CN108888607A - A kind of preparation method of the multifunctional nano pharmaceutical carrier of core-shell structure - Google Patents
A kind of preparation method of the multifunctional nano pharmaceutical carrier of core-shell structure Download PDFInfo
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- 239000003937 drug carrier Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000011258 core-shell material Substances 0.000 title claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 239000002105 nanoparticle Substances 0.000 claims abstract description 31
- 229940079593 drug Drugs 0.000 claims abstract description 24
- 229920002627 poly(phosphazenes) Polymers 0.000 claims abstract description 23
- 239000000126 substance Substances 0.000 claims abstract description 6
- 230000009881 electrostatic interaction Effects 0.000 claims abstract description 5
- 238000011068 loading method Methods 0.000 claims abstract description 5
- 230000002950 deficient Effects 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
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- 239000002904 solvent Substances 0.000 claims description 8
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- -1 alkoxy pyridines Chemical class 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
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- 239000011230 binding agent Substances 0.000 claims description 3
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- 239000007788 liquid Substances 0.000 claims description 3
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 2
- 150000002825 nitriles Chemical class 0.000 claims 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 1
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical compound FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 claims 1
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- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
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- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 1
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- 239000002502 liposome Substances 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
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- 239000000693 micelle Substances 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
- A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
- A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y20/00—Nanooptics, e.g. quantum optics or photonic crystals
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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Abstract
The invention belongs to New Chemical Material preparation technical field, it is related to a kind of having the function of the multifunctional nano pharmaceutical carrier and its preparation process for integrating fluorescence imaging and carrying medicine function of core-shell structure.The pharmaceutical carrier is using rear-earth-doped up-conversion nanoparticles as core, using two-dimentional poly phosphazene nanometer sheet as shell.Two-dimentional poly phosphazene nano material has high-specific surface area, provides steric requirements for drug loading.Two-dimentional poly phosphazene can adsorb electron deficient drug molecule by electrostatic interaction, and have high pH sensibility, realize pH Drug controlled release.It is high that up-conversion nanoparticles have the characteristics that near-infrared excites, fluorescence penetrates depth, signal-to-noise ratio.Two-dimentional poly phosphazene nanometer sheet and up-conversion nanoparticles are organically combined, realize that high load amount, pH are sensitive, the friendly fluorescence of biology is in the multifunctional nano pharmaceutical carrier of one.
Description
Technical field：
The invention belongs to New Chemical Material preparation technical fields, are related to a kind of preparation side of multifunctional nano pharmaceutical carrier
Method, especially a kind of core-shell structure formula Nano medication based on two-dimentional poly phosphazene nanometer sheet and rear-earth-doped up-conversion nanoparticles
Carrier and its preparation process.
Background technique：
With the continuous development and popularization and application of nanotechnology, nano material also obtains extensively in medicine and drug technique
Development and application.In the prior art, the development of Nano medication is that mankind's major disease (such as cancer) provides critical treatment hand
Section.By the way that Nano medication is filled to nano-medicament carrier, medicine stability can be effectively improved, improves the metabolism of drug in vivo
Dynamic process, enhancing administration targeting, reduces the toxicity of the normal tissues such as drug leakage.Currently, the nanometer mainly used
Pharmaceutical carrier has polymer micelle, liposome, dendritic macromole, meso-porous nano silica etc., and nano-medicament carrier
Development have begun to functionalization, intelligent direction development, on the one hand, assign pharmaceutical carrier stimuli responsive characteristic (to light, heat,
The sensitivities such as magnetic), achieve the purpose that control release；On the other hand, the functions such as fluorescence, magnetic resonance imaging are integrated into pharmaceutical carrier
On, achieve the purpose that diagnosis and treatment in one.
