CN105381466B - A kind of optomagnetic temperature-sensitive nano combination drug carrier and preparation method thereof - Google Patents
A kind of optomagnetic temperature-sensitive nano combination drug carrier and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of optomagnetic temperature-sensitive nano combination drug carriers and preparation method thereof, and the invention belongs to pharmaceutical carrier fields.In order to solve the problem of the prior art in terms of preparing optomagnetic temperature-sensitive nano combination drug carrier there are fluorescence, magnetism and Thermo-sensitive is poor and preparation step is unfavorable for industry and generates and propose the preparation method.This method uses N-isopropylacrylamide, ethyl orthosilicate, ZnS:Mn2+Quantum dot and Fe3O4Quantum dot is primary raw material, first with oleic acid to Fe3O4Quantum dot is surface modified；Then by ZnS:Mn2+Quantum dot and Fe3O4Quantum dot is embedded in SiO simultaneously2In；Again with silane coupling agent to SiO2Surface modification double bond；Finally by free radical polymerization coated polymer PNIPAAm, the nano combined pharmaceutical carrier ZnS:Mn of optomagnetic temperature sensitive polymer is realized2+Quantum dot/Fe3O4Quantum dot/SiO2The preparation of/PNIPAAm.
Description
Technical field
The invention belongs to pharmaceutical carrier fields, and in particular to one kind shines, is magnetic, temperature sensitive compound drug carrier material and
Preparation method.
Background technique
It is all Formulations for systemic administration, medicine that common problem, which is oral or injection anticancer drug, in Current cancer therapeutic process
Object can also implement drug effect to healthy cell, so that patients immune system further deteriorates not only to cancer cell.Therefore,
It is badly in need of the nano combined pharmaceutical carrier of design novel non-toxic, allows drug specificity to aim at cancer cell thin without damaging adjacent healthy
To improve the therapeutic efficiency to cancer, and the damage to human body is greatly lowered in born of the same parents.
Temperature sensitive type polymer PNIPAAm (polyisopropyl acrylamide) has good biocompatibility, biodegradable
Property and temperature switch characteristic, preparation method are simple, and stability is good.In recent years, using PNIPAAm and with light, magnetic property
Inorganic composite materials construct nano combined pharmaceutical carrier and have obtained the extensive concern of people, can realize it in vivo using photoluminescent property
Imaging and drug tracking, are oriented to tumor tissues for pharmaceutical carrier using magnetic orientation technology, realize medicine using the Thermo-sensitive of polymer
The controlled release of object.Although by PNIPAAm and inorganic nano material it is compound be very promising medical carrier, system
Standby process also needs to overcome many problems.There are two main problems, and one is that magnetic substance asks the fluorescent quenching of fluorescent material
Topic, one be inorganic material Yu polymer P NIPAAm connectivity problem.Directly affect the magnetism, fluorescence and temperature of product
Sensibility.Furthermore existing preparation method step is difficult to control, and prepared compound property is inhomogenous, is not easy to realize industry
Change.
Summary of the invention
In order to solve the above difficulties, optomagnetic temperature-sensitive nano combination drug carrier provided by the present invention, with ZnS:Mn2+Quantum
Point is used as fluorescence source, with Fe3O4Quantum dot after surface modification, is respectively coated by SiO as magnetic source and with oleic acid2, reuse silane
Coupling agent is to SiO2It is surface modified, finally coats polyisopropyl acrylamide again, form ZnS:Mn2+Quantum dot/Fe3O4Amount
Sub- point/SiO2/ polyisopropyl acrylamide structure.
The optomagnetic temperature-sensitive nano combination drug carrier the preparation method is as follows:
One, by 300~600mg Fe3O4Quantum dot is scattered in 5~20ml water, and the oleic acid of water volume 15~50% is added,
1~6h is reacted under the conditions of 20~60 DEG C, obtains the Fe of oleic acid modified3O4Quantum dot.
Two, by the Fe after oleic acid modified3O4Quantum dot washing, drying are scattered in hexamethylene after pulverizing, and are obtained
Fe3O4Quantum dot ring hexane solution.
