CN115068619B - Preparation method of photo-thermal dual-response composite carrier, prepared composite carrier and application of composite carrier - Google Patents
Preparation method of photo-thermal dual-response composite carrier, prepared composite carrier and application of composite carrier Download PDFInfo
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- CN115068619B CN115068619B CN202110282383.6A CN202110282383A CN115068619B CN 115068619 B CN115068619 B CN 115068619B CN 202110282383 A CN202110282383 A CN 202110282383A CN 115068619 B CN115068619 B CN 115068619B
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- photo
- composite carrier
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- reaction
- thermal dual
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- 239000002131 composite material Substances 0.000 title claims abstract description 126
- 230000004044 response Effects 0.000 title claims abstract description 115
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 91
- 238000001035 drying Methods 0.000 claims abstract description 39
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- 239000003960 organic solvent Substances 0.000 claims abstract description 25
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- 239000002105 nanoparticle Substances 0.000 claims abstract description 17
- 230000004298 light response Effects 0.000 claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- 239000000126 substance Substances 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
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- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- OIWOHHBRDFKZNC-UHFFFAOYSA-N cyclohexyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OC1CCCCC1 OIWOHHBRDFKZNC-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000010363 phase shift Effects 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000012779 reinforcing material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003980 solgel method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- IGVNJALYNQVQIT-UHFFFAOYSA-N tert-butyl 2-bromo-2-methylpropanoate Chemical compound CC(C)(C)OC(=O)C(C)(C)Br IGVNJALYNQVQIT-UHFFFAOYSA-N 0.000 description 1
- 229940043263 traditional drug Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- RUDFQVOCFDJEEF-UHFFFAOYSA-N yttrium(III) oxide Inorganic materials [O-2].[O-2].[O-2].[Y+3].[Y+3] RUDFQVOCFDJEEF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0042—Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/12—Esters of monohydric alcohols or phenols
- C08F220/16—Esters of monohydric alcohols or phenols of phenols or of alcohols containing two or more carbon atoms
- C08F220/18—Esters of monohydric alcohols or phenols of phenols or of alcohols containing two or more carbon atoms with acrylic or methacrylic acids
- C08F220/1811—C10or C11-(Meth)acrylate, e.g. isodecyl (meth)acrylate, isobornyl (meth)acrylate or 2-naphthyl (meth)acrylate
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2438/00—Living radical polymerisation
- C08F2438/01—Atom Transfer Radical Polymerization [ATRP] or reverse ATRP
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A20/00—Water conservation; Efficient water supply; Efficient water use
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Abstract
The invention discloses a preparation method of a photo-thermal dual response composite carrier, which relates to the technical field of high polymer materials and comprises the following steps: (1) Dissolving the up-conversion nano particles and the light response nano gel into a first organic solvent, centrifuging and drying; the mass ratio of the up-conversion nano particles to the light response nano gel is 1:1; (2) Respectively dissolving the product and polydopamine into a second organic solvent, and centrifuging and drying to obtain a photo-thermal dual-response composite carrier; the mass ratio of the product in the step (1) to polydopamine is 1:0.5-1.2. The invention also discloses a photo-thermal dual-response composite carrier prepared by the preparation method and application thereof. The invention has the beneficial effects that: the photo-thermal dual-response composite carrier has excellent photo-conversion performance and photo-thermal conversion performance, and good near infrared light and thermal response performance; has good drug loading and releasing capacity; has excellent biocompatibility and application prospect in the field of drug release.
Description
Technical Field
The invention relates to the technical field of high polymer materials, in particular to a preparation method of a photo-thermal dual-response composite carrier, the prepared composite carrier and application thereof.
Background
The composite material is composed of two or more different materials, and the organic-inorganic composite material belongs to one of the composite materials, and is formed by dispersing inorganic particles in organic polymers for compounding. One of the phases, referred to as the matrix, is the continuous phase throughout the system; the other phase is a reinforcing material, belonging to the dispersed phase. The organic-inorganic composite material not only can overcome the defects of difficult processing of simple inorganic particles, poor stability, low strength and the like of organic polymers, but also can obtain better performance than inorganic particles and organic polymers under the combined action of the two, such as excellent performance in the aspects of mechanics, electricity, heat, optics and the like of materials. These properties are changed with the structure of the material, the composition of the two phases and the proportion of the two phases, and the physical properties of the material can be adjusted by the optimized combination of the two phases to synthesize composite materials with different purposes.
At present, the preparation method of the organic-inorganic composite material mainly comprises an intercalation method, a blending method, a sol-gel method, an in-situ polymerization method, a supermolecule self-assembly method and the like. The blending method is a method for preparing a composite material by uniformly mixing inorganic nanoparticles and polymers or monomers by a physical or chemical method. The method mainly comprises mechanical blending, melt blending, solution blending, emulsion blending and the like, is simple to operate, is suitable for inorganic particles in various forms, and can control the form and the size of the particles by controlling the synthetic route and the reaction condition.
The patent with publication number CN103145920A discloses a preparation method of temperature, pH and ultraviolet light multi-stimulus response semi-interpenetrating network nano composite hydrogel, but a drug transportation carrier is an ultraviolet light response system, and ultraviolet light has the defects of weak penetrating capacity, possibility of damaging organisms by long-time irradiation of the organisms and the like, so that the application of the nano composite hydrogel in actual life is restricted.
Disclosure of Invention
The technical problem to be solved by the invention is that the traditional drug delivery carrier is an ultraviolet light response system, and ultraviolet light has the defects of weak penetrating capacity, possibility of damaging organisms by long-time irradiation of the organisms and the like, so that the application of the drug delivery carrier in actual life is restricted.
The invention solves the technical problems by the following technical means:
the preparation method of the photo-thermal dual-response composite carrier comprises the following steps:
(1) Dissolving the up-conversion nano particles and the light response nano gel into a first organic solvent, centrifuging and drying; the mass ratio of the up-conversion nano particles to the light response nano gel is 1:1;
(2) Respectively dissolving the product obtained in the step (1) and polydopamine into a second organic solvent, centrifuging and drying to obtain a photo-thermal dual-response composite carrier; the mass ratio of the product in the step (1) to the polydopamine is 1:0.5-1.2.