After searching and discovering the prior art, Chinese patent literature CN106806905A, publication date 2017-06-09,
It discloses a kind of collection fluorescence imaging and carries the integrated rare earth upconversion nano pharmaceutical carrier of medicine, which includes tool
Have fluorescence imaging function rare earth upconversion nano particle and be supported on up-conversion nanoparticles surface anti-tumor drug and
It is coated on the amphiphilic polymer molecule distearoylphosphatidylethanolamine-polyethylene glycol (DSPE- of nanoparticle surface
PEG), there is good water-soluble and biocompatibility, surface texture to have for the nano-medicament carrier size uniformity, morphological rules
So that it is enriched in tumor tissues conducive to by EPR effect, realizes drug passive target.Chinese patent literature number
CN106589270A, publication date 2017-04-26 disclose a kind of star-type polymer with fluorescent marker and temperature-responsive
Based medicine carrier, the carrier carry out ring-opening polymerisation as raw material using cyclic ester monomers using star-like initiator and prepare star-like polyesters height
Molecular material, then reacted with dibromo-isobutyl acylbromide and prepare star-like macromole evocating agent, by atom transfer radical polymerization, big
The hydrophilic monomer with temperature-responsive is introduced on initiator molecule, prepares amphiphilic temperature-responsive block copolymer,
It recycles atom transfer radical polymerization to introduce hydroxyethyl methacrylate monomer to provide hydroxyl, then utilizes hydroxyl and fluorescence
The chemical reaction of small molecule prepares the star-type polymer based medicine carrier material with fluorescent marker and temperature-responsive.However,
There are still deficiencies in terms of drug loading and control for pharmaceutical carrier disclosed at present, it is difficult to meet the market requirement with
Curative effect requirement.
Summary of the invention：
It is an object of the invention to overcome disadvantage of the existing technology, design proposes that a kind of collection with core-shell structure is glimmering
Light imaging function and carry medicine function in one, it is more based on two-dimentional poly phosphazene nanometer sheet and rear-earth-doped up-conversion nanoparticles
Function nano pharmaceutical carrier and its preparation process.
To achieve the goals above, the invention is realized by the following technical scheme：First by hexachlorocyclotriph,sphazene and melamine
Amine is proportionally added into solvent, then the dispersion liquid of rear-earth-doped up-conversion nanoparticles is added in the mixed solvent and ties up acid
Agent, then ultrasonic disperse is uniform；Initial product is reacted to obtain by solvent-thermal method or ultrasonic method again；Initial product is carried out respectively from
The heart, hot ethanol must have the multifunctional nano pharmaceutical carrier of core-shell structure after washing, wash and drying；The multifunctional nano drug carries
Body is using rear-earth-doped up-conversion nanoparticles as core, and using two-dimentional poly phosphazene nanometer sheet as shell, two-dimentional poly phosphazene nanometer sheet has height
Ratio surface area structure can provide space for drug loading；Nitrogen phosphorus hexatomic ring in two-dimentional poly phosphazene chemical structure has lonely electricity
Son is right, electron deficient drug molecule can be adsorbed by electrostatic interaction, and electrostatic interaction has high pH sensibility, nano-medicament carrier energy
Adsorbed drug molecule is discharged under mildly acidic conditions, realizes pH control release；Up-conversion nanoparticles have near-infrared excitation,
Fluorescence penetrates depth and the high feature of signal-to-noise ratio, by two-dimentional poly phosphazene nanometer sheet and the organic knot of up-conversion nanoparticles core-shell structure
It closes, it is sensitive, biological friendly in integrated multifunctional nano pharmaceutical carrier to be prepared into the high load amount that is able to achieve, pH.
The chemical composition of rear-earth-doped up-conversion nanoparticles of the present invention is the NaYF of Yb and Ln codope4Nanometer
Brilliant or NaGdF4It is nanocrystalline, wherein Ln Er's, Ho and Tm is one or more, and the preferably high hexagonal phase of crystallinity is nanocrystalline, ruler
Very little is 15~50nm；The concentration of up-conversion nanoparticles in a solvent is 0.1~10mg/mL.
Solvent of the present invention is one of acetone, tetrahydrofuran, acetonitrile, n,N-Dimethylformamide or two kinds
Or three kinds of mixture.
The concentration of hexachlorocyclotriph,sphazene of the present invention in a solvent is 0.1~10mg/mL；Hexachlorocyclotriph,sphazene and three
The molar ratio of poly cyanamid is 1:1.5~1:3.5.