Three, by ZnS:Mn2+Quantum dot is scattered in hexamethylene, obtains ZnS:Mn2+Quantum dot ring hexane solution.
Four, by polyoxyethylenes (5) nonylplenyl ether, branching (Igepal CO-520) is scattered in hexamethylene, Igepal
The ratio between additional amount of CO-520 and hexamethylene is 0.06~0.07:1, and ZnS:Mn is added2+The cyclohexane solution and Fe of quantum dot3O4
Quantum dot ring hexane solution is dispersed to uniformly, addition ammonium hydroxide adjusting pH to alkalinity, and addition hexamethylene total volume 0.15%~
0.8% ethyl orthosilicate (TEOS) reacts 10~40h, obtains ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2It is nano combined
Object is washed after reaction, is dried；Wherein, the ZnS:Mn being added2+Quantum dot ring hexane solution and Fe3O4Amount
ZnS:Mn in son point cyclohexane solution2+Quantum dot and Fe3O4The mass ratio of quantum dot is between 3:1~6:1.
Five, by ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2The hydrochloric acid that nano-complex is dispersed in pH=3~5 is water-soluble
In liquid, 75~85 DEG C of 1~2h of heating obtain the ZnS:Mn of surface hydroxylation2+Quantum dot/Fe3O4Quantum dot/SiO2It is nano combined
Object.
Six, the alcohol-water mixed solution (volume ratio of alcohol to water is 3~5:1) for configuring pH=3~5.5, is added silane coupling agent
The ZnS:Mn of surface hydroxylation is added after silane coupling agent KH570 hydrolysis in KH5702+Quantum dot/Fe3O4Quantum dot/SiO2It receives
Rice compound is surface modified it, and 6~7h is reacted under the conditions of 70~85 DEG C.The wherein addition of silane coupling agent KH570
Amount is the 0.25%~0.5% of alcohol-water mixed solution total volume.
Seven, silane coupling agent is modified into ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex is dispersed in water,
Monomer n-isopropyl acrylamide (NIPAAm), acrylamide (AAm) and N-N- methylene-bisacrylamide (BIS) is added, removes
At 70~80 DEG C after oxygen in dereaction system, the initiator for reaction time is added to obtain ZnS:Mn after 4~6h2+Quantum dot/
Fe3O4Quantum dot/SiO2/ PNIPAAm nano-complex.Wherein, quality is than n-isopropyl acrylamide (NIPAAm): acryloyl
Amine (AAm): N,N methylene bis acrylamide (BIS): silane coupling agent modifies ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2
Nano-complex=4.5~5.5:0.3~0.35:0.4~0.6:1.The initiator is potassium peroxydisulfate (KPS).
Eight, pure ZnS:Mn is obtained after washed, dry2+Quantum dot/Fe3O4Quantum dot/SiO2/ poly- isopropyl propylene
Amide nano-complex.
In step 6, it is two sections of progress that 6~7h is reacted under the conditions of 70~85 DEG C: first reacting 5h under the conditions of 70 DEG C, so
Temperature is increased to 80~85 DEG C afterwards, the reaction was continued, and 1~2h can obtain better effect.
The invention has the advantages that:
1. the present invention uses the method for reverse micro emulsion by ZnS:Mn2+Quantum dot and Fe3O4Quantum dot is coated on SiO simultaneously2
In, it is prepared for having both fluorescence and magnetic silicon ball.Of uniform size, size is controllable, good dispersion.
2. the method for the present invention has carried out surface modification to silicon ball by KH570 silane coupling agent, it is double to substantially increase surface
The grafting rate of key, and then significantly improve grafting rate of the polymer in silicon ball.
3. the present invention uses traditional radical polymerization, there is fluorescence and magnetic titanium dioxide in addition at the beginning of preparation process
Silicon ball, a step are obtained with fluorescence, magnetism and thermally sensitive polymer based nanocomposites, and method is simple, can weigh
Renaturation is good, can control SiO by adjusting TEOS additional amount2The thickness of clad, passes through ZnS:Mn2+Quantum dot and Fe3O4Quantum
The additional proportion adjustment of point can control its fluorescence and magnetic intensity.