The beneficial effects are that: the invention combines the up-conversion nano particles, polydopamine and the photo-response nano gel to realize the construction of the photo-thermal dual-response composite carrier. The prepared photo-thermal dual-response composite carrier has excellent photo-conversion performance and photo-thermal conversion performance, and good near infrared light and thermal response performance.
The photo-thermal dual-response composite carrier prepared by the invention has good drug loading and releasing capacity due to photo-thermal dual response; and has excellent biocompatibility and application prospect in the field of drug release. The release rate of the photo-thermal dual-response composite carrier under the near infrared light is larger than that under the ultraviolet light, which indicates that the photo-thermal dual-response greatly improves the drug release rate of the photo-thermal dual-response composite carrier.
When the mass ratio of the product in the step (1) to polydopamine is 1:0.5-1.2, the product is prepared under near infrared light (3W cm -2 ) After 300s of irradiation, the temperature of the photo-thermal dual-response composite carrier can be increased from 21.1 ℃ to 63.2 ℃.
Preferably, the first organic solvent is selected from one or more of dichloromethane, chloroform, toluene and carbon tetrachloride, and the second organic solvent is selected from one or more of N, N-dimethylformamide, dichloromethane and chloroform.
Preferably, the preparation method of the up-conversion nanoparticle comprises the following steps: dissolving rare earth stearate precursor in a first mixed solvent, adding fluoride to form suspension, transferring to a hydrothermal reaction kettle, heating for reaction, centrifuging after the reaction, washing and drying to obtain the up-conversion nano particles.
Preferably, the first mixed solvent is selected from one or more of a mixture of ethanol and oleic acid, a mixture of water and ethanol and oleic acid; the fluoride is selected from one or more of sodium fluoride, potassium fluoride and calcium fluoride; the temperature of the heating reaction is 150-200 ℃ and the reaction time is 8-16h.
Preferably, the preparation method of the rare earth stearate precursor comprises the following steps: dissolving rare earth element oxide in concentrated nitric acid, stirring and dissolving, heating and volatilizing the solvent to obtain rare earth salt, dissolving the rare earth salt in a third organic solvent, adding an active agent, stirring and dissolving, dripping a fourth organic solvent, refluxing at constant temperature, reacting, distilling under reduced pressure, washing and drying to obtain the product.
Preferably, the oxide of the rare earth element is selected from one or more of ytterbium oxide, erbium oxide, thulium oxide and yttrium oxide; the active agent is one or more selected from stearic acid, oleic acid and lauric acid; the third organic solvent and the fourth organic solvent are selected from one or more of absolute ethyl alcohol, methanol, glycol and ethanol solution of sodium hydroxide; the constant temperature reflux temperature is 50-100 ℃, and the reaction time is 30-60min.
Preferably, the preparation method of the light response nanogel comprises the following steps:
(1) Preparation of a photoresponsive coumarin derivative intermediate I: mixing phenol substances and ester substances, dropwise adding concentrated sulfuric acid, continuing to react after the dropwise adding is finished, separating liquid after the reaction, washing, drying and purifying;
(2) Preparation of photo-responsive coumarin derivatives II: dissolving the product in the step (1) in a fifth organic solvent, adding carboxylic acid substances and a condensation reagent, heating for reaction, separating liquid after the reaction, washing, drying and purifying;
(3) Copper bromide, an amine catalyst and a sixth organic solvent are mixed to prepare a copper complex; adding the copper complex, the photoresponse coumarin derivative II, the ester monomer and the cross-linking agent into deionized water, adding the emulsifying agent and the macromolecular initiator into the mixed solution, reacting under the condition of nitrogen, washing, settling and drying after the reaction to obtain the product.
Preferably, the phenol substance in the step (1) is selected from one or more of resorcinol, catechol and hydroquinone; the ester substance is one or more of ethyl acetoacetate, ethyl 4-chloroacetoacetate and ethyl 2-phenylacetoacetate; the reaction temperature is 0-50 ℃ and the reaction time is 30-60h.
Preferably, the fifth organic solvent in the step (2) is selected from one or more of dichloromethane, chloroform, toluene and N, N-dimethylformamide; the carboxylic acid substance is selected from one or more of benzoic acid, oxalic acid and acrylic acid; the condensation reagent is selected from one or more of N, N-diisopropylcarbodiimide, N-diisopropylethylamine, 1-hydroxy-7-azobenzotriazole and 1, 8-diazabicyclo undec-7-ene; the heating reaction temperature is 40-80 ℃ and the reaction time is 12-20h.
Preferably, the purification steps of step (1) and step (2) each comprise column chromatography, the eluent of the column chromatography is a mixture of petroleum ether and ethyl acetate, and the solvent is removed by reduced pressure distillation.
Preferably, the volume ratio of petroleum ether to ethyl acetate in the eluent is 1-6:1.
Preferably, the amine catalyst is selected from one or more of N, N-dimethyl cyclohexylamine, N-dimethyl benzylamine and pentamethyl diethylenetriamine; the ester monomer is selected from one or more of butyl methacrylate, cyclohexyl methacrylate and isobornyl methacrylate; the cross-linking agent is selected from one or more of ethylene glycol dimethacrylate, polyethylene glycol dimethacrylate and diurea alkyl dimethacrylate; the emulsifier is one or more selected from polyoxyethylene oil ether, castor oil polyoxyethylene ether and fatty alcohol polyoxyethylene ether; the sixth organic solvent is selected from one or more of N, N-dimethylformamide, dichloromethane and chloroform; the reaction temperature is 40-100 ℃ and the reaction time is 2-10h.
Preferably, the preparation method of the macroinitiator comprises the following steps: dissolving an ether substance and an organic amine substance in a seventh organic solvent, dissolving a brominated substance in the seventh organic solvent, dropwise adding a dichloromethane solution of the brominated substance into the mixed solution under the condition of nitrogen, continuing to react under the condition of nitrogen after the dropwise adding is finished, and filtering, washing and drying after the reaction to obtain a product.
