CN105903016A - Preparing method of core-shell structure drug carrier with near-infrared light exciting supermolecule valve light control drug release - Google Patents
Preparing method of core-shell structure drug carrier with near-infrared light exciting supermolecule valve light control drug release Download PDFInfo
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- CN105903016A CN105903016A CN201610421622.0A CN201610421622A CN105903016A CN 105903016 A CN105903016 A CN 105903016A CN 201610421622 A CN201610421622 A CN 201610421622A CN 105903016 A CN105903016 A CN 105903016A
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
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- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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Abstract
The invention belongs to the field of biomedical materials, particularly relates to a preparing method of a core-shell structure drug carrier with near-infrared light exciting supermolecule valve light control drug release, and aims to solve the problems that a diagnosis and treatment agent cannot be controllably released in the aspects of time, space and dosage. The method includes the steps that upconversion nano particle cores are synthesized; upconversion nano particles with shells coated are synthesized; the outer layers of the upconversion nano particles are coated with mesoporous silica; the outer surfaces of the core-shell structure nano particles are modified with amino groups; surfactant is removed to form mesoporous; the outer surfaces of the core-shell structure nano particles are modified with guest molecules; doxorubicin hydrochloride is loaded, and pore passages are blocked. The core-shell structure drug carrier is used in cancer treatment, and timing and quantitative controlled release of anti-cancer drugs in tumor tissue is achieved.
Description
Technical field
The invention belongs to biomedical materials field, be specifically related to a kind of near infrared light and excite the core of the light-operated release of supermolecule valve
The preparation method of shell structure pharmaceutical carrier.
Background technology
Along with the fast development of nanosecond medical science, design and build intelligent response type nano molecular valve treatment of cancer platform, by anticancer
It is transported to cancerous tissue, in lesions position enrichment controlled release, it has also become nanometer medical science important development medicine No leakage
Direction.At present, be used for opening the environmental stimuli intelligent response mode of molecule valve mainly to have: pH, redox, enzyme, light,
Heat etc. are several.Wherein pH, redox, enzyme response are internal controlled release, and response sensitivity is poor, it is difficult to accuracy controlling.Light rings
Answer system because having external controlled release, response sensitivity is high and can pass through the spies such as optical wavelength, power and light application time accuracy controlling
Put and enjoy favor.But visible ray and ultraviolet light are because its penetration power is weak and cell tissue is likely to result in the factors such as damage, in reality
Border application is restricted.
Near infrared light (wavelength 700～900nm) is because having deeper biological tissue's penetration capacity and extremely low biological illumination
Damage, is particularly suitable for building photoresponse type controlled drug delivery systems.Rear-earth-doped up-conversion luminescence nano particle, can be at near-infrared
Under the exciting of light, produce the transmitting in multiband ultraviolet/visible/near infrared region, (the most a certain band of light is used for imaging, other
Band of light is used for treating), therefore in nanometer medical science photochemical reaction, play key player.It is currently based on conversion
Nano material/mesoporous silicon oxide nucleocapsid structure design medicine controlled releasing platform is a recent studies on heat of cancer nanometer treatment technology
Point, it is with up-conversion nanoparticles as core, and external sheath mesoporous silicon oxide is the core shell structure of shell, and mesoporous inside is used for filling
Medicine carrying thing.Under the irradiation of near infrared light, the up-conversion nanoparticles strong energy of organism-absorbing penetration power being phagocytized by cells is low
Near infrared light and on be converted to high UV light-induced of energy and excite various photochemical reaction, thus reach the purpose for the treatment of of cancer.
Medicine controlled releasing advantage based on up-conversion nano material/mesoporous silicon oxide nucleocapsid structure near infrared light response is: achieve light
Deep tissues penetrate light-operated exciting, it is to avoid ultraviolet light direct irradiation penetration depth is shallow, the shortcoming big to biological tissue's injury.
The core key technology of intelligent response type nano molecular valve cancer diagnosis and treatment platform is the design of medicine controlled releasing valve switch.
Macrocycle molecule main body has higher volume of supermolecule " Host-guest " complex compound owing to can be assembled into some guest molecule,
Closure mesoporous silicon oxide duct (diameter 2～4nm), therefore can be as the supermolecule valve of intelligent response type controlled drug delivery systems
Door.These valves mesoporous silicon oxide carrying platform implement medicine controlled releasing mechanism mainly have two kinds: 1, utilize pH, enzyme,
The effect such as glutathione causes connecting the chemical bond rupture between main body or object and silicon ball, and complex compound of blocking up is left away, and valve is beaten
Open；2, utilizing heat, pH separates Subjective and Objective with competition reagent or photoresponse, and complex compound dissociates, and nano-valve is opened.
Wherein the complex compound of photoresponse dissociate molecule valve due to be outside stimulus response, adapt to various environment, have the most excellent
Gesture and potential.But the most relatively fewer to the research of this controlled fashion, the most a small amount of most base of reported in literature
Isomerization in ultraviolet or visible light-inducing azobenzene molecule realizes.Ultraviolet or visible ray are due to biological tissue's penetrability problem
Application is seriously restricted.
Summary of the invention
The present invention be in order to solve diagnosis and treatment reagent can not the problem of controlled release on time, space and dosage, and carry
A kind of near infrared light has been supplied to excite the preparation method of nuclear shell structure drug carrier of the light-operated release of supermolecule valve.
