CN107474191A - A kind of photoresponse type intelligent nano switch and preparation method and application - Google Patents

A kind of photoresponse type intelligent nano switch and preparation method and application Download PDF

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CN107474191A
CN107474191A CN201710757207.7A CN201710757207A CN107474191A CN 107474191 A CN107474191 A CN 107474191A CN 201710757207 A CN201710757207 A CN 201710757207A CN 107474191 A CN107474191 A CN 107474191A
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王斌
陈克复
李金鹏
曾劲松
徐峻
高文花
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South China University of Technology SCUT
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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
    • C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
    • C08F251/02—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof on to cellulose or derivatives thereof
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    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis

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Abstract

The invention belongs to materials science field, discloses a kind of photoresponse type intelligent nano switch and preparation method and application.The preparation method is：Nano-cellulose initiator, 2 (3 ' are prepared respectively, nitro spiral shell [the chromene 2 of 3 ' dimethyl 6,2 ' indoles woodss] 1 ' methyl) acetic acid and 2 (the nitro spiral shell of 3 ', 3 ' dimethyl 6 [indoles of chromene 2,2 ' woods] compounds containing acrylic acid；Photoresponse type nanofiber hydrogel intelligent switch is prepared by two sections of atom transition free radical polymerization reactions.Described photoresponse type intelligent nano switch not only has the advantages of nontoxic, quick response, high sensitivity, and can realize remote control and regulation, has good biocompatibility, can be applicable in medical domain.

Description

A kind of photoresponse type intelligent nano switch and preparation method and application
Technical field
The invention belongs to materials science field, and in particular to a kind of photoresponse type intelligent nano switch and preparation method thereof with Using.
Background technology
Intelligent nano switch can respond to environmental stimuli and cause own physical chemical property to change, in temperature Under the regulation and control of degree, pH, light, magnetic and electric field etc., the effect such as display, sensing, insoluble drug release can be played.
Human body is a complicated system, and the control environment skewness of different zones, cytoplasm pH value is about 7.2, and Environment of other environment as residing for lysosome and endoplasmic reticulum is but acidity.In medical domain, common drug delivery means, treating Outside malignant cell, normal cell can be also killed, greatly reduces therapeutic effect.For problem above, the nanotube switch of controllability Increasingly paid close attention to for field of medicine release by scientific research personnel.Medicine discharges in specified location plays therapeutic effect, avoids Other cells are produced with pathology injury.
In the molecular switch for the controlled release studied at present, there is that the stimuli responsive time is long, sensitivity is low, the scope of application The shortcomings of narrow.
The content of the invention
To solve the shortcomings that prior art and weak point, primary and foremost purpose of the invention is that providing one kind has response fast Controllable, good biocompatibility the photoresponse type intelligent nano switch of speed, switch.
Another object of the present invention is to provide the preparation method of above-mentioned photoresponse type intelligent nano switch.The present invention is made Standby photoresponse type intelligent nano switch, it is gentle reliable, there is higher space and temporal resolution, remote control can be achieved, It is more environmentally-friendly, additional waste will not be produced.
It is yet a further object of the present invention to provide the application of above-mentioned photoresponse type intelligent nano switch.
For achieving the above object, the present invention adopts the following technical scheme that：
A kind of photoresponse type nanofiber hydrogel intelligent switch, the closure state structure such as formula (1) of its intelligent switch It is shown, shown in the structure such as formula (2) of the open mode of intelligent switch：
A kind of photoresponse type nanofiber hydrogel intelligent switch be one kind can quick response and intelligence it is controllable System.
