Oral tryptophan metabolite micelle for treating ulcerative colitis as well as preparation method and application of oral tryptophan metabolite micelle

Abstract

The invention belongs to the technical field of biological medicine and molecular biology, and particularly relates to an oral tryptophan metabolite micelle for treating ulcerative colitis as well as a preparation method and application of the oral tryptophan metabolite micelle. The invention develops an amphiphilic block copolymer PEG-b-pIAA and a self-assembled micelle IAAM thereof, which show unique spatial advantages in treatment of colitis, and have an eEPR effect and a colon enzyme responsive release property. The oral IAAM delivery system enhances secretion of IL-22 by activating AhR in ILC3, obviously promotes intestinal repair and improves colitis treatment, and opens up a new way for clinical application of oral nano-drugs in UC treatment. Therefore, oral delivery of the polymer micelle of the tryptophan metabolite IAA for treating ulcerative colitis is a promising treatment strategy.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine and molecular biology, and specifically relates to an oral tryptophan metabolite micelle for treating ulcerative colitis, and a preparation method and application thereof. Background Art

[0002] The information disclosed in the background of the invention is only intended to enhance the understanding of the overall background of the invention and should not be necessarily regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Ulcerative colitis (UC), one of the two subtypes of inflammatory bowel disease (IBD), is a chronic, relapsing disease that places a heavy burden on healthcare systems around the world. The pathogenesis of UC involves a complex interaction between genetic, environmental, intestinal barrier, and immune response factors. Current treatments include 5-aminosalicylate, corticosteroids, thiopurines, biologics (such as anti-tumor necrosis factor-α, anti-interleukin, and anti-integrin drugs), microbial therapy, and colectomy. However, these treatments often have side effects, limited remission rates, and high costs, and more effective and targeted treatment options are still needed.

[0004] Tryptophan metabolites are key regulators of intestinal and systemic homeostasis, affecting a wide range of physiological processes by activating the aryl hydrocarbon receptor (AhR). These metabolites can modulate immune responses, enhance the intestinal epithelial barrier, regulate gastrointestinal motility, and affect intestinal hormone secretion. Indole-3-acetic acid (IAA) was originally considered to be a crucial auxin in plant growth and development. It is co-produced by plants and microorganisms, and communicates with each other through IAA-mediated signaling mechanisms. IAA is also present in humans. As a key tryptophan-derived metabolite, it regulates mucosal immune responses within the intestinal microenvironment and shows potential for application in disease treatment. Fecal IAA concentrations are reduced in IBD patients, and supplementation with exogenous IAA can further alleviate colitis. Microorganisms exert a therapeutic effect on intestinal inflammation by converting tryptophan to IAA, activating the AhR pathway, enhancing IL-22 expression and promoting intestinal homeostasis. Therefore, the development of effective methods to deliver IAA to the colon is crucial for the treatment of UC.

[0005] Oral administration is a non-invasive, cost-effective treatment with high patient compliance. Polymer nanomicelles are promising carriers for UC treatment due to their biodegradability, water solubility, biocompatibility, biomimetic properties, and storage stability. Due to the destruction of the epithelial barrier and the enrichment of immune cells in colitis, nanoparticles are able to accumulate at the site of colonic ulcers by utilizing the epithelial enhanced permeability and retention (eEPR) effect. In addition, the abundant enzymes in the colon can promote the degradation of prodrugs, ensuring local release of drugs at the site of colitis and improving the therapeutic effect. Therefore, oral delivery of the tryptophan metabolite IAA to the colon is a promising therapeutic strategy for ulcerative colitis. Summary of the invention

[0006] In view of the deficiencies in the prior art, the purpose of the present invention is to provide an oral tryptophan metabolite micelle for the treatment of ulcerative colitis, and a preparation method and application thereof. Specifically, the present invention successfully prepared a self-assembled micelle IAAM based on the amphiphilic block copolymer PEG-b-pIAA, which has the properties of eEPR effect and colon enzyme response release, and shows unique spatial advantages in the treatment of colitis. Oral IAAM can deliver IAA to the site of colon inflammation, significantly promote intestinal repair and improve the therapeutic effect of colitis. Therefore, oral delivery of tryptophan metabolite micelles is a promising treatment strategy for ulcerative colitis. Based on the above research results, the present invention is completed.

