatures with phosphate buffer solution.Release temperature is 20 DEG C, and the consumption of target product and amycin is 1wt%.
Embodiment 5
The preparation method of the organic-inorganic composite microballoons carrier of fluorescence and heat/pH sensitivity, the method specifically comprises the following steps:
(1) at N
2protection, magnetic agitation and pH value are in the sodium hydrate aqueous solution of 11, tellurium powder reacts with sodium borohydride molar concentration ratio, prepare sodium hydrogen telluride presoma, then join in the mixed aqueous solution being dissolved with Caddy (Cleary) and mercaptopropionic acid, hydrogen telluride is received, Caddy (Cleary) and TGA molar concentration rate are 1: 10: 15, is to react 90 DEG C under the alkali condition of 11 at pH, prepares cadmium telluride quantum dot;
(2) cadmium telluride quantum dot is dispersed in the water containing chloroform and surfactant (I), then rotary evaporation removing chloroform and water, obtain the quantum dot that surfactant (I) is stable, then add in the aqueous solution containing sodium hydroxide, ethyl acetate and alkyl silicon (I), react under certain reaction temperature and magnetic agitation, carry out centrifugal after end, wash with ethanol/water mixed solvent; Surfactant (I) described in step (2) is bromohexadecane base trimethylamine; Described alkyl silicon (I) is ethyl orthosilicate; The mass ratio of described cadmium telluride quantum dot and surfactant (I) and chloroform is 10: 100: 10000; The volume ratio of described sodium hydroxide, ethyl acetate and alkyl silicon (I) consumption is 5: 10: 1; Described cadmium telluride quantum dot and the mass volume ratio of sodium hydroxide are 10mg/5ml; Described reaction temperature is 60 DEG C, and the response time is 5h, and the stir speed (S.S.) of magnetic agitation is 300rpm.
(3) step (2) gained sample is added in the ethanol being dissolved with alkyl silicon (II), react under certain reaction temperature and magnetic agitation, then add ammonium nitrate and continue reaction a period of time, product carries out centrifugal, with ethanol/water mixed solvent washing, obtain the porous silicon nanoparticle of load quantum dot; Alkyl silicon (II) described in step (3) is 3-(trimethoxysilyl) propyl acrylate, and the consumption volume ratio of the consumption of alkyl silicon (II) and the consumption of ammonium nitrate and alkyl silicon (I) is 0.1: 5: 50; Described reaction temperature is 40 DEG C, and the response time is 6h.
(4) to being dissolved with NIPA, the porous silicon nanoparticle that step (3) is obtained is added in the aqueous solution of carboxymethyl chitosan and cross-linking agent, at uniform temperature and N
2protection lower magnetic force stirring reaction, then add initiator and surfactant (II) continuation reaction, terminate afterproduct and carry out centrifugal, dialysis, obtain target product; NIPA described in step (4), the mass ratio of carboxymethyl chitosan, cross-linking agent, porous silicon nanoparticle, surfactant (II), initiator is 1: 0.2: 0.02: 1: 0.010: 0.02, described reaction temperature is 20 DEG C, and the response time is 12h.Described cross-linking agent is N,N methylene bis acrylamide, and described surfactant (II) is sodium lauryl sulphate, and described initiator is potassium peroxydisulfate.
(5) amycin aqueous solution is added in the target product after dialysis hatch, then dialysis is to remove the amycin be not loaded into, in the scope that pH value is 6 ~ 8, different pH value is adjusted to, with determined by ultraviolet spectrophotometry amycin release profiles at different temperatures with phosphate buffer solution.Release temperature is 42 DEG C, and the consumption of target product and amycin is 5wt%.
