CN115010913B - PH/reduction dual-response polymer micelle and preparation method and application thereof - Google Patents
PH/reduction dual-response polymer micelle and preparation method and application thereof Download PDFInfo
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/91—Polymers modified by chemical after-treatment
- C08G63/912—Polymers modified by chemical after-treatment derived from hydroxycarboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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Abstract
The application relates to the technical field of polymer micelles, in particular to a pH/reduction dual-response polymer micelle and a preparation method and application thereof. The pH/reduction dual-response polymer micelle structure comprises polyethylene glycol methyl ether methacrylate, epsilon-caprolactone, gamma-amino-epsilon-caprolactone and disulfide bonds, so that after the polymer micelle loads an anticancer drug, the polymer micelle can stably exist in normal intracellular microenvironment conditions, and rapidly release the drug in the acidic and high glutathione environments of tumor cells, and the technical problem that the controlled release performance of the polymer drug-loaded micelle drug in the prior art is still to be improved is solved.
Description
Technical Field
The application relates to the technical field of micelles, in particular to a pH/reduction dual-response polymer micelle and a preparation method and application thereof.
Background
Cancer therapy is an important research area in the medical field of countries around the world. In recent years, medical workers find that the micro-environmental conditions in tumor cells and normal cells are obviously different, for example, the pH in the tumor cells is lower than that in the normal cells, the pH in the tumor cells is 5.0-6.0, and the pH in the normal cells is 7.4; meanwhile, the research also finds that the concentration of glutathione in tumor cells is several times higher than that of normal tissue cells, resulting in a higher reduction response in tumor cells than in normal cells. The difference of the microenvironment conditions in the tumor cells and the normal cells, namely the microenvironment of the tumor cells has high reduction response and subacidity, provides a theoretical basis for medical workers to realize the targeted delivery of anticancer drugs in tumor tissues.
The nano polymer micelle is formed by self-assembly of amphiphilic polymers in water, and the hydrophobic inner core of the micelle can encapsulate insoluble drugs, so that the water solubility of the hydrophobic drugs is improved; the hydrophilic shell can avoid the phagocytosis of micelle by the macrophage system and the nonspecific recognition of reticuloendothelial system, so that the circulation time of the medicine in the body is prolonged; by utilizing the EPR effect of nanometer scale, the polymer drug-loaded micelle can enhance the drug permeability and retention effect, promote the accumulation of the anticancer drug at the tumor tissue part, thereby reducing the toxic and side effects of the drug and improving the treatment effect of the anticancer drug. Meanwhile, the polymer drug-loaded micelle can be further subjected to chemical modification, such as access to a pH response block, a redox response block and the like, so that the drug-loaded micelle stably exists in a normal cell environment and releases drugs at tumor cells, and the targeted delivery of anticancer drugs is realized. However, although various nano-polymer micelles have made great progress in the research of delivery of anticancer drugs, their drug controlled release properties have yet to be further improved.
Disclosure of Invention
In view of the above, the present application provides a pH/reduction dual-response polymer micelle, and a preparation method and application thereof, which are used for solving the technical problem that the drug controlled release performance of the polymer drug-loaded micelle in the prior art needs to be improved.
The first aspect of the present application provides a pH/reduction dual response polymer micelle, wherein the polymer used for preparing the micelle has the structural formula:
wherein x=8 to 23, y=36 to 47, and z=14 to 19.
Preferably, the number average molecular weight of the polymer is 9000 to 18000g/mol.
When the number average molecular weight of the polymer is 9000-18000 g/mol, the critical micelle concentration is low, which is beneficial to self-assembly and formation of polymer micelle.
In a second aspect, the present application provides a method for preparing a pH/reduction dual-response polymer micelle, comprising the steps of:
in the step 1, the first catalyst is stannous octoate, and the ring-opening polymerization reaction is carried out for 24-48 hours at the temperature of 100-130 ℃;
in the step 2, the second catalyst is copper bromide, the ligand is pentamethyl diethyl triamine, and the solvent is tetrahydrofuran or toluene;
in the step 3, the reducing agent is stannous octoate, the temperature of the oil bath reaction is 60-70 ℃ and the time is 12-24 hours.