Acid binding agent of the present invention is the alkoxy pyridines of triethylamine, pyridine or C1~C3, dosage and chlordene ring three
The molar ratio of phosphonitrile is 1:0.15~1:0.01.
Solvent-thermal method of the present invention is that reaction solution is added in the counteracting tank of polytetrafluoroethyllining lining, leads to nitrogen
Counteracting tank is sealed after deoxygenation, is handled 0.5-24 hours at a temperature of 100-280 DEG C.
Ultrasonic method of the present invention be under inert gas shielding environment, under the conditions of ultrasonic water bath to reaction solution ultrasound at
Reason, ultrasonic treatment condition are：Temperature is 10 DEG C to reaction solution reflux temperature, and ultrasonic power is 15~300 watts, and the processing time is
24~240 hours.
Two dimension poly phosphazene nanometer sheet of the present invention is hexachlorocyclotriph,sphazene and melamine copolymerization, molecule knot
Structure formula is：
Shown in the visible attached drawing 2 of the molecular structure.
Compared with prior art, pharmaceutical carrier is with two-dimentional poly phosphazene poly phosphazene for nano-medicament carrier obtained by the present invention
Nanometer layer carrying medicament realizes high drug loading and pH control release, can effectively combine the near-infrared of up-conversion nanoparticles
Fluorescence detection function can effectively avoid injury of the ultraviolet light to organism while realizing high s/n ratio and high detection depth；
Its preparation process is simple, and drug effect performance is good, and controllability is strong, and application environment is friendly.
Detailed description of the invention：
Fig. 1 is rear-earth-doped up-conversion nanoparticles of the present invention-two dimension poly phosphazene nano-medicament carrier structure
Schematic illustration, including two-dimentional poly phosphazene nanoscale twins 1 and up-conversion nanoparticles 2.
Fig. 2 is the chemical molecular principle schematic diagram of two-dimentional poly phosphazene nanoscale twins of the present invention.
Fig. 3 is the transmission electron microscope photo schematic diagram of two-dimentional poly phosphazene nanoscale twins of the present invention.
Fig. 4 is the transmission electron microscope photo schematic diagram of rear-earth-doped up-conversion nanoparticles of the present invention.
Fig. 5 is the transmission of rear-earth-doped up-conversion nanoparticles of the present invention-two dimension poly phosphazene nano-medicament carrier
Electromicroscopic photograph schematic diagram.
Fig. 6 is drug release patterns under the condition of different pH in the embodiment of the present invention 4.
Specific embodiment：
It elaborates with reference to the accompanying drawing and by embodiment to the present invention, to provide detailed embodiment and tool
The operating process of body.
Embodiment 1：
The present embodiment is related to a kind of specific preparation process of the multifunctional nano pharmaceutical carrier of core-shell structure：
(1) NaYF first is moved into the three-necked flask of 100mL4:Yb3+,Er3+It is 1 milliliter of nanoparticle/hexane solution, dense
Degree is 30mg/mL, 30mg containing UCNPs；30mL tetrahydrofuran is added into three-necked flask again, then by 3.48mg chlordene ring three
Phosphonitrile, 2.5mg melamine and 1mL triethylamine are added separately to the mixed solution in the solution of three-necked flask again；
(2) mixed solution in the three-necked flask of step (1) is transferred to the polytetrafluoroethyllining lining that capacity is 50mL again
Counteracting tank in, logical nitrogen goes out the replacement of oxygen in counteracting tank；Then counteracting tank is sealed, is put into 160 DEG C of baking oven and adds
It is heat-treated 3h, then stops heating, cooled to room temperature obtains reaction solution；
(3) after counteracting tank cooled to room temperature, then pass through centrifugation apparatus and be centrifuged the reaction solution in counteracting tank, take it
In solid product, washed repeatedly with methanol solid product 3 times, then wash primary；Finally solid product is lyophilized more up to having
The core-shell structure formula nano-medicament carrier of function.