[0007] In a first aspect, the present invention provides a compound, which is an amphiphilic block copolymer PEG-b-pIAA, and the compound structure is as follows:

[0008]

[0009] Specifically, the synthesis method of the compound PEG-b-pIAA includes: dissolving the esterification product (PEG-DCT) of polyethylene glycol monomethyl ether (mPEG) and 4-cyano-4-((dodecylsulfanylthiocarbonyl)sulfanyl)pentanoic acid (DCT), indole-3-acetic acid monomer (AAMA) and 2,2'-azobisisobutyronitrile (AIBN) in N,N-dimethylformamide (DMF), completely removing oxygen through freeze-thaw cycles, polymerizing at 60-80°C (preferably 70°C) for 1-48h (preferably 24h) by RAFT polymerization, and after the reaction is completed, transferring the reaction system to cold water and opening the lid to quench the reaction, and finally purifying by ether precipitation.

[0010] Furthermore, the molar ratio of PEG-DCT, AAMA and AIBN is 0.1-10:5-500:0.03-3; preferably 1:50:0.3.

[0011] Furthermore, the specific synthesis method of AAMA includes: dissolving IAA, N-(2-hydroxypropyl) methacrylamide (HPMA) and 4-dimethylaminopyridine (DMAP) in anhydrous DMF, dripping 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) into the above reaction solution under an ice-water bath, reacting in an ice bath for 0-5h (preferably 0.5h), washing with water, 1% HCl solution and water in turn, drying with anhydrous Na2SO4, filtering and concentrating to obtain, wherein the molar ratio of IAA, HPMA, DMAP and EDC is 0.1-10:0.1-10:0.05-5:0.3-3, preferably 1:1:0.5:3.

[0012] Furthermore, the PEG-DCT is synthesized by an esterification reaction between the carboxyl group of DCT and the hydroxyl group of mPEG using an N,N'-dicyclohexylcarbodiimide (DCC) / DMAP / dichloromethane (DCM) scheme. Specifically, DCT, DMAP and PEG are dissolved in anhydrous DCM, and DCC is dropped into the above reaction solution under an ice-water bath. After reacting in an ice bath for 6-24 hours (preferably 12 hours), the reaction is continued at room temperature for 12-36 hours (preferably 24 hours); the mixture is filtered, and then purified by precipitation in cold ether, and finally the product is dried overnight in vacuum to obtain a light yellow powder.

[0013] Further, the molar ratio of DCT, DMAP, PEG and DCC is 0.3-30:0.1-10:0.1-10:0.3-30, preferably 3:1:1:3.

[0014] The second aspect of the present invention provides a micelle, specifically an indole-3-acetic acid (IAA) polymer micelle IAAM, which is formed by self-assembly of an amphiphilic block copolymer PEG-b-pIAA.

[0015] Specifically, the outer shell of the micelle is PEG, which ensures the overall stability and hydrophilicity of the micelle; the drug tryptophan metabolite IAA in the inner core is connected to the polymer through an ester bond, which can be released under the action of enzymes in the colon to prevent the drug from leaking before reaching the colon; in addition, the micelles can accumulate in the site of intestinal inflammation through the eEPR effect.

[0016] Furthermore, the micelles have uniform particle sizes of 188.2±4.4 nm and a negative potential.

[0017] Furthermore, the preparation method of the micelles at least comprises:

[0018] S1, synthesis of PEG-b-pIAA;

[0019] S2. Add the PEG-b-pIAA into water to obtain IAAM through self-assembly.

[0020] The third aspect of the present invention provides a use of the above micelle in the preparation of an anti-ulcerative colitis drug.

[0021] It should be noted that, although tryptophan metabolite IAA is used as an example in the present invention to construct tryptophan metabolite micelles for oral delivery to treat ulcerative colitis, based on the inventive concept of the present invention, the construction of corresponding micelles using its tryptophan metabolites also falls within the scope of protection of the present invention.

