Preparation method of levodopa-oleic acid nano-micelle as well as product and application of levodopa-oleic acid nano-micelle

Abstract

The invention relates to the technical field of nano-micelles, in particular to a preparation method of levodopa-oleic acid nano-micelles as well as a product and application of the levodopa-oleic acid nano-micelles. The preparation method of the levodopa-oleic acid nano-micelle comprises the following steps: S1, sequentially dissolving monounsaturated oleic acid, EDC and NHS in an organic solvent to obtain a solution a; adding levodopa methyl ester into the solution a for reaction, dialyzing after the reaction is finished, and freeze-drying to obtain monounsaturated oleic acid-levodopa ester; s2, dissolving monounsaturated oleic acid-levodopa ester in a hydroxyl compound to obtain a solution A; and adding the solution A into water, stirring, dialyzing, and concentrating to obtain the levodopa-oleic acid nano-micelle. The obtained levodopa-oleic acid nano-micelle can improve the stability of the levodopa, improve the blood brain barrier penetrability of the levodopa, improve the utilization rate of the levodopa in the brain, reduce the side effect of the levodopa on the body, and more efficiently treat the Parkinson's disease.

Description

Technical Field

[0001] The invention relates to the technical field of nano micelles, and in particular to a preparation method of levodopa-oleic acid nano micelles, and a product and application thereof. Background Art

[0002] Parkinson's disease (PD) is a neurodegenerative disease characterized by motor symptoms such as bradykinesia, tremor, and rigidity, which can directly threaten human life in severe cases. Parkinson's disease is treated by taking levodopa (L-DOPA) orally. After entering the human body, levodopa (L-DOPA) can be converted into dopamine (DA) by brain decarboxylase (DDC) to relieve symptoms. However, levodopa is a small molecule compound with good hydrophilicity. It is unstable and easily oxidized during systemic circulation and difficult to cross the blood-brain barrier, resulting in poor actual clinical efficacy. What's more serious is that the direct use of levodopa (L-DOPA) for Parkinson's treatment can cause serious side effects, such as short-term side effects including dizziness, headache, vomiting and insomnia, and long-term side effects leading to involuntary movements and movement disorders, which seriously reduce the patient's quality of life and patient compliance.

[0003] A Chinese patent with patent application number CN201710043790.5 discloses a levodopa transdermal patch and a preparation method thereof for the control and treatment of Parkinson's disease, but does not provide a corresponding technical solution for reducing the side effects of levodopa on the body.

[0004] Therefore, reducing the side effects of levodopa, improving the stability of levodopa and its ability to cross the blood-brain barrier are the main technical issues that need to be solved at present. Summary of the invention

[0005] In order to solve the above technical problems, the first aspect of the present invention provides a method for preparing levodopa-oleic acid nano-micelles, comprising the following steps:

[0006] S1. dissolving monounsaturated oleic acid, EDC, and NHS in an organic solvent in sequence to obtain a solution a; adding levodopa methyl ester to the solution a for reaction, and after the reaction is completed, dialyzing and freeze-drying to obtain monounsaturated oleic acid-levodopa ester;

[0007] S2. dissolving monounsaturated oleic acid-levodopa ester in a hydroxy compound to obtain solution A; adding solution A into water, stirring, dialyzing, and concentrating to obtain levodopa-oleic acid nanomicelles.

[0008] In order to achieve a more efficient treatment effect for Parkinson's disease, the inventors discovered during the sample preparation process that the present application uses monounsaturated oleic acid (POA) to modify levodopa (L-DOPA) and prepare monounsaturated oleic acid-levodopa nanomicelles (DOPA-POA NPs), which can increase the stability of levodopa. The formed monounsaturated oleic acid-levodopa nanomicelles improve the blood-brain barrier penetration of levodopa, thereby improving the utilization rate of levodopa in the brain. At the same time, the monounsaturated oleic acid (POA) component can also reduce ROS in the brain lesion area, thereby achieving a more efficient treatment of Parkinson's disease.

[0009] The CAS number of the levodopa methyl ester (DOPA-ME) is 7101-51-1, and it can be obtained through commercial purchase.

[0010] The mass spectrum of the levodopa methyl ester (DOPA-ME) molecule is as follows Figure 2 shown.

[0011] The levodopa methyl ester molecule 1 H NMR spectrum Figure 3 shown.

