CN108969484B - Preparation method of targeted atherosclerotic plaque nano material - Google Patents
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- 208000037260 Atherosclerotic Plaque Diseases 0.000 title claims abstract description 12
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims abstract description 62
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- 229940096998 ursolic acid Drugs 0.000 claims abstract description 46
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- YCLSOMLVSHPPFV-UHFFFAOYSA-N 3-(2-carboxyethyldisulfanyl)propanoic acid Chemical compound OC(=O)CCSSCCC(O)=O YCLSOMLVSHPPFV-UHFFFAOYSA-N 0.000 claims abstract description 38
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- 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
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
The invention provides a preparation method of a targeted atherosclerotic plaque nano material. The method comprises the following steps: firstly, carrying out esterification reaction on dithiodipropionic acid and ursolic acid to generate acyl chloride, then reacting with hyaluronic acid to prepare a nano blank polymer micelle, and then wrapping curcumin in the nano blank polymer micelle by a dialysis method to obtain the curcumin micelle. Has the advantages that: the dithiodipropionic acid has redox sensitivity, disulfide bonds of the dithiodipropionic acid can be broken under the condition of high-activity ROS, and the ursolic acid has the pharmacological action of resisting atherosclerosis and has hydrophobicity; the hyaluronic acid has hydrophilicity and has targeting effect on atherosclerosis. The prepared nano material has AS targeting property and obvious effect.
Description
Technical Field
The invention relates to a preparation method of a targeted atherosclerotic plaque nano material.
Background
In recent years, with the rapid development of economy, the whole society has great changes, the living conditions of people are increasingly improved, the rhythm of life is faster and faster, people have more irregular and unhealthy meals, often eat foods with high fat and high calorie, have irregular diet and have no exercise amount, so that more young people start to have the condition of atherosclerosis. Atherosclerosis is one of the major causes of cardiovascular diseases such as myocardial infarction, stroke, and chronic angiotensin, and the size and composition of atherosclerotic plaques are both related to their pathophysiological behavior. In recent years, targeted therapy of atherosclerosis has become a new research focus, and a targeted drug delivery system (also called targeted delivery system, TDS) refers to a drug delivery system in which a drug is encapsulated in a carrier material, and the carrier delivers the drug to a specific target site through different drug delivery modes so that the drug is gathered at the specific target site. Therefore, there is a need for effective atherosclerotic plaque targeting formulations that address the atherosclerotic problem described above.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of a targeted atherosclerotic plaque nano material. The nano material prepared by the method has obvious targeting property and remarkable effect.
The technical scheme for solving the technical problems is as follows:
a preparation method of a targeted atherosclerotic plaque nano material comprises the following steps:
(1) under ice bath, the oxalyl chloride solution is slowly dripped into the dithiodipropionic acid solution, activated for 10min, and then put into a constant-temperature oil bath kettle to react for 2-3h at 35 ℃; then carrying out rotary evaporation, and adding anhydrous THF for dissolution to obtain a solution A;
the molar ratio of oxalyl chloride to dithiodipropionic acid is 1:1-2: 1;
the concentration of solution A is 6.34X 10-5mol/ml；
(2) Slowly dripping the solution A into an ursolic acid solution containing triethylamine, uniformly mixing, reacting in an oil bath kettle at 35 ℃ for 3-4h, and carrying out rotary evaporation to obtain an ursolic acid dithiodipropionic acid derivative;
the molar ratio of the ursolic acid to the triethylamine is 1:1-1: 2;
the molar ratio of the solution A to the ursolic acid is 1:1-2: 1;
(3) sequentially adding formamide, EDC and DMAP into the ursolic acid dithiodipropionic acid derivative, placing the mixture in a constant-temperature oil bath pan, and activating for 2 hours at the temperature of 0-55 ℃ to obtain a solution B;
ursolic acid dithiodipropionic acid derivative: EDC: the molar ratio of DMAP is 1:1.2: 1;
1mol of ursolic acid dithiodipropionic acid derivative is 3.8X 10 corresponding to formamide4ml；
(4) Mixing and dissolving hyaluronic acid and formamide, then dropwise adding the mixture into the solution B, placing the solution B in a constant-temperature oil bath kettle, and reacting for 24 hours at 55 ℃ to obtain a solution C;
1mol hyaluronic acid corresponds to 20-30ml formamide;
ursolic acid dithiodipropionic acid derivative: the molar ratio of the hyaluronic acid is 1:1-1: 2;
(5) transferring the solution C into a dialysis bag with the molecular weight cutoff of 2000Da, carrying out dialysis reaction, sucking out the retention solution after the dialysis is finished, centrifuging, taking the supernatant, and freeze-drying to obtain a polymer micelle carrier material;
(6) mixing and dissolving a polymer micelle carrier material, formamide and DMSO to obtain a solution D; dissolving curcumin and formamide to obtain a solution E; mixing the solution D and the solution E, transferring the mixture into a dialysis bag with a cut-off molecular weight of 3000Da, carrying out dialysis reaction for 6-24 h, and sucking out the remaining solution for centrifugation after dialysis is finished; taking the supernatant, passing through microporous filter membranes of 0.8 μm and 0.45 μm, and lyophilizing to obtain medicine-carrying curcumin micelle;
10mg of the polymeric micelle carrier material is dissolved in a mixed solution of 3ml of formamide and 3ml of DMSO;
1mg curcumin corresponds to 1ml formamide;
the mass ratio of the polymer micelle material in the solution D to the curcumin in the solution E was 10:1.
