CN115192523B

CN115192523B - Tripterine prodrug self-assembled nanoparticle taking phenylboronate as connecting unit, and preparation method and application thereof

Info

Publication number: CN115192523B
Application number: CN202110390725.6A
Authority: CN
Inventors: 苏江涛
Original assignee: Hubei University of Technology
Current assignee: Hubei University of Technology
Priority date: 2021-04-12
Filing date: 2021-04-12
Publication date: 2023-05-05
Anticipated expiration: 2041-04-12
Also published as: CN115192523A

Abstract

The invention relates to a self-assembled nano particle of a tripterine prodrug taking phenylboronate as a connecting unit, a preparation method and application thereof, wherein polyethylene glycol modified phenylboronate is taken as a connecting unit to generate an amphipathic tripterine polymer prodrug with tripterine and glutathione. The self-assembled nano-particles of the tripterine prodrug disclosed by the invention are good in water solubility, sensitive to pH value, capable of self-assembling to generate nano-micelles, and capable of re-decomposing under an acidic condition to release tripterine. After local administration of imiquimod-induced psoriasis-like skin areas in mice, the in vivo skin retention was high and the relief of inflammatory symptoms was evident.

Description

Tripterine prodrug self-assembled nanoparticle taking phenylboronate as connecting unit, and preparation method and application thereof

Technical Field

The invention belongs to the fields of biological medicine technology, nano medicine and new materials, and in particular relates to an amphipathic tripterine polymer prodrug which is formed by using polyethylene glycol modified phenylboronate as a connecting unit and tripterine and glutathione.

Background

Tripterine is a natural triterpene compound, is one of the monomers obtained by separating and purifying the traditional Chinese medicine tripterine, has multiple pharmacological activities, can inhibit immune response and inflammation, has good anti-tumor activity in recent years, can cause cycle retardation, apoptosis and invasion inhibition of tumor cells, and has definite killing effect on leukemia, multiple myeloma, liver cancer, gastric cancer, prostate cancer, kidney cancer, melanoma, non-small cell lung cancer, glioma and breast cancer; however, the low water solubility of tripterine leads to low bioavailability of the medicine, which causes the limitation of application.

A method for increasing the water solubility of tripterine is to modify chemical structure. For example: by introducing a nitrogen-containing hydrophilic group into the carboxylic acid at the C-28 position and salifying the tripterine derivative, the water solubility and the pharmaceutical property are remarkably improved (patent grant publication No. CN 103524592A); the water-soluble nano particles are obtained by covalent connection with biodegradable water-soluble polymers taking polyamino acid and polyethylene glycol as structural units, and have good water solubility and stability (patent application publication No. CN 110652596B). When a targeting group such as folic acid is introduced into the modified chemical structure, the targeted delivery of the tripterine can be realized. Another approach to increasing the water solubility of tripterine is to design a formulation delivery system. Transdermal administration of the nanoparticle can improve hydration degree of horny layer, and promote drug permeation; can improve the bioavailability of the indissoluble medicine and greatly reduce the toxicity of the medicine caused by oral administration. For example: preparing a lipid carrier with a tripterine nanostructure (patent grant publication number CN 102225205B); a tripterine nanosuspension (patent grant publication No. CN 106309364B) was prepared.

Tripterine is considered an effective means for treating immune-mediated inflammatory diseases, particularly psoriasis. Psoriasis is a common chronic inflammatory disease of the skin. It is easy to recur, can not radically cure, seriously endangers physical and mental health of patients, and is listed as one of ten stubborn diseases in the world by WHO. The global incidence rate of psoriasis is about 1-3%, and the psoriasis patients in China reach 1000 ten thousand people. Psoriasis is thought to be caused by involvement of the skin by an auto-inflammatory reaction caused by abnormal interaction of epidermal keratinocytes (hereinafter, abbreviated as "epidermal cells") with immune cells. The research result of the basic medical college of Shanghai traffic university/Shanghai market immunology institute Wang Honglin team in Immunity is published in 2020, and a new strategy for directly targeting epidermal cells or treating psoriasis is reported. (Excessive Polyamine Generation in Keratinocytes Promotes Self-RNA Sensing by Dendritic Cells in Psoriasis. Immunity 2020,53 (1), 204-216.) nanocarriers are of increasing interest for topical therapeutic administration of skin diseases (psoriasis). How to realize the targeted delivery of the medicine to the skin tissue of psoriasis after local administration, thereby concentrating the medicine on the affected part to exert the medicine effect is the current problem to be solved in the treatment of psoriasis by local administration.

