Double-targeting curcumin polymer, micelle and preparation method thereof

Abstract

The invention discloses a folate receptor mediated reduction-released dual-targeting curcumin polymer micelle and a preparation method thereof. A tumor target molecule folic acid is modified on a biodegradable hydrophilic polyethylene glycol skeleton, and is coupled with curcumin through a disulfide bond to construct an amphiphilic polymer monomer with a high grafting rate, and the molecular formula of the amphiphilic polymer monomer is FA-PEG2K-SS-CUR; the curcumin micelle is prepared by self-assembly through a dialysis method, so that a traditional encapsulation drug loading mode is simplified, the drug is a part of a carrier, and drug leakage is avoided. The polymer micelle obtained by the method has high drug loading rate, stability and biocompatibility, improves the solubility of curcumin in water, enhances the targeted release of tumor cells, reduces the toxic and side effects, and has a higher antitumor effect than the bulk drug.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical preparation characterized by a special physical shape, in particular to a folate receptor-mediated reduction-sensitive dual-targeted curcumin polymer, micelle and a preparation method thereof. Background Art

[0002] At present, malignant tumors have become a common disease that endangers human health, and the mortality rate of advanced cancer is increasing year by year. The mechanism of tumor occurrence is very complex, and most tumors are caused by abnormalities in more than 500 genes. Therefore, the effect and application of single-target anticancer drugs are greatly limited, and multi-target anticancer new drugs have become a new trend for the prevention and treatment of cancer.

[0003] Curcumin is a plant polyphenol extracted from the rhizome of turmeric. It has a wide range of pharmacological effects such as anti-tumor, antioxidant, anti-inflammatory, and neuroprotective. It was listed as a third-generation anticancer chemopreventive agent by the National Cancer Institute of the United States and was included in the United States Pharmacopoeia in 2000. In a phase I clinical trial, it was found that it was very safe when taken orally at a dose of 6g / d for 4-7 weeks. Curcumin can activate tumor cell apoptosis pathways, inhibit tumor microenvironment such as inflammation, angiogenesis, and tumor cell metastasis, and as a natural medicine, it has almost no toxic side effects. Therefore, it shows great research potential in anti-cancer and has received widespread attention from all walks of life. Although curcumin has many potential advantages in the treatment of cancer, it also has many defects, such as low water solubility, strong first-pass effect, unstable physiological pH, and poor oral absorption, which limit its clinical application. Studies have shown that curcumin undergoes rapid primary metabolism after oral administration, and nearly 90% of curcumin is degraded in the liver and small intestine before entering the systemic circulation. Therefore, it brings certain difficulties in clinical application, especially in tumor treatment.

[0004] With the deepening of research, people have made great breakthroughs in the controlled transmission of substances at the molecular level and nanoscale, and nanotechnology has gradually been applied to the medical and pharmaceutical fields. In recent years, various new dosage forms including prodrugs, micelles, liposomes and polymer copolymers have played a certain role in improving the water solubility and stability of curcumin and prolonging the circulation time of drugs in the body.

[0005] Patent CN104257629A discloses a folate receptor-mediated curcumin self-assembled polymer nanomicelle and a preparation method thereof, and discloses a preparation method of RGD-targeted porphyrin polymer nanomicelles. The porphyrin carrier material used in this invention has not been certified by the US FDA and may have potential long-term toxicity.

[0006] Patent CN118403012A discloses a nano polymer micelle loaded with curcumin, a preparation method and an application thereof. The nano micelle is prepared from curcumin, succinate and Pluronic F127 by a thin film hydration method. However, the physical drug-loaded particles are thermodynamically unstable systems, and burst release is inevitable in the human body environment.

[0007] Patent CN110917361A discloses a pH-responsive curcumin succinic anhydride prodrug nano-micelle and its preparation method and application. The invention introduces acid-sensitive succinic anhydride at the end of polyethylene glycol and bonds with the hydrophobic drug curcumin to form an amphiphilic polymer that self-assembles in an aqueous solution to form nano-micelles. Under the action of acidity in cancer cells, the anticancer drug curcumin can be degraded and released, achieving the effect of targeted controlled release. Although it overcomes the material safety and drug release risks, it is not highly selective in the active distribution targeting of the preparation, and there are still deficiencies. Summary of the invention

[0008] The purpose of the present invention is to overcome the defects of the prior art and provide a dual-targeting curcumin polymer, micelle and a preparation method thereof.