4. the present invention is not only easy to operate, step is clear, has environmentally friendly, economic, convenient, simple operation and other advantages, is easy to
Realize large-scale production, while this method preparation polymer nanocomposites even size distribution, have both fluorescence, magnetism and
Temperature sensitivity can be used as medical carrier.
5, target product of the invention fluorescence efficiency with higher, stronger superparamagnetism and be higher than human body temperature
Temperature-sensitive, accommodate very much as bio-pharmaceutical carrier.
Detailed description of the invention
Fig. 1 target product transmission electron microscope photo of the present invention；
Fig. 2 target product light transmittance of the present invention varies with temperature curve graph；
Fig. 3 target product fluorescence emission spectrum of the present invention；
Fig. 4 a target product aqueous dispersion photo of the present invention；
Fig. 4 b target product ultraviolet excitation photo of the present invention；
Fig. 5 hysteresis loop of the present invention (in figure, M is the sample intensity of magnetization, and H is magnetic field strength)；
Target product assembles photo under Fig. 6 external magnetic field.
Specific embodiment
Technical solution of the present invention is further explained and is illustrated in a manner of specific embodiment below.Following embodiment is not
Specified otherwise carries out at normal temperatures and pressures.
Reagent used in the embodiment of the present invention is as follows:
Zinc acetate (Zn (CH3COO)2·2H2O, Shenyang Sinopharm Chemical Reagent Co., Ltd. analyze pure)；
Manganese acetate (Mn (CH3COO)2·4H2O, Aladdin reagent are analyzed pure)；
Oleic acid (C18H34O, Shenyang Sinopharm Chemical Reagent Co., Ltd. analyze pure)；
Enuatrol (C18H33NaO2, Shenyang Sinopharm Chemical Reagent Co., Ltd., chemistry it is pure)；
Ethyl alcohol (C2H6O, Shenyang Sinopharm Chemical Reagent Co., Ltd.) it is that analysis is pure；
Sodium Sulphate Nine Hydroxide (Na2S·9H2O, Shenyang Sinopharm Chemical Reagent Co., Ltd. analyze pure)；
Ferric trichloride (FeCl3·6H2O, Shenyang Sinopharm Chemical Reagent Co., Ltd. analyze pure)；
Frerrous chloride (FeCl2·4H2O, Shenyang Sinopharm Chemical Reagent Co., Ltd. analyze pure)；
Ammonium hydroxide (NH3·H2O, Beijing Chemical Plant analyze pure)；
Macrogol 4000 (PEG 4000) (H (OGH2CH2)nOH, Shenyang Sinopharm Chemical Reagent Co., Ltd., analysis
It is pure)；
Ethyl orthosilicate (TEOS) (C8H20O4Si, Shenyang Sinopharm Chemical Reagent Co., Ltd. analyze pure)；
Hexamethylene (C6H12, Shenyang Sinopharm Chemical Reagent Co., Ltd. analyzes pure)；
γ-(methacryloxypropyl) propyl trimethoxy silicane (silane coupling agent KH570, CH2=C (CH3)COOC3H6Si
(OCH3)3, Sigma-Aldrich, biological reagent)；
N-isopropyl acrylamide (NIPAAm) (C6H11NO, Aladdin reagent are analyzed pure)；
Acrylamide (AAm) (C3H5NO, Aladdin reagent, excellent pure grade)；
Potassium peroxydisulfate (KPS) (K2S2O8, Aladdin reagent, Metal Substrate (metals basis))；
N-N- methylene-bisacrylamide (BIS) (C7H10N2O2, Aladdin reagent, electronic grade reagents)；
Polyoxyethylenes (5) nonylplenyl ether, branching (Igepal CO-520) (C2H4O)n·C15H24O, n~5, I
Fourth reagent).
Embodiment 1
(1) solvent hot preparation zinc sulphide mixes manganese quantum dot: weighing 0.8561g Zn (CH3COO)2·2H2O and 0.0097g
Mn(CH3COO)2·4H2O is poured into the 250ml beaker equipped with 7ml deionized water, magnetic agitation 10min to dissolution.So
It states addition 9.75ml oleic acid, 1.3g enuatrol, 16ml ethyl alcohol in solution, and magnetic agitation 1h upwards in turn afterwards, forms latex A.