A kind of system of photoresponse type intelligent nano switch (i.e. above-mentioned photoresponse type nanofiber hydrogel intelligent switch) Preparation Method, including following operating procedure：
(1) 2- (3 ', 3 '-dimethyl -6- nitros spiral shell [chromene -2,2 '-indoles woods] -1 ' methyl) acetic acid is prepared：1- (2- carboxyethyls) -2,3,3- tri-methyl indole quinoline and 5- nitrosalicylaldehydes are added in ethanol, are stopped after 60~90 DEG C of 12~24h of heating Only, purification obtains product；
(2) 2- (3 ', 3 '-dimethyl -6- nitros spiral shell [chromene -2,2 '-indoles woods] chemical combination containing acrylic acid is prepared Thing：It is dissolved in by the product of step (1) acquisition and containing acyclic compound in tetrahydrofuran, adds a certain amount of 4- dimethylaminos pyrrole Pyridine and N, N '-dicyclohexylcarbodiimide, 2~8h is reacted under first condition of ice bath, rear 12~24h of normal-temperature reaction, is removed after reaction Thick slag purifies to obtain product；
(3) nano-cellulose initiator is prepared：A certain amount of pyridine and bromo isobutyl acylbromide is added into nano-cellulose, 12~36h is reacted at room temperature, and purification obtains product；
(4) 2 sections of atom transition free radical polymerization reactions are carried out：The product of step (3) and step (2) product are separately added into In dimethyl amide, add catalyst and part is reacted, obtain product after purification；
(5) preparation of nano-micelle：It will be configured in the product addition water or cushioning liquid of step (4) certain density molten Liquid, obtain photoresponse type intelligent nano switch.
Room temperature of the present invention refers to 25~27 DEG C.
Preferably, the tri-methyl indole quinolines of 1- (2- carboxyethyls) -2,3,3- and 5- nitrosalicylaldehyde mass ratioes are in step (1) 1：(1.25~2).
Preferably, described in step (2) it is hydroxyethyl methacrylate ester, wherein hydroxyethyl methacrylate containing acyclic compound Ester, 2- (3 ', 3 '-dimethyl -6- nitros spiral shell [chromene -2,2 '-indoles woods] -1 ' methyl) acetic acid, DMAP, N, N ' the amount of substance ratio of-dicyclohexylcarbodiimide is (18~20):(8~10):(1~3):(1~3), more preferably 20: 10:2:1.2~8h, rear 12~24h of normal-temperature reaction are reacted under first condition of ice bath, obtains 2-3- (3 ', 3 '-dimethyl -6- nitro spiral shells [chromene -2,2 '-indoles woods] -1 '-methyl) acrylic acid hydroxyl ester (i.e. described 2- (3 ', 3 '-dimethyl -6- containing acrylic acid Nitro spiral shell [chromene -2,2 '-indoles woods] compound).
Preferably, nano-cellulose, pyridine, bromo isobutyl acylbromide amount of substance ratio are (1~3) in step (3):(8~10): (1~3), more preferably 1:10:1.
The reaction time of step (3) is preferably 12~24h.
Nano-cellulose described in step (3) is prepared by TEMPO oxidizing process, wherein：Every gram of bone dry fiber raw material 0.02~0.05g TEMPO reagents are needed, 3~5mmol NaClO and 0.1~0.3g NaBr, dense slurry is 1%~4%；It is made and receives Rice cellulose is standby after -40 DEG C~0 DEG C freeze-drying.
Preferably, the catalyst described in step (4) is cuprous bromide, and part is three (2- dimethylaminoethyls) amine, and former Sub- transferring free-radical polymerization is carried out under nitrogen protection, and the product of step (2), the product of step (3), catalyst and part add In tube sealing equipped with ethyl acetate, after 70 DEG C of 12~24h of reaction, diluted with tetrahydrofuran, ultrasonication centrifuges after 30 minutes Analysis, products obtained therefrom vacuum drying 24h.
Preferably, step (5) nanotube switch solution concentration is measured using the critical colloid concentration of tensammetric determination.
A kind of described photoresponse type nanofiber hydrogel intelligent switch has higher space and temporal resolution, Remote control can be achieved, it is more environmentally-friendly, it can apply in field of medicaments.
Compared with prior art, the present invention has advantages below and beneficial effect：
(1) present invention prepare photoresponse type intelligent nano switch can remote control and regulation, quick response；(2) prepared by the present invention Photoresponse type intelligent nano switch response process stimulate simple, high sensitivity；(3) photoresponse type prepared by the present invention is intelligently received Meter Kai Guan has biocompatibility, nontoxic, the advantages of being directly metabolized.
Brief description of the drawings
Fig. 1 is the structural representation of photoresponse type intelligent nano of the present invention switch.
Fig. 2 is photoresponse type nano-hydrogel spectrum change before and after by ultraviolet light in present example 1.
Spectrum changes of the Fig. 3 for photoresponse nano-hydrogel in present example 1 by different time ultraviolet excitation.
Embodiment
With reference to embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are unlimited In this.
Medicine is adsorbed by taking pyrene or adriamycin as an example, with reference to Fig. 1, photoresponse type intelligent nano switch of the present invention, is had following Structure：
Wherein, A represents carrier, as nano-cellulose, and B represents loaded article, as slow release molecules pyrene (pyrene) or Ah Mycin DOX.