Preferably, the seventh organic solvent in the step (3) is selected from one or more of dichloromethane, chloroform, toluene and carbon tetrachloride; the ether substance is one or more selected from polyethylene glycol monomethyl ether, polyethylene glycol monobutyl ether and polyethylene glycol allyl alcohol ether; the organic amine substance is selected from one or more of ethylenediamine, triethylamine, isopropylamine and n-butylamine; the brominated substance is selected from one or more of tert-butyl 2-bromoisobutyrate, 2-bromopropane, 2-bromoacetophenone and 2-bromoisobutyryl bromide; the molar ratio of the ether substances to the organic amine substances to the brominated substances is 1:2:2; the reaction temperature is 0-50 ℃ and the reaction time is 10-20h.
Preferably, the preparation method of the polydopamine comprises the following steps: dissolving absolute ethyl alcohol and alkaline solution in deionized water, adding dopamine hydrochloride into the mixed solution to react, centrifuging after the reaction, washing and drying to obtain polydopamine.
Preferably, the alkaline solution is selected from one or more of sodium hydroxide, calcium hydroxide and ammonia water; the volume ratio of the absolute ethyl alcohol to the alkaline solution to the deionized water is 20:8:45; the reaction temperature is 0-50 ℃ and the reaction time is 10-30h.
The invention also provides the photo-thermal dual-response composite carrier prepared by the method.
Preferably, the prepared photo-thermal dual-response composite carrier is dissolved in methanol.
Preferably, the concentration of the photo-thermal dual response composite carrier is not less than 1mg/mL.
The beneficial effects are that: the temperature of the photo-thermal dual-response composite carrier methanol solution is continuously increased along with the increase of the concentration of the solution.
Preferably, the irradiation light source of the photo-thermal dual-response composite carrier is near infrared light.
Preferably, the near infrared light has a power of 3W cm -2 。
The beneficial effects are that: the temperature of the photo-thermal dual-response composite carrier solution is continuously increased with the continuous increase of near infrared light power when the same time (120 s) is irradiated. When the laser power used is 0.5W cm -2 At the same time, after 120s of irradiation, the temperature of the composite carrier solution was increased by 9.9℃under the same conditions as the laser power used was increased to 3.0W cm -2 At this time, the temperature of the composite carrier was raised by 36.6 ℃.
The invention also provides application of the photo-thermal dual-response composite carrier prepared by the preparation method in drug release.
The beneficial effects are that: the photo-thermal dual-response composite carrier can load and release medicines and has better biocompatibility. And the release rate of the photo-thermal dual-response composite carrier under the near infrared light is larger than that under the ultraviolet light, which indicates that the photo-thermal dual-response greatly improves the drug release rate of the photo-thermal dual-response composite carrier.
Preferably, the drug is coumarin 102.
The invention has the advantages that: the invention combines the up-conversion nano particles, the polydopamine and the photo-response nano gel to realize the construction of the photo-thermal dual-response composite carrier, and has excellent photo-conversion performance and photo-thermal conversion performance, and good near infrared light and thermal response performance.
The photo-thermal dual-response composite carrier prepared by the invention has good drug loading and releasing capacity due to photo-thermal dual response; and has excellent biocompatibility and application prospect in the field of drug release. The release rate of the photo-thermal dual-response composite carrier under the near infrared light is larger than that under the ultraviolet light, which indicates that the photo-thermal dual-response greatly improves the drug release rate of the photo-thermal dual-response composite carrier.
Drawings
FIG. 1 is a graph showing the ultraviolet absorption spectrum and fluorescence emission spectrum of the photo-thermal dual response composite carrier UC-NG-PDA1.0 prepared in example 2 of the present invention;
FIG. 2 shows the temperature change of the photo-thermal dual response composite support prepared in example 2-example 5 of the present invention irradiated with near infrared light;
FIG. 3 is a photo-thermal conversion chart of the methanol solution of the photo-thermal dual-response composite carrier prepared in example 2 under the irradiation of near infrared light with different power densities;
FIG. 4 is a photo-thermal conversion chart of photo-thermal dual response composite carrier methanol solutions prepared in example 2 of the present invention under near infrared light irradiation;
FIG. 5 is a standard curve for coumarin 102;
FIG. 6 is a graph showing fluorescence emission spectra of the photo-thermal dual-response composite carrier-loaded coumarin 102 prepared in example 2 under ultraviolet irradiation;
FIG. 7 is a fluorescence emission spectrum of the photo-thermal dual-response composite carrier loaded coumarin 102 prepared in example 2 of the present invention under near infrared light irradiation;
FIG. 8 is a graph showing the cell activity of the photo-thermal dual-response composite vector prepared in example 2 of the present invention cultured in HeLa cells for 24 h.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The test materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Those of skill in the art, without any particular mention of the techniques or conditions, may follow the techniques or conditions described in the literature in this field or follow the product specifications.
Oleic acid: chemical purity of Beijing enoki technologies Co., ltd;
yttria (Y2O 3), ytterbia (Yb 2O 3), thulium oxide (Tm 2O 3): saen chemical technologies limited, analytically pure;
resorcinol: chemical purity of Beijing enoki technologies Co., ltd;
ammonium bifluoride (NH 4HF 2): chemical purity of Beijing enoki technologies Co., ltd;
4-chloroacetoacetic acid ethyl ester: saen chemical technologies limited, analytically pure;
acrylic acid: the chemical reagent factory in Fu morning in Tianjin, the analytical grade;
1, 8-diazabicyclo undec-7-ene (DBU): beijing Michaelia technologies Co., ltd., analytically pure;
polyethylene glycol monomethyl ether: saen chemical technologies limited, chemical purity;
2-bromoisobutyryl bromide: beijing Walker chemical Co., ltd., analytically pure;
pentamethyldiethylenetriamine: beijing chemical plant, analytical grade;
isobornyl methacrylate: a changxing chemical material, a polymerization grade;
polyoxyethylene (20) oil ether ]s 20): ala Ding Shiji, inc;
anhydrous N, N-Dimethylformamide (DMF): "Bailingwei technology Co., ltd., analytically pure;
dopamine (DA): analytical grade of Tianjin Seen Biochemical technologies Co., ltd;
ammonia water: saen chemical technologies limited, analytically pure.