By 0.937g Na2S·9H2O is poured into the 250ml beaker equipped with 7ml deionized water, and magnetic agitation 10min obtains sulphur to dissolving
Change sodium water solution.Sodium sulfide solution is added in latex A, and magnetic agitation 2h obtains solution B, and B solution is transferred to
The temperature that in the reaction kettle of 50ml, reaction kettle is put into drying box, and drying box is arranged is 190 DEG C, reacts 12h.It reacts
The product ethyl alcohol arrived: hexamethylene=1:1 solution centrifuge washing is three times.60 DEG C of dry 5h obtain ZnS:Mn2+Quantum dot.
(2) co-precipitation prepares ferroso-ferric oxide quantum dot: weighing 2.703g FeCl3·6H2O、1.192g FeCl2·
4H2O and 10g PEG 4000 is added in the 500ml three-neck flask for filling 150ml deionized water, mechanical stirring to dissolution.It will
Solution temperature is warming up to 90 DEG C, and 100ml NH is added3·H2O stirs 2h.Products therefrom is centrifuged, with ethyl alcohol and deionization moisture
It Xi Di not be 3 times.In aqueous solution by sample dispersion, Fe is obtained3O4Quantum dot aqueous solution.
(3) oleic acid modified ferroso-ferric oxide quantum dot: the Fe that will be prepared in 300mg step (2)3O4Quantum dot, ultrasound
20min is dispersed in the 100ml conical flask for filling 20ml deionized water, and 5ml oleic acid is then added into conical flask, continues ultrasound
It is placed it in shaking table after 30min, shaking table temperature 60 C, revolving speed 100rpm, reaction time 6h is set.After the reaction was completed, sharp
It removes extra oleic acid three times with ethanol washing, is then dried in vacuo 12h at 60 DEG C, pulverize stand-by, obtain oleic acid and repair
The Fe of decorations3O4Quantum dot.By 10mg Fe3O4Quantum dot is dispersed in 10ml hexamethylene, is made into the Fe that concentration is 1mg/ml3O4Amount
Son point cyclohexane solution.
(4) coated silica: measuring 3.7ml Igepal CO-520, by its ultrasonic disperse in the hexamethylene of 60ml,
Then by 2ml ZnS:Mn2+The cyclohexane solution (5mg/ml) and 2ml Fe of QDs3O4Cyclohexane solution (1mg/ml) simultaneously plus
Enter into above-mentioned solution, stirring 30min makes it be uniformly dispersed, after 0.5ml ammonium hydroxide (25%) is rapidly joined, stir after 1h to body
250 μ l TEOS are added in system, room temperature reaction 15-20h obtains ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2Nano combined material
Material.Final product ethyl alcohol, deionized water are washed for several times, then save product dispersion in ethanol or 60 DEG C of dry 6h are obtained
To grey-brown powder, ZnS:Mn is obtained2+Quantum dot/Fe3O4Quantum dot/SiO2Nanocomposite.
(5) silane coupling agent surface modification: 30mg ZnS:Mn is weighed2+Quantum dot/Fe3O4Quantum dot/SiO2It is nano combined
Material is dispersed in the aqueous hydrochloric acid solution of 40ml PH=4, and ultrasonic 20min makes it be uniformly dispersed, and then dispersion liquid is added
85 DEG C of heating 1-2h in the three-neck flask of 250ml obtain the ZnS:Mn of surface hydroxylation after 10000rpm is centrifuged 5min2+Quantum
Point/Fe3O4Quantum dot/SiO2Nanocomposite.2. measuring the mixed solution (ethyl alcohol: water=4:1) of 40ml PH=4, it is added
0.2ml KH570 is placed in stirring hydrolysis 2h on magnetic stirring apparatus.The ZnS:Mn of surface hydroxylation is added2+Quantum dot/Fe3O4Amount
Sub- point/SiO2Solution is added in the three-neck flask of 250ml after ultrasonic disperse 30min, by three-neck flask by nanocomposite
It is placed in water-bath, 5h is stirred at 70 DEG C, water bath temperature is then increased to 80-85 DEG C, continue to stir 1-2h.To solution
It is centrifuged, using ethanol washing 6 times, centrifugation products therefrom, which is dispersed in ethanol solution, to be saved, and obtains what the surface KH570 was modified
ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2Ethanol solution.
