CN103980434B - A kind of amphipathic nature polyalcohol, its preparation method, composite Nano pharmaceutical carrier and preparation method thereof - Google Patents
A kind of amphipathic nature polyalcohol, its preparation method, composite Nano pharmaceutical carrier and preparation method thereof Download PDFInfo
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- CN103980434B CN103980434B CN201410211483.XA CN201410211483A CN103980434B CN 103980434 B CN103980434 B CN 103980434B CN 201410211483 A CN201410211483 A CN 201410211483A CN 103980434 B CN103980434 B CN 103980434B
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Abstract
The invention provides a kind of amphipathic nature polyalcohol with structure shown in Formulas I.Amphipathic nature polyalcohol is used for preparing composite Nano pharmaceutical carrier by the present invention, and composite Nano pharmaceutical carrier includes the Mn of chemical modification2+Rare earth doped up-conversion nanoparticles and amphipathic nature polyalcohol；Described chemical modification is that alkyl chain, silica and sensitising agent are modified, the Mn of chemical modification2+Rare earth doped up-conversion nanoparticles is hydrophobic material.When with near infrared light composite Nano pharmaceutical carrier, Mn2+Near infrared light is converted to ultraviolet light by rare earth doped up-conversion nanoparticles, ultraviolet light promotes sensitising agent to discharge singlet oxygen, singlet oxygen oxidation amphipathic nature polyalcohol, amphipathic nature polyalcohol is transformed into hydrophilic polymer by ultraviolet light, amphipathic nature polyalcohol is caused to come off, medicine can discharge, and drug on tumor cell has good inhibition；The unnecessary singlet oxygen discharged also can have lethal effect to tumour cell, reaches double therapeutic effect.
Description
Technical field
The invention belongs to technical field of polymer, particularly relate to a kind of amphipathic nature polyalcohol, its preparation method,
Composite Nano pharmaceutical carrier and preparation method thereof.
Background technology
Operation, radiation and chemotherapy are traditional three treatment tumour means greatly, and wherein radiation and chemotherapy is killing
While tumour cell, inevitable injuring normal cell, even band can serve serious complication.
Photodynamic therapy is a kind of novel therapies treating tumour grown up the beginning of the seventies in last century, is one
Planting cold light chemical reaction, fundamental is oxygen, sensitising agent and light source.The principle of photodynamic therapy refers to
After sensitising agent enters human body by intravenous injection, can be formed relatively high in tumor tissues in following period of time
The accumulation of concentration, now irradiates tumor tissues with specific wavelength laser, will activate photosensitizer molecule therein,
In tumor tissues, cause a series of photochemical reaction, generate the singlet oxygen that activity is the strongest, so and raw
Thing big molecule generation oxidation reaction, produces cell toxicant, and cell toxicant causes tumour cell impaired or directly kills
Tumour cell.The feature of photodynamic therapy maximum is: have relative selectivity and tissue to tumour cell
Specifically so that it is apply wide.
Sensitising agent in photodynamic therapy fundamental, in the ideal case, tackles biological substrate itself
Harmless；Can absorb the light of certain wavelength, making cancerous tissue is fluorescence reaction, and can destroy cancer cell and align
Often cell is harmless.And sensitising agent of the prior art can only play under conditions of visible ray or ultraviolet light
Effect, it is seen that light or ultraviolet source energy are relatively big, in use, are likely to result in normal physiological
The damage of tissue；And physiological tissue's penetrability of short wavelength light source is poor.It addition, light of the prior art
The result for the treatment of of photodynamic therapy is more single.
Summary of the invention
In view of this, it is an object of the invention to provide a kind of amphipathic nature polyalcohol, its preparation method, answer
Closing nano-medicament carrier and preparation method thereof, the amphipathic nature polyalcohol that the present invention provides is prepared into as raw material
To composite Nano pharmaceutical carrier there is double therapeutic effect.
The invention provides a kind of amphipathic nature polyalcohol, there is structure shown in Formulas I:
Formulas I；
In Formulas I, described x and y is natural number, 1≤x≤5,3≤y≤15；
Described n is the degree of polymerization, 5≤n≤20；
Described R is the alkyl of carbon number 10～20.
Preferably, described 2≤x≤4,4≤y≤10；
6≤n≤9；
Described R is the alkyl of carbon number 13～18.
The invention provides the preparation method of a kind of amphipathic nature polyalcohol, comprise the following steps:
Under the effect of initiator, will have hydrophobic monomer and the poly-second two of structure shown in Formula II
Alcohol methacrylate carries out polymerisation in a solvent, obtains having two of structure shown in Formulas I
Parent's property polymer；
Formula II；
In Formula II, described R is the alkyl of carbon number 10～20.
Preferably, described R is the alkyl of carbon number 13～18.
Preferably, there is described in hydrophobic monomer and the polyethylene glycol methacrylic acid of structure shown in Formula II
The mass ratio of ester is 1:4～8.
Preferably, the temperature of described polymerisation is 65 DEG C～80 DEG C；
The time of described polymerisation is 6h～8h.
The invention provides a kind of composite Nano pharmaceutical carrier, including following components:
The Mn of chemical modification2+Rare earth doped up-conversion nanoparticles；
With the Mn being wrapped in described chemical modification2+The amphipathic on rare earth doped up-conversion nanoparticles surface
Compound；
Described chemical modification is that alkyl chain, silica and sensitising agent are modified；
Described amphipathic nature polyalcohol is the amphipathic nature polyalcohol described in technique scheme.
Preferably, the Mn of described chemical modification2+Rare earth doped up-conversion nanoparticles and amphipathic nature polyalcohol
Mass ratio be 1:5～7.
Preferably, described sensitising agent includes eosin and/or porphyrin.
The invention provides the preparation method of a kind of composite Nano pharmaceutical carrier, comprise the following steps:
By the Mn of chemical modification2+Rare earth doped up-conversion nanoparticles is with amphipathic nature polyalcohol in a solvent
Carry out self assembly, obtain composite Nano pharmaceutical carrier；
Described amphipathic nature polyalcohol is the amphipathic nature polyalcohol described in technique scheme.
The invention provides a kind of amphipathic nature polyalcohol with structure shown in Formulas I.The present invention will have formula
The amphipathic nature polyalcohol of structure shown in I is used for preparing composite Nano pharmaceutical carrier, and described composite Nano medicine carries
Body includes the Mn of chemical modification2+Rare earth doped up-conversion nanoparticles and be wrapped in described chemical modification
Mn2+The amphipathic nature polyalcohol on rare earth doped up-conversion nanoparticles surface；Described amphipathic nature polyalcohol has
Structure shown in Formulas I, described chemical modification is that alkyl chain, silica and sensitising agent are modified, and described chemistry is repaiied
The Mn of decorations2+Rare earth doped up-conversion nanoparticles is hydrophobic material.The amphipathic that the present invention provides
Compound and the Mn of described chemical modification2+Rare earth doped up-conversion nanoparticles passes through Van der Waals force phase interaction
With, it is achieved amphipathic nature polyalcohol and the Mn of described chemical modification2+Rare earth doped up-conversion nanoparticles from
Assembling, amphipathic nature polyalcohol is wrapped in the Mn of described chemical modification2+Rare earth doped up-conversion nanoparticles
Surface, forms the composite Nano pharmaceutical carrier with nucleocapsid structure.When using near infrared light composite Nano
During pharmaceutical carrier, the Mn of chemical modification2+Near infrared light can be changed by rare earth doped up-conversion nanoparticles
For high frequency ultraviolet light, ultraviolet light promotes sensitising agent to discharge singlet oxygen, singlet oxygen oxidation amphipathic
Compound, amphipathic nature polyalcohol is transformed into hydrophilic polymer by ultraviolet light, causes amphipathic nature polyalcohol from institute
State the Mn of chemical modification2+The surface of rare earth doped up-conversion nanoparticles comes off, and medicine can discharge,
Drug on tumor cell has good inhibition；The unnecessary singlet oxygen discharged also can be to tumour
Cell has lethal effect, reaches double therapeutic effect.
It addition, the composite Nano pharmaceutical carrier that the present invention provides is controlled by the near infrared light that energy is more weak,
On the one hand can be with the time of Drug controlled release and position；On the other hand can also reduce normal physiological group
The infringement knitted.