Preferably, in the step 3, the oil bath reaction further includes: after the oil bath reaction product was diluted with solvent, the catalyst was removed by passing through a neutral alumina column.
Preferably, the eluent of the neutral alumina chromatographic column is tetrahydrofuran.
Preferably, the preparation raw materials of the macromolecular initiator comprise the following components in parts by mass: 49.6 to 66.3 parts by mass of epsilon-caprolactone, 12.8 to 21.6 parts by mass of gamma- (tert-butyl carbamate) -epsilon-caprolactone, 0.05 to 0.06 part by mass of stannous octoate and 0.8 to 1.2 parts by mass of small molecular initiator containing disulfide bonds.
Preferably, before obtaining the macroinitiator, the method further comprises: concentrating, precipitating, filtering and drying, wherein the precipitation is carried out by dissolving the concentrated product in a small amount of methylene dichloride, and transferring the solution into 10 times of cold diethyl ether for precipitating.
Preferably, the preparation raw materials of the reduction response polymer comprise the following components in parts by mass: 3.4 to 4.1 parts by mass of macromolecular initiator, 4.8 to 5.9 parts by mass of polyethylene glycol methyl ether methacrylate, 0.013 to 0.022 part by mass of copper bromide, 0.12 to 0.20 part by mass of pentamethyl diethyl triamine and 0.26 to 0.38 part by mass of stannous octoate.
Preferably, the preparation raw materials of the pH/reduction dual response polymer comprise, in parts by mass: 0.6 to 1.2 parts by mass of a reduction-responsive polymer, and 0.8 to 1.6 parts by mass of trifluoroacetic acid.
In step 3, before obtaining the reduction-responsive polymer, the method further comprises: concentrating, precipitating, filtering, and drying;
the precipitation is carried out by dissolving the concentrated product in a small amount of tetrahydrofuran, and transferring the solution into cold n-hexane with the volume of 10 times for precipitation.
In step 4, before the dual pH/reduction response polymer is obtained, the method further comprises: concentrating, precipitating, filtering, and drying;
the precipitation is carried out by dissolving the concentrated product in a small amount of tetrahydrofuran, and transferring the solution into cold n-hexane with the volume of 10 times for precipitation.
Preferably, the preparation method of the gamma- (tert-butyl carbamate) -epsilon-caprolactone comprises the following steps: dissolving 4- (tert-butyloxycarbonylamino) cyclohexanone and 3-chloroperoxybenzoic acid in dichloromethane, and reacting at 40-50 ℃ for 12-24 h to obtain gamma- (tert-butyl carbamate) -epsilon-caprolactone.
Preferably, the gamma- (tert-butyl carbamate) -epsilon-caprolactone is prepared from the following raw materials in parts by mass: 20.6 to 22.4 parts by mass of 4- (tert-butyloxycarbonylamino) cyclohexanone and 19.3 to 21.8 parts by mass of 3-chloroperoxybenzoic acid.
Preferably, in step 1, the preparation method of the small molecular initiator containing disulfide bonds comprises the following steps: under the protection of inert gas and anhydrous condition, bis (2-hydroxyethyl) disulfide is dissolved in tetrahydrofuran, triethylamine is added, and the mixture is cooled to 0 ℃.2, 4-dibromo isobutyryl bromide is added dropwise and stirred, after the dripping is finished, the reaction is carried out for 1 to 3 hours at the temperature of 0 ℃, and then the reaction is continued for 12 to 24 hours at the room temperature.
Preferably, the tetrahydrofuran is water-removed tetrahydrofuran.
Preferably, the preparation raw materials of the small molecular initiator comprising disulfide bonds comprise the following components in parts by mass: 5.96 to 6.41 parts by mass of bis (2-hydroxyethyl) disulfide, 6.42 to 6.58 parts by mass of triethylamine 4.88 to 4.98 parts by mass of 2, 4-dibromoisobutyryl bromide.
Preferably, after the reaction is finished, the method further comprises concentrating and washing the small molecular initiator containing disulfide bonds;
preferably, the concentrating comprises: performing reduced pressure rotary evaporation on the reaction solution to remove the organic solvent;
the washing includes: the small molecule initiator is washed sequentially with dilute hydrochloric acid, sodium bicarbonate solution and deionized water.