A kind of near infrared light excites the preparation method of the nuclear shell structure drug carrier of the light-operated release of supermolecule valve specifically by following
Step is carried out:
One, synthesis up-conversion nanoparticles kernel: by NaYF4: Yb/Tm up-conversion nanoparticles is scattered in hexamethylene,
Obtain up-conversion nanoparticles kernel；
The up-conversion nanoparticles of two, synthesis cladding shell: add oleic acid, octadecylene and step one in six chloride hydrate yttriums
The up-conversion nanoparticles kernel obtained, obtains reaction system, by the temperature of reaction system under conditions of argon shield and stirring
Degree from room temperature to 160 DEG C, and under conditions of argon shield and temperature are 160 DEG C stir 1.5h, then by temperature from
160 DEG C naturally cool to 50 DEG C, add mixed liquor A, then stir 0.5h under conditions of argon shield and temperature are 50 DEG C,
Again temperature is warming up to 80 DEG C from 50 DEG C, and under conditions of argon shield and temperature are 80 DEG C, keep 30min, then will be anti-
The temperature answering system is warming up to 300 DEG C from 80 DEG C in 20min, and magnetic force under conditions of argon shield and temperature are 300 DEG C
Stirring 1.5h, after reaction terminates, naturally cools to room temperature by reaction system, uses ethanol to be centrifuged separating as solvent
To solid, solid uses methyl alcohol clean 3～5 times, obtain being coated with the yttrium fluoride natrium nano particle of shell, outside being then coated with
The yttrium fluoride natrium nano particle of shell is scattered in hexamethylene, obtains the yttrium fluoride natrium nanoparticle dispersion liquid of core shell structure；Described
The quality of six chloride hydrate yttriums and the volume ratio of oleic acid are 1mg:(0.03～0.04) mL；The quality of described six chloride hydrate yttriums with
The volume ratio of octadecylene is 1mg:(0.09～0.1) mL；The upper conversion nano grain that described six chloride hydrate yttriums and step one obtain
NaYF in sub-kernel4: the mol ratio of Yb/Tm up-conversion nanoparticles is 1:(1～3)；Described mixed liquor A is to be fluorinated
Ammonium and NaOH are dissolved in methyl alcohol, and wherein the quality of ammonium fluoride is 1mg:(0.06～0.07 with the volume ratio of methyl alcohol) mL,
The quality of NaOH and the volume ratio of methyl alcohol are 1mg:(8～12) mL；Described six chloride hydrate yttriums and fluorine in mixed liquor A
The mol ratio changing ammonium is 1:4；
Three, at up-conversion nanoparticles external sheath mesoporous silicon oxide: cetyl trimethylammonium bromide is added to the water
Wiring solution-forming, the yttrium fluoride natrium nanoparticle dispersion liquid of the core shell structure obtained with step 2 by solution at room temperature stirs after mixing
After mixing 2h, ultrasonic 0.5h, obtains ultrasonic solution, is heated to after ultrasonic solution is transparent using hydrogen under conditions of temperature is 80 DEG C
It is 8～10 that sodium hydroxide solution adjusts the pH of ultrasonic solution, is adjusted the ultrasonic solution after pH, then use peristaltic pump with
The speed of 0.5mL/h adds the tetraethoxysilane ethanol solution that concentration is 20% in the ultrasonic solution after adjusting pH after,
Temperature is reacted after 24h under conditions of being 35 DEG C, by being centrifugally separating to obtain solid, solid uses ethanol purge 3～5 times,
Then in vacuum drying chamber, it is vacuum dried 24h, obtains core-shell structure nanometer particle；Cetyl front three described in step 3
The quality of base ammonium bromide and the volume ratio of water are 1mg:0.04mL；The matter of the cetyl trimethylammonium bromide described in step 3
Amount is 1mg:(0.001～0.005 with the volume ratio of the yttrium fluoride natrium nanoparticle dispersion liquid of core shell structure) mL；
Four, core-shell structure nanometer particle outer surface modifies amino: joined by core-shell structure nanometer particle in dry toluene ultrasonic
Add 3-aminopropyl triethoxysilane after dispersion, obtain reactant liquor, reactant liquor is heated back under conditions of nitrogen is protected
After stream 24h, by being centrifugally separating to obtain solid, solid use methyl alcohol clean 3～5 times, then true in vacuum drying chamber
Empty dry 24h, obtains the core-shell structure nanometer particle of the not removed surfactant that surface amino groups is modified；Described in step 4
The quality of core-shell structure nanometer particle and the volume ratio of dry toluene are 1mg:0.1mL；Core shell structure described in step 4 is received
The quality of rice corpuscles is 1mg:(0.0004～0.0008 with the volume ratio of 3-aminopropyl triethoxysilane) mL；
Five, remove surfactant and formed mesoporous: by the nuclear shell structure nano of the not removed surfactant that surface amino groups is modified
Particle is dispersed in methanol solution, is subsequently adding concentrated hydrochloric acid, after stirring 24h under conditions of temperature is 70 DEG C, by centrifugal
Isolated solid, uses solid methyl alcohol to clean 3～5 times, is then vacuum dried 24h in vacuum drying chamber, obtains appearance
The core-shell structure nanometer particle of amino is modified in face；The core of the not removed surfactant that the surface amino groups described in step 5 is modified
The quality of shell structural nano particle and the volume ratio of methanol solution are 1mg:0.1mL；Surface amino groups described in step 5 is modified
The quality of core-shell structure nanometer particle and the volume ratio of concentrated hydrochloric acid of not removed surfactant be 1mg:
(0.00005～0.0002) mL；
Six, guest molecule is modified at core-shell structure nanometer particle outer surface: outer surface is modified the nuclear shell structure nano grain of amino
Son joins in dichloromethane after ultrasonic disperse, is sequentially added into 1, and 2-naphthoquinones-2-two nitrine-5-sulfonic acid chloride and triethylamine, in room temperature
After lower stirring 24h, by being centrifugally separating to obtain solid, solid use methyl alcohol clean 3～5 times, then at vacuum drying chamber
Interior vacuum drying 24h, obtains modifying the core-shell structure nanometer particle of guest molecule；Outer surface described in step 6 modifies amino
The quality of core-shell structure nanometer particle and the volume ratio of dichloromethane be 1mg:0.1mL；Outer surface described in step 6 is repaiied
The core-shell structure nanometer particle of decorations amino is 1:(0.5～0.7 with the mass ratio of 1,2-naphthoquinones-2-two nitrine-5-sulfonic acid chloride)；Step
It is 1mg with the volume ratio of triethylamine that outer surface described in six modifies the quality of core-shell structure nanometer particle of amino:
(0.001～0.005) mL；
Seven, load ADMh and duct closure: the core-shell structure nanometer particle modifying guest molecule is joined hydrochloric acid Ah
Ultrasonic disperse in the mycin aqueous solution, is then stirred at room temperature 24h, then continues at room temperature to stir after being added thereto to beta-schardinger dextrin
Mixing 60h, reaction terminates rear centrifugation, the PBS cleaning that solids uses pH to be 7.4 3～5 times, then
In vacuum drying chamber, it is vacuum dried 24h, obtains near infrared light and excite the core shell structure medicine of the light-operated release of supermolecule valve to carry
Body；The quality of the core-shell structure nanometer particle modifying guest molecule described in step 7 and the volume of the ADMh aqueous solution
Ratio is 1mg:(0.12～0.15) mL；The core-shell structure nanometer particle modifying guest molecule described in step 7 and beta-schardinger dextrin
Mass ratio be 1:(40～60).
Near infrared light prepared by the present invention excites the application of the nuclear shell structure drug carrier of the light-operated release of supermolecule valve to be the reddest
Outer light excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve to study for external near infrared light Drug controlled release
In, specifically used method is as follows: weighs the nuclear shell structure drug carrier of 2.0mg medicine carrying, is placed at the footing of cuvette,
It is slowly added to 2mL PBS (pH=7.4), it is ensured that nano particle is concentrated static, afterwards with laser pair in corner
60min is irradiated in quasi particle, utilizes the concentration of ultraviolet-visual spectrometer monitoring medicine ADMh every 10min.
Weigh the nuclear shell structure drug carrier of 2.0mg medicine carrying, be placed at the footing of cuvette, be slowly added to 2mL phosphate
Cushioning liquid (pH=7.4), it is ensured that nano particle is concentrated static in corner, afterwards with laser alignment particle with 10min as week
Phase carries out intermittent irradiation release, the concentration of ultraviolet-visual spectrometer monitoring medicine ADMh.