Embodiment 2：
The present embodiment is related to the technique that another preparation has core-shell structure formula nano-medicament carrier：
(1) NaYF first is moved into 100mL three-necked flask4:Yb3+,Er3+1 milliliter of nanoparticle/hexane solution, concentration
For 30mg/mL, 30mg containing UCNPs；Again into three-necked flask be added 20mL tetrahydrofuran, be sufficiently mixed it is uniform must go up convert receive
Rice corpuscles tetrahydrofuran solution；Then 3.48mg hexachlorocyclotriph,sphazene, 2.5mg melamine and 1mL triethylamine are separately added into
Mixed solution is obtained into 10mL n,N-Dimethylformamide, then mixed solution is added to the four of above-mentioned up-conversion nanoparticles
Reaction solution is obtained in hydrogen tetrahydrofuran solution；
(2) reaction solution of step (2) is placed in counteracting tank again and reacts 72h under ultrasound environments, reaction process N2Protection surpasses
Acoustical power is 50w, and reaction temperature is 50 DEG C, obtains reactant；
(3) then by centrifugation apparatus by after the reactant centrifugation in counteracting tank, solid product therein is taken, and use methanol
It washes solid product 3 times, then washes primary repeatedly；Finally solid product be lyophilized that there is multi-functional core-shell structure formula nanometer medicine
Object carrier.
Embodiment 3：
The present embodiment is related to the method that the third preparation has multi-functional core-shell structure formula nano-medicament carrier：
(1) NaGdF first is moved into 100mL three-necked flask4:Yb3+,Ho3+(concentration is nanoparticle/hexane solution 1mL
30mg/mL, 30mg containing UCNPs), then into three-necked flask be added 30mL acetone, then by 5.0mg hexachlorocyclotriph,sphazene,
2.5mg melamine and 1mL triethylamine, which are added in three-necked flask solution, obtains reaction solution；
(2) reaction solution of step (1) is transferred in the counteracting tank for the polytetrafluoroethyllining lining that capacity is 50mL again, leads to nitrogen
Gas goes out the replacement of oxygen in counteracting tank；Then counteracting tank is sealed, is put into 140 DEG C of baking oven and handles 8h, be then shut off and add
Heat obtains reactant to counteracting tank cooled to room temperature；
(3) after counteracting tank cooled to room temperature, the reactant in counteracting tank is centrifuged by centrifugation apparatus, is taken
Wherein solid product, and washed repeatedly with methanol solid product 3 times, then wash primary；Finally solid product is lyophilized to have more
The core-shell structure formula nano-medicament carrier of function.
Embodiment 4：
The present embodiment is related to pharmaceutical carrier prepared by embodiment 2 to the load performance of anticancer drug, takes in 10mg embodiment 2
Prepared nano-medicament carrier is scattered in the doxorubicin hydrochloride solution of 5ml 0.5mg/ml under the conditions of sonic oscillation, then
This mixed solution (including diagram) is stirred at room temperature 24 hours, by centrifugation, deionization washing, freeze-drying, obtains load hydrochloric acid
The Nano medication of adriamycin；By carrying out ultraviolet spectral analysis (characteristic peak 490nm) to centrifuged supernatant and cleaning solution and counting
The drugloading rate that can obtain pharmaceutical carrier is calculated up to 143mg/g, much higher than the 14- of other micro Nano materials disclosed in existing technical literature
Load capacity (Y.Dong, S.S.Feng, Poly (D, L-lactide-co-glycolide)/montmorillonite of 24mg/g
nanoparticles for oral delivery of anticancer drugs,Biomaterials,
2005,26(30):6068-6076.)；The present invention has apparent progress meaning.
Embodiment 5：
The present embodiment is related to the external pH control release performance of anticancer drug prepared by embodiment 4, takes in 10mg embodiment 4
The prepared Nano medication for being loaded with Dopamine hydrochloride, and it is dispersed in the phosphoric acid buffer that 20mL pH is respectively 5.59 and 6.81
It in salting liquid, and is vibrated in 37 DEG C of waters bath with thermostatic control, carries out drug release；Interval takes 2mL sample at a fixed time, by micro-
Hole membrane filtration measures the ultra-violet absorption spectrum of filtrate, and the absorbance at characteristic peak (490nm) is substituted into absorbance-concentration
Standard curve, obtains the concentration value of doxorubicin hydrochloride in filtrate, and calculates release amount of medicine, and doxorubicin hydrochloride is under condition of different pH
Release performance it is as shown in Fig. 6.