Example 1
The following takes the preferable raw materials to synthesize the photo-thermal dual response composite carrier as an example to explain the synthesis principle:
the invention prepares a photo-thermal dual-response composite carrier by a solution blending method, firstly prepares up-conversion particles by a hydrothermal method, prepares polydopamine particles by an oxidation self-polymerization method, then prepares photo-response nanogel by an Atom Transfer Radical Polymerization (ATRP) method, and combines the prepared up-conversion particles, polydopamine and the photo-response nanogel to realize the construction of the photo-thermal dual-response composite carrier.
(1) Yttrium oxide (Y) 2 O 3 ) Ytterbium oxide (Yb) 2 O 3 ) Thulium oxide (Tm) 2 O 3 ) Adding the equal oxide into concentrated nitric acid, stirring to dissolve the oxide to form nitrate, and heating to volatilize the solvent to obtain rare earth nitrate powder. Dissolving nitrate powder in absolute ethyl alcohol, adding stearic acid, stirring for dissolution, dropwise adding an ethanol solution of sodium hydroxide, refluxing at constant temperature after the dropwise adding is finished, reacting, distilling under reduced pressure, washing with water and ethanol, and drying to obtain a rare earth stearate precursor, which is named as a product 1; wherein the molar ratio of yttrium oxide to ytterbium oxide to thulium oxide is 40:10:1;
(2) Dissolving the product 1 in a mixed solvent of water, ethanol and oleic acid, adding sodium fluoride, stirring to form a uniform suspension, transferring into a hydrothermal reaction kettle, heating for reaction, centrifuging after reaction, washing with a mixed solution of water and ethanol, and drying to obtain up-conversion nano particles, and naming the up-conversion nano particles as a product 2; wherein the volume ratio of water to ethanol to oleic acid is 2:3:1, and the volume ratio of water to ethanol in the detergent is 1:2;
(3) Mixing resorcinol and 4-chloroacetoacetic acid ethyl ester, dissolving, dropwise adding concentrated sulfuric acid in the stirring process, continuing to react after the dropwise adding, adding ethyl acetate liquid after the reaction, washing with deionized water and saturated sodium chloride solution respectively, drying an organic phase in anhydrous sodium sulfate, purifying by a column chromatography method, wherein the eluent is a mixture of petroleum ether and ethyl acetate with the volume ratio of 4:1, removing a solvent by reduced pressure distillation, and drying in a vacuum drying oven to obtain a photoresponsive coumarin derivative intermediate I, and naming the photoresponsive coumarin derivative intermediate I as a product 3;
(4) Dissolving the product 3 in anhydrous N, N-Dimethylformamide (DMF), adding acrylic acid and 1, 8-diazabicyclo undec-7-ene (DBU) under stirring, heating for reaction, separating the reaction solution by ethyl acetate, washing the reaction solution by deionized water and saturated sodium chloride solution respectively, then placing the organic phase in anhydrous sodium sulfate for drying, purifying by a column chromatography method, wherein the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1, removing the solvent by reduced pressure distillation to obtain light yellow solid, and placing the light yellow solid in a vacuum drying oven for drying to obtain a light-response coumarin derivative II which is named as a product 4;
(5) Dissolving absolute ethyl alcohol and ammonia water in deionized water, adding dopamine hydrochloride into the mixed solution, mixing, stirring for reaction, centrifuging and drying after the reaction to obtain polydopamine particles, and naming a product 5; wherein the volume ratio of the absolute ethyl alcohol to the ammonia water to the deionized water is 20:8:45;
(6) Dissolving polyethylene glycol monomethyl ether and triethylamine in anhydrous dichloromethane, dissolving 2-bromo-isobutyryl bromide in anhydrous dichloromethane, dropwise adding an anhydrous dichloromethane solution of 2-bromo-isobutyryl bromide into the mixed solution under the condition of nitrogen, continuing to react under the condition of nitrogen after the dropwise adding is finished, filtering, washing and drying after the reaction is finished to obtain a macromolecular initiator PEG-Br, and naming the macromolecular initiator PEG-Br as a product 6; wherein the mol ratio of polyethylene glycol monomethyl ether, triethylamine and 2-bromoisobutyryl bromide is 1:2:2;
(7) Copper bromide, pentamethyldiethylenetriamine and N, N-dimethylformamide are mixed to prepare a copper complex; adding copper complex, product 4, isobornyl methacrylate and diurea alkyl dimethacrylate into deionized water, adding polyoxyethylene (20) oil ether and product 6 into the mixed solution, reacting under the condition of nitrogen, washing and settling for three times after the reaction, and drying to obtain photoresponsive nanogel which is named as product 7; wherein the molar ratio of the copper bromide to the pentamethyldiethylenetriamine is 1:1; the molar ratio of the product 4 to the isobornyl methacrylate is 1:10;
(8) Respectively dissolving the product 2 and the product 7 into dichloromethane, stirring and mixing the two, heating and volatilizing the solvent, dissolving the product by hydration ultrasonic, centrifuging and drying to obtain a product 8; respectively dissolving the product 5 and the product 8 into dichloromethane, stirring and mixing, heating and volatilizing the solvent, dissolving by hydration ultrasonic, centrifuging and drying to obtain a photo-thermal dual-response composite carrier; wherein the mass ratio of the product 2 to the product 7 is 1:1, and the mass ratio of the product 5 to the product 8 is 1:1.