[0022] Beneficial technical effects of one or more of the above technical solutions:

[0023] The above technical solution provides a tryptophan metabolite micelle for oral delivery for the treatment of ulcerative colitis. The tryptophan metabolite delivery strategy has been shown to be effective for the treatment of UC. IAA is one of the main tryptophan metabolites produced by the intestinal microbiota, which can promote the secretion of IL-22 by activating the intestinal AhR. However, IAA is a poorly soluble substance and is exposed to the entire gastrointestinal tract, which may lead to potential toxicity and low bioavailability. Therefore, there is an urgent need for appropriate delivery methods to address these challenges. Polymer micelles provide a solution to the above problems. The present invention develops a PEGylated micelle IAAM for local delivery of IAA to inflamed colon areas. The micelle system is designed with a block copolymer, in which IAA is bound to a hydrophobic block through an ester bond. Under the protection of the PEG shell, the IAAM micelle remains intact in the stomach. In addition, IAAM has an eEPR effect and can be enriched in the site of colon inflammation, and then hydrolyzed under the action of colon enzymes to achieve local release of IAA. The IAA portion is the hydrophobic core of the micelle, and as release occurs, the rest of the micelle (an inert water-soluble polymer) continues to pass through the lower digestive tract until it is excreted. IAAM enhances the therapeutic effect on colitis and provides a promising strategy for oral nanomedicine treatment of UC, so the present invention has good practical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0025] Figure 1 : Synthesis diagram of monomer AAMA;

[0026] Figure 2 :Monomer HPMA 1 H-NMR results;

[0027] Figure 3: Monomeric AAMA 1 H-NMR results;

[0028] Figure 4 : Monomeric AAMA 13 C-NMR results;

[0029] Figure 5 :Synthesis routes of PEG-DCT and block copolymers;

[0030] Figure 6 PEG-DCT 1 H-NMR results;

[0031] Figure 7 : PEG-b-pHPMA 1 H-NMR results;

[0032] Figure 8 :PEG-b-pIAA 1 H-NMR results;

[0033] Fig. 9 : Schematic diagram of micelle construction: (a) Synthesis route of PEG-b-pIAA; (b) Schematic diagram of preparation of IAAM using microfluidic technology;

[0034] Fig.10 :Measurement results of Malvern particle size potential analyzer: (a) Particle size distribution of IAAM; (b) Zeta potential distribution;

[0035] Fig.11 : Representative TEM images of micelles: (a) TEM image of IAAM; (b) TEM image of IAAM after overnight incubation in SIF-pH7.4;

[0036] Fig.12 : IAAM storage stability study results;

[0037] Fig.13 :Detection of critical micelle concentration of IAAM;

[0038] Fig.14 :In vitro release curve of IAAM;

[0039] Fig.15 : Distribution of micelles in mice: (a) Oral administration of IR806 and IAAM 806 Fluorescence imaging of the intestine and major organs of mice 6h and 12h after operation; (b) Fluorescence intensity ratio of colon and major organs of the whole body at 12h; (c) Representative immunofluorescence images in colon tissue at 12h. Red arrows and white arrows are areas with high and low dye concentrations, respectively. Pink arrows represent ILC3s;

[0040] Fig.16 :The therapeutic effect of IAAM on DSS-induced colitis in mice: (a) Experimental plan and dosing strategy; (b) Mouse body weight curve; (cd) Colon length of mice after treatment; (e) Histopathological staining of mouse colon sections; (f) Histological score; (g) Relative mRNA levels of ZO-1, Occludin and MUC2 in colon tissues of mice after treatment. DETAILED DESCRIPTION

[0041] It should be noted that the following detailed descriptions are all illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0042] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0043] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in combination with specific embodiments and comparative examples.

[0044] Example:

[0045] 1. Synthesis and characterization of N-(2-hydroxypropyl)methacrylamide (HPMA, 1)

[0046] Isopropanolamine (1.00 g, 13.3 mmol), NaHCO3 (1.20 g, 14.6 mmol) and 30 mL of anhydrous DCM were added to a 100 mL flask and mixed thoroughly. Methacryloyl chloride (1.34 g, 12.6 mmol) was dissolved in 2 mL of anhydrous DCM and then added dropwise to the flask at 0°C. After reacting for 1 h, the reaction was continued at room temperature for 3 h. The solid was filtered out, concentrated by rotary evaporation under reduced pressure, and the obtained concentrated solution was added dropwise to cold acetone for precipitation. The precipitate was collected by filtration to obtain white crystals, which were then dried under vacuum for 24 h.

