CN108676156B - Reduction response type ABC type block polymer and preparation method and application thereof - Google Patents

Reduction response type ABC type block polymer and preparation method and application thereof Download PDF

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CN108676156B
CN108676156B CN201810572297.7A CN201810572297A CN108676156B CN 108676156 B CN108676156 B CN 108676156B CN 201810572297 A CN201810572297 A CN 201810572297A CN 108676156 B CN108676156 B CN 108676156B
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胡志国
喻永杰
王小坤
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Henan Normal University
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C08G65/3328—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof heterocyclic

Abstract

The invention discloses a reduction response type ABC type block polymer and a preparation method and application thereof, belonging to the technical field of reduction response type drug carriers. The invention selects hydrophilic monomethyl ether polyethylene glycol (mPEG), hydrophobic Lactide (LA) and Allyl Glycidyl Ether (AGE) as raw materials, and then combines the light click reaction and the ring-opening polymerization of sulfydryl-olefin to synthesize the polymer mPEG-b-PAGE with a side chain containing a sulfydryl groupSHAnd (4) b-PLLA, then self-assembling the beta-PLLA to form micelles, and oxidizing sulfhydryl groups into disulfide bonds in the presence of hydrogen peroxide to finally synthesize the high-stability reduction response type cross-linked micelles. The cross-linked micelle with disulfide bonds not only contributes to reducing drug leakage and initial quick release, but also has reducibility responsiveness at a diseased part, namely the drug release behavior of the cross-linked micelle is obviously accelerated in the presence of a reducing agent DTT and glutathione, so that the treatment effect is improved.

Description

Reduction response type ABC type block polymer and preparation method and application thereof
Technical Field
The invention belongs to the technical field of reduction-responsive drug carriers, and particularly relates to a reduction-responsive ABC type block polymer and a preparation method and application thereof.
Background
The polymer micelle as a drug delivery carrier has attracted more and more attention because of its characteristics of improving the solubility of hydrophobic drugs and reducing the adsorption of proteins. However, the structure of the polymer micelle changes with the change of the surrounding environment, and is difficult to maintain stable, so that the application range of the micelle is limited. Therefore, in order to enhance the stability and integrity of the micelle structure, it is necessary to modify the polymer segment, introduce a bifunctional group, and crosslink the polymer micelle, thereby immobilizing the structure of the polymer micelle.
The stimulus response type polymer cross-linked micelle mainly refers to a drug carrier which can control the release rate of drugs, change the mode and distribution of the drugs entering the body and realize the purpose of targeted delivery. Has the characteristics of reducing toxic and side effects, being biodegradable, improving the release effect of the medicine and prolonging the circulation time in vivo. There are many reports on this type, such as: temperature-responsive crosslinked micelles, photoresponsive crosslinked micelles, and the like. So far, research on reducing response type polymer cross-linked micelles is increasing, and there is a great development space in the aspect of delivering antitumor drugs, especially disulfide bonds are introduced into amphiphilic polymers which self-assemble to form micelles. Disulfide bonds are stable in the normal environment in the human body (e.g., temperature, oxidative conditions, etc.), however, they are susceptible to cleavage to form sulfhydryl groups in the presence of reducing agents, dithiothreitol or glutathione, which is a reversible process. In addition, the concentration of glutathione in cancer cells is higher than that in normal cells, which more easily breaks the disulfide bonds and releases the drug rapidly.
Based on the method, three monomers, namely hydrophilic monomethyl ether polyethylene glycol (mPEG), hydrophobic Lactide (LA) and Allyl Glycidyl Ether (AGE), are selected as raw materials, triblock polymers with different relative molecular masses are synthesized in a ring-opening polymerization mode, thiol groups are introduced into polymer side chains by adopting a mercapto-olefin light click reaction, and the polymer mPEG-b-PAGE is obtainedSHAnd (4) b-PLLA, then self-assembling the beta-PLLA to form micelles, and oxidizing sulfhydryl groups into disulfide bonds in the presence of hydrogen peroxide to finally synthesize the high-stability reduction response type cross-linked micelles. Meanwhile, the chemical structure of the polymer, the self-assembly behavior in aqueous solution and the in-vitro release of the drug are researched by a series of means.
Disclosure of Invention
The invention aims to provide a reduction response type ABC type block polymer and a preparation method and application thereof. In order to achieve the purpose, the invention adopts the technical scheme that the reduction-responsive ABC type block polymer is characterized in that the structural formula of the reduction-responsive ABC type block polymer is as follows:
Figure BDA0001686240790000021
wherein m, n and y represent the polymerization degree of the polymer.