Disclosure of Invention

The invention aims at providing a tripterine prodrug self-assembled nanoparticle taking phenylboronate as a connecting unit and a preparation method and application thereof.

The invention solves the technical problems by adopting the following scheme:

a self-assembled nano particle of tripterine prodrug with phenylboronate as a connecting unit has a structure shown in the following formula (I):

in formula (I): n=10 to 120, preferably 40 to 60.

Preferably, the tripterine prodrug nano-particles can self-assemble into nano-micelles in water, and the hydration particle size of the obtained nano-micelles is 277.3+/-35.34 nm; the Zeta potential is-15.04.+ -. 1.83mV.

The invention also provides a method for synthesizing the tripterine prodrug self-assembled nanoparticles by taking phenylboronate as a connecting unit, which comprises the following steps:

step 1: obtaining mPEG-APBA shown in a compound 1;

step 2: in a solvent, reacting tripterine with glutathione to synthesize CE-GSH with a structure shown as a compound 2;

step 3: and (3) reacting the solution containing the CE-GSH obtained in the previous step with mPEG-APBA to synthesize the mPEG-APBA-CE with the structure shown as the compound 3.

The synthetic route is as follows:

preferably, in step 1, the mPEG-APBA is obtained by reacting an epoxide containing methoxypolyethylene glycol with m-aminophenylborate in a solvent.

Preferably, in the step 2, the molar ratio of the glutathione to the tripterine is 1:1-8:1, and the reaction temperature is 20-40 ℃.

Preferably, in step 3, the molar ratio of CE-GSH to mPEG-APBA is from 0.5:1 to 1:3.

Preferably, the solvent used in the step 2 is a mixed solution of buffer salt solution and dimethyl sulfoxide, and the pH value of the buffer salt solution is 7.5-10.0.

Preferably, the CE-GSH solution obtained in the step 2 can be directly used in the step 3 without purification, and the reaction condition with mPEG-APBA is that the ultrasonic treatment is carried out for 2-5 minutes at room temperature.

Another object of the present invention is to provide the use of the above-mentioned nanoparticle for the preparation of a medicament for the treatment of psoriasis, which can release tripterine in vivo, in particular to improve the skin retention of tripterine, for the treatment of psoriasis.

The tripterine prodrug self-assembled nanoparticle has good water solubility, is sensitive to pH value, has high in-vivo skin retention after local administration in a skin region of a mouse psoriasis-like skin induced by imiquimod, and can obviously relieve inflammatory symptoms.

Drawings

FIG. 1 shows the self-assembled nanoparticles of the prodrug of tripterine obtained in example 1 and tripterine in DMSO and D ₂ In O solvent ¹ H NMR spectroscopy;

FIG. 2 is a graph showing the particle size stability of the self-assembled nanoparticles of the tripterine prodrug obtained in example 1;

FIG. 3 is a graph showing the potential stability of the self-assembled nanoparticles of the tripterine prodrug obtained in example 1;

FIG. 4 is a graph showing the stability of the self-assembled nanoparticles of the tripterine prodrug obtained in example 1 in solutions with different pH values, wherein ABCDEF represents pure water, 0.9% NaCl solution, pH 1.2 solution, pH 6.8 solution, and pH 7.4 solution, respectively;

FIG. 5 is a Transmission Electron Microscope (TEM) image of the self-assembled nanoparticles of the tripterine prodrug obtained in example 1;

FIG. 6 is an in vitro release profile of the self-assembled nanoparticles of tripterine prodrugs obtained in example 1 at different pH conditions;

FIG. 7 is a graph showing the inhibition of HepG2 cell proliferation by the self-assembled nanoparticles of the tripterine prodrug obtained in example 1;

FIG. 8 is a graph showing the transdermal diffusion test data of the self-assembled nanoparticles of the tripterine prodrug obtained in example 1;

FIG. 9 is a graph showing the effect of the self-assembled nano-particles of the tripterine prodrug obtained in example 1 on treating psoriasis in mice;

FIG. 10 is a schematic slice of the self-assembled nano-particles of the tripterine prodrug obtained in example 1 for treating psoriasis in mice.

Detailed Description

For a better understanding of the present invention, the following examples are further illustrative of the present invention, but the contents of the present invention are not limited to the following examples only.

