CN105903016B - A kind of preparation method of the nuclear shell structure drug carrier of the near infrared light excitation light-operated drug release of supermolecule valve - Google Patents
A kind of preparation method of the nuclear shell structure drug carrier of the near infrared light excitation light-operated drug release of supermolecule valve Download PDFInfo
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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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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- A61K9/141—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
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- 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
A kind of preparation method of the nuclear shell structure drug carrier of the near infrared light excitation light-operated drug release of supermolecule valve.The invention belongs to biomedical materials fields, and in particular to a kind of preparation method of the nuclear shell structure drug carrier of the near infrared light excitation light-operated drug release of supermolecule valve.The present invention is to solve the problems, such as that diagnosis and treatment reagent can not be in the controllable release on time, space and dosage.Method: one, up-conversion nanoparticles kernel is synthesized；Two, the up-conversion nanoparticles of synthesis cladding shell；Three, in up-conversion nanoparticles external sheath mesoporous silicon oxide；Four, amino is modified in core-shell structure nanometer particle outer surface；Five, removal surfactant is formed mesoporous；Six, guest molecule is modified in core-shell structure nanometer particle outer surface；Seven, it loads doxorubicin hydrochloride and duct blocks.The present invention is in treatment of cancer, realizing anticancer drug in tumor tissues timing and quantitative controlled release.
Description
Technical field
The invention belongs to biomedical materials fields, and in particular to a kind of near infrared light excitation light-operated drug release of supermolecule valve
Nuclear shell structure drug carrier preparation method.
Background technique
With the fast development of nanosecond medical science, design and building intelligent response type nano molecular valve treatment of cancer platform will
It is transported to anticancer drug No leakage cancerous tissue, in lesions position enrichment and controlled release, it has also become nanometer medical science is important
Developing direction.Currently, the environmental stimuli intelligent response mode for being used to open molecule valve mainly has: pH, redox, enzyme, light, heat
Etc. several.Wherein pH, redox, enzyme response are internal controlled release, and response sensitivity is poor, it is difficult to accuracy controlling.Photoresponse system
Because having the characteristics that external controlled release, it is high in response to sensitivity and can by optical wavelength, power and light application time accuracy controlling by
Favor.But visible light and ultraviolet light are because its penetration power is weak and may cause the factors such as damage to cell tissue, in practical applications
It is restricted.
Near infrared light (700~900nm of wavelength) is because have deeper biological tissue's penetration capacity and extremely low biology
Illumination damage is particularly suitable for building photoresponse type controlled drug delivery systems.Rear-earth-doped up-conversion luminescence nanoparticle, can be close red
Under the excitation of outer light, generate multiband it is ultraviolet/transmitting in visible/near infrared region, (wherein a certain band of light is for being imaged,
Its band of light is for treating), therefore key player has been played in nanometer medical science photochemical reaction.Currently based on upper conversion
Nano material/mesoporous silicon oxide nucleocapsid structure design medicine controlled release platform is a recent studies on of cancer nanometer treatment technology
Hot spot, it is using up-conversion nanoparticles as core, and external sheath mesoporous silicon oxide is the core-shell structure of shell, and mesoporous inside is for filling
Carry drug.Under the irradiation of near infrared light, the strong energy of up-conversion nanoparticles organism-absorbing penetration power being phagocytized by cells is low
Near infrared light and on be converted to the high various photochemical reactions of UV light-induced excitation of energy, to reach the mesh for the treatment of of cancer
's.It is based on up-conversion nano material/mesoporous silicon oxide nucleocapsid structure near infrared light response medicine controlled releasing advantage: real
The deep tissues for having showed light penetrate light-operated excitation, and it is shallow to avoid ultraviolet light direct irradiation penetration depth, injure to biological tissue big
The shortcomings that.
The core key technology of intelligent response type nano molecular valve cancer diagnosis and treatment platform is medicine controlled releasing valve switch
Design.Macrocycle molecule main body with certain guest molecules due to that can be assembled into higher volume of supermolecule " Host-guest "
Complex compound blocks mesoporous silicon oxide duct (2~4nm of diameter), therefore can be used as the super of intelligent response type controlled drug delivery systems
Molecule valve.These valves mesoporous silicon oxide carrying platform implement medicine controlled releasing mechanism there are mainly two types of: 1, using pH,
The effects of enzyme, glutathione, causes to connect the chemical bond rupture between main body or object and silicon ball, and complex compound of blocking up is left away, valve
It opens；2, using heat, pH separates Subjective and Objective, complex compound dissociation with competition reagent or photoresponse, and nano-valve is opened.
Wherein photoresponse complex compound dissociation molecule valve due to be outside stimulus response, adapt to various environment, have compared with
Big advantage and potential.But on the one hand relatively fewer to the research of this controlled fashion at present, on the other hand a small amount of reported in literature is big
Mostly realized based on ultraviolet or visible light-inducing azobenzene molecule isomerization.Ultraviolet or visible light is due to biological tissue's penetrability
Problem is applied and is seriously restricted.
Summary of the invention
The present invention be in order to solve the problems, such as diagnosis and treatment reagent can not in the controllable release on time, space and dosage,
And provide a kind of preparation method of the nuclear shell structure drug carrier of near infrared light excitation light-operated drug release of supermolecule valve.