The preparation method of the reduction-responsive ABC type block polymer comprises the following steps:
(1) synthesis of amphiphilic Block copolymer mPEG-b-PAGE:
adding sodium hydride into a Schlenk bottle in a nitrogen atmosphere, adding anhydrous THF into the bottle, stirring for more than 20min, stopping stirring, sucking supernatant liquid in the bottle away, then adding mPEG into the Schlenk bottle, putting the bottle into a 100 ℃ oil bath kettle for stirring, after NaH in the bottle is dissolved in the molten mPEG, injecting AGE, sealing the bottle opening, and reacting for 24h in the 100 ℃ oil bath kettle; after the reaction is finished, glacial acetic acid is added to stop the polymerization reaction, after the product is cooled to room temperature, dichloromethane is added to dissolve the product, then the product is separated by adopting a silica gel column chromatography method, isopropanol is firstly used as an eluent to wash away PAGE and other impurities, then isopropanol/chloroform is used for washing, collecting and rotary evaporating are carried out, then the concentrated solution is dissolved by dichloromethane and is subjected to suction filtration to remove silica gel powder, and finally, rotary evaporating, concentrating and vacuum drying are carried out again to obtain mPEG-b-PAGE;
(2) synthesis of triblock Polymer mPEG-b-PAGE-b-PLLA:
firstly, putting a Schlenk bottle into a heating jacket, vacuumizing, introducing nitrogen, cooling the bottle to room temperature, adding L-LA (L-lactide) into the bottle, then putting the bottle into a 40 ℃ oil bath pot, vacuumizing, then adding an initiator mPEG-b-PAGE, adjusting the temperature of the oil bath pot to 120 ℃, after the solid in the bottle is stirred and melted, dropwise adding a catalyst stannous octoate by using an injector, and stirring for reacting for 24 hours;
after the reaction is finished, cooling the reaction product to room temperature, stirring and dissolving the reaction product by using dichloromethane, precipitating the reaction product in cold ether, performing suction filtration to collect a filter cake, and finally performing vacuum drying to obtain a triblock polymer mPEG-b-PAGE-b-PLLA;
(3) triblock polymer mPEG-b-PAGE with side chain containing sulfhydryl groupSH-b-PSynthesis of LLA:
putting a triblock polymer mPEG-b-PAGE-b-PLLA into a Schlenk bottle, then extracting freshly steamed DMF by using an injector and injecting the freshly steamed DMF into the bottle, adding 1, 3-propanedithiol and photosensitizer phenyl bis (2,4, 6-trimethylphenyl acyl) phosphine oxide after all solids in the bottle are stirred and dissolved, covering the bottles by using a box to avoid light, bubbling nitrogen for more than 30min, then putting the bottles into a light curing box, and carrying out irradiation reaction for 2h by using a mercury lamp;
after the reaction is finished, the reaction solution is precipitated by ethyl acetate, and then filter cakes collected by suction filtration are replaced by CH2Cl2Dissolving, repeating the above steps for several times, and vacuum drying the filter cake.
The reduction response type ABC type block polymer is applied to serving as an anticancer drug carrier.
Compared with the prior art, the invention has the following beneficial effects:
1. in the presence of hydrogen peroxide, the synthesized triblock polymer mPEG-b-PAGESHOxidizing sulfhydryl groups in b-PLLA into disulfide bonds, and finally synthesizing the high-stability reduction response type nuclear cross-linked micelle;
2. crosslinked micelles with disulfide bonds on the one hand help to reduce drug leakage and initial burst release; on the other hand, the drug has reducibility responsiveness at the pathological part, and can improve the drug release rate, thereby improving the treatment effect.
