CN108752507A - A kind of enzyme sensitivity and isotope of redox-sensitive double-response type copolymer and its preparation method and application - Google Patents

Abstract

The invention discloses an enzyme-sensitive and redox-sensitive dual-response copolymer, a preparation method and application thereof. The invention belongs to the field of polymer chemistry and the field of pharmaceutical preparations. The present invention uses the valine-citrulline (Val-citrulline (Val-Cit, VC) fragment that can be specifically hydrolyzed by cathepsin B and the disulfide bond that can be reduced by glutathione to combine polyacrylic acid with vitamin E succinate combined to prepare a dual sensitive copolymer polyacrylic acid‑VC‑SS‑vitamin E succinate (PAA‑VC‑SS‑VES). The copolymer has good biocompatibility and strong sensitivity, can self-assemble in water to form nano micelles, can wrap hydrophobic drugs, is mainly used in the treatment of tumor-related diseases, and has the function of intelligently releasing drugs.

Description

An enzyme-sensitive and redox-sensitive dual responsive copolymer and its preparation method and application

technical field

The present invention relates to the fields of pharmaceutical preparations and polymer chemistry, in particular to a dual sensitive copolymer with enzyme sensitivity and redox sensitivity: polyacrylic acid-VC-SS-vitamin E succinate (PAA-VC-SS-VES ) and its preparation method and application.

Background technique

Cancer is the number one disease threatening human life today. The purpose of tumor treatment is to kill cancer cells. Since tumor cells are highly similar to normal cells and have higher vitality, existing non-surgical therapies need to continue to improve the specificity of tumor cells, which requires anticancer drugs It has higher targeting, which is also the challenge that the pharmaceutical industry and scientists have been facing. Targeted therapy for tumors is to selectively concentrate drugs on tumor tissues, thereby improving the efficacy of drugs while reducing side effects on normal tissues. The nano-drug delivery system can specifically or selectively deliver effective anticancer drugs to tumor tissues, and control the dose of drugs in specific physiological parts, thereby reducing the side effects and toxicity of anticancer drugs to non-target parts. At present, the nano-drug delivery system has changed from synthesizing different types of polymers to an intelligent responsive drug delivery system in the tumor microenvironment, using the unique physiological and pathological environment of the tumor to achieve the purpose of targeted drug delivery, which requires the drug delivery system It has good response performance, but often a single intelligent response cannot achieve the desired rapid response release result.

Glutathione (glutathione, GSH) is a tripeptide that naturally exists in the human body. The content of glutathione in tumor tissues and cells is high, but the content of glutathione in normal cells of cancer patients is lower than that of healthy people. High GSH content in tumor cells often leads to drug resistance to chemotherapy. Some researchers have tried to use GSH-depleting drugs such as buthionine sulfate (BSO) to reduce the GSH content in cancer cells. However, the effect of using BSO is limited and not targeted, and the drug will also reduce the content of GSH in normal cells, which further worsens the side effects caused by radiotherapy and chemotherapy. The high concentration of glutathione in the tumor site can reduce the disulfide bond, while the concentration of glutathione in normal tissues and blood vessels is low, the disulfide bond can exist stably, and the high concentration of glutathione itself can also restore the disulfide bond after reducing the disulfide bond. will be oxidized and thus consumed.

Cathepsin B (Cathepsin B, C _B ), from the lysosomal cysteine protease family, is a 30KDa lysosomal cysteine protease. In many cancers, C _B is an important A component of the stroma that helps tumor cells actively invade and metastasize. C _B is not found outside normal cells, but in tumor cells and inflammatory tissues, C _B exists in large quantities. Generally, the fragments of C _B that can be specifically hydrolyzed include phenylalanine-arginine and valine-citrulline acid.

Vitamin E succinate (Vitamin E succinate, VES, C ₃₃ H ₅₄ O ₅ ), a member of vitamin E family, is widely used in health food. It not only has the production and preservation performance of good stability, not easy to absorb moisture, and is not easy to infect bacteria, but also has the function of inhibiting the growth of various tumor cells. Due to its strong hydrophobicity and no effect on the growth of normal cells, it can be used as an excellent hydrophobic material.