[0012] In one embodiment, the levodopa methyl ester can be obtained by the following preparation method:

[0013] Weigh levodopa (25 mmol) and dissolve it in 60 mL of methanol. Add 10 mL of thionyl chloride dropwise under ice bath conditions, react in ice bath for 1 h, and react at room temperature for 24 h. After the reaction is completed, remove methanol by rotary evaporation, add methanol again to dissolve, and rotary evaporation again to remove potential residual thionyl chloride, and place in a low-temperature oven for drying to obtain light brown levodopa methyl ester.

[0014] In one embodiment, 1.0-4.0 mmol of monounsaturated oleic acid, 2.0-8.0 mmol of EDC and 2.0-8.0 mmol of NHS are dissolved in tetrahydrofuran to obtain solution a.

[0015] In one embodiment, the amount of monounsaturated oleic acid in S1 includes but is not limited to 1 mmol, 1.5 mmol, 2 mmol, 2.5 mmol, 3 mmol, 3.5 mmol, and 4 mmol.

[0016] In one embodiment, the monounsaturated oleic acid in S1 is palmitoleic acid, and the CAS number of the palmitoleic acid is 373-49-9.

[0017] In one embodiment, the amount of EDC in S1 includes but is not limited to 2 mmol, 2.5 mmol, 3 mmol, 3.5 mmol, 4 mmol, 4.5 mmol, 5 mmol, 5.5 mmol, 6 mmol, 6.5 mmol, 7 mmol, 7.5 mmol, and 8 mmol.

[0018] In one embodiment, the amount of NHS in S1 includes but is not limited to 2 mmol, 2.5 mmol, 3 mmol, 3.5 mmol, 4 mmol, 4.5 mmol, 5 mmol, 5.5 mmol, 6 mmol, 6.5 mmol, 7 mmol, 7.5 mmol, and 8 mmol.

[0019] In one embodiment, 1.0 mmol of monounsaturated oleic acid, 2.0 mmol of EDC and 2.0 mmol of NHS are dissolved in tetrahydrofuran to obtain solution a.

[0020] The chemical formula of EDC is C8H 17 N3, CAS number is 1378759-90-0.

[0021] The chemical formula of NHS is C4H5NO3, and the CAS number is 6066-82-6.

[0022] In one embodiment, in S1, 2.0-8.0 mmol of levodopa methyl ester is dissolved in tetrahydrofuran and then added to solution a for reaction.

[0023] In one embodiment, in S1, levodopa methyl ester dissolved in tetrahydrofuran is added to solution a under ice bath conditions for reaction, and the reaction time is 0.5-2h.

[0024] In one embodiment, in S1, levodopa methyl ester dissolved in tetrahydrofuran is added to solution a under ice bath conditions for reaction, and the reaction time is 1 hour.

[0025] In one embodiment, in S1, levodopa methyl ester dissolved in tetrahydrofuran is added to solution a under ice bath conditions for reaction and then reacted at 20-30° C. for 20-30 hours.

[0026] In one embodiment, in S1, levodopa methyl ester dissolved in tetrahydrofuran is added to solution a under ice bath conditions for reaction and then reacted at 25° C. for 24 hours.

[0027] In one embodiment, after the reaction in S1 is completed, tetrahydrofuran is removed by rotary evaporation, and the solution is obtained by dissolving with methanol, and the solution is placed in a dialysis bag for 20-30 hours of dialysis.

[0028] In one embodiment, the molecular weight cut-off of the S1 dialysis bag is 3500 Da.

[0029] After the reaction in S1 is completed, tetrahydrofuran is removed by rotary evaporation, and the solution is dissolved with methanol to obtain a solution, which is placed in a dialysis bag for dialysis, with water being changed every 4 hours for a dialysis time of 24 hours.

[0030] The inventors found during the experiment that by using a dialysis bag with a molecular weight cutoff of 3500Da for 20-30h and changing the water every 4h, unreacted EDC, NHS and excess levodopa methyl ester can be removed, thereby increasing the yield of monounsaturated oleic acid-levodopa ester.

[0031] In one embodiment, in S2, 20-60 mg of monounsaturated oleic acid-levodopa ester is weighed and dissolved in a hydroxy compound to obtain solution A.

[0032] In one embodiment, the amount of monounsaturated oleic acid-levodopa ester in S2 includes but is not limited to 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, and 60 mg.

[0033] In one embodiment, the hydroxy compound is methanol.

[0034] In one embodiment, in S2, 20-60 mg of monounsaturated oleic acid-levodopa ester is weighed and dissolved in 5-15 mL of methanol to obtain solution A.

[0035] In one embodiment, the amount of methanol in S2 includes but is not limited to 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, and 15 mL.