Accompanying drawing explanation
Fig. 1 is the Mn in the embodiment of the present invention 12+Rare earth doped up-conversion nanoparticles, chemical modification
Mn2+The transmission electron microscope picture of rare earth doped up-conversion nanoparticles；
Fig. 2 is the Mn in the embodiment of the present invention 12+Rare earth doped up-conversion nanoparticles, chemical modification
Mn2+The grain size distribution of rare earth doped up-conversion nanoparticles；
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the amphipathic nature polyalcohol in the embodiment of the present invention 1；
Fig. 4 is the transmission electron microscope picture of the composite Nano pharmaceutical carrier that the embodiment of the present invention 1 obtains；
Fig. 5 is the grain size distribution of the composite Nano pharmaceutical carrier that the embodiment of the present invention 1 obtains；
Fig. 6 is insoluble drug release and the singlet oxygen release song of the pharmaceutical composition that the embodiment of the present invention 1 obtains
Line chart；
Fig. 7 be the pharmaceutical composition that obtains of the embodiment of the present invention 1 and composite Nano pharmaceutical carrier thin to tumour
The inhibition figure of born of the same parents.
Detailed description of the invention
The invention provides a kind of amphipathic nature polyalcohol, there is structure shown in Formulas I:
Formulas I；
In Formulas I, described x and y is natural number, 1≤x≤5,3≤y≤15；
Described n is the degree of polymerization, 5≤n≤20；
Described R is the alkyl of carbon number 10～20.
In the present invention, described x is natural number, 1≤x≤5, preferably 2≤x≤4；
Described y is natural number, 3≤y≤15, preferably 4≤y≤10；
Described n is the degree of polymerization, 5≤n≤20, preferably 6≤n≤9；
Described R is the alkyl of carbon number 10～20, preferably the alkyl of carbon number 13～18.
The invention provides the preparation method of a kind of amphipathic nature polyalcohol, comprise the following steps:
Under the effect of initiator, will have hydrophobic monomer and the poly-second two of structure shown in Formula II
Alcohol methacrylate carries out polymerisation in a solvent, obtains having two of structure shown in Formulas I
Parent's property polymer；
Formula II；
In Formula II, described R is the alkyl of carbon number 10～20, preferably the alkane of carbon number 13～18
Base.
The present invention does not has special restriction to the source of the described hydrophobic monomer with structure shown in Formula II,
Use the hydrophobic monomer with structure shown in Formula II well known to those skilled in the art, as adopted
Commercial goods with the hydrophobic monomer with structure shown in Formula II, it would however also be possible to employ those skilled in the art
Known to the technical scheme of the preparation hydrophobic monomer with structure shown in Formula II prepare voluntarily, as adopted
It is that method disclosed in CN201310121989.7 is prepared with number of patent application；；Concrete, at this
In bright, described in there is structure shown in Formula II the preparation method of hydrophobic monomer preferably include following steps:
Anthraquinone, trimethylene iodohydrin and sodium dithionite are reacted in a solvent, obtains the first chemical combination
Thing；
Described first compound is reacted in a solvent with alkyl acyl chloride, obtains the second compound, institute
State the alkyl that the alkyl in alkyl acyl chloride is carbon number 10～20；
Described second compound is reacted with methacrylic chloride, obtains having structure shown in Formula II
Hydrophobic monomer.
Anthraquinone, trimethylene iodohydrin and sodium dithionite are reacted by the present invention in a solvent, obtain the first change
Compound.The present invention reacts the most in the presence of a catalyst.The present invention is in order to improve between reaction raw materials
Compatibility, improve reaction efficiency, the most first by anthraquinone, sodium dithionite and catalyst the most in a solvent
Mixing, is added thereto to alkali compounds after stirring, be added thereto to trimethylene iodohydrin after continuing stirring,
The first compound is obtained after reaction.
The present invention does not has special restriction to the source of described catalyst, uses those skilled in the art to know
Catalyst, such as the commercial goods that the trade mark can be used to be adogen (Adogen).?
In the present invention, described catalyst is preferably methyl tricapryl ammonium chloride or methyl three agent in heptan ammonium chloride.
The present invention is in order to distinguish the solvent in following technical proposals, by anthraquinone, trimethylene iodohydrin and Lian Erya
Named first solvent of solvent used when sodium sulphate reacts.In the present invention, described first solvent
It is preferably water and the mixed solution of dichloromethane；The present invention preferably by after saturated for water nitrogen again with dichloromethane
Alkane mixes, and obtains the mixed solution of water and dichloromethane；Described water is preferably with the volume ratio of dichloromethane
1:(1～5), more preferably 1:1.In the present invention, the quality of described anthraquinone and the volume ratio of the first solvent are excellent
Elect 1mg:(100～150 as) mL, more preferably 1mg:(105～140) mL；Described alkali compounds is preferred
For hydroxide, more preferably NaOH or potassium hydroxide.
In the present invention, the mass ratio of described anthraquinone, trimethylene iodohydrin and sodium dithionite is preferably
1:(1～5): (1～5), more preferably 1:2:3；The mass ratio of described anthraquinone and catalyst is preferably 1:(1～4),
More preferably 1:2；Described anthraquinone is preferably 1:(1～3 with the mass ratio of described alkali compounds), more preferably
1:2。
In the present invention, after described anthraquinone, sodium dithionite and catalyst mixing, the time of stirring is preferred
For 3min～10min, more preferably 5min～8min；The time stirred after adding alkali compounds is preferred
For 8min～12min, more preferably 10min；The reactant that preferably will obtain after adding trimethylene iodohydrin
Solution is stirred at room temperature overnight, and obtains the first compound.
The product completing above-mentioned reaction is preferably stood by the present invention, the dichloromethane that will obtain after layering
Wash mutually, be dried, filter, freezing precipitation separates with chromatographic column, obtains the first compound.The present invention couple
The method of described standing does not has special restriction, uses standing technical scheme well known to those skilled in the art
?；The solvent of described washing is preferably water, and the number of times of described washing is preferably 2 times～3 times, more preferably
It it is 2 times；Product after washing is preferably used anhydrous magnesium sulfate to be dried by the present invention, will obtain after filtration
Solid is freezing at-30 DEG C～-10 DEG C to be separated out, more preferably-25 DEG C～-15 DEG C, most preferably-20 DEG C；This
The bright method separating described chromatographic column does not has special restriction, uses look well known to those skilled in the art
The technical scheme that spectrum post separates, present invention preferably employs ethyl acetate and dichloromethane that volume ratio is 1:4
Alkane carries out chromatographic column separation as the eluant, eluent solid to obtaining.
After obtaining the first compound, the present invention by described first compound and alkyl acyl chloride in the second solvent
Reaction, obtains the second compound, and the alkyl in described alkyl acyl chloride is the alkyl of carbon number 10～20.
First compound and pyridine are preferably dissolved in the second solvent by the present invention, then react with described alkyl acyl chloride,
Obtain the second compound；The mass ratio of described first compound and pyridine is preferably (1～5): 1, more preferably
4:1.In the present invention, described pyridine is acid binding agent, it is to avoid the acid that reaction generates affects molecular balance.
In the present invention, the preferably carbonic acid atomicity of the alkyl in described alkyl acyl chloride is the alkyl of 13～18；
More preferably stearyl chloride；Described second solvent is preferably dichloromethane；The quality of described first compound,
The quality of alkyl acyl chloride and the volume ratio of the second solvent are preferably (0.3～0.5) mg:(0.1～0.25) mg:100
ML, more preferably (0.35～0.45) mg:(0.15～0.20) mg:100mL；Described first compound and alkyl
The temperature of acyl chloride reaction is preferably 10 DEG C～40 DEG C, more preferably 20 DEG C～30 DEG C；Described first compound with
The time of alkyl acyl chloride reaction is preferably 1.5h～2.5h, more preferably 2h.
After obtaining the second compound, the second compound and methacrylic chloride are reacted by the present invention,
To the hydrophobic monomer with structure shown in Formula II.The present invention is preferably by described second compound and triethylamine
Being dissolved in the 3rd solvent, the reaction of dropping methacrylic chloride, obtains having formula the most wherein
The hydrophobic monomer of structure shown in II.In the present invention, described 3rd solvent is preferably dichloromethane；Institute
The volume ratio of the quality and the 3rd solvent of stating the second compound is preferably (0.2～0.35) mg:100mL, more excellent
Elect (0.25～0.30) mg:100mL as.In the present invention, described triethylamine is acid binding agent, it is to avoid reaction is raw
The acid become affects molecular balance.