Claims (4)
1. the preparation method of the organic-inorganic composite microballoons carrier of fluorescence and heat/pH sensitivity, it is characterized in that, the method specifically comprises the following steps:
(1) at N
2protection, in magnetic agitation and alkaline aqueous solution, tellurium powder and sodium borohydride react, and prepare sodium hydrogen telluride presoma, then join in the mixed aqueous solution being dissolved with Caddy (Cleary) and mercaptopropionic acid, react in the basic conditions, prepare cadmium telluride quantum dot;
(2) cadmium telluride quantum dot is dispersed in the water containing chloroform and surfactant I, then rotary evaporation removing chloroform and water, obtain the quantum dot that surfactant I is stable, then add in the aqueous solution containing sodium hydroxide, ethyl acetate and alkyl silicon I, react under certain reaction temperature and magnetic agitation, carry out centrifugal after end, wash with ethanol/water mixed solvent;
(3) step (2) gained sample is added be dissolved with in the ethanol of alkyl silicon II, react under certain reaction temperature and magnetic agitation, then add ammonium nitrate and continue reaction a period of time, product carries out centrifugal, with ethanol/water mixed solvent washing, obtain the porous silicon nanoparticle of load quantum dot;
(4) to being dissolved with NIPA, the porous silicon nanoparticle that step (3) is obtained is added in the aqueous solution of carboxymethyl chitosan and cross-linking agent, at uniform temperature and N
2protection lower magnetic force stirring reaction, then add initiator and surfactant II continuation reaction, terminate afterproduct and carry out centrifugal, dialysis, obtain target product;
(5) added in the target product after dialysis by amycin aqueous solution and hatch, then dialysis is to remove the amycin be not loaded into, and is adjusted to different pH value, with determined by ultraviolet spectrophotometry amycin release profiles at different temperatures with phosphate buffer solution;
Surfactant I described in step (2) is bromohexadecane base trimethylamine; Described alkyl silicon I is ethyl orthosilicate; The mass ratio of described cadmium telluride quantum dot and surfactant I and chloroform is 5 ~ 10:50 ~ 100:5000 ~ 10000; The volume ratio of described sodium hydroxide, ethyl acetate and alkyl silicon I consumption is 1 ~ 5:5 ~ 10:0.5 ~ 1; Described cadmium telluride quantum dot and the mass volume ratio of sodium hydroxide are 5 ~ 10mg/1 ~ 5ml; Described reaction temperature is 25 ~ 60 DEG C, and the response time is 5 ~ 10h, and the stir speed (S.S.) of magnetic agitation is 100 ~ 300rpm;
Alkyl silicon II described in step (3) is 3-(trimethoxysilyl) propyl acrylate, and the consumption volume ratio of the consumption of alkyl silicon II and the consumption of ammonium nitrate and alkyl silicon I is 0.05 ~ 0.1:1 ~ 5:10 ~ 50; Described reaction temperature is 20 ~ 40 DEG C, and the response time is 6 ~ 12h;
NIPA described in step (4), the mass ratio of carboxymethyl chitosan, cross-linking agent, porous silicon nanoparticle, surfactant II, initiator is 0.1 ~ 1:0.1 ~ 0.2:0.005 ~ 0.02:0.5 ~ 1:0.005 ~ 0.010:0.005 ~ 0.02, described reaction temperature is 20 ~ 40 DEG C, and the response time is 6 ~ 12h;
Described cross-linking agent is N,N methylene bis acrylamide, and described surfactant II is sodium lauryl sulphate, and described initiator is potassium peroxydisulfate.
2. the preparation method of the organic-inorganic composite microballoons carrier of fluorescence according to claim 1 and heat/pH sensitivity, is characterized in that, the alkaline aqueous solution described in step (1) refers to sodium hydrate aqueous solution, and pH value is 9 ~ 11; Described tellurium powder carries out reacting obtained sodium hydrogen telluride presoma than 1:4 with sodium borohydride molar concentration.
3. the preparation method of the organic-inorganic composite microballoons carrier of fluorescence according to claim 1 and heat/pH sensitivity, it is characterized in that, hydrogen telluride described in step (1) is received, Caddy (Cleary) and mercaptopropionic acid molar concentration rate are 1:5:8 ~ 1:10:15, reaction temperature is 60 ~ 90 DEG C, and system pH is 9 ~ 11.
4. the preparation method of the organic-inorganic composite microballoons carrier of fluorescence according to claim 1 and heat/pH sensitivity, it is characterized in that, the pH value that phosphate buffer solution described in step (5) regulates is 6 ~ 8, release temperature is 20 ~ 42 DEG C, and the consumption of target product and amycin is 1 ~ 5wt%.
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