EXAMPLE 1 Tripterine prodrug Synthesis

Step one: synthesis of methoxypolyethylene glycol epoxide

25g of mPEG2000 (0.0125 mol) was dissolved in 100ml of a solution containing 1% triethanolamine (w/v) in N, N-dimethylformamide and stirred at 40℃for 4h before dissolving to dryness, 2.31g of epichlorohydrin (0.025 mol) was added and the reaction was stirred at room temperature overnight. After adding 50ml of cold diethyl ether, separating out solid, flushing the solid with cold diethyl ether three times, filtering, and drying in vacuum to obtain methoxy polyethylene glycol Epoxide (mPEG-epoxy).

Step two: synthesis of methoxypolyethylene glycol modified m-aminophenylboronic acid

40mg of m-aminophenylboronic acid (0.29 mmol) was added to 6ml of water, then the pH was adjusted to 7.5 with NaOH solution (5 mol/L), dissolved to clear, 80mg of mPEG-epoxy (0.04 mmol) obtained in example 1 was added, the reaction was stirred at 90℃for 24 hours, the aqueous layer was washed with 50ml of dichloromethane and 50ml of diethyl ether successively, the aqueous layer was dialyzed against a dialysis bag (molecular weight cut-off 1 KD), concentrated with a rotary evaporator to give a grey solid, and methoxypolyethylene glycol-modified m-aminophenylboronic acid (mPEG-APBA) was obtained after drying.

Step three: synthesis of glutathione-tripterine conjugate

9mg of tripterine (0.02 mmol), 12mg of glutathione (0.04 mmol) are added into a mixed solution of 1.4ml of DMSO and 0.6ml of ammonium acetate buffer (pH=8.65), and the mixture is reacted for 10min at 25 ℃ under ultrasound, so that the red color of the tripterine is instantly removed, and a solution containing glutathione-tripterine conjugate (CE-GSH) is obtained.

Step four: synthesis of tripterine prodrug self-assembled nanoparticles

80mg of mPEG-APBA (about 0.04 mmol) and a solution containing CE-GSH (about 0.02 mmol) are mixed and reacted for 2-5min at 25 ℃ under ultrasound, the solution is placed in a dialysis bag (the molecular weight cut-off is 14 KD) for dialysis for 48h, a large amount of solids appear in the dialysis bag, the solids are collected after centrifugation (5000 rpm) for 10min, the solids are dissolved in water under ultrasound, and the solution is frozen and dried to obtain the tripterine prodrug self-assembled nano particles.

Structure validation

Use of DMSO-d ₆ And D ₂ O is used as a solvent, and a 300mhz Bruker Avance nuclear magnetic resonance spectrometer is adopted to carry out structural confirmation on the tripterine prodrug self-assembled nanoparticle obtained in the example 1, and the result is shown in figure 1. In a nuclear magnetic resonance spectrogram taking DMSO-d6 as a solvent, characteristic peaks of the self-assembled nanoparticles of the tripterine and the tripterine prodrug are obvious; compared with tripterine, after self-assembled nanoparticles are formed, H at C-6 position and H on phenolic hydroxyl-OH are replaced, and a signal peak disappears. In the nuclear magnetic resonance spectrogram using D2O as a solvent, all characteristic peaks disappear due to the micelle formed by the self-assembled nano particles of the tripterine prodrug. Specific data pairs are shown in table 1.

TABLE 1 assignment and variation of signal peaks in different substances and solvents

Stability investigation

To examine the stability of the celastrol prodrug self-assembled nanoparticles in physiological conditions and in vitro cell culture environments, we selected PBS buffer and DMED high sugar medium solution at ph=7.4 as the sample solutions for stability examination. The test concentration was 1mg/ml. The particle size and zeta potential trend of the self-assembled nano-particles of the tripterine prodrug in the two solutions are respectively measured by a Markov laser particle sizer. The results are shown in FIG. 2 and FIG. 3.

The data show that the self-assembled nano-particles of the tripterine prodrug are relatively stable in PBS buffer solution (pH=7.4), the particle size does not change obviously after 15 days continuously, and the agglomeration phenomenon does not occur; obvious aggregation phenomenon occurs in the high sugar culture medium of DMEM, and the particle size continues to gradually increase. The main reason is probably that the DMEM contains high-concentration glucose, amino acid and other nutrients, and the DMEM is easy to react with boric acid ester bonds in a competition mode to cause partial dissociation of the DMEM, the nano-micelle becomes loose, and the particle size is gradually increased. At the same time, the potential (negatively charged) gradually increases with time, and the trend of the change in PBS buffer (ph=7.4) is more pronounced than that in DMEM high sugar medium, probably due to the higher ionic strength of the former solution.