The principle of the invention is：
The structure of nano-cellulose molecular switch as shown in Figure 1, under natural light, 2-3- (3 ', 3 '-dimethyl -6- nitre Base spiral shell [chromene -2,2 '-indoles woods] -1 '-methyl) acrylic acid hydroxyl ester is closing structure, shows as hydrophobic property, can be a large amount of Adsorb hydrophobic drug.
When the system is by ultraviolet excitation, 2-3- (3 ', 3 '-dimethyl -6- nitros spiral shell [chromene -2,2 '-indoles Woods] -1 '-methyl) acrylic acid hydroxyl ester shows as open loop structure, shows as water-wet behavior, and now the system hydrophobicity reduces, system The molecule of absorption is released.
Photoresponse type intelligent nano switch of the present invention, is prepared, step is as follows using following methods：
(1) 2- (3 ', 3 '-dimethyl -6- nitros spiral shell [chromene -2,2 '-indoles woods] -1 ' methyl) acetic acid is prepared：1- (2- carboxyethyls) -2,3,3- tri-methyl indole quinoline and 5- nitrosalicylaldehydes are added in ethanol, are stopped after 80 DEG C of 12~24h of heating, Sedimentation overnight, is washed 3 times with methanol after product filtering, product is obtained after drying；
(2) 2- (3 ', 3 '-dimethyl -6- nitros spiral shell [chromene -2,2 '-indoles woods] chemical combination containing acrylic acid is prepared Thing：It is dissolved in by the product of step (2) acquisition and containing acyclic compound in tetrahydrofuran, adds a certain amount of 4- dimethylaminos pyrrole Pyridine and N, N '-dicyclohexylcarbodiimide, 2~8h is reacted under first condition of ice bath, rear 12~24h of normal-temperature reaction, is gone out after reaction Thick slag purifies to obtain product；
(3) nano-cellulose initiator is prepared：A certain amount of pyridine and bromo isobutyl acylbromide is added into nano-cellulose, 12~36h is reacted at room temperature, and purification obtains product；
(4) 2 sections of atom transition free radical polymerization reactions are carried out：The product of step (3) and step (2) product are separately added into In dimethyl amide, the catalyst and part of addition are reacted, and obtain product after purification；Described catalyst is bromination Cuprous, part is three (2- dimethylaminoethyls) amine, and ATRP is carried out under nitrogen protection, reaction temperature For 70 DEG C, the reaction time is 12~24h, and the polymer of generation is diluted with tetrahydrofuran, and ultrasonication centrifuges after 30 minutes divides Analyse, 24h is placed under products obtained therefrom vacuum；
(5) product that step (4) obtains passes through the NaH containing absorption medicine2PO4/Na2HPO4Disperseed in cushioning liquid, The pH=7 of cushioning liquid.The concentration of photoresponse nanofiber molecular switch is 1~3mg/mL, and absorption medicine is with pyrene or adriamycin Exemplified by, concentration is 10~20mg/mL.
Further explanation is made to the present invention with reference to instantiation.Nano-cellulose in embodiment passes through TEMPO Oxidizing process is prepared：Every gram of bone dry fiber raw material need 0.02~0.05g TEMPO reagent, 3~5mmol NaClO and 0.1~ 0.3g NaBr, dense slurry is 1%~4%；It is standby after -40 DEG C~0 DEG C freeze-drying that nano-cellulose is made, is numbered and is NCC-05。
Embodiment 1
A kind of preparation method of photoresponse type intelligent nano switch, step are as follows：
(1) nano-cellulose NCC-05 is prepared, and the nano-cellulose suspension of gained is freeze-dried, nano-cellulose NCC-05 preparation process is as follows：
With 250mL mass fractions it is 64%H after 20g bagasse pulps are crushed2SO4Add in round-bottomed flask, stirred under condition of ice bath Mix 1h.Reaction adds distilled water diluting after stopping, and sulfuric acid solution is removed after stratification, then with supercentrifuge centrifugation for several times, Until forming suspension, suspension is installed with bag filter and dialysed 7 days in distilled water, finally obtains NCC- by freeze-drying 05。
(2) 2- (3 ', 3 '-dimethyl -6- nitros spiral shell [chromene -2,2 '-indoles woods] -1 ' methyl) acetic acid is prepared： 3.34g 5- nitrosalicylaldehydes, 32mL absolute ethyl alcohols and a small amount of pyridine is added in 250mL there-necked flasks, oil bath magnetic agitation adds Heat is to 70 DEG C.The 2.19g tri-methyl indole quinolines of 1- (2- carboxyethyls) -2,3,3- are separately dissolved in 80mL absolute ethyl alcohols, are slowly added dropwise In there-necked flask, start logical argon gas, adverse current heats, and reacts 12h, immediately reactant is poured out after stopping reaction, and sedimentation is overnight.Product With filtered on buchner funnel, and washed for several times with absolute methanol, until washing lotion is colourless, 50 DEG C of vacuum drying 72h.