[0009] The present invention breaks through the traditional carrier physical drug encapsulation mode, modifies the tumor target molecule folic acid on the biodegradable hydrophilic polyethylene glycol skeleton, and couples it with curcumin through disulfide bonds, so that the hydrophobic drug becomes a part of the amphiphilic polymer monomer, and the micelles formed by self-assembly in water simplify the use of hydrophobic inert carriers, thereby improving the drug loading rate and drug release stability. The obtained micelles can be effectively enriched around tumor tissues by using the EPR effect in the blood circulation, and are tightly bound to tumor cells due to the surface-modified folic acid ligands and enter the capsule through endocytosis. The glutathione content in tumor cells is three times that of normal cells, which can effectively reduce the disulfide bond rupture to sulfhydryl groups that are harmless to the human body, and release curcumin to play a role.

[0010] The technical solution is as follows:

[0011] The present invention provides a dual-targeted curcumin polymer, characterized in that the molecular formula is: FA-PEG 2K -SS-CUR, the structural formula is as follows:

[0012]

[0013] Its preparation comprises the following steps:

[0014] (1) Activate the carboxyl group of folic acid (FA) and react with single-terminal amino polyethylene glycol (PEG 2K ) undergoes an amide reaction to form folic acid-polyethylene glycol (FA-PEG 2K )polymer;

[0015] (2) Activate the hydroxyl group of the folic acid-modified polyethylene glycol and react it with dithiodipropionic anhydride (DTDPA) to introduce a disulfide bond to generate FA-PEG 2K -SS-COOH polymer;

[0016] (3) Connecting curcumin (CUR) to FA-PEG 2K -The carboxyl end of the SS-COOH polymer is esterified to produce FA-PEG 2K -SS-CUR polymer.

[0017] Furthermore, the step (1) provided by the present invention is specifically:

[0018] Under nitrogen protection, folic acid and triethylamine were dissolved in anhydrous DMF and stirred at room temperature for 15 hours, and then NHS and DCC were added to react for 4 hours; the supernatant was collected by centrifugation, polyethylene glycol was added and stirred for 24 hours; the reaction solution was transferred to a dialysis bag, dialyzed with distilled water for 24 hours, the filtrate was collected by suction, and freeze-dried.

[0019] Preferably, in step (1), the molar ratio of folic acid to triethylamine, NHS, and DCC is 1:1.5:3:1; and the molar ratio of folic acid to polyethylene glycol is (1-2):1.

[0020] The step (2) provided by the present invention is specifically:

[0021] FA-PEG 2K The polymer and DTDPA were dissolved in anhydrous DMF, TEA and DMAP were added, and the mixture was stirred at 45°C for 36 hours. The reaction solution was transferred to a dialysis bag, dialyzed with distilled water for 24 hours, and the filtrate was collected by suction and freeze-dried.

[0022] Preferably, in step (2), FA-PEG 2K The molar ratio of TEA and DMAP is 1:3:2.5; FA-PEG 2K The molar ratio of DTDPA is 1:(5~8).

[0023] The step (3) provided by the present invention is specifically:

[0024] FA-PEG 2K -SS-COOH polymer was dissolved in anhydrous DMF, NHS and DCC were added, the reaction was stirred in an ice-water bath for 4 hours and then continued to react at room temperature for 48 hours; curcumin and DMAP were dissolved in anhydrous DMF and slowly added dropwise, and the reaction was continued for 48 hours; the reaction solution was transferred to a dialysis bag, dialyzed with distilled water for 48 hours, the filtrate was collected by suction, and freeze-dried.

[0025] Preferably, in step (3), FA-PEG 2KThe molar ratio of -SS-COOH to NHS and DCC is 1:8:2; the molar ratio of curcumin to DMAP is 1:1; FA-PEG 2K The molar ratio of -SS-COOH to curcumin is 1:(5-10).