Polyacrylic acid has good biocompatibility, non-toxic and harmless, and can be modified. Polyacrylic acid copolymer selectively enters tumor cells through high permeability of solid tumor tissue, lymphatic reflux disorder and endocytosis, reducing drug side effects. Prolong the residence time of the drug at the tumor site.

Therefore, it is necessary to develop a linker that is sensitive to the pH conditions of tumor tissue, enzyme systems, etc. to connect hydrophilic materials and hydrophobic materials to form amphiphilic polymers that can release drugs from conjugates at tumor sites in a timely manner. Pharmaceutical preparations have practical significance.

Contents of the invention

The purpose of the present invention is to provide an enzyme-sensitive and redox-sensitive dual responsive copolymer, which can be specifically hydrolyzed by cathepsin B and reduced by glutathione at the same time, has good responsiveness, and belongs to a polymer compound.

The technical solution adopted in the present invention is: an enzyme sensitive and redox sensitive dual responsive copolymer, the enzyme sensitive and redox sensitive dual responsive copolymer is polyacrylic acid-VC-SS-vitamin E succinate copolymer Material PAA-VC-SS-VES has the structural formula shown in (I):

In the aforementioned enzyme-sensitive and redox-sensitive dual responsive copolymer, the weight-average molecular weight of the polyacrylic acid chain segment is 2kDa.

A method for preparing an enzyme-sensitive and redox-sensitive dual responsive copolymer, comprising the steps of:

1) Vitamin E succinate (VES) and cystamine dihydrochloride are prepared into vitamin E succinate derivatives; specifically:

Dissolve VES in dichloromethane, stir until completely dissolved, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzo Triazole (HOBT), stirred at room temperature overnight in the dark, added cystamine dihydrochloride to the reaction solution, and added methanol to aid dissolution, adjusted the pH to 7-8 with triethylamine, stirred for 24h, and the obtained product was washed with NaHCO ₃ aqueous solution Washing, adding anhydrous magnesium sulfate to the organic layer, drying, filtering, rotary evaporation under reduced pressure to remove the organic solvent, and vacuum drying to obtain a vitamin E succinate derivative.

2) Prepare Fmoc-Val-Cit by reacting Fmoc-valine (Fmoc-Val) with citrulline (Cit); specifically:

2.1) Dissolve Fmoc-Val and N-hydroxysuccinimide (HOSU) in tetrahydrofuran (THF) for reaction, add dicyclohexylcarbodiimide (DCC), stir at room temperature for 16 hours, filter, wash with THF, and reduce The solvent is removed by distillation to obtain a glassy compound, the intermediate Fmoc-Val-OSU;

2.2) Cit and NaHCO ₃ were dissolved in distilled water, stirred to dissolve, and another intermediate Fmoc-Val-OSU was dissolved in ethylene glycol dimethyl ether (DME), and the mixed solution of Cit and NaHCO ₃ was gradually dissolved in an ice bath. Add dropwise to the DME solution of Fmoc-Val-OSU, add THF at the same time to aid dissolution, and stir overnight; add saturated potassium carbonate to the mixed solution after the reaction, adjust the pH to 8-9, extract with ethyl acetate, and take the water layer , add citric acid solution to the water layer to wash, filter, dissolve the solid in THF, add methanol to help dissolve, remove two-thirds of the solution by rotary evaporation under reduced pressure, add methyl tert-butyl ether, stir overnight, and precipitate out The white solid is the intermediate Fmoc-Val-Cit.

3) Reaction of Fmoc-Val-Cit with vitamin E succinate derivatives to prepare intermediate Fmoc-VC-SS-VES; specifically:

Dissolve Fmoc-Val-Cit in the mixture of dichloromethane and methanol, stir to dissolve, add EDC and HOBT under ice bath, activate for 6 hours, add the dichloromethane solution of vitamin E succinate derivatives, react for 24 hours, Add the mixed solution dropwise to a large amount of ice water, stir for 2 hours, and filter to obtain the intermediate Fmoc-VC-SS-VES.