Example 2
Photo-thermal dual response composite carrier (UC-NG-PDA) 1.0 ) Is prepared by the following steps:
(1) Y is set to 2 O 3 (0.8818g)、Yb 2 O 3 (0.3947g)、Tm 2 O 3 (0.0386 g) is added into 20mL of concentrated nitric acid, heated and stirred to dissolve oxide powder to form nitrate, heated to near dryness and volatilized to remove excessive concentrated nitric acid to obtain rare earth nitrate powder. Dissolving the obtained rare earth nitrate powder in 80mL of absolute ethyl alcohol, adding stearic acid (8.55 g), stirring and dissolving, refluxing and stirring at 78 ℃, dropwise adding 20mL of ethanol solution containing 1.19g of NaOH for 3min, refluxing at constant temperature for 40min after the dropwise adding is finished, obtaining white suspension, distilling under reduced pressure, washing with water for 2 times, washing with ethanol for 1 time, and drying at 60 ℃ for 12h to obtain a rare earth stearate precursor.
(2) Respectively weighing 10mL of water, 15mL of ethanol and 5mL of oleic acid, mixing and stirring to form a uniform solution, adding a rare earth stearate precursor (0.9577 g) and NaF (0.2099 g), stirring the mixture under the assistance of ultrasound for 15min to form a uniform suspension, transferring the mixture into a hydrothermal reaction kettle, reacting for 12h at 180 ℃, discarding the supernatant after the reaction is finished, adding a mixed solvent (volume ratio: chloroform: ethanol=1:6), centrifuging to obtain a white solid, washing three times with a water-ethanol mixed solvent (volume ratio: 1:2), and drying at 60 ℃ for 12h to obtain NaYF 4 : yb, tm up-conversion particles.
(3) Resorcinol (1.1 g) and ethyl 4-chloroacetoacetate (1.65 g) were added to a single-necked flask, and stirred at room temperature for 40min to dissolve, followed by 10mL of concentrated H 2 SO 4 Drop wise into a single-necked flask. After the completion of the dropwise addition, the reaction was carried out at room temperature for 48 hours. After the reaction, 20mL of ethyl acetate was added to a single-necked flask to dissolve the reaction mixture, which was washed with deionized water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography, wherein the eluent was petroleum ether/ethyl acetate in a volume ratio of 4:1. Spin-evaporating to remove solvent to obtain white solid product, and drying at 30deg.C in vacuum drying oven for 24 hr to obtain pure photoresponsive coumarin derivative intermediate I with the following reaction formula:
(4) The photoresponsive coumarin derivative intermediate I (1.23 g) was dissolved in 10mL anhydrous DMF in a single vial, acrylic acid (0.36 g) was added, then 1mL 1, 8-diazabicyclo undec-7-ene was added with stirring and reacted at 60℃for 16h. After the reaction, 20mL of ethyl acetate was added to a single-necked flask to dissolve the reaction solution, 25mL of 1N HCl was added to neutralize the 1, 8-diazabicyclo undec-7-ene in the reaction solution, and the mixture was washed with deionized water and sodium chloride solution, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography, wherein the eluent was petroleum ether/ethyl acetate in a volume ratio of 3:1. Removing the solvent by rotary evaporation to obtain a pale yellow solid product, and drying the pale yellow solid product at 50 ℃ in a vacuum drying oven for 24 hours to finally obtain the pure photoresponse coumarin derivative II, wherein the reaction formula is as follows:
(5) 2mL of absolute ethyl alcohol and 0.8mL of ammonia water are dissolved in 4.5mL of deionized water, stirring is carried out for 20min at room temperature, 0.4g of dopamine is weighed and added into the mixed solution, the color of the mixed solution is changed from colorless to yellow-brown, stirring is continued for reaction for 20h at room temperature, the color of the reaction solution is further deepened along with the extension of the reaction time, and finally the reaction solution is changed into dark brown. After the reaction is finished, centrifuging at 12000rpm for 10min, taking the lower layer solid, and drying in a vacuum drying oven at 52 ℃ for 4h to obtain the product polydopamine particles.
(6) Polyethylene glycol monomethyl ether (mn=2kda) (10 g,5 mmol), triethylamine (1.01 g,10 mmol) and 30mL of anhydrous dichloromethane were added to a 100mL dry three-necked flask, and stirred under ice water bath conditions for 30min. 2-Bromoisobutyryl bromide (2.3 g,10 mmol) was mixed with 10mL of anhydrous dichloromethane and stirred for 10min, after which the mixed solution was transferred to a constant pressure dropping funnel. Then the mixed solution of 2-bromo isobutyryl bromide and dichloromethane in the constant pressure dropping funnel is slowly added dropwise to a three-necked flask under the protection of nitrogen. After the dropwise addition, the reaction is carried out for 1h under the protection of nitrogen, then the ice water bath is removed, and the reaction is continued for 12h under the protection of nitrogen at 25 ℃. After the reaction is finished, filtering off white precipitate in the reaction liquid, supplementing 30mL of dichloromethane solvent, transferring to a separating funnel, washing for 2-3 times by using saturated sodium bicarbonate solution and 10% hydrochloric acid by mass fraction respectively, then drying the organic phase shift to anhydrous sodium sulfate for 30min, finally removing the dichloromethane solvent by rotary evaporation, and drying in vacuum for 2h at 52 ℃ to obtain a macromolecular initiator PEG-Br, wherein the reaction formula is as follows:
(7) 0.0174g (0.078 mmol) of CuBr 2 And 0.0135g (0.078 mmol) of PMDETA ligand dissolved in 3.9mL of N, N-Dimethylformamide (DMF) to prepare Cu II Is a complex of (a) and (b). 3.8g Cu II 0.192g (0.78 mmol) coumarin derivative, 1.73g (7.8 mmol) IBMA, 1.55g (3.3 mmol) UDMA and 35mL deionized water were added to a 100mL Schlenk flask, 1.0g polyoxyethylene (20) oleoether [ (A) ]s 20) emulsifier and 0.2g (0.1 mmol) of macroinitiator PEO-Br were added to the above reaction flask, followed by magnetic stirring for 10min to form a stable emulsion, and oxygen in the Schlenk flask and dissolved oxygen in the emulsion were purged with nitrogen for 30min. After the emulsion is preheated to 50 ℃, 0.24g (1.35 mmol) of ascorbic acid (ASCA) is added to reduce the copper ligand in a high oxidation state to the copper ligand in a low oxidation state, then the reaction is carried out for 3 hours under the protection of nitrogen at 50 ℃, the temperature is increased to 60 ℃ again for continuous reaction for 1 hour, the rotating speed is increased, and the emulsion is completely exposed in the air to contact with oxygen for quenching reaction. After the reaction is finished, pouring out the reaction solution, demulsifying with Ethyl Acetate (EA), layering, pouring out the upper oil phase, adsorbing residual copper ligand in the lower water phase with a neutral alumina chromatographic column for three times to remove, pouring the copper ligand into a large amount of anhydrous diethyl ether, stirring to obtain granular solid, filtering, washing with the anhydrous diethyl ether for 3 times to remove the oil phase and the emulsifier in the product, and finally drying in vacuum to obtain the product photoresponsive nanogel.