Drawings
Gel permeation chromatogram of the polymer of FIG. 1, a: mPEG; b, mPEG-b-PAGE; c, mPEG-b-PAGE-b-PLLA1K；
FIG. 2 gel permeation chromatogram of polymer, a: mPEG; b, mPEG-b-PAGE; c, mPEG-b-PAGE-b-PLLA4K；
FIG. 3 is a transmission electron micrograph, A is mPEG-b-PAGESH-b-PLLA1KA micellar solution; b is mPEG-B-PAGESH-b-PLLA1KA cross-linked micelle solution; c is mPEG-b-PAGESH-b-PLLA4KA micellar solution; d is mPEG-b-PAGESH-b-PLLA4KA cross-linked micelle solution;
FIG. 4 Release Curve of Adriamycin (PBS 7.4, 37 ℃ C.) A: mPEG-b-PAGESH-b-PLLA4KCrosslinked micelles, C: mPEG-b-PAGESH-b-PLLA1KCross-linked micelles; (PBS-DTT, 37 ℃) B: mPEG-B-PAGESH-b-PLLA4KCross-linked micelle, D: mPEG-b-PAGESH-b-PLLA1KCross-linked micelles.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
(1) Synthesis of amphiphilic Block copolymer mPEG-b-PAGE:
Figure BDA0001686240790000031
0.12g of sodium hydride (NaH containing mineral oil, 60%) is weighed into a 100mL Schlenk bottle under nitrogen atmosphere, 10mL of anhydrous THF is extracted by a syringe, the anhydrous THF is added into the bottle, after stirring and washing for about 20min, stirring is stopped, supernatant in the bottle is sucked away, 10.00g of mPEG (Mn 5000) is weighed into the Schlenk bottle, the bottle is placed into a 100 ℃ pot for stirring, after NaH in the bottle is dissolved in the molten mPEG, 2.40mL of AGE is injected, the mouth of the oil bath is sealed, and the oil bath is carried out for 24h at 100 ℃ in the pot.
After the reaction is finished, adding a small amount of glacial acetic acid to terminate the polymerization reaction, cooling the product to room temperature, adding a certain amount of dichloromethane to dissolve the product, separating the product by adopting a silica gel column chromatography method, firstly using isopropanol as an eluent to wash out PAGE and other impurities, then using isopropanol/chloroform to wash, collecting and carrying out rotary evaporation, then dissolving the concentrated solution by using dichloromethane, carrying out suction filtration to remove silica gel powder, and finally carrying out rotary evaporation concentration and vacuum drying again.
(2) Synthesis of triblock Polymer mPEG-b-PAGE-b-PLLA:
Figure BDA0001686240790000041
firstly, a 100mL Schlenk bottle is placed in a heating jacket for vacuumizing and nitrogen is introduced, the vacuumizing and the nitrogen introducing are repeated for three times, after the bottle is cooled to the room temperature, the nitrogen is turned on, a certain amount of L-LA is added, then the bottle is placed in a 40 ℃ oil bath pot for vacuumizing for 20min, then the nitrogen is turned on again, a certain amount of initiator mPEG-b-PAGE is added, the temperature of the oil bath pot is adjusted to 120 ℃, after the solid in the bottle is stirred and melted, 2-3 drops of catalyst stannous octoate are dripped by a syringe, and the stirring reaction is carried out for 24 h.
After the reaction is finished, cooling the reaction product to room temperature, stirring and dissolving the reaction product by using a small amount of dichloromethane, precipitating the reaction product in cold ether, performing suction filtration to collect a filter cake, and finally performing vacuum drying.
TABLE 1 Synthesis data for triblock polymers
Figure BDA0001686240790000042
(3) Triblock polymer mPEG-b-PAGE with side chain containing sulfhydryl groupSH-synthesis of b-PLLA:
Figure BDA0001686240790000043
weighing a certain amount of triblock polymer mPEG-b-PAGE-b-PLLA, putting the triblock polymer mPEG-b-PAGE-b-PLLA into a 100mL Schlenk bottle, then extracting 30mL of freshly distilled DMF by using a syringe, injecting the freshly distilled DMF into the bottle, adding a certain amount of 1, 3-propanedithiol and photosensitizer phenyl bis (2,4, 6-trimethylphenyl acyl) phosphine oxide ([ C ═ C ]: SH: [ photosensitizer ]: 1:20:0.1) after the solid in the bottle is completely stirred and dissolved, covering the bottle with a black carton for shading, blowing nitrogen bubbles for 30min, sealing the bottle mouth, putting the bottle into a photocuring box, and irradiating the bottle by using a mercury lamp for reaction for 2 h.
After the reaction is completed, the reaction solution is precipitated with ethyl acetate, and the collected filter cake is filtered by suction and filtered with CH2Cl2Dissolving, repeating the above steps for several times, and vacuum drying the filter cake.
TABLE 2 Polymer mPEG-b-PAGESHof-b-PLLASynthesizing data
Figure BDA0001686240790000051
As shown in FIGS. 1 and 2, a represents polyethylene glycol (mPEG), b represents polymer mPEG-b-PAGE, and c represents triblock polymer mPEG-b-PAGE-b-PLLA. From the figure we can observe that the time it takes for them to flow through the column decreases from a to c, i.e. their outflow rate is faster and faster, which is indicative of their larger relative molecular mass. In addition, from the analysis of the standard curve, they have a narrow molecular weight distribution, which indicates that the synthesized polymer has a uniform distribution. Thus, it is sufficient to show that we have successfully synthesized the triblock polymer mPEG-b-PAGE-b-PLLA.