[0047] 2. Synthesis and characterization of AAMA (2)

[0048] Dissolve IAA (0.612 g, 3.49 mmol), HPMA (0.500 g, 3.49 mmol) and DMAP (0.213 g, 1.75 mmol) in 20 mL of anhydrous DMF, stir in an ice-water bath, add EDC (2.01 mg, 10.5 mmol), react for 0.5 h, wash with water, 1% HCl solution and water, dry over anhydrous Na2SO4, filter and concentrate to obtain AAMA.

[0049] according to Figure 1 The technical route shown synthesizes monomers HPMA and AAMA. Figure 2 The H NMR spectrum of HPMA, Figure 3 AAMA H NMR spectrum and Figure 4 The AAMA NMR spectrum of PEG-DCT (3) confirmed its successful synthesis.

[0050] DCT (0.182 g, 0.450 mmol), DMAP (0.0183 g, 0.150 mmol) and mPEG (0.75 g, 0.150 mmol) were dissolved in anhydrous DCM (30 mL). DCC (0.0928 g, 0.450 mmol) dissolved in anhydrous DCM (5 mL) was added to the above mixed system in an ice-water bath, and the reaction was continued for 12 h, and then transferred to room temperature and stirred for 36 h. The mixture was filtered and then purified by precipitation in cold ether. The product was dried under vacuum overnight to obtain a light yellow powder. Figure 5 The technical route shown synthesizes the chain transfer agent PEG-DCT and performs subsequent polymerization. Figure 6 Its successful synthesis was confirmed by H NMR spectroscopy.

[0051] 4. Synthesis and characterization of PEG-b-pHPMA (4)

[0052] PEG-b-pHPMA was synthesized by RAFT polymerization, and the specific procedure was as follows: PEG-DCT (0.349 g, 0.0698 mmol), HPMA (0.500 g, 3.49 mmol), and AIBN (0.00344 g, 0.0210 mmol) were dissolved in DMF, and transferred to a Schlenk tube after complete dissolution. After three freeze-thaw cycles of deoxygenation, the reaction solution was placed in a 70°C oil bath and stirred continuously for 24 hours for polymerization synthesis. After the reaction was completed, the reaction system was transferred to cold water and the lid was opened to contact the air to quench the reaction, and finally purified by ether precipitation. The classical RAFT polymerization method was used to carry out the polymerization reaction. First, PEG-DCT was used as a chain transfer agent, AIBN was used as an initiator, and HPMA was used as a monomer to synthesize the hydrophilic block copolymer PEG-b-pHPMA. Figure 7The H-NMR spectrum confirmed its successful synthesis, and the degree of polymerization was 50. The molecular weight measured by GPC was 24300 g / mol (D=1.19), which corresponded to the results of H-NMR spectrum.

[0053] 5. Synthesis of PEG-b-pIAA (5)

[0054] PEG-b-pIAA was synthesized by RAFT polymerization, and the specific procedure was as follows: PEG-DCT (0.179 g, 0.0333 mmol), AAMA (0.500 g, 1.66 mmol), and AIBN (0.00164 g, 0.00999 mmol) were dissolved in DMF, and transferred to a Schlenk tube after complete dissolution. After deoxygenation for three freeze-thaw cycles, the reaction solution was placed in a 70°C oil bath and stirred continuously for 24 hours for polymerization synthesis. After the reaction was completed, the reaction system was transferred to cold water and the lid was opened to contact the air to quench the reaction, and finally purified by ether precipitation. By RAFT polymerization, the amphiphilic block polymer PEG-b-pIAA was synthesized using PEG-DCT as a chain transfer agent and hydrophilic segment, AIBN as an initiator, and AAMA as a monomer. Figure 8 The nuclear magnetic hydrogen spectrum confirmed its successful synthesis, and the degree of polymerization was 12. The molecular weight measured by GPC was 12200g / mol This corresponds to the results of H-NMR spectrum.