(8) Mixing up-conversion particles (50 mg) with lightThe nanogel (50 mg) was dissolved in 15mL of dichloromethane with separate ultrasonic agitation, and then the dichloromethane solution of the photoresponsive nanogel was added drop-wise to the dichloromethane solution of the up-conversion particles being agitated. After the dripping is finished, the solution is continuously stirred to fully mix, then the temperature is raised to 50 ℃, stirring is continuously carried out until the solvent is volatilized, a layer of film is formed, then water is added for hydration, ultrasonic dissolution and centrifugation are carried out, and the composite product (UC-NG) of the upturned nano particles and the nano gel is obtained after vacuum drying at 80 ℃. UC-NG (50 mg) and polydopamine (50 mg) were dissolved in 15mL of methylene chloride with ultrasonic agitation, respectively, and then a methylene chloride solution of polydopamine was added dropwise to the stirred methylene chloride solution of UC-NG. After the dripping is finished, stirring for 30min continuously to fully mix, heating to 50 ℃, stirring continuously until the solvent volatilizes to form a layer of film, adding water for hydration, dissolving by ultrasonic, centrifuging to obtain gray black solid, and drying in vacuum at 80 ℃ to obtain a photo-thermal dual response composite carrier, namely UC-NG-PDA 1.0 。
FIG. 1 shows a photo-thermal dual response composite carrier UC-NG-PDA prepared in this example 1.0 Ultraviolet absorption spectrum and fluorescence emission spectrum of (a). The ultraviolet absorption spectrum of the prepared composite carrier shows a specific absorption peak of coumarin photoresponsive groups in 325-350 nm and an absorption peak of polydopamine in ultraviolet light and visible light ranges, and under the excitation of 980nm near infrared light, up-conversion particles in the composite carrier still have stronger fluorescence emission peaks, and the two peaks are overlapped to a certain extent, so that ultraviolet light emitted by the up-conversion particles after the excitation of 980nm near infrared light can be absorbed by the photoresponsive nanogel to generate photolysis reaction, and the ultraviolet light can be further used for drug response release.
Example 3-example 5
The procedure of example 2 was repeated, except that the mass ratio of the composite product of upturned nanoparticles and nanogels (UC-NG) to polydopamine Particles (PDA) used was different, as shown in Table 1:
the composite carrier products prepared in examples 3-5 were labeled UC-NG-PDA, respectively 0.5 、UC-NG-PDA 0.8 And UC-NG-PDA 1.2 。
Example 6
The purpose of this example is to demonstrate that the photo-thermal dual response composite supports prepared in examples 2-5 have good photo-thermal conversion properties.
The experimental method comprises the following steps: four photo-thermal dual response composite carrier methanol solutions (3 mg mL) were prepared -1 ) Placed in a glass bottle, and then subjected to 980nm near infrared light (3W cm -2 ) And (3) irradiating the methanol solution of the photo-thermal dual-response composite carrier for 300s, so as to ensure that a light spot of near infrared light can cover the test solution, and observing and recording the temperature of a solution system by using a temperature probe.
Experimental results: as shown in fig. 2, with the increase of polydopamine content in the composite carrier, the photo-thermal conversion efficiency was significantly improved, and when the UC-NG/PDA mass ratio was increased from 1:0.5 to 1:1.2, the ratio was increased in the near infrared (3W cm -2 ) After 300s of irradiation, the temperature of the photo-thermal dual-response composite carrier is increased from 21.1 ℃ to 63.2 ℃, which indicates that the further increase of the polydopamine content does not obviously enhance the photo-thermal conversion effect of the composite carrier.
Example 7
The purpose of this example is to illustrate the photo-thermal dual response composite support (UC-NG-PDA) prepared in example 2 1.0 ) The concentration of methanol solution (C) and the power of near infrared light (NIR) used versus UC-NG-PDA 1.0 Is effective in light-heat conversion performance.
The experimental method comprises the following steps: preparing methanol solutions of photo-thermal dual-response composite carriers with different concentrations, placing the methanol solutions in a glass bottle, and then irradiating the methanol solutions of the photo-thermal dual-response composite carriers by using a 980nm near infrared laser to ensure that light spots of near infrared light can cover the test solution, wherein the irradiation power is 3W cm -2 The irradiation time is 120s, and the temperature of the solution system is observed and recorded by using a temperature probe; the power of a 980nm near infrared laser was adjusted to irradiate a methanol solution (3 mg mL) of a photothermal dual response composite carrier -1 ) The light spot of near infrared light can be ensured to cover the test solution, the irradiation time is 120s, and the temperature of the solution system is observed and recorded by using a temperature probe.