Solution state at different pH values

The self-assembled nano-particles of the tripterine prodrug are weighed, dissolved and prepared into sample liquid of 1mg/ml by PBS buffer solution with pH value of 1.2, pH value of 6.8 and pH value of 7.4, 0.9 percent NaCl and purified water respectively, and then respectively placed in a penicillin bottle for ultrasonic treatment for 30min, and the solution state of the self-assembled nano-particles of the tripterine prodrug under different pH values is observed, and the result is shown in figure 4.

The self-assembled nano-particles of the tripterine prodrug are extremely unstable under the acidic condition, and the nano-particles are rapidly dissociated into insoluble tripterine technical product under the condition of pH=1.2 and are suspended on the liquid surface; at ph=7.4 and ph=6.4, only a small amount of tripterine solid floats on the surface, most of the nanoparticles are still dissolved in the solution, and the nanoparticles are uniformly dispersed in purified water and 0.9% sodium chloride, and are relatively slow to dissociate.

In summary, the main reason may be that the DMEM contains high concentration of nutrients such as glucose and amino acids, which are easily subjected to competition reaction with the borate bond to cause partial dissociation thereof, and the nano-micelle becomes loose, so that the particle size gradually increases. Therefore, when the nano particles enter the inside of the cells, the nano particles are also subjected to competition of glucose, amino acid and the like to cause the break of boric acid ester bonds, so that the retention of the tripterine in the skin is increased.

Topographical features

And observing the morphological characteristics of the tripterine prodrug self-assembled nanoparticles by adopting a Transmission Electron Microscope (TEM). The test solution (1 mg/ml) was dropped onto the carbon-coated copper grid, stained with 2% (w/v) phosphotungstic acid, dried and observed. The transmission electron microscope photo can observe that the prepared nano particles are spherical particles with uniform size and good roundness, and the particle size is about 200-300nm. The results are shown in FIG. 5.

In vitro drug release assay

1% aqueous trifluoroacetic acid (TFA) was prepared and mixed with acetonitrile at 1:1 (v/v) as release buffer. Precisely weighing 25mg of tripterine self-assembled nanoparticles, placing the nanoparticles in a 25ml volumetric flask, adding 5ml of methanol, adding 500 mu L of release buffer solution, reacting at room temperature for 10min, adding methanol for dilution and volume fixation, and measuring the in vitro release amount of the tripterine self-assembled nanoparticles to be 13.56% by using a high performance liquid chromatography.

Cumulative release rate determination

5mg of tripterine prodrug self-assembled nanoparticles are weighed, placed in triplicate, and placed in a dialysis bag, and then 1ml of PBS buffer solution (pH=7.4) is added for standby. Preparing PBS buffer solution (pH=7.4) containing 0.5% Tween-80 and 20% ethanol, adding 30ml of the buffer solution into a conical flask, placing a dialysis bag into the conical flask in triplicate, placing the conical flask into a constant temperature shaking table, sampling at 37 ℃ at different time points within 0-24 h respectively, and measuring the content of tripterine in the solution outside the dialysis bag by HPLC. The in vitro release profile of the tripterine self-assembled nanoparticles at ph=7.4 and ph=5 is shown in fig. 6.

Cell experiment

The adherent monolayer HepG2 culture cells are digested by 0.25% trypsin digestion solution, single cell suspension is prepared by using DMEM culture solution containing 10% fetal calf serum, and the concentration of cells in the cell suspension is regulated to be 3 multiplied by 10 ⁸ The cell suspension was inoculated into 96-well plates, 3 plates at a time, 180. Mu.l of the above cell suspension was added per well, and about 540,000 cells per well. Placing the inoculated culture plate into saturated humidity and CO with concentration of 5% at 37deg.C ₂ Culturing in an incubator for 12h, and gently sucking the supernatant in the culture plate and discarding after the cells adhere to the wall.