4) Remove the Fmoc protecting group from the intermediate Fmoc-VC-SS-VES, and react with activated PAA to generate the target product polyacrylic acid-VC-SS-vitamin E succinate copolymer PAA-VC-SS-VES; for:

Dissolve polyacrylic acid PAA in DMF, add EDC and HOBT under ice-cooling, and activate for 4 hours to obtain a DMF solution of activated polyacrylic acid PAA. Dissolve the intermediate Fmoc-VC-SS-VES in THF, add 1,8-diazabicycloundec-7-ene (DBU), stir for 10 minutes to remove the Fmoc protecting group, and then the resulting mixture Add it into the DMF solution of activated polyacrylic acid PAA, stir overnight, spin evaporate the reaction mixture to remove the organic solvent, dialyze for two days, and freeze-dry to obtain the product PAA-VC-SS-VES.

A drug-loaded nano-micelle, the drug and the above-mentioned PAA-VC-SS-VES copolymer are co-dissolved in dichloromethane, the organic solvent is removed by rotary evaporation at 40°C, and distilled water is added, and stirred at 40°C for 20 minutes, that is Drug-loaded nanomicelles were obtained.

The above-mentioned drug-loaded nano-micelle, the drug is selected from camptothecin, paclitaxel, doxorubicin, gambogic acid, curcumin, afatinib, gefitinib, imatinib, soft red Mycin, Nimodipine, Cyclosporine A, or Vincamide. Preferably, the drug is paclitaxel.

The present invention has following beneficial effect:

The dual-response copolymer of the present invention has the characteristics of being specifically hydrolyzed by cathepsin B and reduced by glutathione, which improves the environmental sensitivity of the nano-drug loading system. In vitro release experiments show that compared with only glutathione When the peptide is sensitive, it can release more drugs in a short time under sensitive conditions. Both the PAA at the hydrophilic end and the VES at the hydrophobic end of the polymer are biodegradable, non-toxic and harmless, and have good biocompatibility. The copolymer can spontaneously form nano drug-loaded micelles with hydrophobic drugs in water, and has the function of targeted intelligent release of drugs. Drug release facilitates drug penetration. The present invention designs and develops the PAA-VC-SS-VES copolymer drug delivery system by adopting the dual-response targeted drug delivery technology, and the high-concentration glutathione and cathepsin B in the tumor site as targets, increasing the drug targeting Therapeutic effect, reduce toxic and side effects, thereby improving bioavailability.

Description of drawings

Fig. 1 is the infrared absorption spectrogram of intermediate A, B, C and PAA-VC-SS-VES copolymer.

Figure 2a is the appearance of the prepared PAA-VC-SS-VES copolymer nanomicelle.

Figure 2b shows the Tyndall effect of the prepared PAA-VC-SS-VES copolymer nanomicelle.

Figure 2c is a particle size distribution diagram of the prepared PAA-VC-SS-VES copolymer nanomicelles.

Figure 2d is the zeta potential diagram of the prepared PAA-VC-SS-VES copolymer nanomicelles.

Fig. 3 is a transmission electron microscope image of the prepared PAA-VC-SS-VES copolymer drug-loaded nanomicelle.

Fig. 4 is a graph showing changes in drug release from drug-loaded nanomicelles under different concentrations of glutathione.

Detailed ways

The technical solutions of the present invention will be further described below through specific embodiments. It should be clear to those skilled in the art that the embodiments are only for helping to understand the present invention, and should not be regarded as specific limitations on the present invention.

