CN103524756A - Preparation method of light/pH (potential of hydrogen) sensitive type pyrene functional polymer micelle - Google Patents
Preparation method of light/pH (potential of hydrogen) sensitive type pyrene functional polymer micelle Download PDFInfo
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- CN103524756A CN103524756A CN201310452322.5A CN201310452322A CN103524756A CN 103524756 A CN103524756 A CN 103524756A CN 201310452322 A CN201310452322 A CN 201310452322A CN 103524756 A CN103524756 A CN 103524756A
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Abstract
The invention relates to a preparation method of a light/pH sensitive type pyrene functional polymer micelle and belongs to the field of functional polymer materials. The preparation method comprises the steps as follows: firstly, polymerizable monomer acryloyl chloride is polymerized through free radicals to generate poly acryloyl chloride; then the poly acryloyl chloride and pyrene methanol are subjected to an esterification reaction to graft pyrene functional groups onto the poly acryloyl chloride; and finally, amphiphilic polymers containing the pyrene groups and carboxyl simultaneously are obtained through hydrolysis, and the polymers are prepared into the light/pH sensitive type polymer micelle through a micellization process. The polymer micelle is stable at the room temperature and can load hydrophobic molecules such as nile red and the like. A nano-structure of the polymer micelle can be adjusted and controlled through adjustment and control of ultraviolet irradiation and pH values, so that controlled release of drugs is realized. According to the preparation method, the polymer micelle has the light responsiveness and the pH responsiveness simultaneously, thereby having broad application prospects in the field of the controlled release of the drugs.
Description
Technical field
The invention belongs to polymeric material field, be specifically related to the preparation method of the synthetic and polymkeric substance self-assembled nano micelle of a kind of light and pH amphipathic nature polyalcohol.
Background technology
Polymer micelle is the molecule aggregates of the nano core-shell structure that formed by self-assembly in selective solvent by amphipathy macromolecule.Generally hydrophobic chain and hydrophilic chain, consist of, wherein hydrophobic segment forms micella kernel, and hydrophilic segment forms micella shell, and hydrophobic kernel can be used to embedding medicinal.
Polymer micelle pharmaceutical carrier has the performance of many uniquenesses with respect to other medicines carrier: as medicine is subject to the protection of micella shell, overcome the absorption of the non-tissue such as specially property picked-up or liver, spleen etc. of reticuloendothelial system; The polymer micelle of nanoscale has enhancing and sees through and retention effect, can strengthen the infiltration of medicine to tumor tissues vessel wall, promotes the performance of drug effect in cell; Given polymer micelle natural passive target administration functions; With low-molecular-weight surfactant micellar phase ratio, polymer micelle has lower micelle-forming concentration, thereby has good thermodynamics and kinetics stability.
In recent years, environment-responsive polymkeric substance, as pH responsiveness, temperature-responsive, ionic strength responsiveness, optical Response etc. have caused the extensive concern of researcher.This is mainly because environment-responsive polymkeric substance, in the situation that external environment has subtle change, the variation of polymer molecule chain conformation can occur, make such material that larger physical change or chemical transformation further occur, the stimulation of environment generation reaction to external world rapidly.
At present, polymer micelle, will be first as microcapsule embedded medicine for pharmaceutical carrier and slow-release material; Then drug-carrying polymer micelle is optionally transported to pathological tissues; Finally under body environmental change or outfield stimulation, micellar structure changes, and discharges medicine.
In recent years, the polymer micelle with pH and photoresponse has been reported, but the polymer micelle simultaneously with pH and optic response rarely has report, and along with the development of intelligent material, have multiple response, the polymer materials that structure is clear and definite has been subject to this area researchist's light and has noted more, simultaneously.
Summary of the invention
In order to address the above problem, to the object of the present invention is to provide and there is the polymer micelle preparation method to the Dual Sensitive of light and pH response simultaneously.
First the present invention prepares pyrene functionalized poly acryloyl chloride, so hydrolysis obtain amphipathic nature polyalcohol, this amphipathic nature polyalcohol can be used for preparing doubling sensitivity micella.
A preparation method for the pyrene functionalized polymer micelle of light/pH responsive type, its reaction mechanism is as follows:
The method specifically comprises the following steps:
Step 1. is prepared poly acryloyl chloride: the monomer acrylate chloride of processing, 1.4-dioxane and initiator Diisopropyl azodicarboxylate join in flask, and under the protection of nitrogen, 55 ℃ of successive reactions are 14 hours.For product, petroleum ether precipitation, washing, dry, obtain poly acryloyl chloride.