(4) Drug loading and in vitro drug release
Preparation of polymeric micelle solution
(a) Polymer mPEG-b-PAGESH-b-PLLA1KPreparation of micelle solution:
weighing 200mg of the synthesized polymer mPEG-b-PAGESH-b-PLLA1KAdding 10mg Dithiothreitol (DTT) to a 100mL single-neck flask simultaneously to prevent disulfide bond crosslinking, adding 5mL freshly distilled DMF, dropwise adding 25mL of secondary water after the solid in the flask is dissolved, controlling the dropwise adding speed to be every 35s, stirring for 3h after the dropwise adding is finished, filling the mixture into a 3500Da dialysis bag, and dialyzing for 4 days, wherein 10mg of DTT is required to be added every day during the dialysis. Finally, the mixed solution in the dialysis bag was poured into a 200mL volumetric flask and the volume was determined with secondary water, at which time the micelle solution concentration was 1 mg/mL.
(b) Polymer mPEG-b-PAGESH-b-PLLA4KPreparation of micelle solution:
preparation of micellar solution As above, 20mg of the synthetic polymer mPEG-b-PAGE was weighedSH-b-PLLA4KIn a 100mL single-neck flask, the final micelle solution concentration was 0.1 mg/mL.
② preparation of crosslinked micelle
(a) Polymer mPEG-b-PAGESH-b-PLLA1KPreparation of crosslinked micelles:
200mL of the polymer mPEG-b-PAGE prepared above at a concentration of 1mg/mLSH-b-PLLA1KThe micelle solution is placed in a 500mL single-neck flask, and 2mL of H with the mass fraction of 1 percent is added2O2Then, the mixture was stirred at room temperature for 72 hours, at which time the solution became turbid but no precipitate was generated. Then, the mixture is dried on a freeze dryer, and after the drying is completed, the mixture is dispersed in a small amount of secondary water, and then the mixture is transferred into a 3500Da dialysis bag and dialyzed for 24 hours. And finally, freeze-drying by using a freeze dryer.
(b) Polymer mPEG-b-PAGESH-b-PLLA4KPreparation of crosslinked micelles
Polymer mPEG-b-PAGESH-b-PLLA4KThe preparation method of the crosslinked micelle is as above.
FIG. 3 is a transmission electron micrograph of an uncrosslinked micelle and a crosslinked micelle, and it is clear that the obtained micelle particles have a narrow particle size distribution and good dispersibility. Meanwhile, the appearance of the crosslinked micelle is not changed and is still spherical.
Preparation of drug-loaded micelle
(a) Polymer mPEG-b-PAGESH-b-PLLA1KDrug loading of crosslinked micelles
5mg of DOX & HCl was weighed into a 100mL single-neck flask, 2.50mL of freshly distilled DMF and 3.80. mu.L of triethylamine were added thereto, and after complete dissolution, 30mg of mPEG-b-PAGE was addedSH-b-PLLA1KAfter stirring the crosslinked micelles for 2h at room temperature, they were transferred to a 3500Da dialysis bag and dialyzed for 24 h. And after dialysis is finished, freeze-drying the solution in the dialysis bag on a freeze dryer for later use, wherein the solution needs to be protected from light all the time.
(b) Polymer mPEG-b-PAGESH-b-PLLA4KDrug loading of crosslinked micelles
Polymer mPEG-b-PAGESH-b-PLLA4KThe cross-linked micelle was loaded as above, wherein 2mg of DOX & HCl and 1.50. mu.L of triethylamine were weighed.
In vitro drug release experiment
(a) Drug release in PBS buffer (pH 7.4)
(b) Drug release in 10mmol/L PBS-DTT solution
After testing and calculation, the drug-loading rate and the encapsulation efficiency of the drug-loaded micelle, mPEG-b-PAGESH-b-PLLA1KCross-linked micelles: LC (%) (4.15%), encapsulation EE (%) (25.90%), mPEG-b-PAGESH-b-PLLA4KCross-linked micelles: LC (%). 5.77%, EE (%). 36.74%. FIG. 4 is a graph showing the release of DOX & HCl (doxorubicin hydrochloride) from drug-loaded micelles as a function of time. As is apparent from the figure, the cumulative release amounts of the crosslinked micelles in the presence of only the PBS buffer solution were rarely about 30% and 55%, respectively, while showing a slower release rate. However, after the reducing agent DTT is added, the drug release behavior of the cross-linked drug-loaded micelle is obviously accelerated, and the cumulative release amount of the cross-linked drug-loaded micelle exceeds 50% and even reaches 85% in the first 12 hours. The behavior of the doxorubicin release rate increase in the presence of the reducing agent DTT shows that the cross-linked drug-loaded micelle has a reduction-responsive drug release behavior.