A kind of preparation method of the nuclear shell structure drug carrier of the near infrared light excitation light-operated drug release of supermolecule valve is specifically
It carries out according to the following steps:
One, up-conversion nanoparticles kernel is synthesized: by NaYF4: Yb/Tm up-conversion nanoparticles are scattered in hexamethylene,
Obtain up-conversion nanoparticles kernel；
Two, oleic acid, octadecylene and step the up-conversion nanoparticles of synthesis cladding shell: are added into six chloride hydrate yttriums
One obtained up-conversion nanoparticles kernel, obtains reaction system, by reaction system under conditions of argon gas is protected and is stirred
Temperature from room temperature to 160 DEG C, and argon gas protection and temperature be 160 DEG C under conditions of 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 gas protection and temperature are 50 DEG C,
Temperature is warming up to 80 DEG C from 50 DEG C again, and keeps 30min under conditions of argon gas protection and temperature are 80 DEG C, it then will reaction
The temperature of system is warming up to 300 DEG C in 20min from 80 DEG C, and magnetic force stirs under conditions of argon gas protection and temperature are 300 DEG C
1.5h is mixed, after reaction, by reaction system cooled to room temperature, is centrifuged and is consolidated as solvent using ethyl alcohol
Solid is cleaned 3~5 times using methanol, obtains the yttrium fluoride natrium nanoparticle of cladding shell, then will coat the fluorine of shell by body
Change yttrium sodium nanoparticle to be scattered in hexamethylene, obtains the yttrium fluoride natrium nanoparticle dispersion liquid of core-shell structure；Six hydration
The quality of yttrium chloride and the volume ratio of oleic acid are 1mg:(0.03~0.04) mL；The quality and octadecylene of the six chloride hydrates yttrium
Volume ratio be 1mg:(0.09~0.1) mL；The up-conversion nanoparticles kernel that the six chloride hydrates yttrium and step 1 obtain
Middle NaYF4: the molar ratio of Yb/Tm up-conversion nanoparticles is 1:(1~3)；The mixed liquor A is by ammonium fluoride and sodium hydroxide
In methyl alcohol, wherein the quality of ammonium fluoride and the volume ratio of methanol are 1mg:(0.06~0.07 for dissolution) mL, the matter of sodium hydroxide
Amount and the volume ratio of methanol are 1mg:(8~12) mL；The molar ratio of ammonium fluoride is 1 in the six chloride hydrates yttrium and mixed liquor A:
4；
Three, in up-conversion nanoparticles external sheath mesoporous silicon oxide: cetyl trimethylammonium bromide is added to
Wiring solution-forming in water, in room temperature after the yttrium fluoride natrium nanoparticle dispersion liquid for the core-shell structure that solution and step 2 obtain is mixed
Ultrasound 0.5h, obtains ultrasonic solution after lower stirring 2h, is heated to adopting after ultrasonic solution is transparent under conditions of temperature is 80 DEG C
PH with sodium hydroxide solution adjustment ultrasonic solution is 8~10, ultrasonic solution after being adjusted pH, then use peristaltic pump with
After the tetraethoxysilane ethanol solution that concentration is 20% is added into the ultrasonic solution after adjustment pH in the speed of 0.5mL/h,
After temperature is reacted for 24 hours under conditions of being 35 DEG C, by being centrifugally separating to obtain solid, by solid using ethyl alcohol cleaning 3~5 times, so
It is dried in vacuo in vacuum oven afterwards for 24 hours, obtains core-shell structure nanometer particle；Cetyl trimethyl described in step 3
The quality of ammonium bromide and the volume ratio of water are 1mg:0.04mL；The quality of cetyl trimethylammonium bromide described in step 3
Volume ratio with the yttrium fluoride natrium nanoparticle dispersion liquid of core-shell structure is 1mg:(0.001~0.005) mL；
Four, amino is modified in core-shell structure nanometer particle outer surface: core-shell structure nanometer particle is added in dry toluene
3- aminopropyl triethoxysilane is added after ultrasonic disperse, obtains reaction solution, and reaction solution is added under conditions of nitrogen protection
After heat reflux for 24 hours, by being centrifugally separating to obtain solid, solid is cleaned 3~5 times using methanol, then in vacuum oven
Vacuum drying for 24 hours, obtains the core-shell structure nanometer particle for not removing surfactant of surface amino groups modification；Described in step 4
Core-shell structure nanometer particle quality and dry toluene volume ratio be 1mg:0.1mL；Core-shell structure described in step 4
The quality of nanoparticle and the volume ratio of 3- aminopropyl triethoxysilane are 1mg:(0.0004~0.0008) mL；
Five, removal surfactant is formed mesoporous: the core-shell structure for not removing surfactant that surface amino groups are modified
Nanoparticle is dispersed in methanol solution, and concentrated hydrochloric acid is then added, temperature be 70 DEG C under conditions of stir for 24 hours after, by from
Solid is cleaned 3~5 times using methanol, is then dried in vacuo in vacuum oven for 24 hours, obtained outer by the isolated solid of the heart
The core-shell structure nanometer particle of surface modification amino；The modification of surface amino groups described in step 5 does not remove surfactant
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 are repaired
Decorations the core-shell structure nanometer particle for not removing surfactant quality and concentrated hydrochloric acid volume ratio be 1mg:(0.00005~
0.0002)mL；
Six, guest molecule is modified in core-shell structure nanometer particle outer surface: the core-shell structure of outer surface modification amino is received
After rice corpuscles adding into dichloromethane ultrasonic disperse, 1,2- naphthoquinones -2-, two nitrine -5- sulfonic acid chloride and triethylamine are sequentially added,
After being stirred at room temperature for 24 hours, by being centrifugally separating to obtain solid, solid is cleaned 3~5 times using methanol, it is then dry in vacuum
Vacuum drying for 24 hours, obtains the core-shell structure nanometer particle of modification guest molecule in dry case；The modification of outer surface described in step 6
The quality of the core-shell structure nanometer particle of amino and the volume ratio of methylene chloride are 1mg:0.1mL；Appearance described in step 6
Face modify amino core-shell structure nanometer particle and two nitrine -5- sulfonic acid chloride of 1,2- naphthoquinones -2- mass ratio be 1:(0.5~
0.7)；The quality of core-shell structure nanometer particle of amino is modified in outer surface described in step 6 and the volume ratio of triethylamine is
1mg:(0.001~0.005) mL；
Seven, it loads doxorubicin hydrochloride and duct blocks: the core-shell structure nanometer particle for modifying guest molecule is added to salt
Then ultrasonic disperse in sour adriamycin aqueous solution is stirred at room temperature for 24 hours, then continue after beta-cyclodextrin is added thereto in room temperature
Lower stirring 60h, is centrifugated after reaction, solids use pH for 7.4 phosphate buffer solution clean 3~5 times, then
The core-shell structure drug load for obtaining the near infrared light excitation light-operated drug release of supermolecule valve for 24 hours is dried in vacuo in vacuum oven
Body；The quality of the core-shell structure nanometer particle of guest molecule and the volume of doxorubicin hydrochloride aqueous solution are modified described in step 7
Than for 1mg:(0.12~0.15) mL；The core-shell structure nanometer particle and beta-cyclodextrin of guest molecule are modified described in step 7
Mass ratio be 1:(40~60).
The application of the nuclear shell structure drug carrier of the near infrared light prepared by the present invention excitation light-operated drug release of supermolecule valve is
The nuclear shell structure drug carrier of the nearly infrared ray excited light-operated drug release of supermolecule valve is released for external near infrared light control drug
It puts in research, specifically used method is as follows: weighing the nuclear shell structure drug carrier that 2.0mg carries medicine, be placed into the footing of cuvette
Place, is slowly added to 2mL phosphate buffer solution (pH=7.4), guarantees that nanoparticle is static in corner concentration, later with laser pair
60min is irradiated in quasi particle, utilizes the concentration of ultraviolet-visual spectrometer monitoring drug doxorubicin hydrochloride every 10min.
The nuclear shell structure drug carrier that 2.0mg carries medicine is weighed, is placed at the footing of cuvette, is slowly added to 2mL phosphoric acid
Salt buffer solution (pH=7.4) guarantees that nanoparticle is static in corner concentration, is later week with 10min with laser alignment particle
Phase carries out intermittent irradiation drug release, and ultraviolet-visual spectrometer monitors the concentration of drug doxorubicin hydrochloride.