The third aspect of the present application also provides the use of a polymer micelle having a pH/reduction dual response as a carrier for anticancer drugs.
The pH/reduction dual-response polymer micelle provided by the application is simple to prepare, has higher yield and lower critical micelle concentration, is self-assembled in aqueous solution to form the polymer micelle, and is applied to entrapping anticancer drugs.
Preferably, the anticancer drug is a hydrophobic anticancer drug.
The pH/reduction dual-response polymer micelle provided by the application comprises the hydrophobic block, is suitable for loading of hydrophobic drugs, can solubilize the hydrophobic anticancer drugs, and improves the drug loading capacity of the polymer micelle.
Preferably, the preparation method of the anticancer drug carrier comprises the following steps: the pH/reduction dual response polymer and the hydrophobic anticancer drug are mixed according to the proportion of 3 to 6: 1-3, stirring for 4-12 h, dialyzing with deionized water for 24-72 h, changing deionized water every 3-6 h, and freeze drying.
It should be noted that, when the ratio of the pH/reduction dual response polymer to the hydrophobic anticancer drug is 3-6: 1-3, polymer drug-loaded micelle with evenly distributed particle size and higher drug loading capacity can be obtained.
In summary, the application provides a pH/reduction dual-response polymer micelle and a preparation method and application thereof, wherein the structure of the pH/reduction dual-response polymer micelle comprises polyethylene glycol methyl ether methacrylate, gamma-amino-epsilon-caprolactone, epsilon-caprolactone and disulfide bonds, wherein the polyethylene glycol methyl ether methacrylate is a hydrophilic block, compared with linear polyethylene glycol, the stability of the micelle under neutral conditions can be improved, the epsilon-caprolactone is a hydrophobic block, so that the drug loading capacity of the micelle to a hydrophobic drug can be improved, disulfide bonds are reduction response groups, the gamma-amino-epsilon-caprolactone block can be protonated under acidic conditions, the block is converted into the hydrophilicity by hydrophobicity, so that the micelle has the pH response, and disulfide bonds are broken after exchange reaction of sulfhydryl-disulfide bonds under the reduction conditions, so that the hydrophobic balance of the polymer is changed, and the micelle structure is changed or even disintegrated, thereby realizing targeted release of the drug.
Detailed Description
In order to make the objects, features and advantages of the present invention more obvious and understandable, the technical solutions of the embodiments of the present invention will be clearly and completely described below, and it is apparent that the embodiments described below are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by one of ordinary skill in the art without undue burden from the present disclosure, are within the scope of the present disclosure.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a scheme of a synthetic process for gamma- (tert-butyl carbamate) -epsilon-caprolactone;
FIG. 2 is a synthetic process scheme for a pH/reduction dual response polymer;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the pH/reduction dual response polymer of example 4;
FIG. 4 is a FT-IR spectrum of the pH/reduction dual response polymer before and after hydrolysis reaction in example 4;
FIG. 5 is a gel permeation chromatogram of the pH/reduction dual response polymer of example 4;
FIG. 6 is a graph of the critical micelle concentration measurement of the pH/reduction dual response polymer of example 4;
FIG. 7 is a graph of hollow white gum bundle particle size versus pH for example 8;
FIG. 8 is a transmission electron microscopy image of pH/reduction dual response drug-loaded polymer micelle of example 9;
fig. 9 is an in vitro release profile of a pH/reduction dual response drug loaded polymer micelle of example 10.
Example 1
This example 1 provides a process for the preparation of gamma- (tert-butyl carbamate) -epsilon-caprolactone comprising the steps of:
4- (t-Butyloxycarbonylamino) cyclohexanone (21.3 g,0.1 mol) and 3-chloroperoxybenzoic acid (20.6 g,0.12 mol) were dissolved in anhydrous dichloromethane (100 mL) and the mixture was condensed and refluxed at 43℃for 24h, after the reaction was completed, the dichloromethane was rotary evaporated, the concentrated product was precipitated by dropping into cold diethyl ether having a volume ten times that of the concentrated product, filtered, and dried under vacuum at room temperature for 24h to give gamma- (t-butyl carbamate) -epsilon-caprolactone.