[0036] In one embodiment, in S2, solution A is added to 20-60 mL of water and stirred for 0.5-3 h.

[0037] In one embodiment, in S2, solution A is added dropwise to 20-60 mL of water and stirred for 2 h, then placed in a dialysis bag for 24 h of dialysis, with the water changed every 4 h. After the dialysis, an ultrafiltration tube is used for concentration to obtain 5.0 mg / mL of levodopa-oleic acid nanomicelles (DOPA-POA NPs).

[0038] In order to improve the therapeutic effect of Parkinson's disease and reduce the side effects of levodopa on the body, the inventors found in the experimental process that monounsaturated oleic acid (POA) with good biocompatibility was grafted onto the levodopa molecule through an amidation reaction to synthesize a levodopa-monounsaturated oleic acid amphiphilic levodopa derivative small molecule (DOPA-POA), which improved the hydrophobicity of levodopa and increased the stability of levodopa. The inventors creatively found in the experimental process that the obtained levodopa-oleic acid nano-micelles can increase the performance of levodopa passing through the blood-brain barrier, thereby improving the therapeutic effect of levodopa on Parkinson's disease and reducing its side effects. In addition, the components of monounsaturated oleic acid can further improve the treatment of Parkinson's disease by reducing the level of neuronal oxidative stress.

[0039] The second aspect of the present invention provides a levodopa-oleic acid nano-micelle, which is prepared by the above-mentioned method for preparing the levodopa-oleic acid nano-micelle.

[0040] The third aspect of the present invention provides a levodopa-oleic acid nano-micelle for use in the technical field of treatment of Parkinson's disease.

[0041] Beneficial Effects

[0042] 1. The levodopa-oleic acid nano-micelles provided by the present invention can improve the blood-brain barrier penetration of levodopa, thereby improving the utilization rate of levodopa in the brain.

[0043] 2. The levodopa-oleic acid nanomicelles provided by the present invention can treat Parkinson's disease more effectively.

[0044] 3. The levodopa-oleic acid nano-micelles provided by the present invention can improve the hydrophobicity of levodopa and increase its stability.

[0045] 4. The levodopa-oleic acid nano-micelles provided by the present invention can improve the stability of levodopa, promote its accumulation in the brain, and provide a new method for the treatment of Parkinson's disease.

[0046] 5. The levodopa-oleic acid nano-micelles provided by the present invention reduce the side effects of levodopa on the body, improve the stability of levodopa, and further improve the treatment of Parkinson's disease by reducing the level of neuronal oxidative stress. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 This is a synthetic route for monounsaturated oleic acid-levodopa ester.

[0048] Figure 2 This is the mass spectrum of the levodopa methyl ester molecule.

[0049] Figure 3 For the levodopa methyl ester molecule 1H NMR spectrum.

[0050] Figure 4 This is the mass spectrum of the monounsaturated oleic acid-levodopa ester molecule.

[0051] Figure 5 It is an unsaturated oleic acid-levodopa ester molecule 1 H NMR spectrum.

[0052] Figure 6 This is a transmission electron micrograph of unsaturated oleic acid-levodopa ester.

[0053] Figure 7 This is the critical micelle concentration result of L-dopa-oleic acid nanomicelles.

[0054] Figure 8 This is the test result of the hydrated particle size of L-dopa-oleic acid nanomicelles.

[0055] Fig. 9 These are the stability test results of L-dopa and L-dopa-oleic acid nanomicelles.

[0056] Fig.10 This is the liquid chromatography test result of L-DOPA-oleic acid nanomicelles under the action of DOPA decarboxylase.

[0057] Fig.11 These are the degradation test results of L-DOPA-oleic acid nanomicelles.

[0058] Fig.12 These are the results of the cell uptake test of L-DOPA-oleic acid nanomicelles.

[0059] Fig.13 These are the results of the toxicity test of L-DOPA-oleic acid nanomicelles on cells.

[0060] Fig.14 These are the results of the metabolic distribution test of L-dopa-oleic acid nanomicelles in mice.

[0061] Fig.15 Test results for the treatment of Parkinson's disease with L-dopa-oleic acid nanomicelles1.

[0062] Fig.16 Test results for L-dopa-oleic acid nanomicelles in the treatment of Parkinson's disease2.