In the present invention, the mass ratio of described second compound and triethylamine is preferably (1～5): 1, more preferably
For (2～3): 1；The mass ratio of described second compound and methacrylic chloride is preferably (1～3): 1, more preferably
For (1.5～2.5): 1；The temperature of described second compound and methacrylic chloride reaction is preferably 10 DEG C～40 DEG C,
More preferably 20 DEG C～30 DEG C；The time that described second compound and methacrylic chloride react is preferably 1.5
H～2.5h, more preferably 2h.
Second compound and methacrylic chloride are preferably reacted the crude product obtained and carry out chromatographic column by the present invention
Separate, obtain the hydrophobic monomer with structure shown in Formula II.The side that described chromatographic column is separated by the present invention
Method does not has special restriction, uses the technical scheme that chromatographic column well known to those skilled in the art separates.
Present invention preferably employs ethyl acetate that volume ratio is 1:20 and dichloromethane is thick to obtain as eluant, eluent
Product carries out chromatographic column separation.
The present invention does not has special restriction to the source of described polyethylene glycol methacrylate-styrene polymer, uses ability
Polyethylene glycol methacrylate-styrene polymer known to field technique personnel, as used polyethylene glycol methyl-prop
The commercial goods of olefin(e) acid ester, it would however also be possible to employ well known to those skilled in the art prepare polyethylene glycol methyl-prop
The technical scheme of olefin(e) acid ester is prepared voluntarily, and the present invention does not has special restriction to this.
In the present invention, there is described in hydrophobic monomer and the polyethylene glycol methyl of structure shown in Formula II
The mass ratio of acrylate is preferably 1:4～8, more preferably 1:5～7, most preferably 1:6.
In the present invention, one during described initiator preferably includes peroxide and azo compound or
Multiple, more preferably include one or more in azo two isonitrile, calper calcium peroxide and di-t-butyl peroxide；
The mass ratio of the described hydrophobic monomer with structure shown in Formula II and initiator is preferably
100:(0.5～2), more preferably 100:(0.8～1.5), most preferably 100:1.
In the present invention, there is described in hydrophobic monomer and the polyethylene glycol methyl of structure shown in Formula II
Acrylate carries out polymerisation in the 4th solvent；It is sub-that described 4th solvent preferably includes diformazan
One or more in sulfone, dimethylformamide and cyclohexanone, more preferably include dimethyl sulfoxide and dimethyl
One or both in formamide, most preferably dimethyl sulfoxide；The quality of described initiator and the 4th solvent
Volume ratio be preferably 1mg:(1～5) mL, more preferably 1mg:(2～4) mL, most preferably 1
Mg:(2.5～3.5) mL.
The present invention preferably carries out polymerisation under the protection of nitrogen or inert gas.In the present invention, institute
State inert gas and be preferably argon gas or helium.In the present invention, the temperature of described polymerisation is preferably 65 DEG C
～80 DEG C, more preferably 70 DEG C～75 DEG C；The time of described polymerisation is preferably 6h～8h, more preferably
6.5h～7.5h, most preferably 7h.
After completing polymerisation, obtaining polymeric reaction solution, described polymeric reaction solution includes polymerizate,
The polymerizate solution obtained preferably is separated out polymerizate in the 5th solvent by the present invention, obtains amphipathic
Polymer.In the present invention, described 5th solvent preferably includes ether and/or n-hexane, more preferably second
Ether；The quality of the described hydrophobic monomer with structure shown in Formula II and the volume ratio of the 5th solvent are preferably
1mg～(1～5) mL, more preferably 1mg～(2～4) mL.
The present invention amphipathic nature polyalcohol to obtaining carries out proton nmr spectra qualification, and qualification result shows:
The amphipathic nature polyalcohol that the present invention provides has structure shown in Formulas I.
The invention provides a kind of composite Nano pharmaceutical carrier, including following components:
The Mn of chemical modification2+Rare earth doped up-conversion nanoparticles；
With the Mn being wrapped in described chemical modification2+The amphipathic on rare earth doped up-conversion nanoparticles surface
Compound；
Described chemical modification is that alkyl chain, silica and sensitising agent are modified；
Described amphipathic nature polyalcohol is the amphipathic polymerization described in technique scheme with structure shown in Formulas I
Thing.
The composite Nano pharmaceutical carrier that the present invention provides includes the Mn of chemical modification2+Rare earth doped upper conversion is received
Rice corpuscles, described chemical modification is that alkyl chain, silica and sensitising agent are modified.In the present invention, institute
The preparation method of the rare earth upconversion nano particle stating chemical modification preferably includes following steps:
By Mn2+Rare earth doped up-conversion nanoparticles reacts with tetraethyl orthosilicate, obtains titanium dioxide
The Mn that silicon is modified2+Rare earth doped up-conversion nanoparticles；
By hexadecyl trimethoxy silane and described silicon dioxide modified Mn2+Rare earth doped upper conversion is received
Rice corpuscles reacts, and obtains alkyl chain and silicon dioxide modified Mn2+Rare earth doped upper conversion nano grain
Son；
By activation sensitising agent, gamma-aminopropyl-triethoxy-silane and described alkyl chain and silicon dioxide modified
Mn2+Rare earth doped up-conversion nanoparticles reacts, and obtains the Mn of chemical modification2+Rare earth doped upper turn
Change nano particle.
The present invention is by Mn2+Rare earth doped up-conversion nanoparticles reacts with tetraethyl orthosilicate, obtains
Silicon dioxide modified Mn2+Rare earth doped up-conversion nanoparticles.The present invention is to described Mn2+Rare earth doped
The order of up-conversion nanoparticles and tetraethyl orthosilicate mixing does not has special restriction, preferably contains described
Tetraethyl orthosilicate joins Mn2+In rare earth doped up-conversion nanoparticles.In the present invention, described
Mn2+The quality of rare earth doped up-conversion nanoparticles and the volume ratio of tetraethyl orthosilicate are preferably (6～8)
Mg:(0.05～0.1) mL, more preferably (6.5～7.5) mg:(0.06～0.09) mL.
The present invention is to described Mn2+The source of rare earth doped up-conversion nanoparticles does not has special restriction, adopts
Use Mn well known to those skilled in the art2+Rare earth doped up-conversion nanoparticles, as used
Mn2+The commercial goods of rare earth doped up-conversion nanoparticles, it would however also be possible to employ those skilled in the art know
Preparation Mn2+The technical scheme of rare earth doped up-conversion nanoparticles is prepared voluntarily；Described Mn2+Adulterate dilute
Rare earth element in soil up-conversion nanoparticles preferably includes one or more in Y, Yb and Er；Specifically
, described Mn2+Rare earth doped up-conversion nanoparticles can use document (Chao Wangetc., Adv.
Funct.Mater.2013,23,3077) method described in prepares.In the present invention, described Mn2+Mix
The diameter of miscellaneous rare earth upconversion nano particle is preferably 20nm～30nm.
In the present invention, described Mn2+Rare earth doped up-conversion nanoparticles and tetraethyl orthosilicate preferably exist
6th solvent reacts, obtains silicon dioxide modified Mn2+Rare earth doped up-conversion nanoparticles.
In the present invention, described 6th solvent preferably includes chloroform and/or oxolane, more preferably chloroform.This
Invention is preferably by Mn2+Rare earth doped up-conversion nanoparticles first mixes with the 6th solvent, then with positive silicic acid four
Ethyl ester mixes, and reacts, obtains silicon dioxide modified Mn2+Rare earth doped up-conversion nanoparticles.