Example 1 Polyacrylic acid-VC-SS-vitamin E succinate copolymer PAA-VC-SS-VES

(1) The preparation method is as follows:

1. The synthesis of vitamin E succinate derivative VES-SS-NH ₂ (intermediate A), the specific steps are as follows:

Dissolve vitamin E succinate (VES) (5.30g, 10mmol) in 100mL of dichloromethane, stir in a 250mL round-bottomed flask until completely dissolved, add EDC (13mmol) and HOBT (13mmol) in an ice bath, and store in room temperature. Stir overnight, add cystamine dihydrochloride (6.75g, 30mmol) to the reaction solution, add 30mL of methanol to aid dissolution, add triethylamine to adjust the pH to 7-8, stir for 24h, the obtained product is treated with 1mol/L Wash with NaHCO ₃ aqueous solution, dry the organic layer by adding anhydrous magnesium sulfate, filter, remove dichloromethane by rotary evaporation under reduced pressure at 40°C, and dry in vacuo to obtain 4.72g vitamin E succinate derivative VES-SS-NH ₂ , the intermediate A, Yield 71.1%. MS (ESI) m/z (%): 665.4 [M+H] ⁺ ; IR (KBr, cm-1): 3435, 2922, 2862, 2369, 1647, 1749, 1145, 920. ¹ H NMR(400MHz,CHCl3):δ7.57(s,H),3.3-3.5(m,2H),2.9-3.2(m,2H),2.5(dt,1H),2.4-2.5(m,3H ), 2.1-2.3 (m, 9H), 1.5-1.7 (m, 4H), 1.0-1.4 (m, 17H), 0.5-0.9 (m, 12H).

2. The synthesis of Fmoc-Val-Cit (intermediate B), the specific steps are as follows:

2.1) Fmoc-Val (3.39g, 10mmol) and HOSU (1.15g, 10mmol) were co-dissolved in 50mLTHF, placed in a 100mL round bottom flask for reaction, DCC (3.08g, 10mmol) was added, stirred at room temperature for 16h and then filtered. After washing with THF three times, the solvent was distilled off under reduced pressure to obtain a glassy compound, Fmoc-Val-OSU (10 mmol). MS (ESI) m/z (%): 437.1 [M+H] ⁺ , the compound was directly put into the next reaction without purification.

2.2) Glutamic acid (Cit) (1.84g, 10.5mmol) and NaHCO ₃ (0.89g, 10mmol) were dissolved in 30mL of distilled water and stirred to dissolve. Another intermediate Fmoc-Val-OSU (10mmol) was dissolved in 30mL DME. The mixed solution of Cit and NaHCO ₃ was added dropwise to the DME solution of Fmoc-Val-OSU under ice-cooling, while 10 mL THF was added to aid dissolution, and stirred overnight. Add saturated potassium carbonate to the mixed solution after the reaction, adjust the pH to 8-9, extract three times with 20mL ethyl acetate, take the water layer, add 20mL0.1mol/L citric acid solution to the water layer to wash three times, and make it precipitate White gel-like compound, filtered. Dissolve the white gel-like compound in 50 mL of THF, add 15 mL of methanol to aid dissolution, remove two-thirds of the solution by rotary evaporation under reduced pressure, add 150 mL of methyl tert-butyl ether, stir overnight, a white solid precipitates out, and vacuum-dry to obtain 2.81g of Fmoc-Val-Cit, namely intermediate B, yield 54%. MS (ESI) m/z (%): 495.4 [MH]—; IR (KBr, cm ^-1 ): 3467, 3370, 3299, 3077, 2971, 2934, 2871, 2377, 1640, 1551, 1447, 1399, 1345, 1295, 1239, 1115, 1029, 934, 761, 670, 546. ¹ H NMR (400MHz, DMSO-d6): δ0.86(d,3H),0.89(d,J=3H),1.36–1.73(m,4H),1.94–2.00(m,1H),2.92–2.97 (m,2H),3.92(t,1H),4.12–4.31(m,4H),5.36(br s,2H),5.92(t,1H),7.31–7.52(m,5H),7.75(t, J=7.2Hz, 2H), 7.90(d, 2H), 8.16(d, 1H), 12.50(br, 1H).