[0063] In the figure: DOPA-POA NPs, POA / L-DOPA NPs, POA / L-DOPA represent levodopa-oleic acid nanomicelles; L-DOPA represents levodopa. DETAILED DESCRIPTION

[0064] Example 1

[0065] The first aspect of the present embodiment provides a method for preparing levodopa-oleic acid nanomicelles, comprising the following steps:

[0066] S1. Take 1.0mmol palmitoleic acid, 2.0mmol EDC and 2.0mmol NHS and dissolve them in 20mL tetrahydrofuran to obtain solution a, dissolve 2.0mmol levodopa methyl ester in 10mL tetrahydrofuran, add the solution to solution a for reaction under ice bath condition, the reaction time is 1h, and then react at 25℃ for 24h to obtain a reaction product; remove tetrahydrofuran from the reaction product by rotary evaporation, dissolve it in 20mL methanol to obtain a solution, put the solution into a dialysis bag for dialyzation, change the water every 4h, and the dialysis time is 24h; after the dialysis, place the dialysate in a -20℃ refrigerator for 12h, and then transfer it to a freeze dryer for freeze drying to obtain monounsaturated oleic acid-levodopa ester.

[0067] S2. Weigh 40 mg of monounsaturated oleic acid-levodopa ester and dissolve it in 10 mL of methanol to obtain solution A; use a peristaltic pump to drop solution A into 40 mL of high-purity water at a dropping rate of 4 mL / h, and after stirring for 2 hours, put it into a dialysis bag and dialyze it for 24 hours. Change the water every 4 hours. After the dialysis is completed, use an ultrafiltration tube to concentrate it to obtain levodopa-oleic acid nanomicelles with a concentration of 5.0 mg / mL.

[0068] The molecular weight cut-off of the dialysis bags in S1 and S2 is 3500Da.

[0069] The CAS number of the levodopa methyl ester is 7101-51-1.

[0070] The CAS number of the EDC is 1378759-90-0.

[0071] The CAS number of the NHS is 6066-82-6.

[0072] The synthetic route of the monounsaturated oleic acid-levodopa ester is as follows Figure 1 shown.

[0073] The second aspect of this embodiment provides a levodopa-oleic acid nanomicelle, which is prepared by the above-mentioned preparation method of levodopa-oleic acid nanomicelle.

[0074] In a third aspect, this embodiment provides a levodopa-oleic acid nano-micelle for use in the technical field of treating Parkinson's disease.

[0075] Performance Testing

[0076] The levodopa methyl ester used in Example 1, the monounsaturated oleic acid-levodopa ester obtained in Example 1, and the levodopa-oleic acid nanomicelles obtained in Example 1 were subjected to the following performance tests.

[0077] 1. Mass spectrometry testing of molecules

[0078] Test the mass spectrum of monounsaturated oleic acid-levodopa ester molecule, the test results are as follows Figure 4 shown.

[0079] The mass spectrum of the levodopa methyl ester (DOPA-ME) molecule is as follows Figure 2 shown.

[0080] 2. Molecular 1 H NMR testing

[0081] The levodopa methyl ester molecule 1 H NMR spectrum Figure 3 shown.

[0082] Testing the monounsaturated oleic acid-L-dopa ester molecule 1 H NMR, test results are as follows Figure 5 shown.

[0083] pass Figure 4 and Figure 5 It can be seen that the monounsaturated oleic acid-levodopa ester with high purity can be obtained in the present application.

[0084] 3. Microscopic morphology test

[0085] The microscopic morphology of L-DOPA-oleic acid nanomicelles was tested by transmission electron microscopy (TEM). Figure 6 described.

[0086] pass Figure 6 It can be seen that the size distribution of L-DOPA-oleic acid nanomicelles is 50-200 nm.

[0087] 4. Critical micelle concentration test

[0088] Test method: prepare 2.0μg / mL pyreneacetone solution, take 5μg and put it into a 5mL volumetric flask, dry it in a 50℃ oven, then add different concentrations of levodopa-oleic acid nanomicelles (50, 37.5, 25, 12.5, 10, 6.25, 2.5, 1.25, 1.0, 0.625, 0.25, 0.125, 0.0625μg / mL) into the volumetric flask to make up the volume, ultrasonicate for 10 minutes, measure the fluorescence of the solution, and make a curve with the ratio of fluorescence intensity at 384nm / fluorescence intensity at 373nm and the corresponding levodopa-oleic acid nanomicelle concentration. The test results are as follows: Figure 7 described.

[0089] pass Figure 7It can be seen that the critical micelle concentration of L-dopa-oleic acid nanomicelles is 0.0021 mg / mL.