The present invention is in order to promote Mn2+Rare earth doped up-conversion nanoparticles and the carrying out of tetraethyl orthosilicate reaction,
Preferably at Mn2+Rare earth doped up-conversion nanoparticles and the 6th solvent add surfactant and NaOH
Solution.In the present invention, described surfactant preferably includes cetyl ammonium bromide, cetyl three
One or more in methyl bromide ammonium and neopelex, more preferably cetyl
Ammonium bromide；The mass fraction of described surfactant is preferably 5mmol/L～6mmol/L, more preferably
5.2mmol/L～5.8mmol/L；The mass fraction of described NaOH solution is preferably 1.0mmol/L～2.0
Mmol/L, more preferably 1.2mmol/L～1.8mmol/L；Live in the volume of described NaOH solution, surface
The volume of property agent and Mn2+The mass ratio of rare earth doped up-conversion nanoparticles is preferably (1～5) mL:(1～5)
ML:1mg, more preferably (2～3) mL:(2～3) mL:1mg；The volume of described 6th solvent and Mn2+Mix
The mass ratio of miscellaneous rare earth upconversion nano particle is preferably 1mL:(5～10) mg, more preferably 1mL:(6～9)
Mg, most preferably 1mL:(7～8) mg.
In the present invention, described Mn2+Rare earth doped up-conversion nanoparticles and tetraethyl orthosilicate are carried out instead
The temperature answered is preferably 50 DEG C～55 DEG C, more preferably 55 DEG C；The time of described reaction is preferably 3h～4h,
More preferably 4h.
Complete Mn2+After the reaction of rare earth doped up-conversion nanoparticles and tetraethyl orthosilicate, the present invention is excellent
Remaining surfactant is removed by choosing.The mode that described surfactant is removed by the present invention is the most special
Restriction, it is preferred to use reflux type well known to those skilled in the art remove remaining surfactant；
The temperature of described backflow is preferably 78 DEG C～85 DEG C, more preferably 80 DEG C.
Obtain silicon dioxide modified Mn2+After rare earth doped up-conversion nanoparticles, the present invention is by hexadecane
Base trimethoxy silane and described silicon dioxide modified Mn2+Rare earth doped up-conversion nanoparticles is carried out
Reaction, obtains alkyl chain and silicon dioxide modified Mn2+Rare earth doped up-conversion nanoparticles.The present invention
To described silicon dioxide modified Mn2+Rare earth doped up-conversion nanoparticles and hexadecyl trimethoxy
The order of silane mixture does not has special restriction, is preferably added by described hexadecyl trimethoxy silane
To described silicon dioxide modified Mn2+In rare earth doped up-conversion nanoparticles.In the present invention, described
The volume of hexadecyl trimethoxy silane and Mn2+The mass ratio of rare earth doped up-conversion nanoparticles
It is preferably (0.1～0.3) mL:(6～8) mg, more preferably (0.15～0.25) mL:(6.5～7.5) mg.
In the present invention, described hexadecyl trimethoxy silane and described silicon dioxide modified Mn2+Mix
Miscellaneous rare earth upconversion nano particle preferably reacts in the 7th solvent.In the present invention, the described 7th
Solvent is preferably one or more in alcohol compound, more preferably in ethanol, propyl alcohol and butanol
Plant or multiple, more preferably ethanol；Described 7th solvent and the volume ratio of hexadecyl trimethoxy silane
It is preferably (0.1～0.5): (3～6), more preferably (0.15～0.35): (3.5～5).
In the present invention, described silicon dioxide modified Mn2+Rare earth doped up-conversion nanoparticles and 16
The temperature that alkyl trimethoxysilane carries out reacting is preferably 78 DEG C～85 DEG C, more preferably 80 DEG C；Institute
The time stating reaction is preferably 10h～15h, more preferably 12h.
Obtain alkyl chain and silicon dioxide modified Mn2+After rare earth doped up-conversion nanoparticles, the present invention
Preferably by activation sensitising agent, gamma-aminopropyl-triethoxy-silane and described alkyl chain and silicon dioxide modified
Mn2+Rare earth doped up-conversion nanoparticles reacts, and obtains the Mn of chemical modification2+Rare earth doped upper turn
Change nano particle.The present invention is to described activation sensitising agent, gamma-aminopropyl-triethoxy-silane and described alkyl chain
With silicon dioxide modified Mn2+The order of rare earth doped up-conversion nanoparticles mixing does not has special limit
System, is preferably added sequentially to described alkyl chain by described activation sensitising agent and gamma-aminopropyl-triethoxy-silane
With silicon dioxide modified Mn2+In rare earth doped up-conversion nanoparticles.
The present invention does not has special restriction to the source of activation sensitising agent, uses those skilled in the art to know
Activation sensitising agent, as can use activation sensitising agent commercial goods, it would however also be possible to employ this area
The technical scheme of the preparation activation sensitising agent known to technical staff is prepared voluntarily；Concrete, in the present invention,
The preparation method of described activation sensitising agent preferably includes following steps:
Sensitising agent is activated in the 8th solvent, obtains activating sensitising agent.
In the present invention, described 8th solvent is preferably 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide
And the dimethyl sulphoxide solution of N-hydroxysuccinimide mixture (EDC)；Described sensitising agent preferably includes
Eosin and/or porphyrin, more preferably chlorin-e6；The quality of described sensitising agent, the matter of EDC
The volume ratio of amount, the quality of N-hydroxysuccinimide and dimethyl sulfoxide (DMSO) is preferably (23～28) mg:(5～10)
Mg:(3～8) mg:5mL, more preferably (24～26) mg:(6～9) mg:(4～7) mg:5mL.In the present invention,
The temperature of described activation is preferably 20 DEG C～30 DEG C, more preferably 25 DEG C；The time of described activation is preferably
25min～35min, more preferably 30min.
In the present invention, described activation sensitising agent and described alkyl chain and silicon dioxide modified Mn2+Doping
The mass ratio of rare earth upconversion nano particle is preferably 1:(2～7), more preferably 1:(3～6).
The present invention preferably carries out described activation sensitising agent and described alkyl chain and titanium dioxide under conditions of stirring
The Mn that silicon is modified2+The reaction of rare earth doped up-conversion nanoparticles；The temperature of described reaction is preferably 78 DEG C
～85 DEG C, more preferably 80 DEG C；The time of described reaction is preferably 20h～28h, more preferably 22h～24
H, most preferably 24h.
Complete sensitising agent and described alkyl chain and silicon dioxide modified Mn2+Rare earth doped upper conversion nano grain
After the reaction of son, product is preferably centrifuged and washs by the present invention, obtains the Mn of chemical modification2+
Rare earth doped up-conversion nanoparticles.The present invention does not has special restriction to described centrifugal and washing method,
Use the well known to those skilled in the art centrifugal and technical scheme of washing.
The composite Nano pharmaceutical carrier that the present invention provides includes the Mn being wrapped in described chemical modification2+Adulterate dilute
The amphipathic nature polyalcohol on soil up-conversion nanoparticles surface.The present invention uses amphiphilic described in technique scheme
Property polymer, repeats no more the source of amphipathic nature polyalcohol at this.
In the present invention, described amphipathic nature polyalcohol and the Mn of described chemical modification2+Rare earth doped upper conversion
The mass ratio of nano particle is preferably 5～7:1, more preferably 5.5～6.5:1, most preferably 6:1.
The invention provides the preparation method of a kind of composite Nano pharmaceutical carrier, comprise the following steps:
By the Mn of chemical modification2+Rare earth doped up-conversion nanoparticles is with amphipathic nature polyalcohol in a solvent
Carry out self assembly, obtain composite Nano pharmaceutical carrier；
Described amphipathic nature polyalcohol is the amphipathic nature polyalcohol described in technique scheme.
The present invention uses the Mn of chemical modification described in technique scheme2+Rare earth doped upper conversion nano grain
Son, the Mn to described chemical modification at this2+The source of rare earth doped up-conversion nanoparticles and kind are no longer
Repeat.
The present invention uses amphipathic nature polyalcohol described in technique scheme, carrys out amphipathic nature polyalcohol at this
Source repeats no more.
In the present invention, described amphipathic nature polyalcohol and the Mn of described chemical modification2+Rare earth doped upper conversion
The mass ratio of nano particle is preferably 1:5～7, more preferably 1:5.5～6.5, most preferably 1:6.