Preferably, the activation is carried out for 2 hours at 35 ℃ in a constant-temperature oil bath kettle in the step (3).
Preferably, before the supernatant obtained in the step (6) is filtered through the microporous filter membranes with the diameters of 0.8 μm and 0.45 μm, the supernatant is firstly subjected to ultrasonic treatment for 1min and then filtered through the microporous filter membranes with the diameters of 0.8 μm and 0.45 μm.
Preferably, the dialysis time in the step (6) is 12 h.
Has the advantages that: the dithiodipropionic acid has redox sensitivity, disulfide bonds of the dithiodipropionic acid can be broken under the condition of high-activity ROS, and the ursolic acid has the pharmacological action of resisting atherosclerosis and has hydrophobicity; the hyaluronic acid has hydrophilicity and has targeting effect on atherosclerosis. The nano blank polymer micelle is prepared by esterification reaction of ursolic acid and hyaluronic acid, and the curcumin is used as a model drug to prepare the curcumin-coated nano polymer micelle. The prepared nano material has AS targeting property and obvious effect.
Drawings
FIG. 1 is a hydrogen spectrum of Hyaluronic Acid (HA), Ursolic Acid (UA) and polymeric micelle carrier material according to the present invention;
FIG. 2 is a graph of standard regression of curcumin in accordance with the present invention;
FIG. 3 is a fluorescence intensity spectrum in an experimental example of the present invention.
Detailed Description
According to the application, firstly, dithiodipropionic acid and ursolic acid are subjected to esterification reaction to generate acyl chloride, then the acyl chloride reacts with hyaluronic acid to prepare a nano blank polymer micelle, and then curcumin is wrapped in the nano blank polymer micelle by a dialysis method, so that the curcumin micelle with excellent particle size, encapsulation efficiency and drug loading capacity is obtained.
Dithiodipropionic acid is redox sensitive, and the disulfide bond of the dithiodipropionic acid can be cracked under the condition of high-activity ROS; ursolic Acid (UA), also known as ursolic acid, has hydrophobicity, can reduce the levels of human blood cholesterol and beta-lipoprotein, and has an anti-atherosclerosis effect, so that the application utilizes the effect of the ursolic acid on treating atherosclerosis by reducing blood fat, connects the ursolic acid on hyaluronic acid to form an amphiphilic novel carrier material, and further prepares a reasonable preparation for the targeted treatment of the atherosclerosis; hyaluronic Acid (HA) HAs strong hydrophilicity, and is often modified with some hydrophobic substances to form a novel carrier material. HA HAs strong affinity for atherosclerotic plaques, so modified hyaluronic acid is often used as a carrier material to wrap a drug for targeted therapy of atherosclerosis. The nano blank polymer micelle is prepared by esterification reaction of ursolic acid and hyaluronic acid, and the curcumin is used as a model drug to prepare the curcumin-coated nano polymer micelle. The micelle shell has a proper design of hydrophilicity, so that the medicine has a long circulation effect in vivo, the curative effect is more remarkable, and a plurality of side effects can be reduced.