The self-assembled nanoparticles of the prodrug of tripterine were formulated into 5 μm solutions with PBS at ph=7.4, and tripterine was formulated into 5 μm solutions with DMSO, and diluted into 5, 2.5, 1.25, 0.65, 0.325 μm solutions with DMEM, respectively. A blank group was set, DMEM medium without fetal bovine serum was added, and 6 groups were administered in parallel for each concentration, and incubated for 24h and 48h, respectively. Subsequently, 20. Mu.L of PBS (pH=7.4) solution (5 mg/mL) of MTT was added to each well, and CO was added at a concentration of 5% at 37 ℃ ₂ Incubation for 4h in incubator, aspiration of the liquid from each well, addition of 200 μl of DMSO solution per well, shaking for 15min with a microwell shaker, and measurement of absorbance (a) at 490m with a microplate reader, the results are shown in fig. 7. IC was tested using GraphPad Prism 5 software ₅₀ IC of 24h tripterine ₅₀ IC with value of 0.1458 mu M, tripterine prodrug self-assembled nanoparticle ₅₀ The value was 0.6904. Mu.M, the efficacy of the latter was stronger than that of the former.

In vitro transdermal experiments

20mg of tripterine prodrug self-assembled nanoparticles are weighed into a 10ml volumetric flask, and the volume is fixed by using transdermal feed liquid (PBS buffer solution containing 10% of propylene glycol pH=7.4), so as to obtain 2mg/ml of test stock solution for later use. PBS buffer (ph=7.4) containing 20% ethanol and 0.5% tween-80 was prepared as a transdermal receiving solution for use. Fixing the skin of an isolated mouse between a dosing tank and a receiving tank, wherein the liquid surface of the receiving tank is contacted with a skin dermis layer without leaving a gap; 2ml of test stock solution is respectively injected into the administration pool, 8ml of transdermal receiving solution is respectively added into the receiving pool, the stirring speed is 400r/min, the stirring temperature is 37 ℃ plus or minus 0.1 ℃, 1ml of transdermal receiving solution is respectively taken out of the receiving pool at different time points within 54h, and then fresh transdermal receiving solution with the same temperature and the same volume is supplemented, and the obtained sample is filtered by an organic microporous filter membrane and then tested for the tripterine content. The transdermal cumulative permeation quantity Q and the permeation rate J were calculated respectively according to the following calculation formulas.

Permeation rate j=m/Δt

Wherein Cn is the concentration of the sampling liquid at different sampling points; ci is the concentration of the sampling liquid corresponding to each sampling point; v and Vi are the receiving cell volume and the sampling volume, respectively; a is the transdermal diffusion area (2.88 cm) ² ) The method comprises the steps of carrying out a first treatment on the surface of the Δt is the time interval of the sampling point.

As shown in FIG. 8, the transdermal cumulative permeation of the self-assembled nanoparticles of the tripterine prodrug at 54h is 25.21 mug.cm ^-2 The permeation rate was 0.39. Mu.g.cm ^-2 ·h ^-1 The skin hold-up was 44.31. Mu.g cm ^-2 The method comprises the steps of carrying out a first treatment on the surface of the The reason for low permeability and large retention is probably that the phenylboronate ester bond is easily influenced by pH, sugar and ATP in skin cells and is easily dissociated in the skin cells, so that the tripterine prodrug nano-particles are dissociated in the transdermal process, and the tripterine is retained in tissues to increase the skin retention.

Animal model test

The imiquimod IMQ cream is prepared. The method comprises the following steps: taking 0.6g of stearyl alcohol, 4.1g of vaseline, heating to 50 ℃ for melting, sequentially adding 0.6g of glycerin, 0.6g of tween-80 and 0.6g of IMQ raw material medicines, mixing and homogenizing for 10min, and cooling to obtain (10%) IMQ emulsifiable paste for later use. The blank cream did not contain IMQ, the other ingredients were the same. The backs of the mice were shaved to expose an area of about 2.5X2.5 cm of bare skin, and were subjected to depilation treatment using a self-made depilatory cream, and after two days of feeding, they were divided into two groups: model group and normal group. Self-made IMQ cream is smeared on the exposed skin of the back of the mice in the model group, blank cream is smeared on the same position of the mice in the normal group for 10-12 days, and the paste is smeared for 1 time a day, and about 100mg of cream is smeared each time.