Operation principle:
The present invention utilizes the up-conversion nanoparticles/mesoporous silicon oxide of core shell structure to be situated between as medicine controlled releasing platform, silica
Duct, hole is used for loading cancer therapy drug, modifies near infrared light response supermolecule valve at mesoporous mouth, utilizes biological penetration capacity strong
Near infrared light manipulation molecule valve, it is achieved the light controlled release to medicine.Light-operated mechanism is: host cyclodextrin (macrocycle molecule)
Hydrophobic internal cavities forms complex compound with hydrophobic guest molecules (DNQ) by hydrophobic effect and realizes the closure to mesoporous mouth；At 980nm
Under near infrared light effect, near infrared light is changed into ultraviolet light and near infrared light by up-conversion nano material core, induces supermolecule valve
In Men, the photochemical rearrangement reaction of DNQ, generates hydrophilic product indene carboxylic acid, causes object hydrophobicity to become hydrophily, Subjective and Objective
Originally being destroyed based on hydrophobic complexing, host molecule cyclodextrin is left away, and switch is opened, thus reaches light-operated medicine and release
The purpose put.It addition, near infrared light to have organism penetration capacity strong, little to cellular damage, can external enforcement accurately control
The advantage such as release, utilize near-infrared light source to combine up-conversion and realize one of intelligent response preferred plan.
Beneficial effects of the present invention:
1, present invention design with construct near infrared light based on up-conversion nanoparticles/mesoporous silicon oxide nucleocapsid structure and excite super
The light-operated delivery platforms of molecule valve.At present, near infrared light excites down, makes full use of up-conversion multi-emitting fluorescent belt and excites
Supermolecule valve realizes the document of medication release and has no report.
2, supermolecule valve open first based near infrared light induction object rearrangement reaction, utilize the water miscible sudden change of object break
Bad complexing makes main body leave away, and this process avoids carrying platform and contacts with the direct of stimulus.
3, utilize what near infrared light had to penetrate feature deep, hypotoxic, build in conjunction with up-conversion nanoparticles and there is near-infrared ring
The medicine controlled releasing platform answered, it is achieved regularly, the light-operated insoluble drug release of location, its precision is high, simple to operate.Reported in literature should
Ideal particle diameter for cancer diagnosis and treatment platform should be at below 100nm, to avoid particle with blocking hair during blood body-internal-circulation
Thin blood vessel.Up-conversion nanoparticles prepared by this Platform Designing/mesoporous silicon oxide core-shell structure copolymer diameter of nano particles about 70nm.
Accompanying drawing explanation
Fig. 1 is the transmission that near infrared light prepared by embodiment one excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Electronic Speculum figure；
Fig. 2 is the nitrogen that near infrared light prepared by embodiment one excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Adsorption desorption curve；
Fig. 3 is that near infrared light prepared by embodiment one excites the mesoporous of the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Pore size distribution curve；
Fig. 4 is that the near infrared light that 980nm near-infrared laser excites lower embodiment one to prepare excites the light-operated release of supermolecule valve
The up-conversion fluorescence emission spectrum figure of nuclear shell structure drug carrier；
Fig. 5 is that the near infrared light of embodiment one preparation excites the light-operated release of supermolecule valve before and after 980nm near infrared light
The ultraviolet-visible absorption spectroscopy of nuclear shell structure drug carrier；Wherein 1 for before illumination, and 2 for after illumination；
Fig. 6 is that the near infrared light of embodiment one preparation during different capacity near infrared light excites the light-operated release of supermolecule valve
Nuclear shell structure drug carrier pH value of water solution change curve, wherein 1 be non-illumination embodiment one preparation near infrared light swash
Sending out the nuclear shell structure drug carrier pH value of water solution change curve of the light-operated release of supermolecule valve, 2 near infrared light power are
1W/cm2Time embodiment one preparation near infrared light excite the nuclear shell structure drug carrier aqueous solution of the light-operated release of supermolecule valve
PH value change curve, 3 is 2W/cm near infrared light power2Time embodiment one preparation near infrared light excite supermolecule valve
The nuclear shell structure drug carrier pH value of water solution change curve of light-operated release, 4 is 3W/cm near infrared light power2Time implement
The near infrared light of example one preparation excites the nuclear shell structure drug carrier pH value of water solution change curve of the light-operated release of supermolecule valve；
Fig. 7 is that the near infrared light of embodiment one preparation during different capacity near infrared light excites the light-operated release of supermolecule valve
Nuclear shell structure drug carrier insoluble drug release design sketch, wherein a be non-illumination embodiment one preparation near infrared light excite super
The nuclear shell structure drug carrier drug release patterns of the light-operated release of molecule valve, b be near infrared light power be 1W/cm2Time implement
The near infrared light of example one preparation excites the nuclear shell structure drug carrier drug release patterns of the light-operated release of supermolecule valve, and c is the reddest
Outer luminous power is 2W/cm2Time embodiment one preparation near infrared light excite the core shell structure medicine of the light-operated release of supermolecule valve
Carrier medicament release profiles, d be near infrared light power be 3W/cm2Time embodiment one preparation near infrared light excite supermolecule valve
The nuclear shell structure drug carrier drug release patterns of the light-operated release of door, 1 is illumination stop position；
Fig. 8 be near infrared light power be 2W/cm2Time to embodiment one preparation near infrared light excite the light-operated release of supermolecule valve
Nuclear shell structure drug carrier intermittent irradiation time drug model releasing effect figure, wherein 1 be near-infrared light source close, 2 is near
Infrared light supply is opened.