The information of the experimental medicine and reagent manufacturer used in the application is as follows:
dithiodipropionic acid: shanghai Michelin Biochemical technology, Inc.;
ursolic Acid (UA): XYbscience;
enzyme-cleaved oligomeric sodium Hyaluronate (HA): huaxi Ruida biological medicine limited;
1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC): laddin Chemistry co.ltd;
formamide: yongda chemical reagents, Inc. of Tianjin;
purified water: hangzhou child Haha group, Inc.;
curcumin: denmark chemical reagents ltd, Tianjin;
triethylamine: yongda chemical reagents, Inc. of Tianjin;
n, N-Dimethylformamide (DMF): tianjin Bodi chemical corporation;
anhydrous Tetrahydrofuran (THF): chemical agents of the national drug group, ltd.
The experimental instrument model and manufacturer information are as follows:
constant temperature magnetic stirrer: model 90-1, Shanghai West Analyzer Mill;
heat collection type constant temperature heating magnetic stirrer: model DF-101S, Consortium City Yaohua instruments, Inc.;
qingdaohai refrigerator: BCD-205F, Qingdao Haier Inc.;
a freeze dryer: DRC-1100, Japan science and technology Co., Ltd;
a test tube dryer: type C, zhengzhou great wall science trades ltd;
an ultrasonic cleaner: model SK250, shanghai kodao ultrasonic instruments ltd;
a liquid transferring gun: xinglong laboratory instruments, Inc.;
a micro high-speed centrifuge: model TG-16S, sichuan instruments ltd;
high performance liquid chromatograph: model GB12C, shimadzu corporation;
plastic centrifuge tube: experimental equipment for Kangda in Jiangyan city;
glass instrument: tianjin glass instruments factory;
analytical balance: MP5002 model, ohauss international trade (shanghai) ltd.
Example 1
A preparation method of a targeted atherosclerotic plaque nano material comprises the following steps:
(1) under ice bath, the oxalyl chloride solution is slowly dripped into the dithiodipropionic acid solution, activated for 10min, and then put into a constant-temperature oil bath kettle to react for 2-3h at 35 ℃; then carrying out rotary evaporation, and adding anhydrous THF for dissolution to obtain a solution A;
the molar ratio of oxalyl chloride to dithiodipropionic acid is 1:1-2: 1; the concentration of solution A is 6.34X 10-5mol/ml；
The oxalyl chloride solution is prepared by dissolving oxalyl chloride in anhydrous THF, and 100 μ l of oxalyl chloride solution corresponds to 1ml of anhydrous THF; the dithiodipropionic acid solution is prepared by dissolving dithiodipropionic acid in anhydrous THF, wherein 1mol of dithiodipropionic acid corresponds to 1.05X 104ml anhydrous THF;
(2) slowly dripping the solution A into an ursolic acid solution containing triethylamine, uniformly mixing, reacting in an oil bath kettle at 35 ℃ for 3-4h, and carrying out rotary evaporation to obtain a product ursolic acid dithiodipropionic acid derivative (the specific synthetic route is as follows);
the ursolic acid solution is prepared by dissolving ursolic acid in anhydrous THF; the molar ratio of the ursolic acid to the triethylamine is 1:1-1: 2; the molar ratio of the solution A to the ursolic acid is 1:1-2: 1;
(3) in ursolic acid dithioSequentially adding formamide, EDC and DMAP into the dipropionic acid derivative, placing the mixture in a constant-temperature oil bath, and activating the mixture for 2 hours at the temperature of 55 ℃ to obtain a solution B; ursolic acid dithiodipropionic acid derivative: EDC: the molar ratio of DMAP is 1:1.2: 1; 1mol of ursolic acid dithiodipropionic acid derivative is 3.8X 10 corresponding to formamide4ml；
(4) Mixing and dissolving hyaluronic acid and formamide, then dropwise adding the mixture into the solution B, placing the solution B in a constant-temperature oil bath kettle, and reacting for 24 hours at 35 ℃ to obtain a solution C; 1mol hyaluronic acid corresponds to 20-30ml formamide; ursolic acid dithiodipropionic acid derivative: the molar ratio of the hyaluronic acid is 1:1-1: 2;
(5) transferring the solution C into a dialysis bag with the molecular weight cutoff of 2000Da, carrying out dialysis reaction for not less than 24h, changing water every two to three hours, sucking out the retention solution after dialysis is finished, centrifuging, taking the supernatant, and freeze-drying to obtain the polymeric micelle carrier material (the specific synthetic route is as follows);
as shown in fig. 1, when the hydrogen spectra of Hyaluronic Acid (HA), Ursolic Acid (UA) and the polymeric micelle carrier material are compared, it can be seen that in the hydrogen spectra of the polymeric micelle carrier material, 1.91, 3.11, 3.89, 3.91 are from HA, 0.67, 0.94 are from UA, and further, peaks at 2.55 and 2.95 are from dithiodipropionic acid, and the hydroxyl group of HA HAs a hydroxyl group peak at 4.75, but the peak is not present in the product, indicating that the hydroxyl group of HA HAs reacted, and the product is the polymeric micelle carrier material.