Working principle:
The present invention is using up-conversion nanoparticles/mesoporous silicon oxide of core-shell structure as medicine controlled releasing platform, dioxy
SiClx mesopore orbit is for loading anticancer drug, and modification near infrared light responds supermolecule valve at mesoporous mouth, is penetrated using biology
The strong near infrared light of ability manipulates molecule valve, and the light-operated of drug is released in realization.Light-operated mechanism are as follows: host cyclodextrin (big ring point
Son) closure of hydrophobic internal cavities and hydrophobic guest molecules (DNQ) by hydrophobic effect formation complex compound realization to mesoporous mouth；?
Under the effect of 980nm near infrared light, near infrared light is changed into ultraviolet light and near infrared light by up-conversion nano material core, induces oversubscription
The photochemical rearrangement reaction of DNQ, generates hydrophilic product indene carboxylic acid, object hydrophobicity is caused to become hydrophily, host and guest in sub- valve
Body was destroyed based on hydrophobic complexing originally, and host molecule cyclodextrin is left away, and switch is opened, and was released to reach light-operated drug
The purpose put.In addition, near infrared light has organism penetration capacity strong, small to cellular damage, accurate controlled release can be implemented in vitro
The advantages that, one of intelligent response preferred plan is realized using near-infrared light source combination up-conversion.
Beneficial effects of the present invention:
1, the present invention is designed and is constructed based on up-conversion nanoparticles/mesoporous silicon oxide nucleocapsid structure near-infrared
Light excites the light-operated delivery platforms of supermolecule valve.Currently, making full use of up-conversion multi-emitting fluorescence under near infrared light excitation
Realize that the document of medication release has not been reported with excitation supermolecule valve.
2, rearrangement reaction of the opening of supermolecule valve for the first time based near infrared light induction object, it is water-soluble using object
Mutation, which destroys complexing, makes main body leave away, this process avoids carrying platform and contacts with the direct of stimulus.
3, using near infrared light have the characteristics of penetrating depth, hypotoxicity, built in conjunction with up-conversion nanoparticles have it is close
The medicine controlled releasing platform of infrared response realizes the light-operated drug release of timing, positioning, and precision is high, easy to operate.Reported in literature
Applied to cancer diagnosis and treatment platform ideal particle diameter should in 100nm hereinafter, to avoid particle with blood body-internal-circulation when block
Capillary.Up-conversion nanoparticles/mesoporous silicon oxide core-shell structure copolymer diameter of nano particles about 70nm of this Platform Designing preparation.
Detailed description of the invention
Fig. 1 is the nuclear shell structure drug carrier that near infrared light prepared by embodiment one excites the light-operated drug release of supermolecule valve
Transmission electron microscope picture；
Fig. 2 is the nuclear shell structure drug carrier that near infrared light prepared by embodiment one excites the light-operated drug release of supermolecule valve
Nitrogen adsorption desorption curve；
Fig. 3 is the nuclear shell structure drug carrier that near infrared light prepared by embodiment one excites the light-operated drug release of supermolecule valve
Mesoporous pore size distribution curve；
Fig. 4 is that supermolecule valve is light-operated releases for the near infrared light excitation that excites lower embodiment one to prepare of 980nm near-infrared laser
The up-conversion fluorescence launching light spectrogram of the nuclear shell structure drug carrier of medicine；
Fig. 5 is that supermolecule valve is light-operated releases for the near infrared light excitation that prepared by embodiment one before and after 980nm near infrared light
The ultraviolet-visible absorption spectroscopy of the nuclear shell structure drug carrier of medicine；Wherein 1 is before illumination, 2 is after illumination；
Near infrared light prepared by the embodiment one when Fig. 6 is different capacity near infrared light excites supermolecule valve light-operated
The nuclear shell structure drug carrier pH value of water solution change curve of drug release, wherein 1 near-infrared prepared for the embodiment one of non-illumination
Light excites the nuclear shell structure drug carrier pH value of water solution change curve of the light-operated drug release of supermolecule valve, and 2 be near infrared light power
For 1W/cm2When embodiment one prepare near infrared light excitation the light-operated drug release of supermolecule valve nuclear shell structure drug carrier it is water-soluble
Liquid pH value change curve, 3 be near infrared light power be 2W/cm2When embodiment one prepare near infrared light excite supermolecule valve
The nuclear shell structure drug carrier pH value of water solution change curve of light-operated drug release, 4 be near infrared light power be 3W/cm2When embodiment
The nuclear shell structure drug carrier pH value of water solution change curve of the near infrared light excitation light-operated drug release of supermolecule valve of one preparation；
Near infrared light prepared by the embodiment one when Fig. 7 is different capacity near infrared light excites supermolecule valve light-operated
The nuclear shell structure drug carrier drug release effect picture of drug release, wherein a is that the near infrared light of the preparation of embodiment one of non-illumination swashs
The nuclear shell structure drug carrier drug release patterns of the light-operated drug release of supermolecule valve are sent out, b is that near infrared light power is 1W/cm2When
The nuclear shell structure drug carrier drug release patterns of the near infrared light excitation light-operated drug release of supermolecule valve prepared by embodiment one, c
It is 2W/cm near infrared light power2When embodiment one prepare near infrared light excitation the light-operated drug release of supermolecule valve nucleocapsid knot
Structure pharmaceutical carrier drug release patterns, d are that near infrared light power is 3W/cm2When the near infrared light excitation for preparing of embodiment one it is super
The nuclear shell structure drug carrier drug release patterns of the light-operated drug release of molecule valve, 1 is illumination stop position；
Fig. 8 is that near infrared light power is 2W/cm2When to embodiment one prepare near infrared light excitation supermolecule valve it is light-operated
Drug model releasing effect figure when the nuclear shell structure drug carrier intermittent irradiation of drug release, wherein 1 closes for near-infrared light source, 2
It is opened for near-infrared light source.