Detailed description of the invention
Detailed description of the invention one: a kind of near infrared light of present embodiment excites the core shell structure medicine of the light-operated release of supermolecule valve
The preparation method of thing carrier is carried out the most according to the following steps:
One, synthesis up-conversion nanoparticles kernel: by NaYF4: Yb/Tm up-conversion nanoparticles is scattered in hexamethylene,
Obtain up-conversion nanoparticles kernel；
The up-conversion nanoparticles of two, synthesis cladding shell: add oleic acid, octadecylene and step one in six chloride hydrate yttriums
The up-conversion nanoparticles kernel obtained, obtains reaction system, by the temperature of reaction system under conditions of argon shield and stirring
Degree from room temperature to 160 DEG C, and under conditions of argon shield and temperature are 160 DEG C stir 1.5h, then by temperature from
160 DEG C naturally cool to 50 DEG C, add mixed liquor A, then stir 0.5h under conditions of argon shield and temperature are 50 DEG C,
Again temperature is warming up to 80 DEG C from 50 DEG C, and under conditions of argon shield and temperature are 80 DEG C, keep 30min, then will be anti-
The temperature answering system is warming up to 300 DEG C from 80 DEG C in 20min, and magnetic force under conditions of argon shield and temperature are 300 DEG C
Stirring 1.5h, after reaction terminates, naturally cools to room temperature by reaction system, uses ethanol to be centrifuged separating as solvent
To solid, solid uses methyl alcohol clean 3～5 times, obtain being coated with the yttrium fluoride natrium nano particle of shell, outside being then coated with
The yttrium fluoride natrium nano particle of shell is scattered in hexamethylene, obtains the yttrium fluoride natrium nanoparticle dispersion liquid of core shell structure；Described
The quality of six chloride hydrate yttriums and the volume ratio of oleic acid are 1mg:(0.03～0.04) mL；The quality of described six chloride hydrate yttriums with
The volume ratio of octadecylene is 1mg:(0.09～0.1) mL；The upper conversion nano grain that described six chloride hydrate yttriums and step one obtain
NaYF in sub-kernel4: the mol ratio of Yb/Tm up-conversion nanoparticles is 1:(1～3)；Described mixed liquor A is to be fluorinated
Ammonium and NaOH are dissolved in methyl alcohol, and wherein the quality of ammonium fluoride is 1mg:(0.06～0.07 with the volume ratio of methyl alcohol) mL,
The quality of NaOH and the volume ratio of methyl alcohol are 1mg:(8～12) mL；Described six chloride hydrate yttriums and fluorine in mixed liquor A
The mol ratio changing ammonium is 1:4；
Three, at up-conversion nanoparticles external sheath mesoporous silicon oxide: cetyl trimethylammonium bromide is added to the water
Wiring solution-forming, the yttrium fluoride natrium nanoparticle dispersion liquid of the core shell structure obtained with step 2 by solution at room temperature stirs after mixing
After mixing 2h, ultrasonic 0.5h, obtains ultrasonic solution, is heated to after ultrasonic solution is transparent using hydrogen under conditions of temperature is 80 DEG C
It is 8～10 that sodium hydroxide solution adjusts the pH of ultrasonic solution, is adjusted the ultrasonic solution after pH, then use peristaltic pump with
The speed of 0.5mL/h adds the tetraethoxysilane ethanol solution that concentration is 20% in the ultrasonic solution after adjusting pH after,
Temperature is reacted after 24h under conditions of being 35 DEG C, by being centrifugally separating to obtain solid, solid uses ethanol purge 3～5 times,
Then in vacuum drying chamber, it is vacuum dried 24h, obtains core-shell structure nanometer particle；Cetyl front three described in step 3
The quality of base ammonium bromide and the volume ratio of water are 1mg:0.04mL；The matter of the cetyl trimethylammonium bromide described in step 3
Amount is 1mg:(0.001～0.005 with the volume ratio of the yttrium fluoride natrium nanoparticle dispersion liquid of core shell structure) mL；
Four, core-shell structure nanometer particle outer surface modifies amino: joined by core-shell structure nanometer particle in dry toluene ultrasonic
Add 3-aminopropyl triethoxysilane after dispersion, obtain reactant liquor, reactant liquor is heated back under conditions of nitrogen is protected
After stream 24h, by being centrifugally separating to obtain solid, solid use methyl alcohol clean 3～5 times, then true in vacuum drying chamber
Empty dry 24h, obtains the core-shell structure nanometer particle of the not removed surfactant that surface amino groups is modified；Described in step 4
The quality of core-shell structure nanometer particle and the volume ratio of dry toluene are 1mg:0.1mL；Core shell structure described in step 4 is received
The quality of rice corpuscles is 1mg:(0.0004～0.0008 with the volume ratio of 3-aminopropyl triethoxysilane) mL；
Five, remove surfactant and formed mesoporous: by the nuclear shell structure nano of the not removed surfactant that surface amino groups is modified
Particle is dispersed in methanol solution, is subsequently adding concentrated hydrochloric acid, after stirring 24h under conditions of temperature is 70 DEG C, by centrifugal
Isolated solid, uses solid methyl alcohol to clean 3～5 times, is then vacuum dried 24h in vacuum drying chamber, obtains appearance
The core-shell structure nanometer particle of amino is modified in face；The core of the not removed surfactant that the surface amino groups described in step 5 is modified
The quality of shell structural nano particle and the volume ratio of methanol solution are 1mg:0.1mL；Surface amino groups described in step 5 is modified
The quality of core-shell structure nanometer particle and the volume ratio of concentrated hydrochloric acid of not removed surfactant be 1mg:
(0.00005～0.0002) mL；
Six, guest molecule is modified at core-shell structure nanometer particle outer surface: outer surface is modified the nuclear shell structure nano grain of amino
Son joins in dichloromethane after ultrasonic disperse, is sequentially added into 1, and 2-naphthoquinones-2-two nitrine-5-sulfonic acid chloride and triethylamine, in room temperature
After lower stirring 24h, by being centrifugally separating to obtain solid, solid use methyl alcohol clean 3～5 times, then at vacuum drying chamber
Interior vacuum drying 24h, obtains modifying the core-shell structure nanometer particle of guest molecule；Outer surface described in step 6 modifies amino
The quality of core-shell structure nanometer particle and the volume ratio of dichloromethane be 1mg:0.1mL；Outer surface described in step 6 is repaiied
The core-shell structure nanometer particle of decorations amino is 1:(0.5～0.7 with the mass ratio of 1,2-naphthoquinones-2-two nitrine-5-sulfonic acid chloride)；Step
It is 1mg with the volume ratio of triethylamine that outer surface described in six modifies the quality of core-shell structure nanometer particle of amino:
(0.001～0.005) mL；
Seven, load ADMh and duct closure: the core-shell structure nanometer particle modifying guest molecule is joined hydrochloric acid Ah
Ultrasonic disperse in the mycin aqueous solution, is then stirred at room temperature 24h, then continues at room temperature to stir after being added thereto to beta-schardinger dextrin
Mixing 60h, reaction terminates rear centrifugation, the PBS cleaning that solids uses pH to be 7.4 3～5 times, then
In vacuum drying chamber, it is vacuum dried 24h, obtains near infrared light and excite the core shell structure medicine of the light-operated release of supermolecule valve to carry
Body；The quality of the core-shell structure nanometer particle modifying guest molecule described in step 7 and the volume of the ADMh aqueous solution
Ratio is 1mg:(0.12～0.15) mL；The core-shell structure nanometer particle modifying guest molecule described in step 7 and beta-schardinger dextrin
Mass ratio be 1:(40～60).
Temperature is warming up to 80 DEG C from 50 DEG C in step 2 by present embodiment, under conditions of temperature is 80 DEG C, keeps 30min
In purpose be that methyl alcohol is steamed.
Present embodiment heats in step 3 under conditions of temperature is 80 DEG C 0.5h and treats that the transparent purpose of ultrasonic solution is by ring
Hexane steams.
The purpose being stirred at room temperature 24h in present embodiment step 7 is to ensure that drug molecule can be well into mesopore orbit.
The purpose being persistently stirred at room temperature 60h in present embodiment step 7 is to ensure that host molecule can lead to guest molecule
Cross hydrophobic effect to be fully complexed.
The rotating speed of centrifugation described in present embodiment is 10000r/min.
Detailed description of the invention two: present embodiment is unlike detailed description of the invention one: six chloride hydrate described in step 2
The quality of yttrium and the volume ratio of oleic acid are 1mg:0.035mL.Other steps and parameter are identical with detailed description of the invention one.