Amphipathic nature polyalcohol, in order to distinguish solvent described in technique scheme, is repaiied by the present invention with described chemistry
The Mn of decorations2+It is named 9th molten that rare earth doped up-conversion nanoparticles carries out the solvent of employing during self assembly
Agent.In the present invention, described 9th solvent is preferably oxolane and/or chloroform；Described 9th solvent
Volume is preferably 1mL:(25～35 with the mass ratio of amphipathic nature polyalcohol) mg, more preferably 1mL:(20～30)
mg.The present invention is preferably by amphipathic nature polyalcohol, the doping metal particles rare earth upconversion nano of chemical modification
Carry out ultrasonic after particle and the mixing of the 9th solvent, make each component be uniformly dispersed in the 9th solvent, then enter
Row self assembly.In the present invention, the described ultrasonic time is preferably 10min～60min；More preferably 20
Min～30min.
In the present invention, the temperature of described self assembly is preferably 15 DEG C～40 DEG C, more preferably 20 DEG C～30 DEG C,
Most preferably 25 DEG C；The time of described self assembly is preferably 12h～48h, more preferably 13h～25h,
It is preferably 24h.
9th solvent, after self assembly terminates, is preferably removed, obtains composite Nano pharmaceutical carrier by the present invention.
The present invention, in order to be beneficial to remove the 9th solvent, is preferably added to water in self assembly product, then passes through solvent
9th solvent is removed by the method for volatilization；The present invention preferably accelerates rate of volatilization by the by the method for stirring
Nine solvents remove.In the present invention, the volume ratio of described water and the 9th solvent is preferably 1:(3～8), more excellent
Elect 1:(4～7 as), most preferably 1:5.
Composite Nano pharmaceutical carrier described in technique scheme is carried out medicine carrying by the present invention, and described being combined is received
Rice pharmaceutical carrier carries out the preparation method of medicine carrying, preferably includes following steps:
Chemical modification rare earth upconversion nano particle is mixed with drug solution, obtains the chemistry of carrying medicament
The Mn modified2+Rare earth doped up-conversion nanoparticles；
Mn by the chemical modification of described carrying medicament2+Rare earth doped up-conversion nanoparticles and described amphiphilic
Property polymer carries out self assembly in the tenth solvent, completes medicine carrying, obtains pharmaceutical composition.
The present invention is by the Mn of chemical modification2+Rare earth doped up-conversion nanoparticles mixes with drug solution,
Mn to the chemical modification being loaded with medicine2+Rare earth doped up-conversion nanoparticles.The present invention is to describedization
Learn the Mn modified2+The method that rare earth doped up-conversion nanoparticles mixes with drug solution does not has special limit
System, uses the technical scheme that pharmaceutical carrier well known to those skilled in the art mixes with drug solution.
In the present invention, described amphipathic nature polyalcohol and the Mn of described chemical modification2+Rare earth doped upper conversion
The mass ratio of nano particle is preferably 5～7:1, more preferably 5.5～6.5:1, most preferably 6:1.
The present invention uses the Mn of chemical modification described in technique scheme2+Rare earth doped upper conversion nano grain
Son, does not repeats them here.The present invention does not has special restriction to concentration and the kind of described drug solution,
Those skilled in the art need the drug solution concentration needed for using and kind according to actual clinical.
Obtain the Mn of the chemical modification of carrying medicament2+After rare earth doped up-conversion nanoparticles, the present invention will
The Mn of the chemical modification of described carrying medicament2+Rare earth doped up-conversion nanoparticles and amphipathic nature polyalcohol exist
7th solvent carries out self assembly, obtains pharmaceutical composition.In the present invention, the change of described carrying medicament
Learn the Mn modified2+Have between alkyl chain and the amphipathic nature polyalcohol on rare earth doped up-conversion nanoparticles surface
There is stronger pattern ylid Chuihua molecule intermolecular forces, carry out self assembly so that amphipathic nature polyalcohol is wrapped in load
The Mn of the chemical modification of medicine2+The surface of rare earth doped up-conversion nanoparticles, completes medicine carrying, obtains medicine
Compositions.
The present invention Mn to the chemical modification of described carrying medicament2+Rare earth doped up-conversion nanoparticles, two
The order by merging of parent's property polymer and the tenth solvent does not has special restriction, preferably by described amphipathic polymerization
Thing and the mixing of the tenth solvent, then the Mn of the chemical modification with described carrying medicament2+Rare earth doped upper conversion is received
Rice corpuscles mixes.In the present invention, described tenth solvent is preferably oxolane and/or chloroform；Described
The volume of ten solvents and the mass ratio of amphipathic nature polyalcohol are preferably 1mL:(25～35) mg, more preferably 1
ML:(20～30) mg.
In the present invention, the temperature of described self assembly is preferably 15 DEG C～40 DEG C, more preferably 20 DEG C～30 DEG C,
Most preferably 25 DEG C；The time of described self assembly is preferably 12h～48h, more preferably 13h～25h,
It is preferably 24h.
The present invention, as a example by adriamycin, carries out medicine carrying to described composite Nano pharmaceutical carrier, and detailed process is such as
Under:
It is 25mg/mL by the chemical modification rare earth upconversion nano particle of 10mg and 5mL mass concentration
The adriamycin aqueous solution mixing, obtain load adriamycin chemical modification rare earth upconversion nano particle；
By the chemical modification rare earth upconversion nano particle of described load adriamycin with amphipathic nature polyalcohol four
Hydrogen furans carries out self assembly, obtains loading the composite Nano pharmaceutical carrier of adriamycin.
The invention provides a kind of amphipathic nature polyalcohol with structure shown in Formulas I.The present invention will have formula
The amphipathic nature polyalcohol of structure shown in I is used for preparing composite Nano pharmaceutical carrier, and described composite Nano medicine carries
Body includes the Mn of chemical modification2+Rare earth doped up-conversion nanoparticles and be wrapped in described chemical modification
Mn2+The amphipathic nature polyalcohol on rare earth doped up-conversion nanoparticles surface；Described amphipathic nature polyalcohol has
Structure shown in Formulas I, described chemical modification is that alkyl chain, silica and sensitising agent are modified, and described chemistry is repaiied
The Mn of decorations2+Rare earth doped up-conversion nanoparticles is hydrophobic material.The amphipathic that the present invention provides
Compound and the Mn of described chemical modification2+Rare earth doped up-conversion nanoparticles passes through Van der Waals force phase interaction
With, it is achieved amphipathic nature polyalcohol and the Mn of described chemical modification2+Rare earth doped up-conversion nanoparticles from
Assembling, amphipathic nature polyalcohol is wrapped in the Mn of described chemical modification2+Rare earth doped up-conversion nanoparticles
Surface, forms the composite Nano pharmaceutical carrier with nucleocapsid structure.When using near infrared light composite Nano
During pharmaceutical carrier, near infrared light can be converted to high frequency ultraviolet light, ultraviolet by rare earth upconversion nano particle
Light promotes sensitising agent to discharge singlet oxygen, and singlet oxygen oxidation amphipathic nature polyalcohol, ultraviolet light is by amphiphilic
Property polymer transition becomes hydrophilic polymer, causes amphipathic nature polyalcohol from the Mn of described chemical modification2+Mix
The surface of miscellaneous rare earth upconversion nano particle comes off, and medicine can discharge, and drug on tumor cell has
There is good inhibition；The unnecessary singlet oxygen discharged also can have lethal effect to tumour cell,
Reach double therapeutic effect.
It addition, the composite Nano pharmaceutical carrier that the present invention provides is controlled by the near infrared light that energy is more weak,
On the one hand can be with the time of Drug controlled release and position；On the other hand can also reduce normal physiological group
The infringement knitted.
In order to further illustrate the present invention, a kind of amphipathic present invention provided below in conjunction with embodiment
Compound, its preparation method, composite Nano pharmaceutical carrier and preparation method thereof are described in detail, but not
They can be interpreted as limiting the scope of the present invention.