3. The synthesis of Fmoc-VC-SS-VES (intermediate C), the specific steps are as follows:

Dissolve Fmoc-Val-Cit (2.48g, 5mmol) in a mixed solution of 30mL dichloromethane and 15mL methanol, stir to fully dissolve, add EDC (13mmol) and HOBT (13mmol) under ice cooling, and activate for 6h. Intermediate A (3.32g, 5mmol) was dissolved in 20mL of dichloromethane solution, added to the above mixed solution, stirred overnight, after 24 hours of reaction, the mixed solution was added dropwise into a large amount of ice water, stirred for 2 hours, filtered to obtain 3.14g The white solid Fmoc-VC-SS-VES is intermediate C, and the yield is 55%. MS (ESI) m/z (%): 1165.5 [M+Na] ⁺ ; IR (KBr, cm ^-1 ): 3442, 3292, 3061, 2956, 2920, 2862, 2377, 1734, 1647, 1539, 1444, 1382, 1292, 1242, 1155, 1101, 1029, 732, 667. ¹ H NMR (400MHz, CHCl ₃ ):0.5-0.9(m,12H),1.5-1.7(m,4H),2.1-2.3(m,9H),2.5-2.8(m,10H),3.7(s, 5H), 4.0-4.5(m, 6H), 6.0-6.1(s, 1H), 6.4-6.5(dd, 2H), 7.31–7.52(m, 5H), 7.75(t, J=7.2Hz, 2H) , 7.90 (d, 2H).

4. The synthesis of PAA-VC-SS-VES, the specific steps are as follows:

Polyacrylic acid (PAA) (1 g, 0.5 mmol) was dissolved in 50 mL DMF, EDC (13 mmol) and HOBT (13 mmol) were added under ice cooling, and activated for 4 h to obtain a DMF solution of activated polyacrylic acid PAA. Dissolve the intermediate C (0.314g, 0.5mmol) obtained in step 3 in 20mL THF, add 148μL of DBU (1mmol), stir for 10 minutes to remove the Fmoc protecting group, and add the resulting mixture to the DMF solution of activated polyacrylic acid PAA , stirred overnight, and the reaction mixed solution was rotary evaporated to remove the organic solvent, dialyzed for two days (the average molecular weight of the dialysis bag was 2KDa, and the dialysis medium was distilled water), and the small molecule compounds were removed, and then freeze-dried to obtain the product PAA-VC-SS- VES. IR (KBr, cm ⁻¹ ): 3429, 2941, 2538, 1718, 1554, 1450, 1406, 1269, 1101, 920, 812.

(2) The infrared absorption spectrum of intermediate A, B, C and PAA-VC-SS-VES copolymer is as shown in Figure 1, as seen from Figure 1, compared with Fmoc-VC-SS-VES, the product infrared result It shows a broad single peak at 3429cm ^-1 , which is the second strongest peak in the characteristic area, indicating that it is the carboxyl absorption peak of PAA. Compared with Fmoc-VC-SS-VES, there is a chemical shift at δ12-13 in ¹ H NMR (400MHz, CHCl ₃ ), and micellar experiment also proves that the product is successfully synthesized.

Embodiment 2 PAA-VC-SS-VES micelles and drug-loaded nano micelles

(1) Determination of appearance, particle size and potential of PAA-VC-SS-VES micelles

Dissolve 10 mg of PAA-VC-SS-VES copolymer in 10 mL of distilled water and stir at room temperature for ten minutes. The appearance of the preparation is clear and transparent, as shown in Figure 2a, indicating that the copolymer has excellent solubility. Irradiating the preparation with a beam of light revealed bright pathways, indicating that the PAA-VC-SS-VES copolymer could spontaneously form nanomicelles in water (as shown in Figure 2b). Using a Malvern laser particle size scanner, the particle size of the nanomicelle was measured to be 147.7nm (as shown in Figure 2c), and the potential was -23.2mV (as shown in Figure 2d), indicating that the particle size of the nanomicelle was relatively small , can be enriched in tumor sites, with good stability and dispersion.

(2) Preparation of PAA-VC-SS-VES drug-loaded nanomicelles

The drug-loaded micelles were prepared by thin-film hydration method, 5 mg of paclitaxel and 10 mg of PAA-VC-SS-VES copolymer were dissolved in dichloromethane, the organic solvent was removed by rotary evaporation at 40 °C, and 10 mL of distilled water was added, stirred at 40 °C for 20 Minutes to obtain PAA-VC-SS-VES drug-loaded nanomicelles, pass through a 0.45um microporous membrane, and wait for the next step.