(3) 3.80g steps (2) product, 2.6g hydroxyethyl methacrylates ester and 0.24g DMAPs are added and filled In the there-necked flask for having the 250mL of magnetic stirring apparatus, addition 70mL tetrahydrofurans, which fully dissolve, promotes reaction, and whole process is used Ice bath cools down, and is passed through nitrogen.2.06g N, N '-dicyclohexylcarbodiimide separately are dissolved with 30mL tetrahydrofuran solutions, dropwise Add in reaction vessel, reaction vessel is moved into dark place, after ice bath reacts 2h, reacts at room temperature 12h.After reaction terminates, cross and filter out Thick slag is removed, low-temperature rotary evaporation removes most of tetrahydrofuran, then with water sedimentation is distilled, sediment is dissolved in benzene, filters SP-COOH is removed, low-temperature rotary evaporation removes most of reagent benzene, finally obtains product with petroleum ether precipitation, vacuum drying.
(4) step (1) product of 1.0g drying is added in the refined THF of 50mL, adds 8mL pyridines (100mmol), Stir after dissolving it, be placed in ice-water bath.Then it is 2.18g bromo isobutyl acylbromides (10mmol) is molten with 10mL THF Solution, and be slowly dropped in reaction vessel.Bromo isobutyl acylbromide is added dropwise completely, reacts 12h at room temperature.After reaction completely, Filter and purified with dichloromethane, product is put in 35 DEG C of vacuum drying chambers and dried 3 days.
(5) step (4) product 0.1g, 44.3mg cuprous bromide, 6.8mg tri- (2- dimethylaminoethyls) amine, 1.47g are walked Suddenly (3) product and 2mL ethyl acetate are fitted into tube sealing, are sealed after inflated with nitrogen, after reacting 14h at 70 DEG C, the polymer of generation Diluted with tetrahydrofuran, with centrifugal analysis after ultrasonication 30 minutes, 24h is placed under products obtained therefrom vacuum.
(6) the step of taking 10mg (5) product and 2mg pyrenes are added in 10mL DMSO, pyrene is fully dissolved, and then turn Move in the bag filter of interception 3500, use NaH2PO4/Na2HPO4 cushioning liquid is dialysed 7 days, will contain the nanogel of medicine 0.45 μm of vacuum membrane filtration of solution, removes remnants medicine, obtains final products photoresponse type intelligent nano switch.
The controlled release of pyrene
The releasing effect under different wavelengths of light is switched in order to study photoresponse type intelligent nano, the present invention has carried out following Experiment：The pyrene for weighing certain mass is dissolved in DMSO, and the solution of various concentrations is diluted to deionized water, uses ultraviolet spectra The absorbance in 303nm of bioassay standard solution, establish the standard curve of medicine.5mL medicament-carried nano micelle liquid is taken, by it After being filled to the bag filter that molecular cut off is 14000, (pH 7.4,37 DEG C of temperature) is placed in 200mL PBS, Insoluble drug release is carried out under 354nm ultraviolet lights.
50 μ L buffer solutions are drawn at regular intervals, are diluted with 5mL DMSO, while supplement the buffer solution of same volume, are tieed up Hold system balancing.
Fig. 2 and Fig. 3 is respectively photoresponse type nano-hydrogel spectrum change and light before and after by ultraviolet light in present example 1 Spectrum change of the response nano hydrogel by different time ultraviolet excitation.It is known that the hydrogel is in ultraviolet light from Fig. 2 Lower spectrum is excited to produce fluctuation, it is a kind of nanotube switch of photoresponse to demonstrate the hydrogel.Fig. 3 can be seen that opening for photoresponse The spectral absorption peak value of pass increases with the extension of ultraviolet excitation time, and it is a kind of very high light of sensitivity to illustrate the hydrogel The intelligent nano switch of response.