(6) Mixing and dissolving 10mg of polymer micelle carrier material, 1mL of formamide and 1mL of DMSO to obtain a solution D; dissolving 1mg of curcumin and 1mL of formamide to obtain a solution E; mixing the solution D and the solution E, transferring the mixture into a dialysis bag with the molecular weight cutoff of 3000Da, carrying out dialysis reaction for 12 hours, and sucking out the retention solution for centrifugation after the dialysis is finished; taking supernatant, performing ultrasonic treatment for 1min, filtering with 0.8 μm and 0.45 μm microporous filter membranes, and lyophilizing to obtain medicine-carrying curcumin micelle; 10mg of the polymeric micelle carrier material is dissolved in a mixed solution of 3ml of formamide and 3ml of DMSO; 1mg curcumin corresponds to 1ml formamide; the mass ratio of the polymer micelle material in the solution D to the curcumin in the solution E was 10:1.
Measurement of particle size:
the micelle supernatant was passed through 0.8 μm and 0.45 μm microfiltration membranes in this order, and added to a cuvette, preferably 1/2 to 2/3, and then the particle size was measured by a particle size analyzer, respectively.
The particle size distribution of the polymer micelle of the present application: the average particle size of the micelle supernatant was 465.3nm as measured by a 0.8 μm microfiltration membrane, and 210.5nm as measured by a 0.45 μm microfiltration membrane, with uniform particle size distribution.
Determination of encapsulation efficiency:
the encapsulation Efficiency (EE%) is the ratio of the drug encapsulated in the micelle to the total amount of drug added at the time of dosing. The present application uses HPLC for the determination. Accurately measuring 2mL of micelle solution into a 10mL volumetric flask by using a pipette, adding nine times of volume of absolute ethyl alcohol, diluting and destroying the micelle, after constant volume, taking out a proper amount of solution, passing the solution through a 0.45-micron microporous filter membrane, measuring the absorbance of the solution, and calculating the encapsulation efficiency by using a standard curve of a curcumin standard solution.
Preparing a curcumin standard solution: accurately sucking 10 mug/mL curcumin solution by a pipette gun into 5 10mL volumetric flasks (numbered) with the volume of 0.1mL, 0.5mL, 1mL, 5mL and 10 mL; then the same methanol solution is used for constant volume and is mixed evenly to obtain standard solutions of 0.1 mug/mL, 0.5 mug/mL, 1 mug/mL, 5 mug/mL and 10 mug/mL for standby.
The standard curve measurement method is to measure by high performance liquid chromatography, and is carried out under the detection condition that the detection wavelength is 425nm, and the absorbance of the prepared 5 standard solutions is respectively measured, 2mL of the 5 standard solutions are respectively taken out and pass through a 0.22 mu m microporous filter membrane, then the sample is injected into the high performance liquid chromatography to measure the absorbance, and the absorbance is recorded one by one, and then a regression curve is made according to the relation between the concentration (C) and the absorbance (A) (as shown in figure 2).
High performance liquid chromatography conditions:
a chromatographic column:
ODS-SP (4.6X 250mm, 5 μm); mobile phase: acetonitrile: 5% glacial acetic acid in water 60: 40 (v/v); flow rate: 1 mL/min; column temperature: 35 ℃; sample introduction amount: 20 mu L of the solution; detection wavelength: 425 nm.
The absorbance of each of the 5 standard solutions was measured (see table 1), and a standard curve was drawn to find a regression equation of 138.2C + 16.31.
The encapsulation efficiency of the curcumin-loaded micelle in the application example 1 is 19.7%.
The weight ratio of the polymeric micelle carrier material to the curcumin in the application is 10:1, are important to the present application.
Table 1 curcumin standard solution concentration and absorbance
Stability of micelle:
the micelle solution that has passed through the 0.45 μm microporous membrane is left in a refrigerator at 4 ℃ for one week in the dark, and color change is observed, and then a particle size measurement is performed to see whether it is stable or not.