(3) Transmission electron microscope observation of PAA-VC-SS-VES drug-loaded nanomicelles

The morphology of PAA-VC-SS-VES drug-loaded nanomicelles was observed by transmission electron microscopy. Dilute the prepared drug-loaded nano-micelle solution 5 times, draw 10 μL and drop it on a 200-mesh copper grid, let it dry naturally, and then stain it with 0.2% phosphotungstic acid. After drying, use a transmission electron microscope to observe the nanoparticles As shown in Figure 3, the drug-loaded nano-micelles are in a uniform spherical shape with a particle size of less than 200nm.

(4) In vitro sensitive release assay of PAA-VC-SS-VES drug-loaded nanomicelles

Take 1mL PAA-VC-SS-VES drug-loaded nanomicelles and transfer them into dialysis bags (MWCO, 2kDa), which are recorded as three groups A, B and C, and group A is the control group. Both groups B and C added 10mL PBS (pH7.4), 0.1% (w/v) SDS and GSH10mM as the release medium, group C added 10u cathepsin B to the release medium, and group A did not contain GSH and tissue The dialysate group of protease B was used as the control, the release time was 48 hours, and the temperature was 37°C. At different time intervals, 1 mL of dialysate was taken for HPLC analysis, and 1 mL of corresponding fresh buffer was added to restore the volume. The released drug concentration was detected by high performance liquid chromatography, and the results are shown in Figure 4. It can be seen from Figure 4 that under the condition of no GSH and cathepsin B, the copolymer hardly breaks, and the release amount is small, indicating that it can maintain a certain stability in the normal body, but at the concentration of 10mM glutathione, the release is rapid . Compared with the condition of only glutathione in the dialysate, group C can achieve about 40% of the release amount in 10 hours under the condition of containing cathepsin B and glutathione at the same time, which is about 15% higher than that of group B, indicating that It has better response performance than single-response nanomicelle.

Claims (10)