Step 2. is prepared amphipathic nature polyalcohol: pyrene methyl alcohol and the prepared poly acryloyl chloride of step 1 are mixed, join in anhydrous nitrogen dimethylformamide, reflux 12 hours under nitrogen atmosphere, add subsequently a small amount of water and make unreacted acid chloride groups be hydrolyzed to carboxylic acid.After reaction finishes, reactant is poured in dilute hydrochloric acid, filtered, dry.Finally crude product is dissolved to petroleum ether precipitation with tetrahydrofuran (THF).Filter, dry, obtain amphipathic nature polyalcohol.
The preparation of step 3. polymer micelle: the amphipathic nature polyalcohol that step 2 is obtained is dissolved in tetrahydrofuran (THF), again isopyknic water is slowly added drop-wise in tetrahydrofuran (THF) with the speed of 1.5 microliters per second, the formation of induction micella, treat micelle formation after, the micella that adds rapidly large water gaging to form with " fixing ".Room temperature lower open mouth is placed to volatilize and is removed tetrahydrofuran (THF), obtains polymer micelle.
The polymer micelle of preparation, can be applicable to medicine and controls release aspect according to the method described above, specific as follows:
2 milligrams, polymkeric substance that above-mentioned steps is prepared is dissolved in 1 milliliter of tetrahydrofuran (THF) with 0.2 milligram of Nile red simultaneously, subsequently under the condition stirring, 1 ml deionized water is slowly added drop-wise in tetrahydrofuran solution with the speed of 1.5 microliters per second, after micella to be formed, the micella that adds rapidly 9 ml waters (9 times to tetrahydrofuran (THF) volume) to form with " fixing ", room temperature lower open mouth is placed volatilization and is removed tetrahydrofuran (THF), finally with the membrane filtration of 0.45 micron, falls not wrapped Nile red.
The macromolecular material that this institute uses is a kind of amphipathic nature polyalcohol.Amphipathic nature polyalcohol refers to the polymkeric substance simultaneously in same polymer with two kinds of different in kind phase structures.Amphipathic nature polyalcohol, in selective solvent, can self-assembly form micella.Wherein the spherical micelle of nucleocapsid structure is modal macromolecular self-assembly system, and hydrophilic segment forms shell, and hydrophobic segment forms core.Due to the existence of solvation shell, the micella that amphipathic nature polyalcohol forms can exist for a long time within the scope of finite concentration.
Amphipathic nature polyalcohol micella, as pharmaceutical carrier, has lot of advantages: as external all very stable in vivo in micella, there is good biocompatibility, and the medicine little for solubleness has solublization, and can be as target administration carrier.The hydrophobic kernel of polymer micelle can load hydrophobic drug, and hydrophilic shell can reduce the interaction between micella and mononuclear phygocyte system, avoids by mononuclear phygocyte system huge uptake, and is conducive to the dispersion of micella in water.
Stimulating responsive polymer micella is controlled release field at medicine good application.As pH responsive polymer micella can be stimulated by pH at lesions position, micella pattern changes, and medicine is released.Photoresponse polymer micelle can be realized control drug release of fixed place and time, can control more accurately the release of medicine.
The invention has the beneficial effects as follows: in the present invention, polymkeric substance used is UV-light and pH susceptibility amphipathic nature polyalcohol, there is the ability that forms nano-micelle in the aqueous solution, such micella has ultraviolet light response capacity and pH respondent behavior ability simultaneously, can be used as the novel pharmaceutical modified release carrier of excellent property, function uniqueness.The present invention has broad application prospects in medicine controlled releasing field.
Accompanying drawing explanation
Fig. 1 is the size distribution figure of polymer micelle in water
Fig. 2 is the transmission electron microscope picture of polymer micelle.
Fig. 3 is the photoresponse of parcel Nile red micella.
Fig. 4 is the pH response of parcel Nile red micella.
embodiment
Below in conjunction with specific embodiment, the present invention is done to further explaination, rather than will limit the invention with this.
Embodiment 1
Prepare poly acryloyl chloride: the monomer acrylate chloride (10ml) of processing, Isosorbide-5-Nitrae-dioxane (10ml) and initiator Diisopropyl azodicarboxylate (0.302g) are joined in flask, and 55 ℃ of successive reactions are 14 hours under the protection of nitrogen.Petroleum ether precipitation washed twice for product, at 60 ℃ in vacuum drying oven dry 6 hours.