Example 2
This example 2 provides a process for the preparation of small molecule initiators containing disulfide bonds comprising the steps of:
bis (2-hydroxyethyl) disulfide (15.425 g,100 mmol) and a stirrer were added to a 100mL anhydrous anaerobic reaction flask, sealed with a reverse-mouth rubber stopper, evacuated-purged with nitrogen three times, 100mL anhydrous tetrahydrofuran and anhydrous triethylamine (13.900 mL,100 mmol) were added with a syringe under nitrogen atmosphere, and ice-cooled to 0 ℃.2, 4-dibromoisobutyryl bromide (9.88 mL,80 mmol) was added dropwise with stirring, the reaction was continued at 0℃for 3h after the addition, then at room temperature for 24h, the insoluble triethylamine salt was removed by filtration, and the filtrate was distilled off with rotation and diluted with dichloromethane. Washing with dilute hydrochloric acid solution, sodium bicarbonate solution and deionized water for three times, drying overnight with anhydrous magnesium sulfate, filtering, concentrating filtrate by rotary evaporation, and vacuum drying the obtained product at 40 ℃ for 12h to obtain the small molecular initiator containing disulfide bonds.
Example 3
This example 3 provides a process for preparing a macroinitiator comprising the steps of:
the small molecular initiator (0.244 g,0.8 mmol) prepared in example 2 and gamma- (tert-butyl carbamate) -epsilon-caprolactone (3.46 g,15.0 mmol) were put into a 100ml anhydrous anaerobic reaction bottle, sealed with a reverse-mouth rubber stopper, evacuated-purged three times with nitrogen, epsilon-caprolactone (5.70 g,50.0 mmol) and stannous octoate (0.00916 g,0.02 mmol) as catalysts were respectively added by syringe, placed in an oil bath at 130 ℃ for reaction for 24 hours, cooled to room temperature after the reaction, dissolved with a small amount of dichloromethane, the reaction solution was added dropwise to cold diethyl ether of which the volume is ten times that of the solution, stirred to precipitate, filtered, and vacuum-dried at room temperature for 12 hours to obtain the product macromolecular initiator.
Example 4
This example 4 provides a process for preparing a pH/reduction dual response polymer comprising the steps of:
step 2A solution of trifluoroacetic acid (1.2 g,10 mmol) in 5mL of anhydrous dichloromethane was slowly added to a solution of reduction-responsive polymer (0.8 g,0.9mmol of gamma- (tert-butyl carbamate) -epsilon-caprolactone) in 5mL of anhydrous dichloromethane, the reaction was stirred at room temperature for 24h and after the reaction was completed, the dichloromethane was rotary evaporated. The crude product was dissolved in a small amount of tetrahydrofuran and precipitated twice in a volume of ten times its amount of frozen n-hexane, filtered off with suction, and the residual solvent was removed by vacuum pumping to obtain a pH/reduction dual response polymer.
Example 5
This example 5 provides a process for preparing a pH/reduction dual response polymer comprising the steps of:
step 2A solution of trifluoroacetic acid (1.2 g,10 mmol) in 5mL of anhydrous dichloromethane was slowly added to a solution of reduction-responsive polymer (1.0 g,0.9mmol of gamma- (tert-butyl carbamate) -epsilon-caprolactone) in 5mL of anhydrous dichloromethane. The reaction was stirred at room temperature for 24h and after the end of the reaction the dichloromethane was rotary evaporated. The crude product was dissolved in a small amount of tetrahydrofuran and precipitated twice in frozen n-hexane in a volume ten times its amount, and suction filtered. Residual solvent is removed by vacuum pumping, and the pH/reduction dual-response polymer is obtained.
Example 6
This example 6 provides a process for preparing a pH/reduction dual response polymer comprising the steps of:
step 2A solution of trifluoroacetic acid (1.2 g,10 mmol) in 5mL of anhydrous dichloromethane was slowly added to a solution of reduction-responsive polymer (1.1 g,0.9mmol of gamma- (tert-butyl carbamate) -epsilon-caprolactone) in 5mL of anhydrous dichloromethane. The reaction was stirred at room temperature for 24h and after the end of the reaction the dichloromethane was rotary evaporated. The crude product was dissolved in a small amount of tetrahydrofuran and precipitated twice in frozen n-hexane in a volume ten times its amount, and suction filtered. Residual solvent is removed by vacuum pumping, and the pH/reduction dual-response polymer is obtained.