Detailed description of the invention three: present embodiment is unlike detailed description of the invention one or two: six hydration described in step 2
The quality of yttrium chloride and the volume ratio of octadecylene are 1mg:0.098mL.Other steps and parameter and detailed description of the invention one or two
Identical.
Detailed description of the invention four: present embodiment is unlike one of detailed description of the invention one to three: described in step 2 six
Chloride hydrate yttrium is 1:2 with the mol ratio of up-conversion nanoparticles kernel.Other steps and parameter and detailed description of the invention one to three
One of identical.
Detailed description of the invention five: present embodiment is unlike one of detailed description of the invention one to four: described in step 3
The quality of cetyl trimethylammonium bromide with the volume ratio of the yttrium fluoride natrium nanoparticle dispersion liquid of core shell structure is
1mg:0.003mL.Other steps and parameter are identical with one of detailed description of the invention one to four.
Detailed description of the invention six: present embodiment is unlike one of detailed description of the invention one to five: described in step 4
The quality of core-shell structure nanometer particle is 1mg:0.0006mL with the volume ratio of 3-aminopropyl triethoxysilane.Other steps
And parameter is identical with one of detailed description of the invention one to five.
Detailed description of the invention seven: present embodiment is unlike one of detailed description of the invention one to six: described in step 5
The quality of core-shell structure nanometer particle of the not removed surfactant that surface amino groups is modified with the volume ratio of concentrated hydrochloric acid is
1mg:0.0001mL.Other steps and parameter are identical with one of detailed description of the invention one to six.
Detailed description of the invention eight: present embodiment is unlike one of detailed description of the invention one to seven: described in step 6
It is 1:0.68 that outer surface modifies the core-shell structure nanometer particle of amino with the mass ratio of 1,2-naphthoquinones-2-two nitrine-5-sulfonic acid chloride.Its
His step and parameter are identical with one of detailed description of the invention one to seven.
Detailed description of the invention nine: present embodiment is unlike one of detailed description of the invention one to eight: described in step 6
It is 1mg:0.003mL with the volume ratio of triethylamine that outer surface modifies the quality of core-shell structure nanometer particle of amino.Other steps
And parameter is identical with one of detailed description of the invention one to eight.
Detailed description of the invention ten: present embodiment is unlike one of detailed description of the invention one to nine: described in step 7
Modifying the core-shell structure nanometer particle of guest molecule with the mass ratio of beta-schardinger dextrin is 1:50.Other steps and parameter are real with concrete
Execute one of mode one to nine identical.
By following example checking beneficial effects of the present invention:
Embodiment one: a kind of near infrared light of the present embodiment excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Preparation method is carried out the most according to the following steps:
One, by six chloride hydrate yttriums (210.8mg, 0.695mmoL), six hydrous ytterbium chlorides (116.2mg, 0.3mmoL)
Join in three neck round bottom flask with six hydrous thulium chlorides (1.9mg, 0.005mmoL), be subsequently adding 6mL oleic acid and 5mL
Octadecylene；In the case of logical argon gas, stir the mixture for and be heated to 160 DEG C and keep 30min, add 10mL subsequently
Octadecylene, mixture naturally cools to 50 DEG C after stirring 1.5h under conditions of temperature is 160 DEG C；10mL is added in mixture
The ammonium fluoride (148.2mg, 4mmoL) that methyl alcohol dissolves and NaOH (100mg, 2.5mmoL) solution, keep 50 DEG C
Stirring 30min nucleation, boils off methyl alcohol under conditions of temperature is 80 DEG C afterwards, mixture is heated in 20min 300 DEG C
And keep 1h under magnetic stirring, after reaction terminates, mixture is down to naturally room temperature, adds ethanol, product centrifuge
It is centrifuged under 10000 turns, uses ethanol purge solid, this process 3 times repeatedly；The NaYF finally obtained4: Yb/Tm is upper to be turned
Change nano particle to be distributed in 10mL hexamethylene, obtain up-conversion nanoparticles core；
The up-conversion nanoparticles of two, synthesis cladding shell: add in six chloride hydrate yttriums (151.7mg, 0.5mmoL)
6mL oleic acid, 15mL octadecylene and up-conversion nanoparticles kernel, obtain reaction system, in argon shield and the condition of stirring
Lower by the temperature of reaction system from room temperature to 160 DEG C, and under conditions of argon shield and temperature are 160 DEG C stir 1.5h,
Then temperature is naturally cooled to 50 DEG C from 160 DEG C, add mixed liquor A, be then 50 DEG C in argon shield and temperature
Under the conditions of stir 0.5h, then temperature is warming up to 80 DEG C from 50 DEG C, and keeps under conditions of argon shield and temperature are 80 DEG C
30min, is then warming up to 300 DEG C from 80 DEG C by the temperature of reaction system in 20min, and in argon shield and temperature is
Magnetic agitation 1.5h under conditions of 300 DEG C, after reaction terminates, naturally cools to room temperature by reaction system, uses ethanol as molten
Agent is centrifuged isolated solid, and solid uses methyl alcohol clean 3～5 times, obtains being coated with the yttrium fluoride natrium nanoparticle of shell
Son, is then scattered in the yttrium fluoride natrium nano particle of cladding shell in 10mL hexamethylene, obtains the yttrium fluoride of core shell structure
Sodium nanoparticle dispersion liquid；Described mixed liquor A be by ammonium fluoride (74.1mg, 2mmol) and NaOH (50mg,
1.25mmol) it is dissolved in 5mL methyl alcohol；Described six chloride hydrate yttriums and NaYF in up-conversion nanoparticles kernel4: Yb/Tm
The mol ratio of up-conversion nanoparticles is 1:(1～3)；
Three, at up-conversion nanoparticles external sheath mesoporous silicon oxide: 200mg cetyl trimethylammonium bromide is added
Wiring solution-forming in 8mL water, in room temperature after mixing the yttrium fluoride natrium nanoparticle dispersion liquid of solution and 600 μ L core shell structures
Ultrasonic 0.5h after lower stirring 2h, obtains ultrasonic solution, is heated to after ultrasonic solution is transparent adopting under conditions of temperature is 80 DEG C
The pH adjusting ultrasonic solution with sodium hydroxide solution is 8～10, is adjusted the ultrasonic solution after pH, then uses peristaltic pump
It is molten so that the speed of the 0.5mL/h ultrasonic solution after adjusting pH to add the tetraethoxysilane ethanol that 1.5mL concentration is 20%
After liquid, after reacting 24h under conditions of temperature is 35 DEG C, by being centrifugally separating to obtain solid, solid is used ethanol purge
3～5 times, in vacuum drying chamber, then it is vacuum dried 24h, obtains core-shell structure nanometer particle；
Four, core-shell structure nanometer particle outer surface modify amino: 100mg core-shell structure nanometer particle is joined 10mL without
Water-toluene adds after ultrasonic disperse 60 μ L 3-aminopropyl triethoxysilanes, obtains reactant liquor, reactant liquor is protected at nitrogen
After being heated to reflux 24h under conditions of protecting, by being centrifugally separating to obtain solid, solid is used methyl alcohol cleaning 3～5 times, then
In vacuum drying chamber, it is vacuum dried 24h, obtains the nuclear shell structure nano grain of the not removed surfactant that surface amino groups is modified
Son；
Five, remove surfactant and formed mesoporous: the nucleocapsid knot of the not removed surfactant that 100mg surface amino groups is modified
Structure nano particle is dispersed in 10mL methanol solution, is subsequently adding 100 μ L concentrated hydrochloric acids, stirs under conditions of temperature is 70 DEG C
After mixing 24h, by being centrifugally separating to obtain solid, solid use methyl alcohol clean 3～5 times, then true in vacuum drying chamber
Empty dry 24h, obtains outer surface and modifies the core-shell structure nanometer particle of amino；
Six, guest molecule is modified at core-shell structure nanometer particle outer surface: 100mg outer surface is modified the core shell structure of amino
Nano particle joins in 10mL dichloromethane after ultrasonic disperse, is sequentially added into 68mg 1,2-naphthoquinones-2-two nitrine-5-sulfonic acid chloride
With 0.3mL triethylamine, after being stirred at room temperature 24h, by being centrifugally separating to obtain solid, solid use methyl alcohol clean 3～5
Secondary, in vacuum drying chamber, then it is vacuum dried 24h, obtains modifying the core-shell structure nanometer particle of guest molecule；
Seven, load ADMh and duct closure: the core-shell structure nanometer particle that 30mg modifies guest molecule joins
4mL concentration be 0.5mg/mL the ADMh aqueous solution in ultrasonic disperse, be then stirred at room temperature 24h, more wherein
Persistently being stirred at room temperature 60h after adding 150mg beta-schardinger dextrin, reaction terminates rear centrifugation, and solids uses pH to be 7.4
PBS clean 3～5 times, then in vacuum drying chamber be vacuum dried 24h, obtain near infrared light and excite oversubscription
The nuclear shell structure drug carrier of the light-operated release of sub-valve.