Specific embodiment
Specific embodiment 1: a kind of nucleocapsid knot of near infrared light excitation light-operated drug release of supermolecule valve of present embodiment
What the preparation method of structure pharmaceutical carrier specifically carried out according to the following steps:
One, up-conversion nanoparticles kernel is synthesized: by NaYF4: Yb/Tm up-conversion nanoparticles are scattered in hexamethylene,
Obtain up-conversion nanoparticles kernel；
Two, oleic acid, octadecylene and step the up-conversion nanoparticles of synthesis cladding shell: are added into six chloride hydrate yttriums
One obtained up-conversion nanoparticles kernel, obtains reaction system, by reaction system under conditions of argon gas is protected and is stirred
Temperature from room temperature to 160 DEG C, and argon gas protection and temperature be 160 DEG C under conditions of 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 gas protection and temperature are 50 DEG C,
Temperature is warming up to 80 DEG C from 50 DEG C again, and keeps 30min under conditions of argon gas protection and temperature are 80 DEG C, it then will reaction
The temperature of system is warming up to 300 DEG C in 20min from 80 DEG C, and magnetic force stirs under conditions of argon gas protection and temperature are 300 DEG C
1.5h is mixed, after reaction, by reaction system cooled to room temperature, is centrifuged and is consolidated as solvent using ethyl alcohol
Solid is cleaned 3~5 times using methanol, obtains the yttrium fluoride natrium nanoparticle of cladding shell, then will coat the fluorine of shell by body
Change yttrium sodium nanoparticle to be scattered in hexamethylene, obtains the yttrium fluoride natrium nanoparticle dispersion liquid of core-shell structure；Six hydration
The quality of yttrium chloride and the volume ratio of oleic acid are 1mg:(0.03~0.04) mL；The quality and octadecylene of the six chloride hydrates yttrium
Volume ratio be 1mg:(0.09~0.1) mL；The up-conversion nanoparticles kernel that the six chloride hydrates yttrium and step 1 obtain
Middle NaYF4: the molar ratio of Yb/Tm up-conversion nanoparticles is 1:(1~3)；The mixed liquor A is by ammonium fluoride and sodium hydroxide
In methyl alcohol, wherein the quality of ammonium fluoride and the volume ratio of methanol are 1mg:(0.06~0.07 for dissolution) mL, the matter of sodium hydroxide
Amount and the volume ratio of methanol are 1mg:(8~12) mL；The molar ratio of ammonium fluoride is 1 in the six chloride hydrates yttrium and mixed liquor A:
4；
Three, in up-conversion nanoparticles external sheath mesoporous silicon oxide: cetyl trimethylammonium bromide is added to
Wiring solution-forming in water, in room temperature after the yttrium fluoride natrium nanoparticle dispersion liquid for the core-shell structure that solution and step 2 obtain is mixed
Ultrasound 0.5h, obtains ultrasonic solution after lower stirring 2h, is heated to adopting after ultrasonic solution is transparent under conditions of temperature is 80 DEG C
PH with sodium hydroxide solution adjustment ultrasonic solution is 8~10, ultrasonic solution after being adjusted pH, then use peristaltic pump with
After the tetraethoxysilane ethanol solution that concentration is 20% is added into the ultrasonic solution after adjustment pH in the speed of 0.5mL/h,
After temperature is reacted for 24 hours under conditions of being 35 DEG C, by being centrifugally separating to obtain solid, by solid using ethyl alcohol cleaning 3~5 times, so
It is dried in vacuo in vacuum oven afterwards for 24 hours, obtains core-shell structure nanometer particle；Cetyl trimethyl described in step 3
The quality of ammonium bromide and the volume ratio of water are 1mg:0.04mL；The quality of cetyl trimethylammonium bromide described in step 3
Volume ratio with the yttrium fluoride natrium nanoparticle dispersion liquid of core-shell structure is 1mg:(0.001~0.005) mL；
Four, amino is modified in core-shell structure nanometer particle outer surface: core-shell structure nanometer particle is added in dry toluene
3- aminopropyl triethoxysilane is added after ultrasonic disperse, obtains reaction solution, and reaction solution is added under conditions of nitrogen protection
After heat reflux for 24 hours, by being centrifugally separating to obtain solid, solid is cleaned 3~5 times using methanol, then in vacuum oven
Vacuum drying for 24 hours, obtains the core-shell structure nanometer particle for not removing surfactant of surface amino groups modification；Described in step 4
Core-shell structure nanometer particle quality and dry toluene volume ratio be 1mg:0.1mL；Core-shell structure described in step 4
The quality of nanoparticle and the volume ratio of 3- aminopropyl triethoxysilane are 1mg:(0.0004~0.0008) mL；
Five, removal surfactant is formed mesoporous: the core-shell structure for not removing surfactant that surface amino groups are modified
Nanoparticle is dispersed in methanol solution, and concentrated hydrochloric acid is then added, temperature be 70 DEG C under conditions of stir for 24 hours after, by from
Solid is cleaned 3~5 times using methanol, is then dried in vacuo in vacuum oven for 24 hours, obtained outer by the isolated solid of the heart
The core-shell structure nanometer particle of surface modification amino；The modification of surface amino groups described in step 5 does not remove surfactant
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 are repaired
Decorations the core-shell structure nanometer particle for not removing surfactant quality and concentrated hydrochloric acid volume ratio be 1mg:(0.00005~
0.0002)mL；
Six, guest molecule is modified in core-shell structure nanometer particle outer surface: the core-shell structure of outer surface modification amino is received
After rice corpuscles adding into dichloromethane ultrasonic disperse, 1,2- naphthoquinones -2-, two nitrine -5- sulfonic acid chloride and triethylamine are sequentially added,
After being stirred at room temperature for 24 hours, by being centrifugally separating to obtain solid, solid is cleaned 3~5 times using methanol, it is then dry in vacuum
Vacuum drying for 24 hours, obtains the core-shell structure nanometer particle of modification guest molecule in dry case；The modification of outer surface described in step 6
The quality of the core-shell structure nanometer particle of amino and the volume ratio of methylene chloride are 1mg:0.1mL；Appearance described in step 6
Face modify amino core-shell structure nanometer particle and two nitrine -5- sulfonic acid chloride of 1,2- naphthoquinones -2- mass ratio be 1:(0.5~
0.7)；The quality of core-shell structure nanometer particle of amino is modified in outer surface described in step 6 and the volume ratio of triethylamine is
1mg:(0.001~0.005) mL；
Seven, it loads doxorubicin hydrochloride and duct blocks: the core-shell structure nanometer particle for modifying guest molecule is added to salt
Then ultrasonic disperse in sour adriamycin aqueous solution is stirred at room temperature for 24 hours, then continue after beta-cyclodextrin is added thereto in room temperature
Lower stirring 60h, is centrifugated after reaction, solids use pH for 7.4 phosphate buffer solution clean 3~5 times, then
The core-shell structure drug load for obtaining the near infrared light excitation light-operated drug release of supermolecule valve for 24 hours is dried in vacuo in vacuum oven
Body；The quality of the core-shell structure nanometer particle of guest molecule and the volume of doxorubicin hydrochloride aqueous solution are modified described in step 7
Than for 1mg:(0.12~0.15) mL；The core-shell structure nanometer particle and beta-cyclodextrin of guest molecule are modified described in step 7
Mass ratio be 1:(40~60).
Temperature is warming up to 80 DEG C from 50 DEG C in step 2 in present embodiment, is kept under conditions of temperature is 80 DEG C
Purpose in 30min is to steam methanol.
Heating 0.5h waits for the transparent purpose of ultrasonic solution under conditions of temperature is 80 DEG C in step 3 in present embodiment
It is to steam hexamethylene.
The purpose being stirred at room temperature in present embodiment step 7 for 24 hours is to guarantee that drug molecule can be well into mesoporous hole
Road.
The purpose that 60h is persistently stirred at room temperature in present embodiment step 7 is to guarantee host molecule and guest molecule energy
Enough sufficiently it is complexed by hydrophobic effect.
The revolving speed of centrifuge separation described in present embodiment is 10000r/min.
Specific embodiment 2: the present embodiment is different from the first embodiment in that: six hydration described in step 2
The quality of yttrium chloride and the volume ratio of oleic acid are 1mg:0.035mL.Other steps and parameter are same as the specific embodiment one.