Embodiment 1
By the MnCl of 1.2mL0.5mol/L2, the Y (NO of 2mL0.5mol/L3)3、1.8mL0.2mol/L
Yb (NO3)3Er (NO with 0.2mL0.2mol/L3)3Joining in mixed liquor, described mixed liquor comprises
0.6gNaOH、3mLH2O, 10mL oleic acid and 20mL ethanol；Then 4mL is contained 8mmolNaF
The aqueous solution be added drop-wise in above-mentioned mixed liquor, stirring 15min after, pour 60mL polytetrafluoroethyllining lining into
Reactor in, at 200 DEG C heat 8h, be centrifuged after cooling, obtain Mn2+Rare earth doped upper turn
Change nano particle (Mn2+The UCNP of doping)；
By 7.5mg Mn2+The UCNP of doping is dispersed in 1mL chloroform, is subsequently poured into 10mL0.1
In the cetyl ammonium bromide solution of mol/L, ultrasonic to clear, after being centrifuged and washing 2 times with water, point
It is dissipated in 10mL5.4mmol/L cetyl ammonium bromide and 1.4mmol/LNaOH solution, drips at 55 DEG C
Adding 0.075mL tetraethyl orthosilicate, after 4h, centrifuge washing obtains silicon dioxide modified Mn2+Doping
Rare earth upconversion nano particle (UCNP@SiO2)；
By 25mg chlorin-e6, at 8mg EDC (1.0eq) and the DMSO of 5mg NHS (1.0eq)
Solution activates 30min, obtains activating chlorin-e6；
The present invention uses alcohol reflux mode to remove unreacted cetyl ammonium bromide at 80 DEG C；To removing
Remove the UCNP@SiO of cetyl ammonium bromide2Middle addition 0.2mL cetyl trimethyl siloxanes, 12h
Rear centrifuge washing；Gained is centrifuged product be dispersed in 5mL ethanol, adds gamma-aminopropyl-triethoxy silicon
Alkane, activation chlorin-e6, stirring, it is centrifuged after reaction 24h washing with ethanol, obtains chemistry and repair
The Mn of decorations2+Rare earth doped up-conversion nanoparticles (CCUCNPs)；
The present invention Mn to obtaining2+Rare earth doped up-conversion nanoparticles and the Mn of chemical modification2+Adulterate dilute
Soil up-conversion nanoparticles carries out transmission electron microscopy respectively, implements as it is shown in figure 1, Fig. 1 is the present invention
Mn in example 12+Rare earth doped up-conversion nanoparticles, the Mn of chemical modification2+Rare earth doped upper conversion is received
The transmission electron microscope picture of rice corpuscles；Wherein, a is Mn2+The transmission electron microscope of rare earth doped up-conversion nanoparticles
Figure, b is the Mn of chemical modification2+The transmission electron microscope picture of rare earth doped up-conversion nanoparticles.Can from Fig. 1
To find out, the Mn of chemical modification2+There is obvious silica on rare earth doped up-conversion nanoparticles surface,
Silicon dioxide layer surface after alkyl chain and sensitising agent are modified still remains intact.
The present invention Mn to obtaining2+Rare earth doped up-conversion nanoparticles and the Mn of chemical modification2+Adulterate dilute
Soil up-conversion nanoparticles carries out dynamic light scattering test, as in figure 2 it is shown, Fig. 2 is the embodiment of the present invention 1
In Mn2+Rare earth doped up-conversion nanoparticles, the Mn of chemical modification2+Rare earth doped upper conversion nano grain
The grain size distribution of son, wherein,For Mn2+The grain size distribution of rare earth doped up-conversion nanoparticles,Mn for chemical modification2+The grain size distribution of rare earth doped up-conversion nanoparticles.Permissible by Fig. 2
Find out, the Mn of chemical modification2+Rare earth doped up-conversion nanoparticles keeps preferably dispersiveness, and particle diameter exists
About 50nm.
By 2.57g anthraquinone, 4.3g sodium dithionite, 4.64g methyl tricapryl ammonium chloride joins 150mL
In the mixed solvent of nitrogen saturation water and 150mL dichloromethane, after stirring 5min, add 4.94g hydrogen-oxygen
Change sodium, drip 9.0g3-iodo-1-propyl alcohol after continuing stirring 10min, be stirred overnight under room temperature, stratification
After, dichloromethane is dried with anhydrous magnesium sulfate after washing twice mutually, filters, freezing precipitation at-20 DEG C, Gu
Body purifies (ethyl acetate/dichloromethane, 1/4) through chromatographic column and obtains the first intermediate；In the middle of 0.4g first
Body and 0.1g pyridinium dissolution are in 100mL dry methylene chloride, and nitrogen protection is lower drips 0.185g stearoyl
Chlorine, purifies (ethyl acetate/dichloromethane, 1/20) through chromatographic column after reaction 2h and obtains the second intermediate；
0.25g the second intermediate and 0.1g triethylamine being dissolved in 100mL dry methylene chloride, nitrogen is protected
Lower dropping 0.104g methacrylic chloride, reaction 2h after through chromatographic column purify (ethyl acetate/dichloromethane,
1/20) hydrophobic monomer is obtained.
The present invention hydrophobic monomer to obtaining carries out proton nmr spectra qualification, hydrogen nuclear magnetic resonance modal data
For: 1HNMR (400MHz): 8.24 (d, 4H, antharacene), 7.48 (d, 4H, anthracene), 6.18
(s, 1H, CCH2), 5.60 (s, 1H, CCH2), 4.64 (t, J=6.0,2H, CH2OCO), 4.53 (t, J=6.4,
2H,CH2OCO),4.29(m,4H,CH2CH2O),2.45-2.35(m,6H,CH2CH2OCO,
COCH2CH2),2.01(s,3H,CH3),1.69-1,65(m,2H,CH2CH2CH2),1.29-1.25(m,
30H, CH2), 0.88 (t, J=13.2,3H, CH2CH3)；
Test result shows: hydrophobic monomer has structure shown in Formula II；
By 200mg hydrophobic monomer, 1.2g polyethylene glycol methacrylate-styrene polymer-950 and 3mg azo two
Isobutyronitrile (AIBN) is dissolved in 7mL dimethyl sulfoxide, reacts 7h under nitrogen protection at 70 DEG C, 500
ML ether separates out and obtains amphipathic nature polyalcohol (PM)；
The present invention amphipathic nature polyalcohol to obtaining carries out proton nmr spectra qualification, as it is shown on figure 3, Fig. 3
Hydrogen nuclear magnetic resonance spectrogram for the amphipathic nature polyalcohol in the embodiment of the present invention 1；Qualification result shows: two
Parent's property polymer has structure shown in Formulas I, and wherein R is C17H35, x:y=1:6.
5mgCCUCNP obtained above is scattered in and is dissolved with amphipathic nature polyalcohol (30mg)
In tetrahydrofuran solution, (1mL) carries out self assembly, additionally dropping 5mL deionized water, and
Being stirred overnight until oxolane volatilization is clean, now amphipathic nature polyalcohol is forming the process of micella
In CCUCNP is wrapped in by middle meeting, obtain composite Nano pharmaceutical carrier.
The present invention carries out transmissioning electric mirror test, as shown in Figure 4, Fig. 4 to the composite Nano pharmaceutical carrier obtained
For the transmission electron microscope picture of the composite Nano pharmaceutical carrier that the embodiment of the present invention 1 obtains, wherein, A is dioxy
SiClx, B is amphipathic nature polyalcohol.As seen from Figure 4, CCUCNP is through amphipathic nature polyalcohol bag
Smooth surface and the border of the composite Nano pharmaceutical carrier obtained after wrapping up in thicken.
The present invention carries out dynamic light scattering test, such as Fig. 5 to the composite Nano pharmaceutical carrier obtained
Shown in, Fig. 5 is the grain size distribution of the composite Nano pharmaceutical carrier that the embodiment of the present invention 1 obtains.From Fig. 5
It can be seen that the composite Nano pharmaceutical carrier that the embodiment of the present invention 1 obtains keeps good dispersiveness, grain
Footpath is at about 65nm.
The present invention is used for studying the release situation of composite Nano pharmaceutical carrier using adriamycin as aids drug.
CCUCNP obtained above is added 5mg in amphipathic nature polyalcohol self assembling process
Adriamycin, obtains pharmaceutical composition；Pharmaceutical composition is dispersed in phosphate buffer solution,
At 980nm light source (0.5W cm-2) irradiate release situation and the list of lower drugs composition
The release conditions of line state oxygen.