[0026] Preferably, in step (3), FA-PEG 2K -SS-CUR polymer drug loading rate is 8.1% to 10.9%. Among them, the preparation steps and reactions of the dual-targeted curcumin polymer provided by the present invention are all carried out in a dry and dark environment; the reaction raw material PEG 2K The relative molecular weight is 2000; the molecular weight cut-off of the dialysis bag is 2000Da.

[0027] The present invention also provides a method for preparing dual-targeted curcumin polymer micelles, the specific steps of which are:

[0028] The curcumin polymer was dissolved in DMSO, and distilled water was slowly added dropwise with stirring. The solution was transferred to a 2000Da dialysis bag and dialyzed in distilled water to remove the solvent. The solution was then filtered through a 0.45 μm microporous filter membrane to obtain curcumin polymer micelles.

[0029] Furthermore, the curcumin polymer micelles are spherical in shape and have a particle size of 79.14±2.2 nm.

[0030] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0031] (1) The dual-targeting curcumin polymer, micelle and preparation method thereof provided by the present invention utilize covalent bonds to couple hydrophobic drugs with hydrophilic polymers, thereby reducing the use of hydrophobic inert carriers, avoiding the sudden release phenomenon of physical encapsulation, increasing its stability and achieving a sustained release effect.

[0032] (2) The dual-targeted curcumin polymer, micelle and preparation method thereof provided by the present invention use a carrier material polyethylene glycol that has been certified by the FDA, and metabolites such as folic acid and disulfide bonds are non-toxic and harmless or can be provided as raw materials for cell growth.

[0033] (3) The present invention provides a dual-targeted curcumin polymer, micelle and preparation method thereof, which has the beneficial effect that compared with the raw material drug, the preparation has improved the distribution targeting and drug release targeting to tumor cells, allowing the drug to quickly reach the tumor cells, reducing unnecessary consumption, and accurately and efficiently exerting the drug effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Example 1, Example 2, Example 3 polymer reaction flow chart.

[0035] Figure 2 Example 4 Polymer H NMR Spectrum ( 1 HMR) diagram.

[0036] Figure 3 Transmission electron microscopy image of the dual-targeted curcumin polymer micelles prepared in Example 4.

[0037] Figure 4 Particle size distribution of dual-targeted curcumin polymer micelles prepared in Example 4.

[0038] Figure 5 FA-PEG described in Example 6 2K -SS-CUR micelles and FA-PEG 2K -SS-COOH polymer hemolysis rate bar graph.

[0039] Figure 6 FA-PEG described in Example 7 2K -In vitro release curves of SS-CUR micelles and curcumin raw materials.

[0040] Figure 7 FA-PEG described in Example 8 2K -Bar graph of the inhibition rate of SS-CUR micelles, FA-PEG-SS-COOH polymers and curcumin raw materials on MCF-7 cells.

[0041] Figure 8 FA-PEG described in Example 9 2K -SS-CUR / C-6 micelle, PEG 2K - Fluorescence images of SS-CUR / C-6 micelles and C-6 uptake in MCF-7 cells. DETAILED DESCRIPTION

[0042] The following description sets forth many specific details to fully understand the present invention. However, the present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar modifications without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific implementation disclosed below.

[0043] Example 1-1: FA-PEG 2K Preparation of polymers

[0044] 111.1 mg of folic acid and 53 μL of triethylamine were dissolved in 4 mL of anhydrous DMF and stirred at room temperature in the dark for 15 h. Then, 8.4 mg of NHS and 34.4 mg of DCC were added and reacted for 4 h to produce a yellow precipitate. The mixture was centrifuged at 5000 rpm for 5 min, the supernatant was collected, and 500 mg of polyethylene glycol was added and stirred for 24 h. The reaction solution was transferred to a dialysis bag with a molecular weight cutoff of 2000 Da, and dialyzed with distilled water for 24 h, with the water changed every 2 h. The filtrate was then collected by suction and freeze-dried.

[0045] Example 1-2: FA-PEG 2K Preparation of polymers

[0046] 167.6 mg of folic acid and 80 μL of triethylamine were dissolved in 4 mL of anhydrous DMF and stirred at room temperature in the dark for 15 h. Then, 12.7 mg of NHS and 51.8 mg of DCC were added and reacted for 4 h to produce a yellow precipitate. The mixture was centrifuged at 5000 rpm for 5 min, the supernatant was collected, 500 mg of polyethylene glycol was added and stirred for 24 h. The reaction solution was transferred to a dialysis bag with a molecular weight cutoff of 2000 Da, dialyzed with distilled water for 24 h, the water was changed every 2 h, and then filtered, the filtrate was collected, and freeze-dried.