Specific embodiment 3: the present embodiment is different from the first and the second embodiment in that: six described in step 2
The quality of chloride hydrate yttrium and the volume ratio of octadecylene are 1mg:0.098mL.Other steps and parameter and specific embodiment one
Or two is identical.
Specific embodiment 4: unlike one of present embodiment and specific embodiment one to three: institute in step 2
The molar ratio for stating six chloride hydrate yttriums and up-conversion nanoparticles kernel is 1:2.Other steps and parameter and specific embodiment
One of one to three is identical.
Specific embodiment 5: unlike one of present embodiment and specific embodiment one to four: institute in step 3
The volume ratio of the yttrium fluoride natrium nanoparticle dispersion liquid of the quality and core-shell structure for the cetyl trimethylammonium bromide stated is
1mg:0.003mL.Other steps and parameter are identical as one of specific embodiment one to four.
Specific embodiment 6: unlike one of present embodiment and specific embodiment one to five: institute in step 4
The quality for the core-shell structure nanometer particle stated and the volume ratio of 3- aminopropyl triethoxysilane are 1mg:0.0006mL.Other steps
Rapid and parameter is identical as one of specific embodiment one to five.
Specific embodiment 7: unlike one of present embodiment and specific embodiment one to six: institute in step 5
State surface amino groups modification the quality for the core-shell structure nanometer particle for not removing surfactant and the volume ratio of concentrated hydrochloric acid be
1mg:0.0001mL.Other steps and parameter are identical as one of specific embodiment one to six.
Specific embodiment 8: unlike one of present embodiment and specific embodiment one to seven: institute in step 6
The core-shell structure nanometer particle of outer surface modification amino and the mass ratio of two nitrine -5- sulfonic acid chloride of 1,2- naphthoquinones -2- stated are 1:
0.68.Other steps and parameter are identical as one of specific embodiment one to seven.
Specific embodiment 9: unlike one of present embodiment and specific embodiment one to eight: institute in step 6
The quality of core-shell structure nanometer particle and the volume ratio of triethylamine for the outer surface modification amino stated are 1mg:0.003mL.Other
Step and parameter are identical as one of specific embodiment one to eight.
Specific embodiment 10: unlike one of present embodiment and specific embodiment one to nine: institute in step 7
The core-shell structure nanometer particle of modification guest molecule and the mass ratio of beta-cyclodextrin stated are 1:50.Other steps and parameter and tool
One of body embodiment one to nine is identical.
Beneficial effects of the present invention are verified by following embodiment:
Embodiment one: a kind of core-shell structure drug of near infrared light excitation light-operated drug release of supermolecule valve of the present embodiment carries
What the preparation method of body specifically carried out according to the following steps:
One, by six chloride hydrate yttriums (210.8mg, 0.695mmoL), six hydrous ytterbium chlorides (116.2mg, 0.3mmoL) and
Six hydrous thulium chlorides (1.9mg, 0.005mmoL) are added in three neck round bottom flask, and 6mL oleic acid and 5mL octadecylene is then added；
In the case where logical argon gas, 160 DEG C of holding 30min are stirred the mixture for and be heated to, 10mL octadecylene is then added, mixed
Object naturally cools to 50 DEG C after stirring 1.5h under conditions of temperature is 160 DEG C；The dissolution of 10mL methanol is added into mixture
Ammonium fluoride (148.2mg, 4mmoL) and sodium hydroxide (100mg, 2.5mmoL) solution keep 50 DEG C of stirring 30min nucleation, later
Methanol is boiled off under conditions of temperature is 80 DEG C, mixture is heated to 300 DEG C in 20min and is kept under magnetic stirring
Mixture is down to room temperature naturally, ethyl alcohol is added by 1h after reaction, and product is centrifuged under 10000 turns with centrifuge, uses second
Alcohol cleaning solid, this process 3 times repeatedly；The NaYF finally obtained4: Yb/Tm up-conversion nanoparticles are distributed to 10mL hexamethylene
In, obtain up-conversion nanoparticles core；
Two, it the up-conversion nanoparticles of synthesis cladding shell: is added in six chloride hydrate yttriums (151.7mg, 0.5mmoL)
6mL oleic acid, 15mL octadecylene and up-conversion nanoparticles kernel, obtain reaction system, under conditions of argon gas is protected and is stirred
By the temperature of reaction system from room temperature to 160 DEG C, and 1.5h is stirred under conditions of argon gas protection and temperature are 160 DEG C,
Then temperature is naturally cooled to 50 DEG C from 160 DEG C, adds mixed liquor A, the item for being then 50 DEG C in argon gas protection and temperature
0.5h is stirred under part, then temperature is warming up to 80 DEG C from 50 DEG C, and keep under conditions of argon gas protection and temperature are 80 DEG C
Then the temperature of reaction system is warming up to 300 DEG C by 30min in 20min from 80 DEG C, and be 300 in argon gas protection and temperature
Magnetic agitation 1.5h under conditions of DEG C, after reaction, by reaction system cooled to room temperature, using ethyl alcohol as solvent into
Row is centrifugally separating to obtain solid, and solid is cleaned 3~5 times using methanol, obtains the yttrium fluoride natrium nanoparticle of cladding shell, so
It afterwards disperses the yttrium fluoride natrium nanoparticle for coating shell in 10mL hexamethylene, obtains the yttrium fluoride natrium nanoparticle of core-shell structure
Sub- dispersion liquid；The mixed liquor A is to be dissolved in ammonium fluoride (74.1mg, 2mmol) and sodium hydroxide (50mg, 1.25mmol)
In 5mL methanol；NaYF in the six chloride hydrates yttrium and up-conversion nanoparticles kernel4: Yb/Tm up-conversion nanoparticles rub
You are than being 1:(1~3)；
Three, in up-conversion nanoparticles external sheath mesoporous silicon oxide: 200mg cetyl trimethylammonium bromide is added
Enter the wiring solution-forming into 8mL water, in room temperature after solution is mixed with the yttrium fluoride natrium nanoparticle dispersion liquid of 600 μ L core-shell structures
Ultrasound 0.5h, obtains ultrasonic solution after lower stirring 2h, is heated to adopting after ultrasonic solution is transparent under conditions of temperature is 80 DEG C
PH with sodium hydroxide solution adjustment ultrasonic solution is 8~10, ultrasonic solution after being adjusted pH, then use peristaltic pump with
The tetraethoxysilane ethanol solution that 1.5mL concentration is 20% is added into the ultrasonic solution after adjustment pH for the speed of 0.5mL/h
Afterwards, after being reacted for 24 hours under conditions of temperature is 35 DEG C, by being centrifugally separating to obtain solid, by solid using ethyl alcohol cleaning 3~5
It is secondary, it is then dried in vacuo in vacuum oven for 24 hours, obtains core-shell structure nanometer particle；
Four, core-shell structure nanometer particle outer surface modify amino: by 100mg core-shell structure nanometer particle be added to 10mL without
60 μ L 3- aminopropyl triethoxysilanes are added in water-toluene after ultrasonic disperse, obtain reaction solution, reaction solution is protected in nitrogen
After being heated to reflux for 24 hours under conditions of shield, by being centrifugally separating to obtain solid, solid is cleaned 3~5 times using methanol, is then existed
Vacuum drying for 24 hours, obtains the core-shell structure nanometer particle for not removing surfactant of surface amino groups modification in vacuum oven；