[0090] 5. Hydration particle size test

[0091] Test method: Take 2mL of L-dopa-oleic acid nanomicelle solution and place it in a 2-way cuvette. Test the hydrated particle size of the solution at 25°C on a particle size analyzer. The test results are as follows: Figure 8 described.

[0092] pass Figure 8 It can be seen that the change rate of the hydrated particle size of the L-dopa-oleic acid nanomicelles over time is small, indicating that the L-dopa-oleic acid nanomicelles have excellent stability.

[0093] 6. Stability test

[0094] (1) 5 mg of levodopa and levodopa-oleic acid nano-micelles were added to 4 mL of pH 7.4 PBS (0.01 M) buffer and left for 24 h. The test results are shown in Fig. 9 .

[0095] (2) 0.1 mg of DOPA decarboxylase was added to 5 mg of L-DOPA-oleic acid nanomicelles, and the liquid chromatography peak area of ​​the L-DOPA-oleic acid nanomicelles when not mixed with DOPA decarboxylase was tested by a liquid chromatography tester, and the liquid chromatography peak area of ​​the L-DOPA-oleic acid nanomicelles when the L-DOPA-oleic acid nanomicelles were mixed with DOPA decarboxylase for 4 h and 12 h; the test results are shown in Fig.10 .

[0096] pass Fig. 9 It can be seen that when L-dopa is placed in PBS buffer, it will oxidize to black, while L-dopa-oleic acid nanomicelles will not oxidize to black when placed in PBS buffer.

[0097] pass Fig.10 It can be seen that under the action of dopa decarboxylase, the liquid chromatography peak area of ​​levodopa-oleic acid nanomicelles hardly changes, indicating that monounsaturated oleic acid can prevent the decarboxylation of levodopa in levodopa-oleic acid nanomicelles.

[0098] 7. Degradation test

[0099] 5 mg of levodopa-oleic acid nano-micelles were added to 4 mL of PBS (0.01 M) buffer at pH 7.4 to test the release of the active ingredients in the levodopa-oleic acid nano-micelles, and the molecular mass spectrometry of the active ingredients in the levodopa-oleic acid nano-micelles after release was tested. The test results are as follows: Fig.11 shown.

[0100] pass Fig.11It can be seen that L-dopa-oleic acid nanomicelles can degrade and release L-dopa methyl ester, L-dopa, dopamine, and monounsaturated oleic acid.

[0101] 8. Cellular Toxicity Test

[0102] Test method:

[0103] (1) 20 μg of FITC-labeled L-dopa-oleic acid nanoparticles (FITC: L-dopa-oleic acid nanoparticles: 1:20) were used to incubate the cells with 5.0 × 10 3) Co-cultured and stained with DAPI, the fluorescence signal changes of nerve cells were observed using a confocal fluorescence microscope. The test results are shown in Fig.12 .

[0104] (2) 20 μg of L-dopa-oleic acid nano-micelles were used to treat nerve cells (5.0*10 3 ) were co-cultured, and the cells were stained with 1 μM calcein-AM propidium iodide staining reagent and co-incubated for 30 minutes. Finally, the cell staining results were observed using a confocal fluorescence microscope. The test results are shown in Fig.13 .

[0105] pass Fig.12 It can be seen that green fluorescence appears in the cells, which proves that L-dopa-oleic acid nanomicelles can be taken up by cells.

[0106] pass Fig.13 It can be seen from the results of cell live and dead staining that the L-DOPA-oleic acid nanomicelle group showed strong green fluorescence (representing living cells) and almost no red fluorescence (representing dead cells), proving that the L-DOPA-oleic acid nanomicelles are very safe and non-toxic to cells.

[0107] 9. Metabolic distribution test in mice

[0108] Test method: 4.0 mg of L-dopa-oleic acid nano-micelles were labeled with 0.5 mg of ICG, and then 100 μL was injected into 8-week-old healthy mice via the tail vein. The small animal in vivo imaging instrument was then used to detect the fluorescence changes in the body and the fluorescence changes in the main tissues (brain, heart, liver, spleen, lung and kidney) of the mice at 12h and 24h after drug injection (excitation wavelength 780nm, emission fluorescence wavelength 800nm). The test results are as follows: Fig.14 shown.

[0109] pass Fig.14As shown, ICG fluorescence signals obviously appeared in the brain, indicating that L-dopa-oleic acid nanomicelles could cross the blood-brain barrier and be enriched in the brain, and fluorescence could still be detected even 24 hours after administration, indicating that L-dopa-oleic acid nanomicelles had a longer brain residence time, unlike L-dopa small molecules that were quickly metabolized and disappeared from the body.

