Preparation method and application of nanoparticles based on pB and ASD conjugates

Abstract

The preparation method and application of pB and ASD conjugate nanoparticles are based on the preparation of nanoparticles with high stability and high drug loading rate, and the PEG coating is used to efficiently cross the gastrointestinal barrier, thereby improving the oral bioavailability and delivery efficiency of ASD, reducing toxic side effects, and improving the therapeutic effect of ASD on metabolic diseases. The method includes: (1) synthesizing a phenylboronic acid derivative monomer B; (2) synthesizing a phenylboronic acid polymer pB by RAFT, whose main chain contains a phenylboronic acid group; (3) connecting pB and ASD through a phenylboronic acid and sugar ring on ASD to form a pB and ASD conjugate pB-ASD. Due to its amphiphilicity, pB-ASD self-assembles to form nanoparticles PB@ASD NPs; (4) dripping a PEG aqueous solution into the PB@ASD NPs, modifying the PEG coating through electrostatic interaction, and obtaining the final nanoparticles CPB@ASD NPs.

Description

Technical Field

[0001] The present invention relates to the technical field of nanomedicine, and in particular to a method for preparing nanoparticles based on a conjugate of pB (i.e., phenylboronic acid polymer) and ASD (i.e., Akebia saponin D), and application of the method for preparing nanoparticles based on the conjugate of pB and ASD in metabolic diseases. Background Art

[0002] Akebia saponin D (ASD) is a type of triterpenoid saponin extracted from the root of the Chinese herbal medicine Dipsacus asper. ASD can play a role in anti-metabolic syndrome, prevent atherosclerosis, reduce non-alcoholic fatty liver disease, prevent diabetic nephropathy, and fight osteoporosis. However, studies have found that ASD has a low bioavailability (0.025%) and a short half-life (2.54 hours), and its rapid body clearance seriously restricts its in vivo therapeutic effect. Therefore, by improving the bioavailability of Akebia saponin D and extending its half-life, it is expected to improve its in vivo efficacy.

[0003] Nano drug delivery systems have shown great advantages in improving drug bioavailability and delivery efficiency. Nanocarriers can not only protect drugs and reduce the impact of defense mechanisms in the body, but also have good stability and drug loading capacity. At present, common drug loading strategies for nano delivery systems include: first, through hydrophilic and hydrophobic interactions in water-oil systems, using carriers such as polymers and liposomes to encapsulate drugs in the core of nanoparticles; second, through the covalent binding of drugs and polymers to form polymer-drug conjugates, and then self-assemble to form nanoparticles to improve drug loading efficiency and nanoparticle stability; third, through the covalent and non-covalent binding of drugs and drugs, carrier-free nano drugs are formed. At present, the main obstacles to the clinical transformation of nano drugs are low drug loading rate, lack of controlled drug release, and biosafety. Therefore, designing nanoparticle carrier systems with high drug loading rate and controllable drug release capacity will be an important platform to circumvent many problems that plague nano therapy.

[0004] Oral administration has the advantages of convenient administration, good patient compliance, and high safety. It is the most commonly used method of administration in clinical practice. However, oral administration must go through the harsh gastrointestinal tract (GIT) barrier. On the one hand, the GIT environment is acidic and rich in a large number of enzymes, which makes the drug easily degraded and ineffective after oral administration into the GIT. On the other hand, the surface of the intestinal epithelial tissue is covered with a mucus layer, and the intestinal epithelial cells are tightly connected. This mucus barrier and cell barrier seriously hinder the penetration and absorption of nanomedicines in the intestine. In order to overcome the GIT barrier, researchers have developed a series of oral nanomedicines. Polyethylene glycol (PEG) coatings and zwitterionic nanocarriers have significant advantages in overcoming the mucus barrier by reducing the interaction between nanomedicines and mucus proteins. Summary of the invention

[0005] In order to overcome the defects of the prior art, the technical problem to be solved by the present invention is to provide a method for preparing nanoparticles based on the conjugate of pB and ASD, which prepares nanoparticles with high stability and high drug loading rate, and uses PEG coating modification to efficiently cross the gastrointestinal barrier, thereby improving the oral bioavailability and delivery efficiency of ASD, reducing toxic side effects, and improving the therapeutic effect of ASD on metabolic diseases.