Five, removal surfactant is formed mesoporous: the nucleocapsid for not removing surfactant that 100mg surface amino groups are modified
Structure nano particle is dispersed in 10mL methanol solution, and 100 μ L concentrated hydrochloric acids are then added, and is stirred under conditions of temperature is 70 DEG C
After for 24 hours, by being centrifugally separating to obtain solid, solid is cleaned 3~5 times using methanol, then vacuum is dry in vacuum oven
It is dry for 24 hours, obtain outer surface modification amino core-shell structure nanometer particle；
Six, guest molecule is modified in core-shell structure nanometer particle outer surface: by the nucleocapsid knot of the outer surface 100mg modification amino
Structure nanoparticle is added in 10mL methylene chloride after ultrasonic disperse, sequentially adds 68mg 1, two nitrine -5- sulphur of 2- naphthoquinones -2-
Acyl chlorides and 0.3mL triethylamine, after being stirred at room temperature for 24 hours, by being centrifugally separating to obtain solid, by solid using methanol cleaning 3
~5 times, the core-shell structure nanometer particle for obtaining modification guest molecule for 24 hours is then dried in vacuo in vacuum oven；
Seven, it loads doxorubicin hydrochloride and duct blocks: the core-shell structure nanometer particle of 30mg modification guest molecule is added
The ultrasonic disperse into the doxorubicin hydrochloride aqueous solution that 4mL concentration is 0.5mg/mL, is then stirred at room temperature for 24 hours, then thereto
60h is persistently stirred at room temperature after 150mg beta-cyclodextrin is added, is centrifugated after reaction, solids uses pH for 7.4
Phosphate buffer solution is cleaned 3~5 times, is then dried in vacuo in vacuum oven for 24 hours, and near infrared light excitation supermolecule is obtained
The nuclear shell structure drug carrier of the light-operated drug release of valve.
Fig. 1 is the nuclear shell structure drug carrier that near infrared light prepared by embodiment one excites the light-operated drug release of supermolecule valve
Transmission electron microscope picture；The nuclear shell structure drug carrier of the near infrared light excitation light-operated drug release of supermolecule valve has as can be seen from Figure 1
The nucleocapsid structure of size uniformity is in monodisperse status, and the size of nanoparticle is 70nm or so after mesoporous silicon sphere cladding.
Fig. 2 is the nuclear shell structure drug carrier that near infrared light prepared by embodiment one excites the light-operated drug release of supermolecule valve
Nitrogen adsorption desorption curve；Fig. 3 is the core-shell structure medicine that near infrared light prepared by embodiment one excites the light-operated drug release of supermolecule valve
The mesoporous pore size distribution curve of object carrier；The presence of nitrogen adsorption desorption higher-pressure region hysteresis loop shows as can be seen from Figures 2 and 3
Synthetic material be it is mesoporous, aperture is in 2.3nm or so.Mesoporous to can be used to load drug, surface can further modify supermolecule valve,
For near infrared light Drug controlled release.
Fig. 4 is that supermolecule valve is light-operated releases for the near infrared light excitation that excites lower embodiment one to prepare of 980nm near-infrared laser
The up-conversion fluorescence launching light spectrogram of the nuclear shell structure drug carrier of medicine；As can be seen from the figure in the excitation of 980nm laser
Under, near infrared light excites the nuclear shell structure drug carrier of the light-operated drug release of supermolecule valve to generate shining for three wave bands, respectively
365nm ultraviolet light, 450nm visible light and 800nm near infrared light, wherein ultraviolet light and near infrared light are for exciting supermolecule valve
Control release is carried out to drug.
Fig. 5 is that supermolecule valve is light-operated releases for the near infrared light excitation that prepared by embodiment one before and after 980nm near infrared light
The ultraviolet-visible absorption spectroscopy of the nuclear shell structure drug carrier of medicine；Wherein 1 is before illumination, 2 is after illumination；As can be seen from the figure
After 980nm near infrared light, near infrared light excites the nuclear shell structure drug carrier of the light-operated drug release of supermolecule valve in 330nm
It almost disappears with ultraviolet and visible absorption peak at 399nm, it was demonstrated that the ultraviolet or near infrared emission fluorescence induction core-of upper conversion nano core
Photochemical reaction has occurred in core/shell nanoparticles surface guest molecule.
Near infrared light prepared by the embodiment one when Fig. 6 is different capacity near infrared light excites supermolecule valve light-operated
The nuclear shell structure drug carrier pH value of water solution change curve of drug release, wherein 1 near-infrared prepared for the embodiment one of non-illumination
Light excites the nuclear shell structure drug carrier pH value of water solution change curve of the light-operated drug release of supermolecule valve, and 2 be near infrared light power
For 1W/cm2When embodiment one prepare near infrared light excitation the light-operated drug release of supermolecule valve nuclear shell structure drug carrier it is water-soluble
Liquid pH value change curve, 3 be near infrared light power be 2W/cm2When embodiment one prepare near infrared light excite supermolecule valve
The nuclear shell structure drug carrier pH value of water solution change curve of light-operated drug release, 4 be near infrared light power be 3W/cm2When embodiment
The nuclear shell structure drug carrier pH value of water solution change curve of the near infrared light excitation light-operated drug release of supermolecule valve of one preparation；From
In figure it can be seen that after 980nm near infrared light, near infrared light excites the core-shell structure medicine of the light-operated drug release of supermolecule valve
Object carrier aqueous solution pH value is decreased obviously, it was demonstrated that above conversion nano core is ultraviolet or its surface of near infrared emission fluorescence induction
Photochemical reaction has occurred in DNQ molecule, generates hydrophilic product indene carboxylic acid, and the water solubility of object becomes hydrophilic from hydrophobic；It is identical
In time, laser power is bigger, and pH value variation is bigger, shows that DNQ molecular photochemistry reaction rate increases with laser power and increased
Greatly.
Embodiment two: 3.0Wcm-2Light-operated drug release under the continuous 60min irradiation of power density near-infrared laser:
The core-shell structure drug for weighing the near infrared light excitation light-operated drug release of supermolecule valve that 2.0mg embodiment one obtains carries
Body is placed at the footing of cuvette, is slowly added to 2mL phosphate buffer solution (pH=7.4), guarantees nanoparticle in corner
It concentrates static, carries out Continuous irradiation 60min with laser alignment particle later, utilize ultraviolet-visual spectrometer tracking and testing drug salts
The concentration of sour adriamycin obtains Cumulative release amount versus time curve, it was demonstrated that light-operated drug release.Equally weigh 2.0mg
The nuclear shell structure drug carrier for the near infrared light excitation light-operated drug release of supermolecule valve that embodiment one obtains carries out sky in the dark
It is white to put medicine experiment, it is added 2mL phosphate buffer solution (pH=7.4), ultraviolet-visual spectrometer takes identical time interval measurement
The concentration of drug changes.