Preparing test medicine cream. The method comprises the following steps: taking 0.6g of stearyl alcohol, 4.1g of vaseline, heating to 50 ℃ for melting, sequentially adding 0.6g of glycerin, 0.6g of tween-80 and 20ml of tripterine prodrug self-assembled nano micelle solution (1 mg/ml), mixing and homogenizing for 10min, and cooling to obtain test drug emulsifiable paste for later use.

54 mice (weight 18-22 g) of the IMQ induction model group are divided into three groups of mild, moderate and severe according to psoriasis-like skin damage area and disease severity, and 18 mice in each group. Dividing the mice with the same symptoms into three groups, namely a blank control group, a positive control group and a tested group, wherein 6 mice are in each group; wherein, the blank control group is treated by the blank cream; the positive control group is smeared with tacrolimus ointment for treatment; the tested group is coated with the test drug cream for 7-10 days.

The mice were photographed every three days to record skin loss changes and the results are shown in fig. 9.

A is a normal mouse skin chart: the skin is smooth and has no wrinkles and red spots; b is a mild mouse symptomatic chart: macroscopic erythema, skin folds, raised bumps on the back of mice, slight microscopic scales; c is a mouse symptom map: the red plaque is densely covered with a small amount of flaky scale skin folds are obvious; d is a severe mouse: the skin damage of the mice is hypertrophic, the back is raised, the red spots are obviously dark red, the whole skin damage surface is covered with large scales, and the scales are thicker and layered.

Mice in the tested group are treated by the tripterine nano micelle for 9 days, the skin of the mice is gradually changed into a bulge, and the erythema and the psoriasis are reduced.

Pathological tissue section map

Pathological tissue sections of the psoriasis model blank, test and negative control are shown in fig. 10.

Compared with the blank control group, the IMQ model group has thicker acantha layer, and has wide tissue fibrosis with different degrees, extends to sebaceous glands, is infiltrated by inflammatory cells and has serious tissue fibrosis. Following treatment with the different formulations, the test groups showed reduced white scales and erythema. HE-stained skin sections showed reduced inflammatory cells, excessive keratinization and insufficient keratinization in the test group compared to the IMQ model group. The Messon-stained skin sections showed a significant decrease in tissue fibrosis in the test group and a return to normal, as compared to the IMQ model group.

While the invention has been described with respect to the preferred embodiments, it will be understood that the invention is not limited thereto, but is capable of modification and variation without departing from the spirit of the invention, as will be apparent to those skilled in the art.

Claims

1. The self-assembled nano-particle of the tripterine prodrug taking phenylboronate as a connecting unit is characterized by having a structure as shown in the following formula (I):

in formula (I): n=10-120.

2. The self-assembled nano-particle of tripterine prodrug with phenylboronate as a connecting unit according to claim 1, wherein the nano-particle can be self-assembled into nano-micelle in water, and the hydration particle size of the obtained nano-micelle is 277.3+/-35.34 nm; the zeta potential was-15.04.+ -. 1.83mV.

3. The synthesis method of the tripterine prodrug self-assembled nanoparticle with phenylboronate as a connecting unit is characterized by comprising the following steps of:

step 1: to give mPEG-APBA (compound 1);

step 2: reacting tripterine with glutathione in a solvent to obtain CE-GSH (compound 2);

step 3: mixing the solution containing CE-GSH obtained in the previous step with mPEG-APBA for reaction to obtain mPEG-APBA-CE (compound 3), wherein the synthetic route is as follows:

4. the method of claim 3, wherein in step 1, mPEG-APBA is obtained by reacting an epoxide containing methoxypolyethylene glycol with m-aminophenylboronic acid in a solvent.

5. The method of claim 3, wherein in step 2, the molar ratio of glutathione to tripterine is 1:1-8:1, and the reaction temperature is 20-40 ℃.

6. A method of synthesis according to claim 3, wherein in step 3 the molar ratio of CE-GSH to mPEG-APBA is from 0.5:1 to 1:3.

7. The method according to claim 3, wherein the solvent used in the step 2 is a mixed solution of a buffer salt solution and dimethyl sulfoxide, and the pH value of the buffer salt solution is 7.5-10.0.

8. A method according to claim 3, wherein the CE-GSH solution from step 2 is used directly in step 3 without purification, and the reaction conditions with mPEG-APBA are room temperature ultrasound for 2-5 minutes.

9. Use of a nanoparticle according to any one of claims 1 to 2 or a nanoparticle obtained by a synthetic method according to any one of claims 3 to 8 for the preparation of a medicament for the treatment of psoriasis.