The foregoing embodiments illustrate the principles, principal features and advantages of the invention, and it will be understood by those skilled in the art that the invention is not limited to the foregoing embodiments, which are merely illustrative of the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the principles of the invention.

Claims (1)

1. The application of the reduction-responsive ABC type block polymer crosslinked micelle as an anticancer drug carrier is characterized in that the preparation process of the reduction-responsive ABC type block polymer crosslinked micelle comprises the following steps:
(1) synthesis of amphiphilic Block copolymer mPEG-b-PAGE:
adding sodium hydride into a Schlenk bottle in a nitrogen atmosphere, adding anhydrous tetrahydrofuran THF into the bottle, stirring for more than 20min, stopping stirring, sucking supernatant liquid in the bottle away, then adding mPEG into the Schlenk bottle, putting the bottle into a 100 ℃ oil bath pot, stirring, injecting allyl glycidyl ether AGE after NaH in the bottle is dissolved in the molten mPEG, sealing the bottle mouth, and reacting in the 100 ℃ oil bath pot for 24 h; after the reaction is finished, glacial acetic acid is added to stop the polymerization reaction, after the product is cooled to room temperature, dichloromethane is added to dissolve the product, then the product is separated by adopting a silica gel column chromatography method, isopropanol is firstly used as an eluent to wash away PAGE and other impurities, then isopropanol/chloroform is used for washing, collecting and rotary evaporating are carried out, then the concentrated solution is dissolved by dichloromethane and is subjected to suction filtration to remove silica gel powder, and finally, rotary evaporating, concentrating and vacuum drying are carried out again to obtain mPEG-b-PAGE;
(2) synthesis of triblock Polymer mPEG-b-PAGE-b-PLLA:
firstly, putting a Schlenk bottle into a heating jacket, vacuumizing, introducing nitrogen, adding L-lactide into the bottle after the bottle is cooled to room temperature, then putting the bottle into a 40 ℃ oil bath pot, vacuumizing, then adding an initiator mPEG-b-PAGE, adjusting the temperature of the oil bath pot to 120 ℃, dropwise adding a catalyst stannous octoate by using an injector after solid in the bottle is stirred and melted, and stirring and reacting for 24 hours;
after the reaction is finished, cooling the reaction product to room temperature, stirring and dissolving the reaction product by using dichloromethane, precipitating the reaction product in cold ether, performing suction filtration to collect a filter cake, and finally performing vacuum drying to obtain a triblock polymer mPEG-b-PAGE-b-PLLA;
(3) triblock polymer mPEG-b-PAGE with side chain containing sulfhydryl groupSH-synthesis of b-PLLA:
putting a triblock polymer mPEG-b-PAGE-b-PLLA into a Schlenk bottle, then extracting freshly distilled dimethylformamide DMF (dimethyl formamide) by using a syringe to inject into the bottle, adding 1, 3-propanedithiol and photosensitizer phenyl bis (2,4, 6-trimethylphenyl acyl) phosphine oxide after all solids in the bottle are stirred and dissolved, covering the bottles by using a box to prevent light, bubbling nitrogen for more than 30min, then putting the bottles into a photocuring box, irradiating and reacting by using a mercury lamp for more than 2h, after the reaction is finished, precipitating reaction liquid by using glacial ethyl ether, and performing suction filtration on collected filter cakes by using CH2Cl2Dissolving, repeating the above steps for several times, and finally vacuum drying the filter cake;
(4) in the presence of hydrogen peroxide, the triblock polymer mPE with the side chain containing sulfhydryl groups synthesized in the step (3)G-b-PAGESHOxidizing sulfhydryl groups in b-PLLA into disulfide bonds, and finally synthesizing the reduction-responsive ABC type block polymer crosslinked micelle;
the prepared reduction response type ABC type block polymer crosslinked micelle is used as an anticancer drug carrier, the anticancer drug is adriamycin, the crosslinked micelle containing disulfide bonds is not only beneficial to reducing drug leakage and initial quick release, but also has reduction responsiveness at a diseased part, namely, the drug release behavior of the crosslinked micelle is obviously accelerated in the presence of reducing agents dithiothreitol DTT and glutathione, so that the treatment effect is improved.
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