The micelle solution after the micelle solution is placed for one week has no obvious change in color and no obvious particles, and the micelle solution placed for one week is subjected to particle size measurement. The micelle solution after being left for one week is measured to obtain an average particle size of 217.7nm, and the micelle solution before one week is measured to obtain an average particle size of 210.5nm, so that the prepared micelle solution has good stability.
Example 2
Example 2 was prepared according to the same method as example 1. Except that the reaction was carried out in a constant temperature oil bath in the step (3) at 0 ℃ for 2 hours.
Example 3
Example 3 was prepared according to the same method as example 1. Except that the reaction was carried out in a constant temperature oil bath in the step (3) at 35 ℃ for 2 hours.
The effect of different temperatures on micelle size and encapsulation efficiency in examples 1, 2 and 3 was examined as shown in table 2.
TABLE 2 Effect of different temperatures on micelle size and encapsulation efficiency
As can be seen from table 2, the effect of activation temperature on particle size and encapsulation efficiency is significant for the present application. The optimum activation temperature is 35 ℃.
Example 4
Example 4 was prepared according to the same method as example 1. Except that the supernatant in step (6) was passed directly through 0.8 μm and 0.45 μm microfiltration membranes without sonication.
Example 5
Example 5 was prepared according to the same method as example 1. Except that the supernatant in step (6) was sonicated for 0.5min and then passed through 0.8 μm and 0.45 μm microfiltration membranes.
The particle size and the encapsulation efficiency were measured. The effect of different sonication times on micelle size and encapsulation efficiency in examples 1, 4 and 5 is shown in table 3.
TABLE 3 Effect of different sonication times on micelle size and encapsulation efficiency
As can be seen from table 3, the effect of sonication time on particle size and encapsulation efficiency is significant for the present application. The ultrasonic time is 1min, which is the optimal ultrasonic time.
Example 6
Example 6 was prepared according to the same method as example 1. Except that the dialysis reaction in step (6) was carried out for 6 hours.
Example 7
Example 7 was prepared according to the same method as example 1. Except that the dialysis reaction in step (6) was carried out for 18 hours.
Example 8
Example 8 was prepared according to the same method as example 1. Except that the dialysis reaction in step (6) was carried out for 24 hours.
The results of the different dialysis times on micelle size and encapsulation efficiency in examples 1, 6, 7 and 8 are shown in table 4.
TABLE 4 Effect of different dialysis times on micelle size and encapsulation efficiency
As can be seen from Table 4, the effect of dialysis time on particle size and encapsulation efficiency is important in the present application. When the dialysis time is 12h, the optimal dialysis time is obtained.
Example 9
Example 9 was prepared according to the same method as example 1. Except that 5mg of the polymeric micelle carrier material was used in step (6).
Example 10
Example 10 was prepared according to the same method as example 1. Except that 15mg of the polymeric micelle carrier material was used in step (6).
The results of the effect of different amounts on micelle size and encapsulation efficiency in examples 1, 9 and 10 are shown in table 5.
TABLE 5 Effect of different dosage ratios on micelle size and encapsulation efficiency
As can be seen from Table 5, the effect of the amount of different polymeric materials on the particle size and encapsulation efficiency of the present application is important. When the ratio of the high polymer material to the curcumin is 10:1, the optimal material dosage is obtained.
Pharmacodynamic evaluation and results:
1. in vitro cell uptake assay
The prepared nano material is subjected to preliminary pharmacodynamic tests, the nano preparation carrying curcumin is incubated with Human Umbilical Vein Endothelial Cells (HUVEC), the damage of LPS induced human umbilical vein endothelial cells is further verified to be used as an atherosclerosis vascular damage model, and the in-vitro targeting of the carrier is preliminarily evaluated according to the ingestion condition of the drug delivery system. The results show that the preparation group takes obviously and has obvious targeting property, and the curcumin solution group basically does not take.
2. Preliminary evaluation of in vivo targeting
Apolipoprotein E (ApoE) is a polymorphic protein involved in the transformation and metabolism of lipoproteins, and its gene can regulate many biological functions and is closely related to the development of atherosclerosis. ApoE-/-The mouse can generate serious hypercholesterolemia under the condition of being fed by high-fat feed, and can spontaneously form atherosclerotic plaques, the plaque distribution and the pathological characteristics of the mouse are very similar to those of human AS plaques, and the mouse is an ideal animal model for researching AS. The test was performed with ApoE-/-Mice are fed with high-fat feed to establish an atherosclerosis model, and pathological evaluation and preparation targeting research are carried out on the atherosclerosis model.