The present invention detects the concentration of former Doxorubicin solution and the adriamycin of centrifuged supernatant, by solution
The contrast of fluorescence intensity (λ ex=475nm and λ em=592nm) and pharmaceutical standards curve values can calculate
Go out；Insoluble drug release is characterized by the absorption intensity of indicator N, N-dimethyl-4-nitrosoaniline
During the concentration of singlet oxygen.As shown in Figure 6, Fig. 6 is the embodiment of the present invention to test result
The insoluble drug release of 1 pharmaceutical composition obtained and singlet oxygen releasing curve diagram, wherein curve 1 is near-infrared
Light irradiates the drug release profiles of prescribe medicine compositions, and curve 2 is the list of pharmaceutical composition under near infrared light
Line state oxygen evolution curve, curve 3 is the drug release profiles of pharmaceutical composition under solar radiation, and curve 4 is day
Light irradiates the singlet oxygen release profiles of prescribe medicine compositions.
As seen from Figure 6, under solar radiation, medicine and singlet oxygen are seldom from carrier
Discharge, the most just reduce the medicine side effect to normal physiological tissue.It addition, at near-infrared
Under illumination, amphipathic nature polyalcohol occurs fracture to come off from silicon ball surface, and medicine can be in time in carrier
Discharge, the most also have a certain amount of singlet oxygen to discharge to solution, illustrate that this is combined and receive
Rice pharmaceutical carrier has the highest sensitivity near infrared light, and composite Nano pharmaceutical carrier can be used for medicine
Thing controls release and the photodynamic therapy of cancer.
Composite Nano pharmaceutical carrier obtained above (is not i.e. loaded with the composite Nano medicine of adriamycin by the present invention
Thing carrier) and pharmaceutical composition (being i.e. loaded with the composite Nano pharmaceutical carrier of adriamycin) be loaded into people respectively
In oral squamous carcinoma cell (KB cell), the survival rate of cell under research different condition, as it is shown in fig. 7,
Fig. 7 is that the pharmaceutical composition that obtains of the embodiment of the present invention 1 and composite Nano pharmaceutical carrier are to tumour cell
Inhibition figure, wherein, 1a and 1b is control group, after not adding the lasting 20min of any nano particle
Cell survival rate；Cell survival rate when 2a is just to have added composite Nano pharmaceutical carrier, 2b is for just to add
Enter cell survival rate during pharmaceutical composition；3a is that the cell after adding composite Nano pharmaceutical carrier 5min is deposited
Motility rate, 3b is the cell survival rate after adding pharmaceutical composition 5min；4a is for adding composite Nano medicine
Cell survival rate after carrier 10min, 4b is the cell survival rate after adding pharmaceutical composition 10min；
5a is the cell survival rate after adding composite Nano pharmaceutical carrier 15min, and 5b is for adding pharmaceutical composition
Cell survival rate after 15min；6a is the cell survival rate after adding composite Nano pharmaceutical carrier 20min,
6b is the cell survival rate after adding pharmaceutical composition 20min.
From figure 7 it can be seen that nano particle enters after cell, under suitable illumination condition, be loaded with Ah
The composite Nano pharmaceutical carrier of mycin has good inhibition to tumour cell, meanwhile, is not loaded with Ah mould
The composite Nano pharmaceutical carrier of element also has certain lethal effect, and this is the list owing to discharging during this
Line state oxygen (1O2) inhibitory action to tumour cell, be equivalent to simple optical dynamic therapy；It is loaded with adriamycin
Composite Nano pharmaceutical carrier tumour cell is had best inhibition, thus demonstrate composite Nano medicine
After the carrier loaded medicine of thing, tumour cell is had chemotherapy and photodynamics under near infrared light
Therapy double therapeutic effect.
Embodiment 2
By the MnCl of 1.2mL0.5mol/L2, the Y (NO of 2mL0.5mol/L3)3、1.8mL0.2mol/L
Yb (NO3)3Er (NO with 0.2mL0.2mol/L3)3Joining in mixed liquor, described mixed liquor comprises
0.6gNaOH、3mLH2O, 10mL oleic acid and 20mL ethanol；Then 4mL is contained 8mmolNaF
The aqueous solution be added drop-wise in above-mentioned mixed liquor, stirring 15min after, pour 60mL polytetrafluoroethyllining lining into
Reactor in, at 200 DEG C heat 8h, be centrifuged after cooling, obtain Mn2+Rare earth doped upper turn
Change nano particle (Mn2+The UCNP of doping)；
By 7.5mg Mn2+The UCNP of doping is dispersed in 1mL chloroform, is subsequently poured into 10mL0.1
In the cetyl ammonium bromide solution of mol/L, ultrasonic to clear, after being centrifuged and washing 2 times with water, point
It is dissipated in 10mL5.6mmol/L cetyl ammonium bromide and 1.6mmol/LNaOH solution, drips at 55 DEG C
Adding 0.075mL tetraethyl orthosilicate, after 4h, centrifuge washing obtains silicon dioxide modified Mn2+Doping
Rare earth upconversion nano particle (UCNP@SiO2)；
By 25mg chlorin-e6, at 8mg EDC (1.0eq) and the DMSO of 5mg NHS (1.0eq)
Solution activates 30min, obtains activating chlorin-e6；
The present invention uses alcohol reflux mode to remove unreacted cetyl ammonium bromide at 80 DEG C；To removing
Remove the UCNP@SiO of cetyl ammonium bromide2Middle addition 0.1mL cetyl trimethyl siloxanes, 16h
Rear centrifuge washing；Gained is centrifuged product be dispersed in 5mL ethanol, adds gamma-aminopropyl-triethoxy silicon
Alkane, activation chlorin-e6, stirring, it is centrifuged after reaction 24h washing with ethanol, obtains chemistry and repair
The Mn of decorations2+Rare earth doped up-conversion nanoparticles (CCUCNPs)；
By 2.57g anthraquinone, 4.3g sodium dithionite, 4.64g methyl three heptyl ammonium chloride (Adogen) adds
Enter in the mixed solvent of 150mL nitrogen saturation water and 150mL dichloromethane, add after stirring 5min
4.94g NaOH, drips 9.0g3-iodo-1-propyl alcohol after continuing stirring 10min, is stirred overnight under room temperature,
After stratification, dichloromethane is dried with anhydrous magnesium sulfate after washing twice mutually, filters, freezing at-20 DEG C
Separating out, solid purifies (ethyl acetate/dichloromethane, 1/4) through chromatographic column and obtains the first intermediate；By 0.4g
First intermediate and 0.1g pyridinium dissolution are in 100mL dry methylene chloride, and nitrogen protection is lower to be dripped
0.185g stearyl chloride, purifies (ethyl acetate/dichloromethane, 1/20) through chromatographic column after reaction 2h and obtains
Second intermediate；0.25g the second intermediate and 0.1g triethylamine are dissolved in 100mL dry methylene chloride
In, the lower dropping 0.104g methacrylic chloride of nitrogen protection, purify (acetic acid through chromatographic column after reaction 2h
Ethyl ester/dichloromethane, 1/20) obtain hydrophobic monomer.
By 200mg hydrophobic monomer, 1.4g polyethylene glycol methacrylate-styrene polymer-950 and 3mg azo two
Isobutyronitrile (AIBN) is dissolved in 7mL dimethyl sulfoxide, reacts 7h under nitrogen protection at 70 DEG C, 500
ML ether separates out and obtains amphipathic nature polyalcohol (PM)；
5mgCCUCNP obtained above is scattered in and is dissolved with amphipathic nature polyalcohol (25mg)
In tetrahydrofuran solution, (1mL) carries out self assembly, additionally dropping 5mL deionized water, and
Being stirred overnight until oxolane volatilization is clean, now amphipathic nature polyalcohol is forming the process of micella
In CCUCNP is wrapped in by middle meeting, obtain composite Nano pharmaceutical carrier.