(6) surface grafting polymerization object: by the ZnS:Mn of the KH570 modification of step (5) synthesis2+Quantum dot/Fe3O4Quantum
Point/SiO2Nanocomposite is washed with deionized three times, and is dispersed in ultrasound 20min in 100ml deionized water, then will
It is added in the four-neck flask of 250ml, is placed in water-bath, thereto be added 0.150g NIPAAm, 9.4mg AAm and
The BIS of 0.015g is stirred at 200 rpm with mechanical stirring stick, and logical nitrogen deoxygenates 0.5h.Then water-bath is warming up to 70
DEG C, it is added KPS 1.5ml (4mg/ml), reaction time 4h.It is centrifuged and benefit is washed with deionized three times, be subsequently placed in vacuum
Drying obtains target product ZnS:Mn for 24 hours in freeze drier2+Quantum dot/Fe3O4Quantum dot/SiO2/PNIPAAm。
Embodiment 2
Embodiment 1 be preferred embodiment of the present invention, in addition to the method and step that embodiment 1 is described, by the additional amount of raw material with
Reaction condition run business into particular one micromodification change, analyzed referring to existing method and according to reaction principle, disclosed in summary of the invention of the invention
Reaction condition changes the material alterations that will not cause the method for the present invention, and the present invention may be implemented.Such as: the embodiment of the present invention
In 1 when modifying using oleic acid ferroso-ferric oxide surface, the oleic acid of deionized water volume 15%~50% is added, instead
At once it is reacted 1~6 hour at 20~60 DEG C.The specific steps of coated silica can refer to the prior art, further hydroxyl
The hydroxyl of surface silica dioxide can be realized in 75~85 DEG C of 1~2h of heating under conditions of pH=3~5 when baseization processing
Change.The additional amount of KH570 is 0.1~0.2mL/40mL alcohol solution when heating modifies surface using silane coupling agent,
And it needs to carry out under conditions of PH=3~5.5.Present invention ZnS:Mn during the preparation process2+Quantum dot and Fe3O4Quantum dot
Mass ratio can preferably ensure magnetic and fluorescence effect in 3:1~6:1.It is added surfactant Igepal CO-520's
It uses and is controlled and extraordinary effect is coated with for silica between 0.06~0.07:1, improve the present invention
Technical effect.
Embodiment 3
Structure and function characterize
The present invention respectively characterizes target product from structure and function, to target product in a manner of transmission electron microscope
Structure is characterized, as shown in Figure 1, black region is ZnS:Mn2+Quantum dot or Fe3O4Quantum dot, surface Dark grey area
Domain is surface coated SiO2, outermost layer light gray areas is PNIPAAm.
Functional characterization of the invention is divided into temperature-sensing property characterization, magnetic characterization and characteristics of luminescence characterization.
The present invention varies with temperature curve by light transmittance and characterizes to its temperature-sensing property.As shown in Fig. 2, target product
Phase transition temperature be 41.1 DEG C, greater than 37 DEG C of body temperature of human body, therefore the temperature of control vector can be passed through and realize drug
Controlled release.
Fig. 3 is target product ZnS:Mn of the present invention2+Quantum dot/Fe3O4Quantum dot/SiO2The fluorescence emission of/PNIPAAm
Spectrum, from figure 3, it can be seen that the luminous peak position of target product is in 592.7nm.The present invention is under the conditions of 365nm ultraviolet excitation
The target sample aqueous solution of brown issues glassy yellow fluorescence (as shown in figures 4 a and 4b).Illustrate target product ZnS:Mn2+Quantum
Point/Fe3O4Quantum dot/SiO2/ PNIPAAm can be used as fluorescent marker application in vivo.
By Fig. 5, it can be seen that, target product of the present invention has superparamagnetism.Targeting experiment is carried out to solution using magnet
Target product ZnS:Mn is assembled in (as shown in Figure 6), discovery solution side2+Quantum dot/Fe3O4Quantum dot/SiO2/ PNIPAAm,
Solution colour becomes milky by brown, illustrates target product ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2/ PNIPAAm can
To realize that targeting is mobile under the action of external magnetic field, the positioning release of drug is realized.