Embodiment 2
A kind of preparation method of photoresponse type intelligent nano switch, step are as follows：
(1) nano-cellulose NCC-05 is prepared, and the nano-cellulose suspension of gained is freeze-dried, nano-cellulose NCC-05 preparation process is as follows：
By 20g bagasse pulps crush after with 250mL (64wt%) H2SO4Add in round-bottomed flask, 1h is stirred under condition of ice bath. Reaction adds distilled water diluting after stopping, and sulfuric acid solution is removed after stratification, then with supercentrifuge centrifugation for several times, until shape Into suspension, suspension is installed with bag filter and dialysed 7 days in distilled water, finally obtains NCC-05 by freeze-drying.
(2) 2- (3 ', 3 '-dimethyl -6- nitros spiral shell [chromene -2,2 '-indoles woods] -1 ' methyl) acetic acid is prepared： 1.67g 5- nitrosalicylaldehydes, 32mL absolute ethyl alcohols and a small amount of pyridine is added in 250mL there-necked flasks, oil bath magnetic agitation adds Heat is to 70 DEG C.The 2.19g tri-methyl indole quinolines of 1- (2- carboxyethyls) -2,3,3- are separately dissolved in 80mL absolute ethyl alcohols, are slowly added dropwise In there-necked flask, start logical argon gas, adverse current heats, and reacts 24h, immediately reactant is poured out after stopping reaction, and sedimentation is overnight.Product With filtered on buchner funnel, and washed for several times with absolute methanol, until washing lotion is colourless, 50 DEG C of vacuum drying 72h.
(3) 3.80g steps (2) product, 1.3g hydroxyethyl methacrylates ester and 0.24g DMAPs are added and are equipped with In the 250mL of magnetic stirring apparatus there-necked flask, addition 70mL tetrahydrofurans, which fully dissolve, promotes reaction, whole process ice Bath cooling, and it is passed through nitrogen.Separately with 30mL tetrahydrofuran solutions dissolving 2.06g N, N '-dicyclohexylcarbodiimide, add dropwise Enter in reaction vessel, reaction vessel is moved into dark place, after ice bath reacts 4h, reacts at room temperature 24h.After reaction terminates, it is filtered to remove Thick slag, low-temperature rotary evaporation removes most of tetrahydrofuran, then with water sedimentation is distilled, sediment is dissolved in benzene, crosses and filters out SP-COOH is removed, low-temperature rotary evaporation removes most of reagent benzene, finally obtains product with petroleum ether precipitation, vacuum drying.
(4) step (1) product of 1.0g drying is added in the refined THF of 50mL, adds 8mL pyridines, stir After dissolving it, it is placed in ice-water bath.Then 1.59g bromo isobutyl acylbromides 10mL THF are dissolved, and be slowly dropped to anti- Answer in container.Bromo isobutyl acylbromide is added dropwise completely, reacts 24h at room temperature.After reaction completely, filter and carried with dichloromethane Pure, product is put in 35 DEG C of vacuum drying chambers and dried 3 days.
(5) step (4) product 0.1g, 44.3mg cuprous bromide, 3.4mg tri- (2- dimethylaminoethyls) amine, 2.21g are walked Suddenly (3) product and 2mL ethyl acetate are fitted into tube sealing, are sealed after inflated with nitrogen, after reacting 12h at 70 DEG C, the polymer of generation Diluted with tetrahydrofuran, with centrifugal analysis after ultrasonication 30 minutes, 24h is placed under products obtained therefrom vacuum.
(6) step (5) product and 2mg pyrenes for taking 15mg are added in 10mL DMSO, pyrene is fully dissolved, and then shift Into the bag filter of interception 3500, NaH is used2PO4/Na2HPO4 cushioning liquid is dialysed 7 days, and the nanogel for containing medicine is molten 0.45 μm of vacuum membrane filtration of liquid, removes remnants medicine, obtains final products photoresponse type intelligent nano switch.