The results show that compared with the normal group, the serum TC (total cholesterol) and TG (triglyceride) contents (mmol/L) of the model group are obviously increased (P is less than 0.01) (AS shown in Table 6), and further show that the prepared nano preparation has certain AS targeting property and obvious effect.
Table 6 test results of TC and TG in test examples
| Group of | TC | TG | LDL-C | HDL-C |
| Normal group | 3.21±0.11 | 0.36±0.05 | 0.93±0.12 | 1.42±0.32 |
| Model set | 20.22±1.24** | 1.07±0.21** | 1.29±0.15** | 0.89±0.27** |
On this basis, in vivo imaging studies were performed, and the fluorescence intensity of the targeted agent group was analyzed quantitatively to be 1.8 times higher by the fluorescence intensity.
The application takes ursolic acid and hyaluronic acid as main bodies, the ursolic acid and hyaluronic acid react to form a carrier material, then the carrier material is used for encapsulating a medicine to prepare a preparation, and the particle size, the potential and the medicine loading rate of the preparation are measured to design a new dosage form for treating atherosclerosis in a targeted manner. The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The above-described embodiments of the invention are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims, and not by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (3)
1. A preparation method of a targeted atherosclerotic plaque nano material is characterized by comprising the following steps:
(1) under ice bath, the oxalyl chloride solution is slowly dripped into the dithiodipropionic acid solution, activated for 10min, and then put into a constant-temperature oil bath kettle to react for 2-3h at 35 ℃; then carrying out rotary evaporation, and adding anhydrous THF for dissolution to obtain a solution A;
the molar ratio of oxalyl chloride to dithiodipropionic acid is 1:1-2: 1;
the concentration of solution A is 6.34X 10-5mol/ml；
(2) Slowly dripping the solution A into an ursolic acid solution containing triethylamine, uniformly mixing, reacting in an oil bath kettle at 35 ℃ for 3-4h, and carrying out rotary evaporation to obtain an ursolic acid dithiodipropionic acid derivative;
the molar ratio of the ursolic acid to the triethylamine is 1:1-1: 2;
the molar ratio of the solution A to the ursolic acid is 1:1-2: 1;
(3) sequentially adding formamide, EDC and DMAP into the ursolic acid dithiodipropionic acid derivative, placing the mixture in a constant-temperature oil bath pan, and activating for 2 hours at the temperature of 0-55 ℃ to obtain a solution B;
ursolic acid dithiodipropionic acid derivative: EDC: the molar ratio of DMAP is 1:1.2: 1;
1mol of ursolic acid dithiodipropionic acid derivative is 3.8X 10 corresponding to formamide4ml；
(4) Mixing and dissolving hyaluronic acid and formamide, then dropwise adding the mixture into the solution B, placing the solution B in a constant-temperature oil bath kettle, and reacting for 24 hours at 55 ℃ to obtain a solution C;
1mol hyaluronic acid corresponds to 20-30ml formamide;
ursolic acid dithiodipropionic acid derivative: the molar ratio of the hyaluronic acid is 1:1-1: 2;
(5) transferring the solution C into a dialysis bag with the molecular weight cutoff of 2000Da for dialysis reaction, sucking out the retention solution after the dialysis is finished, centrifuging, taking the supernatant, and freeze-drying to obtain a polymer micelle carrier material;
(6) mixing and dissolving a polymer micelle carrier material, formamide and DMSO to obtain a solution D; dissolving curcumin and formamide to obtain a solution E; mixing the solution D and the solution E, transferring the mixture into a dialysis bag with the molecular weight cutoff of 3000Da, carrying out dialysis reaction for 6-24 h, sucking out the retention solution after dialysis is finished, and centrifuging; taking supernatant, performing ultrasonic treatment for 1min, filtering with 0.8 μm and 0.45 μm microporous filter membranes, and lyophilizing to obtain medicine-carrying curcumin micelle;
10mg of the polymeric micelle carrier material is dissolved in a mixed solution of 3ml of formamide and 3ml of DMSO;
1mg curcumin corresponds to 1ml formamide;
the mass ratio of the polymer micelle material in the solution D to the curcumin in the solution E was 10:1.
2. The method according to claim 1, wherein the step (3) is carried out in a constant temperature oil bath at 35 ℃ for 2 hours.
3. The method according to claim 1, wherein the dialysis time in the step (6) is 12 hours.
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