[0047] Example 1-3: FA-PEG 2K Preparation of polymers

[0048] Take 220.5 mg of folic acid and 105 μL of triethylamine and dissolve them in 4 mL of anhydrous DMF. Stir and react in the dark at room temperature for 15 hours. Then, add 16.7 mg of NHS and 68.1 mg of DCC and react for 4 hours to produce a yellow precipitate. Centrifuge at 5000 rpm for 5 minutes, collect the supernatant, add 500 mg of polyethylene glycol and stir to react for 24 hours. Transfer the reaction solution to a dialysis bag with a molecular weight cutoff of 2000 Da, dialyze with distilled water for 24 hours, change the water every 2 hours, then filter, collect the filtrate, and freeze-dry.

[0049] Example 2-1: FA-PEG 2K Preparation of -SS-COOH polymer

[0050] Take 180mg FA-PEG 2K The polymer and 75 mg DTDPA were dissolved in 3 mL of anhydrous DMF, and then 43 μL TEA and 22.5 mg DMAP were added. The mixture was stirred at 45 °C in the dark for 36 h under nitrogen protection. The reaction solution was transferred to a dialysis bag with a molecular weight cutoff of 2000 Da and dialyzed with distilled water for 24 h, with the water changed every 2 h. The filtrate was then filtered and collected and freeze-dried.

[0051] Example 2-2: FA-PEG 2K Preparation of -SS-COOH polymer

[0052] Take 180mg FA-PEG 2K The polymer and 100.0 mg DTDPA were dissolved in 3 mL of anhydrous DMF, and then 43 μL of TEA and 22.5 mg of DMAP were added. The mixture was stirred at 45 °C in the dark for 36 h under nitrogen protection. The reaction solution was transferred to a dialysis bag with a molecular weight cutoff of 2000 Da and dialyzed with distilled water for 24 h, with the water changed every 2 h. The filtrate was then filtered and collected and freeze-dried.

[0053] Example 2-3: FA-PEG 2K Preparation of -SS-COOH polymer

[0054] Take 180mg FA-PEG 2K The polymer and 112.1 mg DTDPA were dissolved in 3 mL of anhydrous DMF, and then 43 μL of TEA and 22.5 mg of DMAP were added. The mixture was stirred at 45 °C in the dark for 36 h under nitrogen protection. The reaction solution was transferred to a dialysis bag with a molecular weight cutoff of 2000 Da and dialyzed with distilled water for 24 h, with the water changed every 2 h. The filtrate was then filtered and collected and freeze-dried.

[0055] Example 3-1: FA-PEG 2K Preparation of -SS-CUR polymer

[0056] Take 50mg FA-PEG 2K -SS-COOH polymer was dissolved in 3 mL of anhydrous DMF, and 18.6 mg of NHS and 7.8 mg of DCC were added. The mixture was stirred in an ice-water bath for 4 h under light-proof conditions and then continued to react at room temperature for 48 h. 36.8 mg of curcumin and 12.3 mg of DMAP were dissolved in 1 mL of anhydrous DMF and slowly added with a syringe, and the reaction was continued for 48 h. The reaction solution was transferred to a dialysis bag with a molecular weight cutoff of 2000 Da, and dialyzed with distilled water for 48 h, with the water changed every 2 h. The filtrate was then filtered, collected, and freeze-dried.

[0057] Example 3-2: FA-PEG 2K Preparation of -SS-CUR polymer

[0058] Take 50mg FA-PEG 2K-SS-COOH polymer was dissolved in 3 mL of anhydrous DMF, and 18.6 mg of NHS and 7.8 mg of DCC were added. The mixture was stirred in an ice-water bath for 4 h under light-proof conditions and then continued to react at room temperature for 48 h. 54.7 mg of curcumin and 18.5 mg of DMAP were dissolved in 1 mL of anhydrous DMF and slowly added with a syringe, and the reaction was continued for 48 h. The reaction solution was transferred to a dialysis bag with a molecular weight cutoff of 2000 Da, and dialyzed with distilled water for 48 h, with the water changed every 2 h. The filtrate was then filtered, collected, and freeze-dried.