Experimental results: as shown in fig. 3, the temperature of the photo-thermal dual-response composite carrier solution is continuously increased with the continuous increase of near infrared light power at the same time (120 s) of irradiation. When the laser power used is 0.5W cm -2 At the same time, after 120s of irradiation, the temperature of the composite carrier solution was increased by 9.9℃under the same conditions as the laser power used was increased to 3.0W cm -2 At this time, the temperature of the composite carrier was raised by 36.6 ℃. The above results also prove that the synthesized photo-thermal dual-response composite carrier has good photo-thermal conversion performance. In addition, as can be seen from FIG. 4, the infrared light (3.0W cm -2 ) When the same time (120 s) is irradiated downwards, the temperature of the methanol solution of the photo-thermal dual-response composite carrier is continuously increased along with the increase of the concentration of the solution, and the synthesized photo-thermal dual-response composite carrier is proved to have excellent photo-thermal conversion performance.
Example 8
The purpose of this example is to illustrate that the photo-thermal dual response composite carrier prepared in example 2 is capable of loading the hydrophobic guest molecule coumarin 102. Since the prepared photothermal dual-response composite carrier has hydrophobicity, coumarin 102 can be loaded in the photothermal dual-response composite carrier by utilizing the hydrophobic effect.
The experimental method comprises the following steps: 50mg of the photo-thermal dual-response composite carrier is weighed and dissolved in 5mL of anhydrous tetrahydrofuran, ultrasound is used for fully dissolving the carrier, 20mg of coumarin 102 is weighed and dissolved in 2mL of anhydrous tetrahydrofuran, ultrasound is used for fully dissolving the coumarin, then tetrahydrofuran solution of the coumarin 102 is dropwise added into tetrahydrofuran solution of the photo-thermal dual-response composite carrier, stirring is carried out for uniformly mixing the solution, and the mixed solution is dialyzed for two days by deionized water until the tetrahydrofuran is completely removed. Filtering out insoluble coumarin 102, then putting into a refrigerator for freezing, and then freeze-drying by using a freeze dryer to obtain a photo-thermal dual-response composite carrier loaded with coumarin 102, which is used as a research experiment for researching stimulus response release of the photo-thermal dual-response composite carrier;
preparing a series of methanol solutions of coumarin 102 with different concentrations, measuring the maximum absorbance at 391nm by using an ultraviolet spectrophotometer, and fitting by using origin to obtain a standard equation between the coumarin 102 solutions with different concentrations and the maximum absorbance.
Dissolving the photo-thermal dual-response composite carrier loaded with coumarin 102 in methanol solution, testing its maximum absorbance at 391nm with ultraviolet spectrophotometer, repeating the test for three times to obtain average value, and taking into the standard equation of coumarin 102, and calculating to obtain the mass of coumarin 102 loaded with composite carrier as m 2 The mass of coumarin 102 just started to be put into is m 1 The mass of the composite carrier without coumarin 102 in the blank is m 0 . The calculation formulas of the loading rate (DL) and the Encapsulation Rate (ER) of the photothermal dual-response composite carrier loaded with coumarin 102 are as follows:
experimental results: fig. 5 is a standard curve of coumarin 102, and the loading rate and encapsulation rate of coumarin 102 by the photo-thermal dual-response composite carrier are shown in table 2, which can effectively load drugs.
Table 2 blank and load comparison of composite carriers
Example 9
The purpose of this example is to illustrate the photo-thermal dual response composite support (UC-NG-PDA) prepared in example 2 1.0 ) Can release the coumarin 102 loaded with the hydrophobic guest molecule under the stimulation of 365nm ultraviolet light and 980nm near infrared light.
Testing photo-thermal dual response composite using ultraviolet spectrophotometerThe ultraviolet degradation of the carrier takes methanol as solvent, and the photo-thermal dual response composite carrier is prepared into coumarin photo-response group with the concentration of 1 multiplied by 10 -4 mol·L -1 And the absorption peak of the solution in the ultraviolet light region of 200nm-600nm is detected.
For all light response release experiments, the light-heat dual response composite carrier loaded with coumarin 102 is used for preparing the light-heat dual response composite carrier with the concentration of 0.02mg mL -1 Is tested for fluorescence change of coumarin 102 and is investigated for stimulus-responsive release.
The composite carrier loaded with coumarin 102 was dissolved in 5mL of methanol, and the maximum absorbance at 391nm was measured by an ultraviolet spectrophotometer, and the cumulative release amount of coumarin 102 was calculated by the addition method.
Experimental results: as shown in fig. 6, the fluorescence intensity of the photo-thermal dual-response composite carrier loaded with coumarin 102 is continuously reduced along with the extension of irradiation time under the irradiation of 365nm ultraviolet light, and after the irradiation for 20min, the fluorescence intensity is reduced by 48.8%, which means that under the irradiation of ultraviolet light, the composite carrier loaded with coumarin 102 is subjected to the action of ultraviolet light to crack the photo-response nanogel, and the coumarin 102 encapsulated in the composite carrier is released, so that the fluorescence intensity is continuously reduced. Under the same conditions, as shown in fig. 7, the fluorescence intensity of the photo-thermal dual-response composite carrier loaded with coumarin 102 is obviously reduced under the irradiation of 980nm near infrared light, and after 20min of irradiation, the fluorescence intensity is reduced by 76.4%, which is far higher than the fluorescence reduction degree of the photo-thermal dual-response composite carrier under ultraviolet light, which is caused by the dual effects of photo response and thermal response. Also shows that under the action of near infrared light, the dual action of light and heat is more beneficial to the degradation of the composite carrier and the drug release.
Example 10
The purpose of this example is that the photo-thermal dual response composite carriers prepared in comparative examples 2-5 have different release rates to the loaded hydrophobic guest molecule coumarin 102 under the stimulation of 365nm ultraviolet light and 980nm near infrared light. Table 3 shows the release rates of four photothermal dual response composite carriers for coumarin 102 upon irradiation with uv light and near ir light.
Compared with four composite carriers, the release rate of coumarin 102 is not greatly different under ultraviolet light and near infrared light; compared with ultraviolet light and near infrared light, the highest release rate of the photo-thermal dual-response composite carrier to coumarin 102 after the photo-thermal dual-response composite carrier irradiates for 20min under the ultraviolet light can reach 58.8%, the highest release rate of the photo-thermal dual-response composite carrier to coumarin 102 after the photo-thermal dual-response composite carrier irradiates for 20min under the near infrared light can reach 79.4%, the release rate of the photo-thermal dual-response composite carrier is far higher than the release rate of the photo-thermal dual-response composite carrier to coumarin 102 under the ultraviolet light, and the release rates of the four photo-thermal dual-response composite carriers under the near infrared light are all higher than the release rate under the ultraviolet light, which indicates that the photo-thermal dual-response greatly improves the drug release rate of the photo-thermal dual-response composite carrier.