[0055] 6. Preparation and Characterization of IAAM Micelles

[0056] The polymer micelle drug delivery platform IAAM was prepared by self-assembly. PEG-b-pIAA (5 mg) was dissolved in DMSO (0.1 mL), then slowly dripped into water (0.9 mL) in an ultrasonic bath, and ultrasonication was continued for 30 minutes to form IAAM micelles. To remove DMSO, centrifuge at 7000 rpm for 10 minutes, discard the supernatant, and redissolve the precipitate with water. Fig. 9 As shown in Figure 1, micelles were prepared by self-assembly. The particle size of IAAM was 188.2±4.4nm, and the potential was -10.05±0.54mV. Transmission electron microscopy results showed that the above morphologies were relatively round. The particle size distribution and potential of micelles are shown in Figure 1. Fig.10 Representative transmission electron microscopy images are shown in Fig.11 shown.

[0057] 7. Stability Study of IAAM

[0058] IAAM was placed in a 4°C refrigerator, and its particle size and polydispersity index (PDI) were tested at the same time point every day for 30 consecutive days. The stability of IAAM was preliminarily evaluated by observing the changes in micelle particle size and PDI. The storage stability of IAAM at 4°C was preliminarily investigated. Fig.12 As shown, the particle size of IAAM did not change significantly within 30 days, and the PDI was less than 0.3, which proved that IAAM had good initial stability.

[0059] 8. Measurement of critical micelle concentration

[0060] The critical micelle concentration of IAAM was determined by fluorescence spectroscopy using pyrene as a hydrophobic fluorescent probe. -7 The polymer solution with a concentration of 1.0 mg / mL was mixed with the pyrene solution, and the final pyrene concentration was 6 × 10 -3 mg / mL. The emission spectra of the samples were recorded on a fluorescence spectrophotometer at 20°C using 335 nm as the excitation wavelength. The ratio between the 1st (373 nm) and 3rd (384 nm) vibrational electronic bands of pyrene was plotted against the concentration of the polymer. Finally, the critical micelle concentration of IAAM was calculated using the fluorescence ratio and the sample concentration. Fig.13 As shown, the critical micelle concentration (CMC) of IAAM is 0.00103 mg / mL, indicating that it has a high tendency to form micelles in solution.

[0061] IX. In vitro drug release

[0062] Artificial gastric juice and artificial intestinal fluid (SIF-pH 6) were used for in vitro release analysis. The pH value of artificial intestinal fluid was adjusted to 7.4 by adding 0.1 M NaOH solution. IAAM was dispersed in 1 mL of SGF, SIF-pH6 and SIF-pH 7.4, respectively, and incubated at 37 °C. The release solutions at different time points were centrifuged at 7000 r / min for 10 min, and the supernatant was filtered with a 0.22 μm filter. The IAA concentration was measured using HPLC at an absorption wavelength of 221 nm. Fig.14 We evaluated its release under in vitro conditions, including simulated gastric fluid (SGF) and simulated intestinal fluid (SIF-pH 6 and SIF-pH 7.4) that simulate physiological environments. IAAM is relatively stable in the acidic gastric environment. In contrast, in simulated intestinal fluid, IAAM undergoes cleavage of the ester bond under the action of colon enzymes to release free IAA.

[0063] 10. Characterization of the distribution of micelles in mice

[0064] Male C57BL / 6 mice were treated with 3.0% (w / v) DSS for 6 days, and the distribution of the preparation in the gastrointestinal tract was investigated using a small animal near-infrared fluorescence in vivo imaging system to evaluate the accumulation of IAAM in the site of colon inflammation. Mice were given IR806 and its labeled IAAM (IAAM) by gavage. 806 ). After 6 h or 12 h, the mice were euthanized, the main organs were collected, and the fluorescence intensity of the main organs was measured. Fig.15 Compared with the free IR806 group, IAAM 806 The group had a higher percentage of fluorescence intensity in the colon, while lower signals were observed in the small intestine and liver. At the same time, compared with free dye, the nanoparticles can enter the base of the crypts and lamina propria and directly act on innate lymphoid cells type 3 (ILC3s). The nanoparticles have an eEPR-driven enrichment effect at ulcer sites in colitis. In addition, the PEG surface and negative corona charge of IAAM enable it to bypass absorption in the small intestine and promote selective targeting of positively charged inflamed colon sites. These results demonstrate the potential of IAAM as a targeted drug delivery to sites of colonic inflammation.