Embodiment 3
A kind of preparation method of photoresponse type intelligent nano switch, step are as follows：
(1) nano-cellulose NCC-05 is prepared, and the nano-cellulose suspension of gained is freeze-dried, nano-cellulose NCC-05 preparation process is as follows：
By 20g bagasse pulps crush after with 250mL (64wt%) H2SO4Add in round-bottomed flask, 1h is stirred under condition of ice bath. Reaction adds distilled water diluting after stopping, and sulfuric acid solution is removed after stratification, then with supercentrifuge centrifugation for several times, until shape Into suspension, suspension is installed with bag filter and dialysed 7 days in distilled water, finally obtains NCC-05 by freeze-drying.
(2) 2- (3 ', 3 '-dimethyl -6- nitros spiral shell [chromene -2,2 '-indoles woods] -1 ' methyl) acetic acid is prepared： 2.51g 5- nitrosalicylaldehydes are added in 250mL there-necked flasks, 32mL absolute ethyl alcohols and a small amount of pyridine, oil bath magnetic agitation add Heat is to 70 DEG C.The 2.19g tri-methyl indole quinolines of 1- (2- carboxyethyls) -2,3,3- are separately dissolved in 80mL absolute ethyl alcohols, are slowly added dropwise In there-necked flask, start logical argon gas, adverse current heats, and reacts 18h, immediately reactant is poured out after stopping reaction, and sedimentation is overnight.Product With filtered on buchner funnel, and washed for several times with absolute methanol, until washing lotion is colourless, 50 DEG C of vacuum drying 72h.
(3) 5.70g steps (2) product, 2.6g hydroxyethyl methacrylates ester and 0.24g DMAPs are added and are equipped with In the 250mL of magnetic stirring apparatus there-necked flask, addition 70mL tetrahydrofurans, which fully dissolve, promotes reaction, whole process ice Bath cooling, and it is passed through nitrogen.Separately with 30mL tetrahydrofuran solutions dissolving 2.06g N, N '-dicyclohexylcarbodiimide, add dropwise Enter in reaction vessel, reaction vessel is moved into dark place, after ice bath reacts 2h, reacts at room temperature 12h.After reaction terminates, it is filtered to remove Thick slag, low-temperature rotary evaporation removes most of tetrahydrofuran, then with water sedimentation is distilled, sediment is dissolved in benzene, crosses and filters out SP-COOH is removed, low-temperature rotary evaporation removes most of reagent benzene, finally obtains product with petroleum ether precipitation, vacuum drying.
(4) step (1) product of 1.0g drying is added in the refined THF of 50mL, adds 8mL pyridines, stir After dissolving it, it is placed in ice-water bath.Then 1.64g bromo isobutyl acylbromides 10mL THF are dissolved, and be slowly dropped to anti- Answer in container.Bromo isobutyl acylbromide is added dropwise completely, reacts 18h at room temperature.After reaction completely, filter and carried with dichloromethane Pure, product is put in 35 DEG C of vacuum drying chambers and dried 3 days.
(5) step (4) product 0.1g, 44.3mg cuprous bromide, 3.4mg tri- (2- dimethylaminoethyls) amine, 1.47g are walked Suddenly (3) product and 2mL ethyl acetate are fitted into tube sealing, are sealed after inflated with nitrogen, after reacting 24h at 70 DEG C, the polymer of generation Diluted with tetrahydrofuran, with centrifugal analysis after ultrasonication 30 minutes, 24h is placed under products obtained therefrom vacuum.
(6) the step of taking 20mg (5) product and 2mg pyrenes are added in 10mL DMSO, pyrene is fully dissolved, and then turn Move in the bag filter of interception 3500, use NaH2PO4/Na2HPO4 cushioning liquid is dialysed 7 days, will contain the nanogel of medicine 0.45 μm of vacuum membrane filtration of solution, removes remnants medicine, obtains final products photoresponse type intelligent nano switch.
In summary, the photoresponse type intelligent nano switch that prepared by the present invention can be applicable to the drug delivery neck of medical domain Domain.Absorption has fluorescent medicine, when system is by ultraviolet excitation, nanotube switch in photoresponse nanofiber system Show as hydrophily, the medicine in system will discharge, and pass through fluoroscopic examination.The system shows molecular switch Matter, this method is simple and easy, and a kind of thinking is provided for nanometer delivery systems.This molecular switch is applied to biomedical lead Domain, hydrophobic anticancer drug can be adsorbed in system, and carry and discharged at carcinogenesis cell, the treatment to cancer cell can be achieved, Reduce side effect simultaneously.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment Limitation, other any Spirit Essences without departing from the present invention with made under principle change, modification, replacement, combine, simplification, Equivalent substitute mode is should be, is included within protection scope of the present invention.