Embodiment three: 2Wcm-2Light-operated drug release under the continuous 60min irradiation of power density near-infrared laser: it operated
Journey is identical as embodiment two.
Near infrared light prepared by the embodiment one when Fig. 7 is different capacity near infrared light excites supermolecule valve light-operated
The nuclear shell structure drug carrier drug release effect picture of drug release, wherein a is that the near infrared light of the preparation of embodiment one of non-illumination swashs
The nuclear shell structure drug carrier drug release patterns of the light-operated drug release of supermolecule valve are sent out, b is that near infrared light power is 1W/cm2When
The nuclear shell structure drug carrier drug release patterns of the near infrared light excitation light-operated drug release of supermolecule valve prepared by embodiment one, c
It is 2W/cm near infrared light power2When embodiment one prepare near infrared light excitation the light-operated drug release of supermolecule valve nucleocapsid knot
Structure pharmaceutical carrier drug release patterns, d are that near infrared light power is 3W/cm2When the near infrared light excitation for preparing of embodiment one it is super
The nuclear shell structure drug carrier drug release patterns of the light-operated drug release of molecule valve, 1 is illumination stop position；As can be seen from the figure
Not having the control group of illumination, (curve a), does not put medicine substantially, illustrates that supermolecule valve effectively blocks duct.When with near-infrared laser
After irradiation, all curves show accumulative drug release, increase obviously, illustrate under near infrared light, object photochemical rearrangement is anti-
Beta-cyclodextrin should be caused to leave away, supermolecule valve is opened, drug release.With the increase of laser power density, drug
Burst size gradually increases, and shows that the system can be by adjusting laser power size, the accurately release of regulating medicine.When illumination stops
After only, drug release also stops (in Fig. 7 after 60min) therewith, shows that the system has sensitive response to the switch of light source.
Example IV: 2.0Wcm-2Light-operated drug release under power density near-infrared laser 10min period intermittent irradiation:
The core-shell structure drug for weighing the near infrared light excitation light-operated drug release of supermolecule valve that 2.0mg embodiment one obtains carries
Body is placed at the footing of cuvette, is slowly added to 2mL phosphate buffer solution (pH=7.4), guarantees nanoparticle in corner
It concentrates static, carries out intermittent irradiation drug release by the period of 10min with laser alignment particle later, ultraviolet-visual spectrometer monitors medicine
The concentration of object doxorubicin hydrochloride.
Fig. 8 is that near infrared light power is 2W/cm2When to embodiment one prepare near infrared light excitation supermolecule valve it is light-operated
Drug model releasing effect figure when the nuclear shell structure drug carrier intermittent irradiation of drug release, wherein 1 closes for near-infrared light source, 2
It is opened for near-infrared light source；As can be seen from the figure the nuclear shell structure drug carrier of the near infrared light excitation light-operated drug release of supermolecule valve
The accurate release of drug can be realized under laser power size and the regulation of the double mode of light source switch.This life complicated for reply
Substance environment, raising therapeutic efficiency and reduction toxic side effect have great importance.
Claims (10)
1. a kind of preparation method of the nuclear shell structure drug carrier of the near infrared light excitation light-operated drug release of supermolecule valve, feature exist
The preparation method that the nuclear shell structure drug carrier of the light-operated drug release of supermolecule valve is excited near infrared light is specifically according to the following steps
It carries out:
One, up-conversion nanoparticles kernel is synthesized: by NaYF4: Yb/Tm up-conversion nanoparticles are scattered in hexamethylene, are obtained
Conversion nanoparticles kernel；
Two, the up-conversion nanoparticles of synthesis cladding shell: oleic acid, octadecylene and step 1 is added into six chloride hydrate yttriums and obtains
The up-conversion nanoparticles kernel arrived, obtains reaction system, by the temperature of reaction system under conditions of argon gas is protected and is stirred
From room temperature to 160 DEG C, and 1.5h is stirred under conditions of argon gas protection and temperature are 160 DEG C, then by temperature from 160 DEG C
50 DEG C are naturally cooled to, mixed liquor A is added, 0.5h is then stirred under conditions of argon gas protection and temperature are 50 DEG C, then will
Temperature is warming up to 80 DEG C from 50 DEG C, and keeps 30min under conditions of argon gas protection and temperature are 80 DEG C, then by reaction system
Temperature be warming up to 300 DEG C from 80 DEG C in 20min, and magnetic agitation under conditions of argon gas protection and temperature are 300 DEG C
1.5h by reaction system cooled to room temperature, is centrifuged as solvent using ethyl alcohol and is consolidated after reaction
Solid is cleaned 3~5 times using methanol, obtains the yttrium fluoride natrium nanoparticle of cladding shell, then will coat the fluorine of shell by body
Change yttrium sodium nanoparticle to be scattered in hexamethylene, obtains the yttrium fluoride natrium nanoparticle dispersion liquid of core-shell structure；Six hydration
The quality of yttrium chloride and the volume ratio of oleic acid are 1mg:(0.03~0.04) mL；The quality and octadecylene of the six chloride hydrates yttrium
Volume ratio be 1mg:(0.09~0.1) mL；The up-conversion nanoparticles kernel that the six chloride hydrates yttrium and step 1 obtain
Middle NaYF4: the molar ratio of Yb/Tm up-conversion nanoparticles is 1:(1~3)；The mixed liquor A is by ammonium fluoride and sodium hydroxide
In methyl alcohol, wherein the quality of ammonium fluoride and the volume ratio of methanol are 1mg:(0.06~0.07 for dissolution) mL, the matter of sodium hydroxide
Amount and the volume ratio of methanol are 1mg:(8~12) mL；The molar ratio of ammonium fluoride is 1 in the six chloride hydrates yttrium and mixed liquor A:
4；
Three, in up-conversion nanoparticles external sheath mesoporous silicon oxide: cetyl trimethylammonium bromide is added to the water
Wiring solution-forming stirs at room temperature after mixing the yttrium fluoride natrium nanoparticle dispersion liquid for the core-shell structure that solution and step 2 obtain
Ultrasound 0.5h after 2h is mixed, ultrasonic solution is obtained, is heated under conditions of temperature is 80 DEG C after ultrasonic solution is transparent using hydrogen
Sodium hydroxide solution adjust ultrasonic solution pH be 8~10, the ultrasonic solution after being adjusted pH, then use peristaltic pump with
After the tetraethoxysilane ethanol solution that concentration is 20% is added into the ultrasonic solution after adjustment pH in the speed of 0.5mL/h,
After temperature is reacted for 24 hours under conditions of being 35 DEG C, by being centrifugally separating to obtain solid, by solid using ethyl alcohol cleaning 3~5 times, so
It is dried in vacuo in vacuum oven afterwards for 24 hours, obtains core-shell structure nanometer particle；Cetyl trimethyl described in step 3
The quality of ammonium bromide and the volume ratio of water are 1mg:0.04mL；The quality of cetyl trimethylammonium bromide described in step 3