[0065] XI. Evaluation of the therapeutic effect of colitis in mice

[0066] To investigate the effect of IAAM on colitis, mice were treated with 3.0% (w / v) DSS for 6 days and began dosing (50 mg / kg / day, 200 μL) the day after colitis induction. Body weight was recorded daily to determine the percentage of body weight change. Colon length was measured and colon samples were collected for further analysis. Fig.16 As shown, IAAM had a better inhibitory effect on inflammation compared with IAA, accompanied by weight loss and restoration of colon length. Histopathological analysis further demonstrated that IAAM reduced DSS-induced crypt structural erosion, epithelial damage, and inflammatory cell infiltration. In addition, assessment of intestinal barrier function showed increased mRNA levels of ZO-1, Occludin, and MUC2. Overall, IAAM provides a more efficient therapeutic strategy to alleviate DSS-induced colitis inflammation and maintain colon barrier integrity

[0067] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound, characterized in that The compound is an amphiphilic block copolymer PEG-b-pIAA, and the compound structure is as follows:

2. The method for preparing the compound according to claim 1, characterized in that: The esterification product of polyethylene glycol monomethyl ether and 4-cyano-4-((dodecylsulfanylthiocarbonyl)sulfanyl)pentanoic acid PEG-DCT, indole-3-acetic acid monomer and 2,2'-azobisisobutyronitrile are mixed in N,N-dimethylformamide, and oxygen is completely removed by freeze-thaw cycles. The polymerization is carried out at 60-80°C for 1-48h by RAFT polymerization. After the reaction is completed, the reaction system is transferred to cold water and the lid is opened to quench the reaction, and finally purified by ether precipitation.

3. The method for preparing the compound according to claim 2, characterized in that: The molar ratio of the esterification product PEG-DCT, indole-3-acetic acid monomer and 2,2'-azobisisobutyronitrile is 0.1-10:5-500:0.03-3.

4. The method for preparing the compound according to claim 2, characterized in that: The specific synthesis method of indole-3-acetic acid monomer is as follows: indole-3-acetic acid, N-(2-hydroxypropyl)methacrylamide and 4-dimethylaminopyridine are dissolved in anhydrous dichloromethane, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is dropped into the above reaction solution, reacted in an ice bath, washed with water, hydrochloric acid solution and water in sequence, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the monomer, wherein the molar ratio of indole-3-acetic acid, N-(2-hydroxypropyl)methacrylamide, 4-dimethylaminopyridine and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 0.1-10:0.1-10:0.05-5:0.3-3.

5. The method for preparing the compound according to claim 2, characterized in that: The esterification product PEG-DCT was synthesized by esterification reaction between the carboxyl group of 4-cyano-4-((dodecylsulfanylthiocarbonyl)sulfanyl)pentanoic acid and the hydroxyl group of polyethylene glycol monomethyl ether using N,N'-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, and dichloromethane.

6. A micelle, characterized in that: The micelle is obtained by self-assembly of the compound as claimed in claim 1.

7. The micelle according to claim 6, characterized in that: The outer shell of the micelle is PEG-terminated, and the drug color in the inner core is indole-3-acetic acid, which is connected to the polymer through an ester bond.

8. The method for preparing micelles according to claim 6, characterized in that: The preparation steps at least include: S1. Synthesis of amphiphilic block copolymer PEG-b-pIAA: mainly including PEG-DCT, indole-3-acetic acid monomer and 2,2'-azobisisobutyronitrile; S2. Add the amphiphilic block copolymer PEG-b-pIAA into water to obtain polymer micelle IAAM through self-assembly.

9. Use of the micelles as claimed in claims 6-7 in the preparation of anti-ulcerative colitis drugs.

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