TABLE 3 Release Rate of four photo-thermal Dual response composite Carriers for coumarin 102
Example 11
Determination of the photo-thermal Dual response composite Carrier (UC-NG-PDA) prepared in example 2 1.0 ) Is defined by the formula (I):
HeLa cells purchased from Shanghai Song Van Biotech Co., ltd were used at 5.0X10% 3 Cell/well density seeded into 96-well plates at 5% co 2 Culturing in an incubator at 37 ℃ for 24 hours; gradually diluting the dimethyl sulfoxide (DMSO) solution containing the composite carrier to a series of different concentrations with a complete DMEM culture medium, wherein the concentration range is 1-20 mug mL -1 The method comprises the steps of carrying out a first treatment on the surface of the Respectively adding DMSO solutions with different concentrations and containing the composite carrier into a pore plate with cells in advance (the control group is not added with the DMSO solution containing the composite carrier, 100 mu L of complete DMEM culture medium is added), and continuously culturing at 37 ℃ for 24 hours; MTT solution (5 mg mL) was added to each well -1 ) Culturing at 37℃for 4h. The culture broth was removed, 150. Mu.L of DMSO was added, the plate was shaken to stain it uniformly, and the absorbance at 490nm was measured with a microplate reader. The relative cell viability was calculated from the ratio of absorbance to control wells as follows:
wherein: OD is the experimental value of wells containing different concentrations of the analyte, OD C Control value, OD of wells without detection and MTT only 0 Is the background value of wells to which no test substance and MTT were added.
Experimental results: FIG. 8 is a graph of cell activity, and the prepared photo-thermal dual-response composite carrier has good biocompatibility.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (8)
1. A preparation method of a photo-thermal dual response composite carrier is characterized by comprising the following steps: the method comprises the following steps:
(1) Dissolving the up-conversion nano particles and the light response nano gel into a first organic solvent, centrifuging and drying; the mass ratio of the up-conversion nano particles to the light response nano gel is 1:1;
the preparation method of the up-conversion nano-particles comprises the following steps: dissolving a rare earth stearate precursor in a first mixed solvent, adding fluoride to form suspension, transferring to a hydrothermal reaction kettle, heating for reaction, centrifuging after the reaction, washing and drying to obtain up-conversion nano particles;
the preparation method of the light response nanogel comprises the following steps:
A. preparation of a photoresponsive coumarin derivative intermediate I: mixing phenol substances and ester substances, dropwise adding concentrated sulfuric acid, continuing to react after the dropwise adding is finished, separating liquid after the reaction, washing, drying and purifying; the phenol substances in the step A are selected from one or more of resorcinol, catechol and hydroquinone; the ester substance is one or more of ethyl acetoacetate, ethyl 4-chloroacetoacetate and ethyl 2-phenylacetoacetate;
B. preparation of photo-responsive coumarin derivatives II: dissolving the product in the step A in a fifth organic solvent, adding carboxylic acid substances and a condensation reagent, heating for reaction, separating liquid after the reaction, washing, drying and purifying;
C. copper bromide, an amine catalyst and a sixth organic solvent are mixed to prepare a copper complex; adding a copper complex, a photoresponsive coumarin derivative II, an ester monomer and a cross-linking agent into deionized water, adding an emulsifying agent and a macromolecular initiator into the mixed solution, reacting under the condition of nitrogen, washing, settling and drying after the reaction to obtain a product;
(2) Respectively dissolving the product obtained in the step (1) and polydopamine into a second organic solvent, centrifuging and drying to obtain a photo-thermal dual-response composite carrier; the mass ratio of the product in the step (1) to the polydopamine is 1:0.5-1.2.
2. The method for preparing the photo-thermal dual-response composite carrier according to claim 1, which is characterized in that: the first organic solvent is selected from one or more of dichloromethane, chloroform, toluene and carbon tetrachloride, and the second organic solvent is selected from one or more of N, N-dimethylformamide, dichloromethane and chloroform.
3. The method for preparing the photo-thermal dual-response composite carrier according to claim 1, which is characterized in that: the first mixed solvent is selected from one or more of a mixture of ethanol and oleic acid, a mixture of water and ethanol and oleic acid; the fluoride is selected from one or more of sodium fluoride, potassium fluoride and calcium fluoride; the temperature of the heating reaction is 150-200 ℃, and the reaction time is 8-16h.
4. The method for preparing the photo-thermal dual-response composite carrier according to claim 1, which is characterized in that: the preparation method of the rare earth stearate precursor comprises the following steps: dissolving rare earth element oxide in concentrated nitric acid, stirring and dissolving, heating and volatilizing the solvent to obtain rare earth salt, dissolving the rare earth salt in a third organic solvent, adding an active agent, stirring and dissolving, dripping a fourth organic solvent, refluxing at constant temperature, reacting, distilling under reduced pressure, washing and drying to obtain the product.
5. The method for preparing the photo-thermal dual-response composite carrier according to claim 1, which is characterized in that: the reaction temperature in the step A is 0-50 ℃ and the reaction time is 30-60h.
6. The method for preparing the photo-thermal dual-response composite carrier according to claim 1, which is characterized in that: the preparation method of the polydopamine comprises the following steps: dissolving absolute ethyl alcohol and alkaline solution in deionized water, adding dopamine hydrochloride into the mixed solution to react, centrifuging after the reaction, washing and drying to obtain polydopamine.
7. A photo-thermal dual response composite carrier made by the method of any one of claims 1-6.
8. Use of a photo-thermal dual response composite carrier prepared by the method of any one of claims 1-6 in the preparation of a medicament.
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