Claims (9)

  1. A kind of 1. photoresponse type intelligent nano switch, it is characterised in that closure state structure such as formula (1) institute of its intelligent switch Show, shown in the structure such as formula (2) of the open mode of intelligent switch：
  2. 2. a kind of preparation method of photoresponse type intelligent nano switch, it is characterised in that comprise the following steps：
    (1) 2- (3 ', 3 '-dimethyl -6- nitros spiral shell [chromene -2,2 '-indoles woods] -1 ' methyl) acetic acid is prepared：1- (2- carboxylics Ethyl) -2,3,3- tri-methyl indole quinolines and 5- nitrosalicylaldehydes add in ethanol, stop after 60~90 DEG C of 12~24h of heating, carry It is pure to obtain product；
    (2) 2- (3 ', 3 '-dimethyl -6- nitros spiral shell [chromene -2,2 '-indoles woods] compounds containing acrylic acid are prepared：Will Step (1) obtain product and be dissolved in containing acyclic compound in tetrahydrofuran, add a certain amount of DMAP and N, N '-dicyclohexylcarbodiimide, 2~8h is reacted under first condition of ice bath, rear 12~24h of normal-temperature reaction, thick slag is removed after reaction Purifying obtains product；
    (3) nano-cellulose initiator is prepared：A certain amount of pyridine and bromo isobutyl acylbromide, room temperature are added into nano-cellulose 12~36h of lower reaction, purification obtain product；
    (4) 2 sections of atom transition free radical polymerization reactions are carried out：The product of step (3) and step (2) product are separately added into two In methyl diamides, add catalyst and part is reacted, obtain product after purification；
    (5) preparation of nano-micelle：The product of step (4) is added in water or cushioning liquid and is configured to certain density solution, Obtain photoresponse type intelligent nano switch.
  3. A kind of 3. preparation method of photoresponse type intelligent nano switch according to claim 2, it is characterised in that step (1) 1- (2- carboxyethyls) -2,3,3- tri-methyl indoles quinolines and 5- nitrosalicylaldehydes mass ratio are 1 in：(1.25~2).
  4. A kind of 4. preparation method of photoresponse type intelligent nano switch according to claim 2, it is characterised in that step (2) described in is hydroxyethyl methacrylate ester containing acyclic compound, wherein hydroxyethyl methacrylate ester, 2- (3 ', 3 '-dimethyl -6- Nitro spiral shell [chromene -2,2 '-indoles woods] -1 ' methyl) acetic acid, DMAP, N, N '-dicyclohexylcarbodiimide Amount of substance ratio be (18~20):(8~10):(1~3):(1~3).
  5. A kind of 5. preparation method of photoresponse type intelligent nano switch according to claim 2, it is characterised in that step (3) nano-cellulose, pyridine, bromo isobutyl acylbromide amount of substance ratio are (1~3) in:(8~10):(1~3).
  6. A kind of 6. preparation method of photoresponse type intelligent nano switch according to claim 2, it is characterised in that step (3) nano-cellulose described in is prepared by TEMPO oxidizing process, wherein：Every gram of bone dry fiber raw material needs 0.02~0.05g TEMPO reagents, 3~5mmol NaClO and 0.1~0.3g NaBr, dense slurry is 1%~4%；Nano-cellulose is made after -40 DEG C~0 DEG C of freeze-drying is standby.
  7. A kind of 7. preparation method of photoresponse type intelligent nano switch according to claim 2, it is characterised in that step (3) reaction time is 12~24h.
  8. A kind of 8. preparation method of photoresponse type intelligent nano switch according to claim 2, it is characterised in that step (4) catalyst described in is cuprous bromide, and part is three (2- dimethylaminoethyls) amine, and ATRP is in nitrogen Carried out under gas shielded, the product of step (2), the product of step (3), catalyst and part add the tube sealing equipped with ethyl acetate In, after 70 DEG C of 12~24h of reaction, diluted with tetrahydrofuran, ultrasonication centrifugal analysis after 30 minutes, products obtained therefrom vacuum is done Dry 24h.
  9. 9. a kind of photoresponse type intelligent nano described in claim 1 switchs the application in field of medicaments.
CN201710757207.7A 2017-08-29 2017-08-29 A kind of photoresponse type intelligent nano switch and preparation method and application Pending CN107474191A (en)

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