[0059] Example 3-3: FA-PEG 2K Preparation of -SS-CUR polymer

[0060] Take 50mg FA-PEG 2K -SS-COOH polymer was dissolved in 3 mL of anhydrous DMF, and 18.6 mg of NHS and 7.8 mg of DCC were added. The mixture was stirred in an ice-water bath for 4 h under light-proof conditions and then continued to react at room temperature for 48 h. 72.5 mg of curcumin and 24.5 mg of DMAP were dissolved in 1 mL of anhydrous DMF and slowly added with a syringe, and the reaction was continued for 48 h. The reaction solution was transferred to a dialysis bag with a molecular weight cutoff of 2000 Da, and dialyzed with distilled water for 48 h, with the water changed every 2 h. The filtrate was then filtered, collected, and freeze-dried.

[0061] Example 4: Structure determination and grafting rate calculation

[0062] Take a small amount of polymer solids from Example 1, Example 2, and Example 3 and dissolve them in 0.5 mL DMSO-d 6 The sample was transferred to a nuclear magnetic resonance tube and placed in a 600 MHz nuclear magnetic resonance instrument for field scanning recording to obtain a hydrogen nuclear magnetic resonance spectrum.

[0063] like Figure 2 , 1 The peak at 2.5ppm in HNMR is the signal of DMSO-d6, and the appearance of 8.6-8.5ppm (a) and 3.4-3.6ppm (e+f) signals indicates that folic acid and PEG 2K The signal at 2.9-2.7ppm (e+h+i+j) indicates that DTDPA is successfully introduced; the signal at 3.8-3.7ppm proves that the curcumin polymer is successfully synthesized. The grafting rate of the polymer obtained in Example 1, Example 2, and Example 3, i.e., the micelle drug loading rate, is calculated from the peak area of ​​each characteristic signal.

[0064] Example 5: Preparation of curcumin polymer micelles

[0065] Weigh 20 mg FA-PEG 2K-SS-CUR polymer was dissolved in 1.5 mL DMSO, and 1 mL distilled water was added under slow stirring. The solution was transferred to a dialysis bag with a molecular weight cutoff of 2000 Da and dialyzed in distilled water for 24 h, with the water changed every 2 h. Finally, the solution was filtered through a 0.45 μm water filter membrane to obtain a micellar solution.

[0066] Example 6: Hemolytic study

[0067] Take fresh healthy plasma containing 50 mg / mL EDTA sodium, centrifuge to remove serum, and wash with saline. Dilute red blood cells to a 2% (v / v) suspension. Prepare different concentrations of FA-PEG by diluting with saline. 2K -SS-CUR micelles and FA-PEG 2K -SS-COOH solution. Take 2 mL of red blood cell suspension and add 2 mL of micelles and FA-PEG with different concentration gradients. 2K -SS-COOH solution, the mixture was incubated in a constant temperature shaking water bath at 37°C for 0.5h, centrifuged at 5000rpm for 40min, and the supernatant was taken to measure the absorbance at λ=545nm. Another 2mL of red blood cell suspension was added with the same volume of physiological saline and distilled water as negative and positive controls, respectively, and the hemolysis rate (HR) was calculated according to the following formula:

[0068]

[0069] like Figure 5 As shown, the hemolysis rates of FA-PEG-SS-CUR micelles and FA-PEG-SS-COOH materials are both less than 5.0%, indicating that the micelles and metabolites have good biocompatibility and can be used for injection within the range required for the hemolysis of biomaterials.

[0070] Example 7: In vitro release assay

[0071] (1) Experimental samples

[0072] Curcumin micelles prepared according to the method of Example 5 of the present invention; curcumin raw material.

[0073] (2) Release medium

[0074] Contains 1% (v / v) Tween-80, 30% (v / v) ethanol, DTT (50×10 -3 M) phosphate buffer, pH = 7.2.