Fig. 1 is the transmission that near infrared light prepared by embodiment one excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Electronic Speculum figure；Near infrared light excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve to have size as can be seen from Figure 1
Homogeneous nucleocapsid structure, in monodisperse status, after mesoporous silicon sphere cladding, the size of nano particle is about 70nm.
Fig. 2 is the nitrogen that near infrared light prepared by embodiment one excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Adsorption desorption curve；Fig. 3 is that the near infrared light of embodiment one preparation excites the core shell structure medicine of the light-operated release of supermolecule valve to carry
The mesoporous pore size distribution curve of body；The existence of nitrogen adsorption desorption higher-pressure region hysteresis loop shows to close as can be seen from Figures 2 and 3
It is mesoporous for becoming material, and aperture is at about 2.3nm.Mesoporous can be used to load medicine, surface can modify supermolecule valve further,
For near infrared light Drug controlled release.
Fig. 4 is that the near infrared light that 980nm near-infrared laser excites lower embodiment one to prepare excites the light-operated release of supermolecule valve
The up-conversion fluorescence emission spectrum figure of nuclear shell structure drug carrier；As can be seen from the figure under the exciting of 980nm laser instrument,
Near infrared light excite the light-operated release of supermolecule valve nuclear shell structure drug carrier produce three wave bands luminescence, respectively 365
Nm ultraviolet light, 450nm visible ray and 800nm near infrared light, wherein ultraviolet light and near infrared light are used for exciting supermolecule valve
Door is controlled release to medicine.
Fig. 5 is that the near infrared light of embodiment one preparation excites the light-operated release of supermolecule valve before and after 980nm near infrared light
The ultraviolet-visible absorption spectroscopy of nuclear shell structure drug carrier；Wherein 1 for before illumination, and 2 for after illumination；As can be seen from the figure exist
After 980nm near infrared light, near infrared light excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve at 330nm
Almost disappear with ultraviolet and visible absorption peak at 399nm, it was demonstrated that the ultraviolet of upper conversion nano core or near infrared emission fluorescence induction core
-core/shell nanoparticles surface guest molecule there occurs photochemical reaction.
Fig. 6 is that the near infrared light of embodiment one preparation during different capacity near infrared light excites the light-operated release of supermolecule valve
Nuclear shell structure drug carrier pH value of water solution change curve, wherein 1 be non-illumination embodiment one preparation near infrared light swash
Sending out the nuclear shell structure drug carrier pH value of water solution change curve of the light-operated release of supermolecule valve, 2 near infrared light power are
1W/cm2Time embodiment one preparation near infrared light excite the nuclear shell structure drug carrier aqueous solution of the light-operated release of supermolecule valve
PH value change curve, 3 is 2W/cm near infrared light power2Time embodiment one preparation near infrared light excite supermolecule valve
The nuclear shell structure drug carrier pH value of water solution change curve of light-operated release, 4 is 3W/cm near infrared light power2Time implement
The near infrared light of example one preparation excites the nuclear shell structure drug carrier pH value of water solution change curve of the light-operated release of supermolecule valve；
As can be seen from the figure, after 980nm near infrared light, near infrared light excites the core shell structure of the light-operated release of supermolecule valve
Pharmaceutical carrier pH value of water solution is decreased obviously, it was demonstrated that the ultraviolet of upper conversion nano core or its surface of near infrared emission fluorescence induction
DNQ molecule there occurs photochemical reaction, generates hydrophilic product indene carboxylic acid, and the water solubility of object is become hydrophilic from hydrophobic；Phase
With in the time, laser power is the biggest, and pH value changes the most greatly, shows that DNQ molecular photochemistry reaction rate increases with laser power
Add and increase.
Embodiment two: 3.0Wcm-2Light-operated insoluble drug release under power density near-infrared laser continuous 60min irradiation:
The near infrared light that weighing 2.0mg embodiment one obtains excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve,
It is placed at the footing of cuvette, is slowly added to 2mL PBS (pH=7.4), it is ensured that nano particle is in corner
Concentrate static, carry out Continuous irradiation 60min with laser alignment particle afterwards, utilize ultraviolet-visual spectrometer tracking and testing medicine
The concentration of ADMh, obtains Cumulative release amount versus time curve, it was demonstrated that light-operated insoluble drug release.Weigh 2.0 equally
The near infrared light that mg embodiment one obtains excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve to carry out in the dark
Blank puts medicine experiment, adds 2mL PBS (pH=7.4), and ultraviolet-visual spectrometer takes identical time interval
Measure the change in concentration of medicine.
Embodiment three: 2Wcm-2Light-operated insoluble drug release under power density near-infrared laser continuous 60min irradiation: operated
Journey is identical with embodiment two.