Claims (6)
1. a kind of optomagnetic temperature-sensitive nano combination drug carrier, it is characterised in that: be coated with SiO on surface2ZnS:Mn2+Quantum dot
SiO is coated with surface2Fe3O4The external sheath of quantum dot has polyisopropyl acrylamide, constitutes nano-complex；It is described
Fe3O4Oleic acid surface modification is passed through on the surface of quantum dot, and preparation step is specific as follows:
One, by Fe3O4Quantum dot is dispersed in water, Fe3O4The mass volume ratio of quantum dot and water is 15 ~ 120 mg/ml, and water is added
The oleic acid of volume 15% ~ 50% reacts 1 ~ 6h under the conditions of 20 ~ 60 DEG C, obtains the Fe of oleic acid modified3O4Quantum dot；
Two, by the Fe after oleic acid modified3O4Quantum dot washing, drying are scattered in hexamethylene after pulverizing, and obtain Fe3O4Amount
Son point cyclohexane solution；
Three, by ZnS:Mn2+Quantum dot is scattered in hexamethylene, obtains ZnS:Mn2+Quantum dot ring hexane solution；
Four, by polyoxyethylenes (5) nonylplenyl ether, branching is scattered in hexamethylene, polyoxyethylenes (5) nonylplenyl ether,
The additional amount volume ratio of branching and hexamethylene is 0.06 ~ 0.07:1, and ZnS:Mn is added2+The cyclohexane solution and Fe of quantum dot3O4
Quantum dot ring hexane solution is dispersed to uniformly, and ammonium hydroxide is added and adjusts pH to alkalinity, hexamethylene total volume 0.15% ~ 0.8% is added
Ethyl orthosilicate reacts 10 ~ 40h, obtains ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex, after reaction
It washed, be dried；Wherein, the ZnS:Mn being added2+Quantum dot ring hexane solution and Fe3O4Quantum dot ring hexane solution
Middle ZnS:Mn2+Quantum dot and Fe3O4The mass ratio of quantum dot is between 3:1 ~ 6:1；
Five, by ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex is dispersed in the aqueous hydrochloric acid solution of pH=3 ~ 5, and 75
~ 85 DEG C of 1 ~ 2h of heating, obtain the ZnS:Mn of surface hydroxylation2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex；
Six, the alcohol-water mixed solution of pH=3 ~ 5.5 is configured, silane coupling agent KH570 is added, to silane coupling agent KH570 water
The ZnS:Mn of surface hydroxylation is added in Xie Hou2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex is surface modified it,
6 ~ 7h is reacted under the conditions of 70 ~ 85 DEG C；Wherein, the additional amount of silane coupling agent KH570 is alcohol-water mixed solution total volume
0.25%~0.5%；The volume ratio of second alcohol and water is 3 ~ 5:1 in the alcohol-water mixed solution；
Seven, silane coupling agent is modified into ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex is dispersed in water, and is added
Monomer n-isopropyl acrylamide, acrylamide and N-N- methylene-bisacrylamide, remove in reaction system after oxygen 70 ~
80 DEG C, the initiator for reaction time is added to obtain ZnS:Mn after 4 ~ 6h2+Quantum dot/Fe3O4Quantum dot/SiO2/ poly- isopropyl third
Acrylamide nano-complex；Wherein, n-isopropyl acrylamide in mass ratio: acrylamide: N, N- methylene bisacrylamide acyl
Amine: silane coupling agent modifies ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex=4.5 ~ 5.5:0.3 ~ 0.35:
0.4~0.6:1。
2. a kind of preparation method of optomagnetic temperature-sensitive nano combination drug carrier described in claim 1, the specific steps are as follows:
One, by Fe3O4Quantum dot is dispersed in water, Fe3O4The mass volume ratio of quantum dot and water is 15 ~ 120 mg/ml, and water is added
The oleic acid of volume 15% ~ 50% reacts 1 ~ 6h under the conditions of 20 ~ 60 DEG C, obtains the Fe of oleic acid modified3O4Quantum dot；