[0075] (3) Experimental methods

[0076] Take 3 mL of curcumin micelles (containing 3.5 mg of curcumin) and 3.5 mg of free curcumin API solution and put them into a dialysis bag with a molecular weight cutoff of 2000 Da, immerse them in 47 mL of release medium, and place them in a constant temperature water bath oscillating box (37°C, 100 rpm). Renew the release medium at the specified time interval. Select a specific time point to sample 3.0 mL of the release medium and add an equal amount of fresh release medium. The sample is measured by UV spectrophotometer at λ max =The absorbance of the solution was detected at a wavelength of 435 nm, and the cumulative release of curcumin was calculated.

[0077] like Figure 6 The release curve shows that under a reducing environment, the disulfide bonds in the polymer micelles can be successfully broken and the drug can be released. Compared with the API, the micelle release is relatively slow. This is because the micelle release process mainly includes two stages: first, the DTT in the release medium enters the dialysis bag, the reduction breaks the disulfide bonds, and the curcumin is first released from the micelles, and then diffuses into the release cup through the dialysis bag. It can be concluded that this programmed release mode is regulated by the intracellular environment and presents an obvious slow-controlled release effect.

[0078] Example 8: Cytotoxicity Experiment

[0079] MCF-7 cells in the logarithmic growth phase were cultured in RMPI1640 (10% bovine serum) at 37°C and 5% CO. 2 Culture. Adjust the cell concentration to 5000 cells / well and inoculate into 96-well culture plates. Incubate at 37°C for 24 hours. After the cells adhere to the wall, add a series of concentrations of curcumin solution, FA-PEG 2K -SS-CUR micelle solution and FA-PEG 2K -SS-COOH solution, set up 6 replicate wells for each concentration, and incubate at 37°C, 5% CO 2 The cells were incubated for 24 or 48 h under the conditions of , and the untreated cells were used as the control group. After the incubation was completed, the drug-containing culture medium was discarded, and 100 μL of fresh culture medium and 10 μL of CCK-8 reagent were added to each well. After continuing to culture for 30 min, the absorbance was measured at 450 nm.

[0080] Depend on Figure 7 The cell inhibition rate showed that curcumin polymer micelles had better anti-tumor effect than the raw material drug, and the inhibition effect was time- and dose-dependent; while FA-PEG 2K -SS-COOH carriers consistently showed a lower cell inhibition rate, which fully demonstrated the metabolic safety of polymer micelles.

[0081] Example 9: Targeted uptake investigation

[0082] According to Example 4 of the present invention, FA-PEG labeled with coumarin-6 (C-6) was prepared. 2K -SS-CUR / C-6 micelles and PEG without folic acid modification 2K -SS-CUR / C-6 micelles were used to investigate the targeting effect of micelles.

[0083] The experimental steps are as follows: MCF-7 cells were cultured at 1×10 5 The cells were seeded in a 6-well plate at a density of 10 cells / mL and allowed to adhere. After the cells adhered, FA-PEG was added to the wells. 2K -SS-CUR / C-6 micelle, PEG 2K -SS-CUR / C-6 micelles and free C-6, so that the C-6 concentration in the wells is 2μg / mL; after incubation for 2h or 4h, the medium is removed, and the dead cells and residual drugs are washed away; the cells are fixed with 4% paraformaldehyde for 20min and stained with DAPI for 5min; after washing with PBS, the cells are observed and photographed under a microscope. The excitation wavelengths of DAPI and C-6 are set to 350nm and 450nm, respectively.

[0084] Depend on Figure 8 It can be concluded from the fluorescence intensity that compared with free drugs, polymer micelles can significantly increase the rate of drug entry into cells, especially folic acid-modified targeted polymer micelles, which have higher uptake efficiency.

Claims

1. A dual-targeting curcumin polymer, characterized in that: Molecular formula: FA-PEG 2K -SS-CUR, the structural formula is as follows:

2. According to claim 1, a dual-targeting curcumin polymer, its preparation comprises the following steps: (1) Activate the carboxyl group of folic acid (FA) and react with single-terminal amino polyethylene glycol (PEG 2K ) undergoes an amide reaction to form folic acid-polyethylene glycol (FA-PEG 2K )polymer; (2) Activate the hydroxyl group of the folic acid-modified polyethylene glycol and react it with dithiodipropionic anhydride (DTDPA) to introduce a disulfide bond to generate FA-PEG 2K -SS-COOH polymer; (3) Connecting curcumin (CUR) to FA-PEG 2K -The carboxyl end of the SS-COOH polymer is esterified to produce FA-PEG 2K -SS-CUR polymer.