Fig. 7 is that the near infrared light of embodiment one preparation during different capacity near infrared light excites the light-operated release of supermolecule valve
Nuclear shell structure drug carrier insoluble drug release design sketch, wherein a be non-illumination embodiment one preparation near infrared light excite super
The nuclear shell structure drug carrier drug release patterns of the light-operated release of molecule valve, b be near infrared light power be 1W/cm2Time implement
The near infrared light of example one preparation excites the nuclear shell structure drug carrier drug release patterns of the light-operated release of supermolecule valve, and c is the reddest
Outer luminous power is 2W/cm2Time embodiment one preparation near infrared light excite the core shell structure medicine of the light-operated release of supermolecule valve
Carrier medicament release profiles, d be near infrared light power be 3W/cm2Time embodiment one preparation near infrared light excite supermolecule valve
The nuclear shell structure drug carrier drug release patterns of the light-operated release of door, 1 is illumination stop position；As can be seen from the figure there is no light
According to control group (curve a), does not the most put medicine, illustrates that supermolecule valve effectively blocks duct.When irradiating with near-infrared laser
After, all curves show accumulative insoluble drug release, increase substantially, illustrate under near infrared light, and object photochemical rearrangement reacts
Causing beta-schardinger dextrin to be left away, supermolecule valve is opened, insoluble drug release.Along with the increase of laser power density, medicine
Burst size is gradually increased, and shows that this system can be by regulation laser power size, the accurately release of regulating medicine.Work as illumination
After stopping, insoluble drug release stops (in Fig. 7 after 60min) the most therewith, shows that this system has sensitivity to the switch of light source
Response.
Embodiment four: 2.0Wcm-2Light-operated insoluble drug release under power density near-infrared laser 10min cycle intermittent irradiation:
The near infrared light that weighing 2.0mg embodiment one obtains excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve,
It is placed at the footing of cuvette, is slowly added to 2mL PBS (pH=7.4), it is ensured that nano particle is in corner
Concentrating static, carry out intermittent irradiation release with 10min for the cycle with laser alignment particle afterwards, ultraviolet-visual spectrometer is monitored
The concentration of medicine ADMh.
Fig. 8 be near infrared light power be 2W/cm2Time to embodiment one preparation near infrared light excite the light-operated release of supermolecule valve
Nuclear shell structure drug carrier intermittent irradiation time drug model releasing effect figure, wherein 1 be near-infrared light source close, 2 is near
Infrared light supply is opened；As can be seen from the figure near infrared light excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve can be
The accurate release of medicine is realized under the double mode regulation and control of laser power size and light source switch.This is for the biocycle of reply complexity
Border, raising therapeutic efficiency and minimizing toxic and side effect have great importance.
Claims (10)
1. near infrared light excites the preparation method of nuclear shell structure drug carrier for the light-operated release of supermolecule valve, and its feature exists
The preparation method exciting the nuclear shell structure drug carrier of the light-operated release of supermolecule valve near infrared light is entered the most according to the following steps
Row:
One, synthesis up-conversion nanoparticles kernel: by NaYF4: Yb/Tm up-conversion nanoparticles is scattered in hexamethylene,
Obtain up-conversion nanoparticles kernel；
The up-conversion nanoparticles of two, synthesis cladding shell: add oleic acid, octadecylene and step one in six chloride hydrate yttriums
The up-conversion nanoparticles kernel obtained, obtains reaction system, by the temperature of reaction system under conditions of argon shield and stirring
Degree from room temperature to 160 DEG C, and under conditions of argon shield and temperature are 160 DEG C stir 1.5h, then by temperature from
160 DEG C naturally cool to 50 DEG C, add mixed liquor A, then stir 0.5h under conditions of argon shield and temperature are 50 DEG C,
Again temperature is warming up to 80 DEG C from 50 DEG C, and under conditions of argon shield and temperature are 80 DEG C, keep 30min, then will
The temperature of reaction system is warming up to 300 DEG C from 80 DEG C in 20min, and under conditions of argon shield and temperature are 300 DEG C
Magnetic agitation 1.5h, after reaction terminates, naturally cools to room temperature by reaction system, uses ethanol to be centrifuged point as solvent
From obtaining solid, solid uses methyl alcohol clean 3～5 times, obtain being coated with the yttrium fluoride natrium nano particle of shell, then will bag
The yttrium fluoride natrium nano particle covering shell is scattered in hexamethylene, obtains the yttrium fluoride natrium nanoparticle dispersion liquid of core shell structure；
The described quality of six chloride hydrate yttriums and the volume ratio of oleic acid are 1mg:(0.03～0.04) mL；Described six chloride hydrate yttriums
Quality is 1mg:(0.09～0.1 with the volume ratio of octadecylene) mL；The upper conversion that described six chloride hydrate yttriums obtain with step one
NaYF in nano particle kernel4: the mol ratio of Yb/Tm up-conversion nanoparticles is 1:(1～3)；Described mixed liquor A be by
Ammonium fluoride and NaOH are dissolved in methyl alcohol, and wherein the quality of ammonium fluoride is 1mg:(0.06～0.07 with the volume ratio of methyl alcohol)
ML, the quality of NaOH and the volume ratio of methyl alcohol are 1mg:(8～12) mL；Described six chloride hydrate yttrium and mixed liquor A
The mol ratio of middle ammonium fluoride is 1:4；
Three, at up-conversion nanoparticles external sheath mesoporous silicon oxide: cetyl trimethylammonium bromide is added to the water
Wiring solution-forming, the yttrium fluoride natrium nanoparticle dispersion liquid of the core shell structure obtained with step 2 by solution at room temperature stirs after mixing
After mixing 2h, ultrasonic 0.5h, obtains ultrasonic solution, is heated to after ultrasonic solution is transparent using under conditions of temperature is 80 DEG C
It is 8～10 that sodium hydroxide solution adjusts the pH of ultrasonic solution, is adjusted the ultrasonic solution after pH, then uses peristaltic pump
After the speed of the 0.5mL/h ultrasonic solution after adjusting pH to add the tetraethoxysilane ethanol solution that concentration is 20%,
React after 24h under conditions of temperature is 35 DEG C, by being centrifugally separating to obtain solid, solid used ethanol purge 3～5 times,
Then in vacuum drying chamber, it is vacuum dried 24h, obtains core-shell structure nanometer particle；Cetyl three described in step 3
The quality of methyl bromide ammonium and the volume ratio of water are 1mg:0.04mL；Cetyl trimethylammonium bromide described in step 3
Quality is 1mg:(0.001～0.005 with the volume ratio of the yttrium fluoride natrium nanoparticle dispersion liquid of core shell structure) mL；
Four, core-shell structure nanometer particle outer surface modifies amino: joined by core-shell structure nanometer particle in dry toluene ultrasonic
Add 3-aminopropyl triethoxysilane after dispersion, obtain reactant liquor, reactant liquor is heated back under conditions of nitrogen is protected
After stream 24h, by being centrifugally separating to obtain solid, solid use methyl alcohol clean 3～5 times, then true in vacuum drying chamber
Empty dry 24h, obtains the core-shell structure nanometer particle of the not removed surfactant that surface amino groups is modified；Described in step 4
The quality of core-shell structure nanometer particle and the volume ratio of dry toluene be 1mg:0.1mL；Core shell structure described in step 4