Example 7
In this example 7, the pH/reduction dual-response polymer prepared in example 4 was subjected to critical micelle concentration test by a fluorescent probe method, and the test steps include:
Example 8
This example 8 is the self-assembly behavior above CMC for the pH/reduced dual response polymer prepared in example 4 and the blank micelle size at different pH by DLS test.
Wherein the self-assembly behavior comprises: accurately weighing 30mg of the pH/reduction dual-response polymer prepared in the example 4, dissolving in 30mL of dimethyl sulfoxide, transferring into a dialysis bag (MWCO 3500) after complete dissolution, dialyzing with 1L of deionized water for 48h, and replacing a dialysis medium every 4h to obtain a blank micelle solution with the concentration of 1 mg/mL;
blank micelle particle sizes at different pH include: the blank micelle solution was divided into 10 parts, the pH was adjusted to 3 to 10, and after stabilizing for a while, the particle size at each pH was measured by dynamic light scattering.
Example 9
This example 9 is an anticancer drug loading test on the pH/reduction dual response polymer prepared in example 4, and characterizes the particle size distribution and morphology thereof.
The anticancer drug loading test includes: accurately weighing 30mg of pH/reduction dual-response polymer, dissolving in 30mL of dimethyl sulfoxide, accurately adding 15mg of taxol after complete dissolution, stirring at room temperature in a dark place for 4h, transferring into a dialysis bag (MWCO 3500), dialyzing with 1L of deionized water for 48h, and replacing dialysis medium every 4h. The micelle solution was filtered through a filter head having a pore size of 0.45 μm and freeze-dried.
Particle size distribution and morphology characterization are shown in figure 8, the particle size and particle size distribution are measured by adopting a dynamic light scattering method, the average particle size of the pH/reduction dual-response polymer micelle loaded with the anticancer drug is 229.6nm, and the particle size distribution is 0.218. The morphology was spherical by TEM observation.
Example 10
This example 10 is a drug release test of the anticancer drug-loaded pH/reduction dual-response polymer micelle prepared in example 9, comprising the steps of:
four 5mg of pH/reduction double-responsive micelles carrying the anticancer drug prepared in example 9 were accurately weighed and dissolved in 5mL of buffer solutions of pH 5.0, pH 7.4, pH 5.0/10mM DTT and pH 7.4/10mM DTT, respectively. After sufficient dissolution, the mixed solution was placed in a dialysis bag (MWCO 3500), which was then immersed in 95mL of the corresponding buffer solution described above. The temperature was set at 37℃and the stirring speed was 100rpm. 4mL of the sample was taken at regular intervals and 4mL of fresh buffer was added. Measuring the concentration of paclitaxel in the release liquid at different times by ultraviolet spectrophotometry, and drawing an in vitro release curve;
as a result, referring to fig. 9, it can be seen from fig. 9 that in a normal blood environment (pH 7.4/0mM DTT), the drug release rate is slow, the cumulative release amount in 6 hours is less than 10%, and the cumulative release amount in 120 hours is less than 20%, so that the loss of the drug in the normal blood circulation process of the human body can be effectively reduced; in the environment of pH 5.0/10mM DTT, the drug-loaded micelle release rate is rapid, the cumulative release is about 30% in 12 hours, and the cumulative release amount reaches 67% in 120 hours. Under four experimental conditions, no burst release phenomenon occurs, and the requirement of slow and controlled release is met.
The above embodiments are merely for illustrating the technical solution of the present application, and not for limiting the same; although the present application has been described in detail with reference to the foregoing embodiments, it should 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 corresponding technical solutions.
Claims (10)
2. the pH/reduced dual response polymer micelle of claim 1, wherein the pH/reduced dual response polymer has a number average molecular weight of 9000-18000 g/mol.