Prepare polyacrylic acid pyrene methyl esters-acrylic copolymer: by poly acryloyl chloride (0.91g, 10mmol), triethylamine (1.68mol, 12mmol), pyrene methyl alcohol (0.25g, 1mmol) is dissolved in DMF (60ml), 60 ℃ of stirring reactions 12 hours.Add 3ml deionized water to make unreacted acid chloride groups be hydrolyzed to carboxylic acid, react 10 minutes.Reactant is poured in dilute hydrochloric acid (0.01mol/L, 500ml), and 70 ℃ are stirred 10 minutes.Cooling, filtration, dry (50 ℃, 5h).Crude product is dissolved in tetrahydrofuran (THF) (10~20ml), pours petroleum ether precipitation (40~50ml) into, repeats twice.Filter dry (50 ℃, 4~5h).The final synthetic amphipathic nature polyalcohol to UV-light and pH sensitivity.
The structure of the amphipathic multipolymer of dual environmental sensitivity of the present invention is confirmed through nuclear-magnetism: by regulating poly acryloyl chloride and the ratio of pyrene methyl alcohol monomer can prepare the subject polymer of different percentage of grafting.
The polymkeric substance of 2mg embodiment 0025 preparation is dissolved in 1ml tetrahydrofuran (THF), slowly the deionized water of 1ml is splashed in tetrahydrofuran solution subsequently, stir, micella to be formed adds large water gaging with fixing micella morphological structure later, under room temperature, volatilizees and removes tetrahydrofuran (THF).Transmission electron microscope shows that the micellar structure forming is spherical, and dynamic light scattering shows that the average hydration diameter of micella is 105nm, and polydispersity coefficient is below 0.1, and size is homogeneous relatively.
The dual environment sensitive polymer of the present invention micella response performance is analyzed
(1) optical property analysis
Parcel Nile red polymer micelle solution prepared by the embodiment fluorescent emission spectrogram under 365nm ultraviolet lighting is shown in accompanying drawing 3.Can see, along with the growth of ultraviolet lighting time, the emission peak that Nile red is positioned at 610nm place declines gradually, and after for some time, peak value disappears, and this shows that hydrophobic Nile red progressively discharges from micella kernel, and such micella has optical Response.
(2) pH value sensitive property analysis
The micellar solution of parcel Nile red prepared by above-described embodiment, is adjusted to the polymer micelle solution of different pH values by aqueous hydrochloric acid and aqueous sodium hydroxide solution.Accompanying drawing 4 is the fluorogram of parcel Nile red polymer micelle solution under condition of different pH, can see, under acidic conditions, part Nile red is discharged; And under alkaline condition, all Nile reds are discharged, this shows that such micella has pH responsiveness.
Claims (2)
1. a preparation method for the pyrene functionalized polymer micelle of light/pH responsive type, is characterized in that preparation process is as follows:
Step 1. is prepared poly acryloyl chloride: by monomer acrylate chloride, solvent 1-4 dioxane and initiator Diisopropyl azodicarboxylate join in flask, and under the protection of nitrogen, 55 ℃ of successive reactions are 14 hours; Petroleum ether precipitation for product, washing, dryly obtain pure poly acryloyl chloride;
Step 2. is prepared amphipathic nature polyalcohol: pyrene methyl alcohol and the prepared poly acryloyl chloride of step 1 are mixed, wherein the mol ratio of pyrene methyl alcohol and poly acryloyl chloride is 1:9, join in anhydrous nitrogen dimethylformamide, under nitrogen atmosphere, reflux 12 hours, add subsequently a small amount of water to make unreacted acid chloride groups be hydrolyzed to carboxylic acid.After reaction finishes, reactant is poured in dilute hydrochloric acid, filtered, dry; Finally crude product is dissolved to petroleum ether precipitation with tetrahydrofuran (THF).Filter, dry, obtain pure amphipathic nature polyalcohol;
The preparation of step 3. polymer micelle: the amphipathic nature polyalcohol that step 2 is obtained is dissolved in tetrahydrofuran (THF), again isopyknic water is slowly added drop-wise in tetrahydrofuran (THF) subsequently, after micella to be formed, the micella that adds rapidly large water gaging to form with " fixing ", room temperature lower open mouth is placed volatilization and is removed tetrahydrofuran (THF).
2. the preparation method of a kind of light/pH responsive type pyrene graftomer micella according to claim 1, is characterized in that described polymer micelle has UV-light and pH response simultaneously, can, under the stimulation of UV-light and pH, control the release of medicine.
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