Two, by the Fe after oleic acid modified3O4Quantum dot washing, drying are scattered in hexamethylene after pulverizing, and obtain Fe3O4Amount
Son point cyclohexane solution；
Three, by ZnS:Mn2+Quantum dot is scattered in hexamethylene, obtains ZnS:Mn2+Quantum dot ring hexane solution；
Four, by polyoxyethylenes (5) nonylplenyl ether, branching is scattered in hexamethylene, polyoxyethylenes (5) nonylplenyl ether,
The additional amount volume ratio of branching and hexamethylene is 0.06 ~ 0.07:1, and ZnS:Mn is added2+The cyclohexane solution and Fe of quantum dot3O4
Quantum dot ring hexane solution is dispersed to uniformly, and ammonium hydroxide is added and adjusts pH to alkalinity, hexamethylene total volume 0.15% ~ 0.8% is added
Ethyl orthosilicate reacts 10 ~ 40h, obtains ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex, after reaction
It washed, be dried；Wherein, the ZnS:Mn being added2+Quantum dot ring hexane solution and Fe3O4Quantum dot ring hexane solution
Middle ZnS:Mn2+Quantum dot and Fe3O4The mass ratio of quantum dot is between 3:1 ~ 6:1；
Five, by ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex is dispersed in the aqueous hydrochloric acid solution of pH=3 ~ 5, and 75
~ 85 DEG C of 1 ~ 2h of heating, obtain the ZnS:Mn of surface hydroxylation2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex；
Six, the alcohol-water mixed solution of pH=3 ~ 5.5 is configured, silane coupling agent KH570 is added, to silane coupling agent KH570 water
The ZnS:Mn of surface hydroxylation is added in Xie Hou2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex is surface modified it,
6 ~ 7h is reacted under the conditions of 70 ~ 85 DEG C；Wherein, the additional amount of silane coupling agent KH570 is alcohol-water mixed solution total volume
0.25%~0.5%；The volume ratio of second alcohol and water is 3 ~ 5:1 in the alcohol-water mixed solution；
Seven, silane coupling agent is modified into ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex is dispersed in water, and is added
Monomer n-isopropyl acrylamide, acrylamide and N-N- methylene-bisacrylamide, remove in reaction system after oxygen 70 ~
80 DEG C, the initiator for reaction time is added to obtain ZnS:Mn after 4 ~ 6h2+Quantum dot/Fe3O4Quantum dot/SiO2/ poly- isopropyl third
Acrylamide nano-complex；Wherein, n-isopropyl acrylamide in mass ratio: acrylamide: N, N- methylene bisacrylamide acyl
Amine: silane coupling agent modifies ZnS:Mn2+Quantum dot/Fe3O4Quantum dot/SiO2Nano-complex=4.5 ~ 5.5:0.3 ~ 0.35:
0.4~0.6:1。
3. the preparation method of optomagnetic temperature-sensitive nano combination drug carrier according to claim 2, it is characterised in that: step 7
Pure ZnS:Mn is obtained after washing, drying after the completion2+Quantum dot/Fe3O4Quantum dot/SiO2/ polyisopropyl acrylamide
Nano-complex.
4. the preparation method of optomagnetic temperature-sensitive nano combination drug carrier according to claim 2, it is characterised in that: described to draw
Hair agent is potassium peroxydisulfate.
5. the preparation method of optomagnetic temperature-sensitive nano combination drug carrier according to claim 2, it is characterised in that: step 6
In, it is two sections of progress that 6 ~ 7h is reacted under the conditions of 70 ~ 85 DEG C: first under the conditions of 70 DEG C 5h is reacted, temperature is then increased to 80 ~
85 DEG C, the reaction was continued 1 ~ 2h.
6. the preparation method of optomagnetic temperature-sensitive nano combination drug carrier according to claim 2, it is characterised in that: step 7
Middle n-isopropyl acrylamide: acrylamide: N,N methylene bis acrylamide: silane coupling agent modifies ZnS:Mn2+Quantum
Point/Fe3O4Quantum dot/SiO2Nano-complex=5:0.31:0.5:1.
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