The quality of nano particle is 1mg:(0.0004～0.0008 with the volume ratio of 3-aminopropyl triethoxysilane) mL；
Five, remove surfactant and formed mesoporous: by the nuclear shell structure nano of the not removed surfactant that surface amino groups is modified
Particle is dispersed in methanol solution, is subsequently adding concentrated hydrochloric acid, after stirring 24h under conditions of temperature is 70 DEG C, by centrifugal
Isolated solid, uses solid methyl alcohol to clean 3～5 times, is then vacuum dried 24h in vacuum drying chamber, outside obtaining
The core-shell structure nanometer particle of amino is modified on surface；The not removed surfactant that surface amino groups described in step 5 is modified
The quality of core-shell structure nanometer particle and the volume ratio of methanol solution are 1mg:0.1mL；Surface amino groups described in step 5 is repaiied
The quality of core-shell structure nanometer particle of the not removed surfactant of decorations and the volume ratio of concentrated hydrochloric acid are 1mg:
(0.00005～0.0002) mL；
Six, guest molecule is modified at core-shell structure nanometer particle outer surface: outer surface is modified the nuclear shell structure nano grain of amino
Son joins in dichloromethane after ultrasonic disperse, is sequentially added into 1, and 2-naphthoquinones-2-two nitrine-5-sulfonic acid chloride and triethylamine, in room temperature
After lower stirring 24h, by being centrifugally separating to obtain solid, solid use methyl alcohol clean 3～5 times, then at vacuum drying chamber
Interior vacuum drying 24h, obtains modifying the core-shell structure nanometer particle of guest molecule；Outer surface described in step 6 modifies ammonia
The quality of the core-shell structure nanometer particle of base and the volume ratio of dichloromethane are 1mg:0.1mL；Outer surface described in step 6
Modifying the core-shell structure nanometer particle of amino with the mass ratio of 1,2-naphthoquinones-2-two nitrine-5-sulfonic acid chloride is 1:(0.5～0.7)；Step
It is 1mg with the volume ratio of triethylamine that outer surface described in rapid six modifies the quality of core-shell structure nanometer particle of amino:
(0.001～0.005) mL；
Seven, load ADMh and duct closure: the core-shell structure nanometer particle modifying guest molecule is joined hydrochloric acid Ah
Ultrasonic disperse in the mycin aqueous solution, is then stirred at room temperature 24h, then continues at room temperature after being added thereto to beta-schardinger dextrin
Stirring 60h, reaction terminates rear centrifugation, the PBS cleaning that solids uses pH to be 7.4 3～5 times, so
After in vacuum drying chamber be vacuum dried 24h, obtain near infrared light and excite the core shell structure medicine of the light-operated release of supermolecule valve
Carrier；The quality of the core-shell structure nanometer particle modifying guest molecule described in step 7 and the body of the ADMh aqueous solution
Long-pending ratio is 1mg:(0.12～0.15) mL；The core-shell structure nanometer particle modifying guest molecule described in step 7 and β-ring
The mass ratio of dextrin is 1:(40～60).
A kind of near infrared light the most according to claim 1 excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Preparation method, it is characterised in that described in step 2, the quality of six chloride hydrate yttriums with the volume ratio of oleic acid is
1mg:0.035mL。
A kind of near infrared light the most according to claim 1 excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Preparation method, it is characterised in that described in step 2, the quality of six chloride hydrate yttriums with the volume ratio of octadecylene is
1mg:0.098mL。
A kind of near infrared light the most according to claim 1 excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Preparation method, it is characterised in that the up-conversion nanoparticles kernel that described in step 2, six chloride hydrate yttriums and step one obtain
Mol ratio be 1:2.
A kind of near infrared light the most according to claim 1 excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Preparation method, it is characterised in that the nucleocapsid that the quality of cetyl trimethylammonium bromide described in step 3 and step 2 obtain
The volume ratio of the yttrium fluoride natrium nanoparticle dispersion liquid of structure is 1mg:0.003mL.
A kind of near infrared light the most according to claim 1 excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Preparation method, it is characterised in that the quality of the core-shell structure nanometer particle that the step 3 described in step 4 obtains and 3-ammonia third
The volume ratio of ethyl triethoxy silicane alkane is 1mg:0.0006mL.
A kind of near infrared light the most according to claim 1 excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Preparation method, it is characterised in that the not removed surfactant that surface amino groups that step 4 described in step 5 obtains is modified
The quality of core-shell structure nanometer particle and the volume ratio of concentrated hydrochloric acid are 1mg:0.0001mL.
A kind of near infrared light the most according to claim 1 excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Preparation method, it is characterised in that outer surface that the described step 5 described in step 6 obtains is modified the core shell structure of amino and is received
Rice corpuscles is 1:0.68 with the mass ratio of 1,2-naphthoquinones-2-two nitrine-5-sulfonic acid chloride.
A kind of near infrared light the most according to claim 1 excites the nuclear shell structure drug carrier of the light-operated release of supermolecule valve
Preparation method, it is characterised in that outer surface that the step 5 described in step 6 obtains modifies the nuclear shell structure nano grain of amino
The quality of son is 1mg:0.003mL with the volume ratio of triethylamine.
A kind of near infrared light the most according to claim 1 excites the core shell structure medicine of the light-operated release of supermolecule valve to carry
The preparation method of body, it is characterised in that the core-shell structure nanometer particle modifying guest molecule that step 6 described in step 7 obtains
It is 1:50 with the mass ratio of beta-schardinger dextrin.
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| CN106634957A (en) * | 2016-12-14 | 2017-05-10 | 上海交通大学 | Surface modification method of up-conversion nano material |
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| CN108096586A (en) * | 2017-12-05 | 2018-06-01 | 上海大学 | Double-bang firecracker based on manganese dioxide modification answers preparation method, product and the application of drug delivery system |
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| CN106893055B (en) * | 2017-03-15 | 2019-02-01 | 北京科技大学 | A kind of preparation and its application with quadruple responsiveness block copolymer |
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| CN113777100B (en) * | 2021-08-27 | 2022-11-01 | 厦门大学 | Quantitative substance controlled release system and method based on host-guest action |
| CN113927027A (en) * | 2021-09-16 | 2022-01-14 | 福建医科大学孟超肝胆医院(福州市传染病医院) | Near-infrared region-excited rare earth nanocrystal loaded with viroid hollow manganese oxide and preparation method and application thereof |
| CN113975411A (en) * | 2021-11-01 | 2022-01-28 | 哈尔滨工程大学 | Preparation method of near-infrared light response up-conversion mesoporous tin dioxide diagnosis and treatment nanocapsule |
| CN113975411B (en) * | 2021-11-01 | 2023-02-03 | 哈尔滨工程大学 | Preparation method of near-infrared light response up-conversion mesoporous tin dioxide diagnosis and treatment nanocapsule |
| CN115197689A (en) * | 2022-07-06 | 2022-10-18 | 河南理工大学 | Functionalized up-conversion nanoparticles of photooxidized protein and preparation method and application thereof |
| CN115197689B (en) * | 2022-07-06 | 2024-05-10 | 河南理工大学 | Functionalized up-conversion nanoparticle of photo-oxidized protein, and preparation method and application thereof |
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