Claims (9)
1. a kind of preparation method of the pharmaceutical carrier based on two-dimentional poly phosphazene nanometer sheet and rear-earth-doped up-conversion nanoparticles,
It is characterized in that, includes the following steps：
First hexachlorocyclotriph,sphazene and melamine are proportionally added into solvent, then are added on rear-earth-doped in the mixed solvent
The dispersion liquid and acid binding agent of conversion nanoparticles, then ultrasonic disperse is uniform；React first by solvent-thermal method or ultrasonic method again
Beginning product；Initial product is centrifuged respectively, hot ethanol is washed, wash and dry after must have the multifunctional nano of core-shell structure
Pharmaceutical carrier.
2. preparation method according to claim 1, which is characterized in that the change of the rear-earth-doped up-conversion nanoparticles
Group is nanocrystalline as the NaYF4 of Yb and Ln codope or NaGdF4 is nanocrystalline, wherein one kind or more of Ln Er, Ho and Tm
Kind, the preferably high hexagonal phase of crystallinity is nanocrystalline, having a size of 15~50nm；The concentration of up-conversion nanoparticles in a solvent is
0.1~10mg/mL.
3. preparation method according to claim 1, which is characterized in that the solvent be acetone, tetrahydrofuran, acetonitrile,
One of n,N-Dimethylformamide or two or three of mixture.
4. preparation method according to claim 1, which is characterized in that the concentration of the hexachlorocyclotriph,sphazene in a solvent
For 0.1~10mg/mL；The molar ratio of hexachlorocyclotriph,sphazene and melamine is 1:1.5~1:3.5.
5. preparation method according to claim 1, which is characterized in that the acid binding agent be triethylamine, pyridine or C1~
The molar ratio of the alkoxy pyridines of C3, dosage and hexachlorocyclotriph,sphazene is 1:0.15~1:0.01.
6. preparation method according to claim 1, which is characterized in that the solvent-thermal method be reaction solution is added to it is poly-
In the counteracting tank of tetrafluoroethene liner, counteracting tank is sealed after logical nitrogen deoxygenation, 0.5-24 is handled at a temperature of 100-280 DEG C
Hour.
7. preparation method according to claim 1, which is characterized in that the ultrasonic method is in inert gas shielding environment
Under, reaction solution is ultrasonically treated under the conditions of ultrasonic water bath, ultrasonic treatment condition is：Temperature is 10 DEG C warm to reaction solution reflux
Degree, ultrasonic power are 15~300 watts, and the processing time is 24~240 hours.
8. the nano-medicament carrier being prepared using method according to any one of claims 1 to 7, it is characterized in that：This is more
Function nano pharmaceutical carrier is using rear-earth-doped up-conversion nanoparticles as core, using two-dimentional poly phosphazene nanometer sheet as shell, the poly- phosphine of two dimension
Nitrile nanometer sheet has high proportion surface area structure, can provide space for drug loading；Nitrogen phosphorus in two-dimentional poly phosphazene chemical structure
Hexatomic ring has lone electron pair, electron deficient drug molecule can be adsorbed by electrostatic interaction, and electrostatic interaction has high pH sensibility,
Nano-medicament carrier can discharge adsorbed drug molecule under mildly acidic conditions, realize pH control release；Up-conversion nanoparticles
Have the characteristics that near-infrared excitation, fluorescence penetrates depth and signal-to-noise ratio is high, by two-dimentional poly phosphazene nanometer sheet and up-conversion nanoparticles
Core-shell structure organically combines, and is prepared into the high load amount that is able to achieve, pH sensitivity, the friendly multifunctional nano drug in one of biology and carries
Body.
9. nano-medicament carrier according to claim 8, which is characterized in that the two-dimentional poly phosphazene nanometer sheet is chlordene
Three phosphonitrile of ring and melamine copolymerization, molecular structural formula are：
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