Volume ratio with the yttrium fluoride natrium nanoparticle dispersion liquid of core-shell structure is 1mg:(0.001~0.005) mL；
Four, amino is modified in core-shell structure nanometer particle outer surface: core-shell structure nanometer particle being added in dry toluene ultrasonic
3- aminopropyl triethoxysilane is added after dispersion, obtains reaction solution, and reaction solution is heated back under conditions of nitrogen protection
After flowing for 24 hours, by being centrifugally separating to obtain solid, solid is used into methanol cleaning 3~5 times, then the vacuum in vacuum oven
Drying for 24 hours, obtains the core-shell structure nanometer particle for not removing surfactant of surface amino groups modification；Core described in step 4
The quality of shell structural nano particle and the volume ratio of dry toluene are 1mg:0.1mL；Nuclear shell structure nano described in step 4
The quality of particle and the volume ratio of 3- aminopropyl triethoxysilane are 1mg:(0.0004~0.0008) mL；
Five, removal surfactant is formed mesoporous: the nuclear shell structure nano for not removing surfactant that surface amino groups are modified
Particle is dispersed in methanol solution, and the concentrated hydrochloric acid that concentration is 36%~38% is then added, stirs under conditions of temperature is 70 DEG C
After mixing for 24 hours, by being centrifugally separating to obtain solid, solid is used into methanol cleaning 3~5 times, then the vacuum in vacuum oven
Drying for 24 hours, obtains the core-shell structure nanometer particle of outer surface modification amino；The modification of surface amino groups described in step 5 does not remove
The volume ratio of the quality and methanol solution of removing the core-shell structure nanometer particle of surfactant is 1mg:0.1mL；Institute in step 5
The quality and concentration of the core-shell structure nanometer particle for not removing surfactant for the surface amino groups modification stated are 36%~38%
Concentrated hydrochloric acid volume ratio be 1mg:(0.00005~0.0002) mL；
Six, guest molecule is modified in core-shell structure nanometer particle outer surface: by the nuclear shell structure nano grain of outer surface modification amino
After sub- adding into dichloromethane ultrasonic disperse, 1,2- naphthoquinones -2-, two nitrine -5- sulfonic acid chloride and triethylamine are sequentially added, in room
After the lower stirring for 24 hours of temperature, by being centrifugally separating to obtain solid, solid is cleaned 3~5 times using methanol, then in vacuum oven
Interior vacuum drying for 24 hours, obtains the core-shell structure nanometer particle of modification guest molecule；Amino is modified in outer surface described in step 6
Core-shell structure nanometer particle quality and methylene chloride volume ratio be 1mg:0.1mL；It repairs outer surface described in step 6
The mass ratio of the core-shell structure nanometer particle and two nitrine -5- sulfonic acid chloride of 1,2- naphthoquinones -2- of adoring amino is 1:(0.5~0.7)；Step
It is 1mg that the quality of the core-shell structure nanometer particle of amino and the volume ratio of triethylamine are modified in outer surface described in rapid six:
(0.001~0.005) mL；
Seven, doxorubicin hydrochloride and duct is loaded to block: by the core-shell structure nanometer particle for modifying guest molecule be added to hydrochloric acid Ah
Then ultrasonic disperse in mycin aqueous solution is stirred at room temperature for 24 hours, then continue to stir at room temperature after beta-cyclodextrin is added thereto
60h is mixed, is centrifugated after reaction, solids uses pH to clean 3~5 times for 7.4 phosphate buffer solution, then true
Vacuum drying for 24 hours, obtains the nuclear shell structure drug carrier of the near infrared light excitation light-operated drug release of supermolecule valve in empty drying box；Step
The quality of core-shell structure nanometer particle of guest molecule is modified described in rapid seven and the volume ratio of doxorubicin hydrochloride aqueous solution is
1mg:(0.12~0.15) mL；The core-shell structure nanometer particle of guest molecule and the matter of beta-cyclodextrin are modified described in step 7
Amount is than being 1:(40~60).
2. a kind of nuclear shell structure drug carrier of near infrared light excitation light-operated drug release of supermolecule valve according to claim 1
Preparation method, it is characterised in that the quality of six chloride hydrate yttriums described in step 2 and the volume ratio of oleic acid are 1mg:
0.035mL。
3. a kind of nuclear shell structure drug carrier of near infrared light excitation light-operated drug release of supermolecule valve according to claim 1
Preparation method, it is characterised in that the quality of six chloride hydrate yttriums described in step 2 and the volume ratio of octadecylene are 1mg:
0.098mL。
4. a kind of nuclear shell structure drug carrier of near infrared light excitation light-operated drug release of supermolecule valve according to claim 1
Preparation method, it is characterised in that the up-conversion nanoparticles kernel that six chloride hydrate yttriums described in step 2 and step 1 obtain
Molar ratio be 1:2.
5. a kind of nuclear shell structure drug carrier of near infrared light excitation light-operated drug release of supermolecule valve according to claim 1
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.
6. a kind of nuclear shell structure drug carrier of near infrared light excitation light-operated drug release of supermolecule valve according to claim 1
Preparation method, it is characterised in that the quality and 3- ammonia third of three obtained core-shell structure nanometer particles the step of described in step 4
The volume ratio of ethyl triethoxy silicane alkane is 1mg:0.0006mL.
7. a kind of nuclear shell structure drug carrier of near infrared light excitation light-operated drug release of supermolecule valve according to claim 1
Preparation method, it is characterised in that the modification of surface amino groups that step 4 described in step 5 obtains does not remove surfactant
The volume ratio for the concentrated hydrochloric acid that the quality and concentration of core-shell structure nanometer particle are 36%~38% is 1mg:0.0001mL.
8. a kind of nuclear shell structure drug carrier of near infrared light excitation light-operated drug release of supermolecule valve according to claim 1
Preparation method, it is characterised in that the core-shell structure of the step 5 obtains described in step 6 outer surface modification amino is received
The mass ratio of rice corpuscles and two nitrine -5- sulfonic acid chloride of 1,2- naphthoquinones -2- is 1:0.68.
9. a kind of nuclear shell structure drug carrier of near infrared light excitation light-operated drug release of supermolecule valve according to claim 1
Preparation method, it is characterised in that the nuclear shell structure nano grain of five obtained outer surfaces modification amino the step of described in step 6
The quality of son and the volume ratio of triethylamine are 1mg:0.003mL.
10. a kind of core-shell structure drug of near infrared light excitation light-operated drug release of supermolecule valve according to claim 1 carries
The preparation method of body, it is characterised in that the core-shell structure nanometer particle for the modification guest molecule that step 6 described in step 7 obtains
Mass ratio with beta-cyclodextrin is 1:50.
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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 |
| 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 |
| 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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