Embodiment 3
By the MnCl of 1.2mL0.5mol/L2, the Y (NO of 2mL0.5mol/L3)3、1.8mL0.2mol/L
Yb (NO3)3Er (NO with 0.2mL0.2mol/L3)3Joining in mixed liquor, described mixed liquor comprises
0.6gNaOH、3mLH2O, 10mL oleic acid and 20mL ethanol；Then 4mL is contained 8mmolNaF
The aqueous solution be added drop-wise in above-mentioned mixed liquor, stirring 15min after, pour 60mL polytetrafluoroethyllining lining into
Reactor in, at 200 DEG C heat 8h, be centrifuged after cooling, obtain Mn2+Rare earth doped upper turn
Change nano particle (Mn2+The UCNP of doping)；
By 7.5mg Mn2+The UCNP of doping is dispersed in 1mL chloroform, is subsequently poured into 10mL0.1
In the cetyl ammonium bromide solution of mol/L, ultrasonic to clear, after being centrifuged and washing 2 times with water, point
It is dissipated in 10mL5.8mmol/L cetyl ammonium bromide and 1.6mmol/LNaOH solution, drips at 55 DEG C
Adding 0.075mL tetraethyl orthosilicate, after 4h, centrifuge washing obtains silicon dioxide modified Mn2+Doping
Rare earth upconversion nano particle (UCNP@SiO2)；
By 25mg chlorin-e6, at 8mg EDC (1.0eq) and the DMSO of 5mg NHS (1.0eq)
Solution activates 30min, obtains activating chlorin-e6；
The present invention uses alcohol reflux mode to remove unreacted cetyl ammonium bromide at 80 DEG C；To removing
Remove the UCNP@SiO of cetyl ammonium bromide2Middle addition 0.3mL cetyl trimethyl siloxanes, 18h
Rear centrifuge washing；Gained is centrifuged product be dispersed in 5mL ethanol, adds gamma-aminopropyl-triethoxy silicon
Alkane, activation chlorin-e6, stirring, it is centrifuged after reaction 24h washing with ethanol, obtains chemistry and repair
The Mn of decorations2+Rare earth doped up-conversion nanoparticles (CCUCNPs)；
By 2.57g anthraquinone, 4.3g sodium dithionite, 4.64g methyl tricapryl ammonium chloride joins 150mL
In the mixed solvent of nitrogen saturation water and 150mL dichloromethane, after stirring 5min, add 4.94g hydrogen-oxygen
Change sodium, drip 9.0g3-iodo-1-propyl alcohol after continuing stirring 10min, be stirred overnight under room temperature, stratification
After, dichloromethane is dried with anhydrous magnesium sulfate after washing twice mutually, filters, freezing precipitation at-20 DEG C, Gu
Body purifies (ethyl acetate/dichloromethane, 1/4) through chromatographic column and obtains the first intermediate；In the middle of 0.4g first
Body and 0.1g pyridinium dissolution are in 100mL dry methylene chloride, and nitrogen protection is lower drips 0.185g stearoyl
Chlorine, purifies (ethyl acetate/dichloromethane, 1/20) through chromatographic column after reaction 2h and obtains the second intermediate；
0.25g the second intermediate and 0.1g triethylamine being dissolved in 100mL dry methylene chloride, nitrogen is protected
Lower dropping 0.104g methacrylic chloride, reaction 2h after through chromatographic column purify (ethyl acetate/dichloromethane,
1/20) hydrophobic monomer is obtained.
By 200mg hydrophobic monomer, 1.0g polyethylene glycol methacrylate-styrene polymer-950 and 3mg azo two
Isobutyronitrile (AIBN) is dissolved in 7mL dimethyl sulfoxide, reacts 7h under nitrogen protection at 70 DEG C, 500
ML ether separates out and obtains amphipathic nature polyalcohol (PM)；
5mgCCUCNP obtained above is scattered in and is dissolved with amphipathic nature polyalcohol (20mg)
In tetrahydrofuran solution, (1mL) carries out self assembly, additionally dropping 5mL deionized water, and
Being stirred overnight until oxolane volatilization is clean, now amphipathic nature polyalcohol is forming the process of micella
In CCUCNP is wrapped in by middle meeting, obtain composite Nano pharmaceutical carrier.
As seen from the above embodiment, the invention provides a kind of amphipathic polymerization with structure shown in Formulas I
Thing.The amphipathic nature polyalcohol with structure shown in Formulas I is used for preparing composite Nano pharmaceutical carrier by the present invention,
Described composite Nano pharmaceutical carrier includes the Mn of chemical modification2+Rare earth doped up-conversion nanoparticles and parcel
Mn in described chemical modification2+The amphipathic nature polyalcohol on rare earth doped up-conversion nanoparticles surface；Described
Amphipathic nature polyalcohol has structure shown in Formulas I, and described chemical modification is alkyl chain, silica and sensitising agent
Modify, the Mn of described chemical modification2+Rare earth doped up-conversion nanoparticles is hydrophobic material.This
The amphipathic nature polyalcohol of bright offer and the Mn of described chemical modification2+Rare earth doped up-conversion nanoparticles passes through
Van der Waals force interacts, it is achieved amphipathic nature polyalcohol and the Mn of described chemical modification2+Rare earth doped upper turn
Changing the self assembly of nano particle, amphipathic nature polyalcohol is wrapped in the Mn of described chemical modification2+On rare earth doped
The surface of conversion nanoparticles, forms the composite Nano pharmaceutical carrier with nucleocapsid structure.When with near-infrared
When light irradiates composite Nano pharmaceutical carrier, near infrared light can be converted to height by rare earth upconversion nano particle
Frequently ultraviolet light, ultraviolet light promotes sensitising agent to discharge singlet oxygen, and singlet oxygen aoxidizes amphipathic nature polyalcohol,
Amphipathic nature polyalcohol is transformed into hydrophilic polymer by ultraviolet light, causes amphipathic nature polyalcohol from described chemistry
The Mn modified2+The surface of rare earth doped up-conversion nanoparticles comes off, and medicine can discharge, medicine
Tumour cell is had good inhibition；The unnecessary singlet oxygen discharged also can be to tumour cell
There is lethal effect, reach double therapeutic effect.
It addition, the composite Nano pharmaceutical carrier that the present invention provides is controlled by the near infrared light that energy is more weak,
On the one hand can be with the time of Drug controlled release and position；On the other hand can also reduce normal physiological group
The infringement knitted.
The above is only the preferred embodiment of the present invention, it is noted that general for the art
For logical technical staff, under the premise without departing from the principles of the invention, it is also possible to make some improvement and profit
Decorations, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (5)
1. a composite Nano pharmaceutical carrier, including following components:
The Mn of chemical modification2+Rare earth doped up-conversion nanoparticles；
With the Mn being wrapped in described chemical modification2+The amphipathic on rare earth doped up-conversion nanoparticles surface
Compound；
Described chemical modification is that cetyl, silica and sensitising agent are modified；
Described amphipathic nature polyalcohol has a structure shown in Formulas I:
In Formulas I, x and y is natural number, 1≤x≤5,3≤y≤15；N is the degree of polymerization, 5≤n≤20；R
For the alkyl that carbon number is 10～20.
Composite Nano pharmaceutical carrier the most according to claim 1, it is characterised in that in Formulas I, x
It is natural number with y, 2≤x≤4,4≤y≤10；N is the degree of polymerization, 6≤n≤9；R is that carbon number is
The alkyl of 13～18.
Composite Nano pharmaceutical carrier the most according to claim 1, it is characterised in that described chemistry is repaiied
The Mn of decorations2+The mass ratio of rare earth doped up-conversion nanoparticles and amphipathic nature polyalcohol is 1:5～7.
Composite Nano pharmaceutical carrier the most according to claim 1, it is characterised in that described sensitising agent
Including eosin and/or porphyrin.
5. a preparation method for composite Nano pharmaceutical carrier, comprises the following steps:
By the Mn of chemical modification2+Rare earth doped up-conversion nanoparticles is with amphipathic nature polyalcohol in a solvent
Carry out self assembly, obtain composite Nano pharmaceutical carrier；
Described chemical modification is that cetyl, silica and sensitising agent are modified；
Described amphipathic nature polyalcohol has a structure shown in Formulas I:
In Formulas I, x and y is natural number, 1≤x≤5,3≤y≤15；N is the degree of polymerization, 5≤n≤20；R
For the alkyl that carbon number is 10～20.
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| CN104673753B (en) * | 2015-02-02 | 2017-07-14 | 中南大学 | It is a kind of to control H near infrared light2Composite nanoparticle of S releases and its preparation method and application |
| JP6833174B2 (en) * | 2015-12-23 | 2021-02-24 | 川崎化成工業株式会社 | Polymer photopolymerization sensitizer |
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| CN110075306B (en) * | 2019-04-28 | 2020-11-06 | 大连理工大学 | Preparation method of near-infrared light-controlled visible drug carrier |
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