3. The method for preparing the pH/reduction dual response polymer micelle as claimed in claim 1, which is characterized by comprising the following steps:
step 1, under the protection of inert gas and anhydrous and anaerobic conditions, the methodγ(tert-butyl carbamate)εCaprolactone (III),εMixing caprolactone, a small molecular initiator containing disulfide bonds and a first catalyst, and then carrying out ring-opening polymerization reaction to obtain a large molecular initiator;
step 2, mixing polyethylene glycol methyl ether methacrylate, a macromolecular initiator, a solvent, a second catalyst and a ligand in a nitrogen atmosphere, freezing, pumping and heating for three times, and stirring at room temperature to obtain a catalyst complex;
step 3, stirring the catalyst complex and a reducing agent, and then carrying out oil bath reaction to obtain a reduction response polymer;
step 4, dissolving the reduction response polymer and trifluoroacetic acid in dichloromethane, and stirring for reaction to obtain a pH/reduction dual response polymer;
step 5, the pH/reduction dual-response polymer obtained in the step 4 is dialyzed to obtain a pH/reduction dual-response polymer micelle;
in the step 1, the first catalyst is stannous octoate, and the ring-opening polymerization reaction is carried out for 24-48 hours at 100-130 ℃;
in the step 2, the second catalyst is copper bromide, the ligand is pentamethyl diethyl triamine, and the solvent is tetrahydrofuran or toluene;
in the step 3, the reducing agent is stannous octoate, the temperature of the oil bath reaction is 60-70 ℃, and the time is 12-24 hours.
4. Root of Chinese characterThe method for preparing a pH/reduction dual response polymer micelle as in claim 3, wherein the method comprises the steps ofγ(tert-butyl carbamate)εThe preparation method of the caprolactone comprises the following steps: dissolving 4- (tert-butyloxycarbonylamino) cyclohexanone and 3-chloroperoxybenzoic acid in dichloromethane, and reacting for 12-24 hours at 40-50 ℃ to obtainγ(tert-butyl carbamate)εCaprolactone.
5. A method for preparing a pH/reduced dual response polymer micelle according to claim 3, wherein the method for preparing a small molecular initiator containing disulfide bonds comprises: under the protection of inert gas and under the anhydrous condition, dissolving bis (2-hydroxyethyl) disulfide in tetrahydrofuran, adding triethylamine, cooling to 0 ℃, dropwise adding 2, 4-dibromoisobutyryl bromide, stirring, reacting for 1-3 h at 0 ℃ after the dropwise adding, and then continuing to react for 12-24 h at room temperature.
6. The method for preparing a pH/reduction dual-response polymer micelle according to claim 3, wherein the preparation raw materials of the macroinitiator comprise, in parts by mass: 49.6-66.3 parts by massε12.8 to 21.6 parts by mass of caprolactoneγ(tert-butyl carbamate)ε0.05-0.06 part by mass of caprolactone, 0.8-1.2 parts by mass of stannous octoate and small molecule initiator containing disulfide bonds.
7. A method of preparing a pH/reduction dual response polymer micelle according to claim 3, wherein the preparation raw materials of the reduction response polymer include: 3.4-4.1 parts by mass of a macromolecular initiator, 4.8-5.9 parts by mass of polyethylene glycol methyl ether methacrylate, 0.013-0.022 part by mass of copper bromide, 0.12-0.20 part by mass of pentamethyl diethyl triamine and 0.26-0.38 part by mass of stannous octoate.
8. The method for preparing a pH/reduced dual response polymer micelle according to claim 3, wherein the preparation raw materials of the pH/reduced dual response polymer comprise, in parts by mass: 0.6 to 1.2 parts by mass of a reduction-responsive polymer, and 0.8 to 1.6 parts by mass of trifluoroacetic acid.
9. Use of the pH/reduced dual-response polymer micelle of any one of claims 1 to 2 or the pH/reduced dual-response polymer micelle prepared by the preparation method of any one of claims 3 to 8 as an anticancer drug carrier.
10. The use according to claim 9, wherein the method of preparing the anticancer drug carrier comprises: the pH/reduction dual response polymer micelle and the hydrophobic anticancer drug are mixed according to the proportion of 3-6: 1-3, stirring for 4-12 h, dialyzing with deionized water for 24-72 h, changing deionized water every 3-6 h, and freeze-drying.
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