[0110] 10. Test of Levodopa-oleic acid nano-micelles for the treatment of Parkinson's disease

[0111] Mice weighing 20 g were divided into four groups and received different treatments: Group 1 consisted of normal mice; Group 2 consisted of Parkinson's disease mice, which received no treatment; Group 3 consisted of Parkinson's disease mice, which were treated by injection of L-dopa; and Group 4 consisted of Parkinson's disease mice, which were treated by injection of L-dopa-oleic acid nano-micelles.

[0112] Treatment method: The drug was administered by tail vein injection. The three groups of mice were injected with 200 μL of L-dopa (4.0 mg / mL) every 3 days for 1 month. The four groups of mice were injected with 200 μL of L-dopa-oleic acid nano-micelles (4.0 mg / mL) every 3 days for 1 month. After 1 month of treatment, their movement trajectories in the mine experiment were monitored, and at the end of the treatment, the brain tissue of the mice was taken and stained for TH and TNF-α. The test results are as follows: Fig.15 and Fig.16 .

[0113] Three groups of mice were injected with L-dopa, and four groups of mice were injected with L-dopa-oleic acid nano-micelles. Fig.15 It can be seen that after the four groups of mice were injected with L-dopa-oleic acid nano-micelles, the TH in their brain tissues recovered well and TNF-α decreased. This shows that L-dopa-oleic acid nano-micelles can significantly improve the therapeutic efficacy of L-dopa on Parkinson's disease. Fig.16 It can be seen that in the mine experiment, the movement routes and distances of mice in the L-dopa-oleic acid nanomicelle treatment group were significantly improved, further proving that L-dopa-oleic acid nanomicelles have a good effect in improving Parkinson's disease.

Claims

1. A method for preparing levodopa-oleic acid nanomicelles, characterized in that: The following steps are involved: S1. Dissolving monounsaturated oleic acid, EDC, and NHS in an organic solvent in sequence to obtain a solution a; adding levodopa methyl ester to the solution a for reaction, and after the reaction, dialyzing and freeze-drying to obtain monounsaturated oleic acid-levodopa ester; S2. dissolving monounsaturated oleic acid-levodopa ester in a hydroxy compound to obtain solution A; adding solution A into water, stirring, dialyzing, and concentrating to obtain levodopa-oleic acid nanomicelles.

2. The method for preparing levodopa-oleic acid nano-micelles according to claim 1, characterized in that: In the S1, 1.0-4.0 mmol of monounsaturated oleic acid, 2.0-8.0 mmol of EDC and 2.0-8.0 mmol of NHS are dissolved in tetrahydrofuran to obtain solution a.

3. The method for preparing levodopa-oleic acid nanomicelles according to claim 1, characterized in that: In the S1, 2.0-8.0 mmol of levodopa methyl ester is dissolved in tetrahydrofuran, and then added into solution a for reaction.

4. The method for preparing levodopa-oleic acid nanomicelles according to claim 3, characterized in that: In S1, levodopa methyl ester dissolved in tetrahydrofuran is added to solution a under ice bath conditions to react for 0.5-2 hours.

5. The method for preparing levodopa-oleic acid nanomicelles according to claim 4, characterized in that: In S1, levodopa methyl ester dissolved in tetrahydrofuran is added to solution a under ice bath conditions for reaction and then reacted at 20-30° C. for 20-30 hours.

6. The method for preparing the levodopa-oleic acid nanomicelles according to any one of claims 1 to 5, characterized in that: After the reaction in S1 is completed, tetrahydrofuran is removed by rotary evaporation, and the solution is dissolved with methanol to obtain a solution, which is placed in a dialysis bag for 20-30 hours of dialysis.

7. The method for preparing levodopa-oleic acid nanomicelles according to claim 1, characterized in that: In the S2, 20-60 mg of monounsaturated oleic acid-levodopa ester is weighed and dissolved in a hydroxy compound to obtain a solution A.

8. The method for preparing levodopa-oleic acid nanomicelles according to claim 7, characterized in that: In S2, solution A is added to 20-60 mL of water and stirred for 0.5-3 h.

9. A levodopa-oleic acid nanomicelle, characterized in that: The levodopa-oleic acid nanomicelles are prepared according to the preparation method of any one of claims 1 to 8.

10. A use of the levodopa-oleic acid nanomicelles as claimed in claim 9, characterized in that: The levodopa-oleic acid nano micelles are used in the technical field of Parkinson's disease treatment.

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