1. An enzyme-sensitive and redox-sensitive dual-response copolymer is characterized in that the enzyme-sensitive and redox-sensitive dual-response copolymer is polyacrylic acid-VC-SS-vitamin E succinate copolymer PAA -VC-SS-VES has a structural formula as shown in (I): 2. An enzyme sensitive and redox sensitive dual responsive copolymer according to claim 1, characterized in that the polyacrylic acid segment weight average molecular weight is 2kDa. 3. The preparation method of a kind of enzyme-sensitive and redox-sensitive dual responsive copolymer described in claim 1 or 2, is characterized in that, comprises the steps: 1) Vitamin E succinate (VES) and cystamine dihydrochloride are prepared into vitamin E succinate derivatives; 2) Prepare Fmoc-Val-Cit by reacting Fmoc-valine (Fmoc-Val) with citrulline (Cit); 3) reacting Fmoc-Val-Cit with a vitamin E succinate derivative to prepare the intermediate Fmoc-VC-SS-VES; 4) Remove the Fmoc protecting group from the intermediate Fmoc-VC-SS-VES, react with activated polyacrylic acid PAA, and generate the target product polyacrylic acid-VC-SS-vitamin E succinate copolymer (PAA-VC-SS- VES). 4. preparation method according to claim 3 is characterized in that, step 1) vitamin E succinate (VES) and cystamine dihydrochloride are prepared into vitamin E succinate derivatives, and concrete steps are as follows: Dissolve vitamin E succinate (VES) in dichloromethane, stir until completely dissolved, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1 -Hydroxybenzotriazole, stirred at room temperature overnight in the dark, added cystamine dihydrochloride to the reaction solution, and added methanol to aid dissolution, adjusted the pH to 7-8 with triethylamine, stirred for 24h, and the obtained product was washed with NaHCO ₃ The aqueous solution was washed, the organic layer was dried by adding anhydrous magnesium sulfate, filtered, the organic solvent was removed by rotary evaporation under reduced pressure, and the vitamin E succinate derivative was obtained by vacuum drying. 5. preparation method according to claim 3, is characterized in that, step 2) Fmoc-valine (Fmoc-Val) is prepared into Fmoc-Val-Cit with citrulline (Cit) reaction, concrete steps are as follows: 1) Dissolve Fmoc-Val (Fmoc-Val) and N-hydroxysuccinimide in tetrahydrofuran for reaction, add dicyclohexylcarbodiimide, stir at room temperature for 16 hours, filter, wash with tetrahydrofuran, and distill under reduced pressure Remove the solvent to obtain the intermediate Fmoc-Val-OSU; 2) Dissolve citrulline (Cit) and NaHCO ₃ in distilled water, stir to dissolve; take another intermediate Fmoc-Val-OSU and dissolve it in ethylene glycol dimethyl ether, and dissolve citrulline (Cit) in an ice bath The mixed solution of NaHCO ₃ was added dropwise to the ethylene glycol dimethyl ether solution of Fmoc-Val-OSU, and tetrahydrofuran was added to aid dissolution, and stirred overnight; saturated potassium carbonate was added to the reacted mixed solution to adjust the pH to 8 After -9, extract with ethyl acetate, take the water layer, add citric acid solution to the water layer to wash, filter, dissolve the solid in tetrahydrofuran, add methanol to help dissolve, remove two-thirds of the solution by rotary evaporation under reduced pressure, add Methyl tert-butyl ether was stirred overnight, and a white solid was precipitated, which was the intermediate Fmoc-Val-Cit. 6. The preparation method according to claim 3, wherein step 3) reacts Fmoc-Val-Cit with vitamin E succinate derivatives to prepare intermediate Fmoc-VC-SS-VES, and the specific steps are as follows: Dissolve Fmoc-Val-Cit in the mixture of dichloromethane and methanol, stir to dissolve, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1- Hydroxybenzotriazole, after activation for 6 hours, add a dichloromethane solution of vitamin E succinate derivatives, react for 24 hours, add the mixed solution dropwise to a large amount of ice water, stir for 2 hours, and filter to obtain the intermediate Fmoc-VC-SS -VES. 7. preparation method according to claim 3, is characterized in that, step 4), intermediate Fmoc-VC-SS-VES is taken off Fmoc protecting group, reacts with the polyacrylic acid (PAA) of activation, generates target product polyacrylic acid (PAA). Acrylic acid-VC-SS-vitamin E succinate copolymer (PAA-VC-SS-VES), the specific steps are as follows: Polyacrylic acid (PAA) is dissolved in ethylene glycol dimethyl ether, and 1-( 3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, activated for 4h, to obtain the ethylene glycol dimethyl ether solution of activated polyacrylic acid (PAA); The intermediate Fmoc-VC-SS-VES was dissolved in tetrahydrofuran, 1,8-diazabicycloundec-7-ene was added, stirred for 10 minutes to remove the Fmoc protecting group, and then the resulting mixture was added to the activated In the ethylene glycol dimethyl ether solution of polyacrylic acid (PAA), stir overnight, and the reaction mixed solution is rotary evaporated to remove the organic solvent, dialyzed for two days, and freeze-dried to obtain the product PAA-VC-SS-VES. 8. A drug-loaded nano-micelle, characterized in that the drug and the PAA-VC-SS-VES copolymer described in claim 1 are co-dissolved in dichloromethane, and the organic solvent is removed by rotary evaporation under reduced pressure at 40°C. Add distilled water and stir at 40°C for 20 minutes to obtain drug-loaded nanomicelles. 9. a kind of drug-loaded nano-micelle according to claim 8, is characterized in that, described medicine is selected from camptothecin, paclitaxel, doxorubicin, gambogic acid, curcumin, afatinib, gemini Fitinib, imatinib, daunorubicin, nimodipine, cyclosporine A, or vinblastamide. 10. The drug-loaded nanomicelle according to claim 9, wherein the drug is paclitaxel.