3. A dual-targeting curcumin polymer according to claim 2, characterized in that: The folic acid carboxyl group is activated and reacts with polyethylene glycol to generate FA-PEG 2K The specific steps of polymer are: Under nitrogen protection, folic acid and triethylamine were dissolved in anhydrous DMF and stirred at room temperature for 15 hours, and then NHS and DCC were added for 4 hours; the supernatant was collected by centrifugation, polyethylene glycol was added and stirred for 24 hours; the reaction solution was transferred to a dialysis bag, dialyzed with distilled water for 24 hours, filtered, the filtrate was collected, and freeze-dried; Preferably, the molar ratio of folic acid to triethylamine, NHS, and DCC is 1:1.5:3:1; the molar ratio of folic acid to polyethylene glycol is (1-2):

1.

4. A dual-targeting curcumin polymer according to claim 2, characterized in that: The polyethylene glycol modified with folic acid is activated and reacted with DTDPA to introduce a disulfide bond to generate FA-PEG 2K The specific steps of -SS-COOH polymerization are: FA-PEG 2K The polymer and dithiodipropionic anhydride were dissolved in anhydrous DMF, TEA and DMAP were added, and the mixture was stirred at 45°C for 36 hours; the reaction solution was transferred to a dialysis bag, dialyzed with distilled water for 24 hours, filtered, the filtrate was collected, and freeze-dried; Preferably, FA-PEG 2K The molar ratio of TEA and DMAP is 1:3:2.5; FA-PEG 2K The molar ratio of DTDPA is 1:(5~8).

5. A dual-targeting curcumin polymer according to claim 2, characterized in that: The curcumin is linked to FA-PEG 2K -The carboxyl end of the SS-COOH polymer is esterified to produce FA-PEG 2K The specific steps of SS-CUR polymer are: FA-PEG 2K -SS-COOH polymer was dissolved in anhydrous DMF, NHS and DCC were added, and the reaction was continued for 48 hours at room temperature after stirring in an ice-water bath; curcumin and DMAP were dissolved in anhydrous DMF and slowly added dropwise, and the reaction was continued for 48 hours; the reaction solution was transferred to a dialysis bag, dialyzed with distilled water for 48 hours, filtered, the filtrate was collected, and freeze-dried; Preferably, FA-PEG 2K The molar ratio of -SS-COOH to NHS and DCC is 1:8:2; the molar ratio of curcumin to DMAP is 1:1; FA-PEG 2K The molar ratio of -SS-COOH to curcumin is 1:(5-10).

6. Curcumin according to claim 5 is connected to FA-PEG 2K -The carboxyl end of the SS-COOH polymer is esterified to produce FA-PEG 2K -SS-CUR polymers are characterized by As described above, FA-PEG 2K -SS-CUR polymer drug loading rate is 8.1% to 10.9%.

7. The specific steps of generating the polymer according to claim 3, claim 4 and claim 5, characterized in that: All reactions were carried out in a dry and dark environment; the reaction raw material PEG 2K The relative molecular weight is 2000; the molecular weight cut-off of the dialysis bag is 2000Da.

8. A dual-targeted curcumin polymer micelle and a preparation method thereof, characterized in that: The step of preparing the dual-targeting curcumin polymer according to claim 1 into a dual-targeting curcumin polymer micelle is specifically: The curcumin polymer was dissolved in DMSO, and distilled water was slowly added dropwise with stirring. The solution was transferred to a 2000Da dialysis bag and dialyzed in distilled water to remove the solvent. The solution was then filtered through a 0.45 μm microporous filter membrane to obtain curcumin polymer micelles.

9. A dual-targeting curcumin polymer micelle according to claim 8, characterized in that: The drug loading rate is 8.1% to 10.9%; the morphology is spherical; and the particle size is 79.14±2.2nm.

10. The dual-targeting curcumin polymer micelle according to claim 8, characterized in that: It can be used as an effective ingredient in the preparation of drugs for anti-tumor related diseases.

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