[0006] The technical solution of the present invention is: the preparation method of the pB and ASD conjugate nanoparticles comprises the following steps:

[0007] (1) Synthesis of phenylboronic acid derivative monomer B;

[0008] (2) synthesizing phenylboronic acid polymer pB by reversible addition-fragmentation chain transfer polymerization (RAFT), the main chain of which contains phenylboronic acid groups;

[0009] (3) pB and ASD are connected by forming a phenylboronic acid ester bond with the sugar ring on ASD to form a pB-ASD conjugate. Due to its amphiphilicity, pB-ASD self-assembles to form nanoparticles PB@ASD NPs, where ASD is Akebia saponin D.

[0010] (4) Add PEG aqueous solution into PB@ASD NPs to modify the PEG coating through electrostatic interaction to obtain the final nanoparticles CPB@ASD NPs.

[0011] The CPB@ASD NPs of the present invention have a narrow and adjustable particle size distribution, high ASD loading efficiency and stability, can efficiently cross the gastrointestinal barrier, increase intestinal absorption, protect the activity of ASD during circulation and transportation to target organs or tissues, reduce toxic side effects, and improve drug delivery efficiency. In a mouse metabolic-related fatty liver disease model, compared with the same dose of small molecule ASD, CPB@ASD NPs showed significantly enhanced therapeutic effects on metabolic-related fatty liver disease and obesity, and can significantly improve dyslipidemia, impaired glucose tolerance and insulin resistance.

[0012] Also provided is an application of nanoparticles based on the pB and ASD conjugate, which is used in preparing drugs for treating metabolism-related fatty liver disease and obesity.

[0013] Also provided is an application of nanoparticles based on the pB and ASD conjugate, which is used in preparing drugs for improving dyslipidemia, impaired glucose tolerance or insulin resistance. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 The synthetic route of 3-acrylamidophenylboronic acid monomer B is shown.

[0015] Figure 2 Shown is the synthetic route for phenylboronic acid polymer pB.

[0016] Figure 3 Shown is the synthetic route of the conjugate of phenylboronic acid polymer (pB) and akebia saponin D (ASD), pB-ASD.

[0017] Figure 4 Shown is the H NMR spectrum of 3-acrylamidophenylboronic acid monomer B.

[0018] Figure 5 Shown is the H-NMR spectrum of phenylboronic acid polymer pB.

[0019] Figure 6 A, 6B, and 6C are the particle size, potential, and polydispersity index (PDI) of the nanoparticles, respectively.

[0020] Figure 7 A and 7B are the standard curve of ASD and the drug loading rate of ASD in CPB@ASD NPs, respectively. Concentration refers to the concentration.

[0021] Figure 8 A, 8B, 8C, and 8D are the liver images of mice in the Control group, HFFD group, ASD group, and CPB@ASD NPs group after treatment, respectively.

[0022] Fig. 9 A, 9B, 9C are the liver weight, mouse body weight, and liver index (liver weight / body weight*100%) of mice in the Control group, HFFD group, ASD group, and CPB@ASD NPs group after treatment, respectively. Among them, Control group: C57BL / 6 mice were given normal diet and water; HFFD group: C57BL / 6 mice were given a high-fat and high-sugar diet; ASD group: C57BL / 6 mice were given a high-fat and high-sugar diet and treated with ASD; CPB@ASD NPs group: C57BL / 6 mice were given a high-fat and high-sugar diet and treated with CPB@ASD NPs.

[0023] Fig.10 These are the hematoxylin-eosin (H&E) staining images of the livers of mice in the Control group, HFFD group, ASD group, and CPB@ASD NPs group after treatment. Fig.10 A, 10B, 10C, and 10D are pictures magnified 10 times. Fig.10 E, 10F, 10G, and 10H are images magnified 20 times.

[0024] Fig.11A, 11B, and 11C are the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in the blood of mice in the Control group, HFFD group, ASD group, and CPB@ASD NPs group after treatment, respectively.

[0025] Fig.12 A, 12B, and 12C are the levels of low-density lipoprotein cholesterol (LDL), triglyceride (TG), and total cholesterol (CHO) in the blood of mice in the Control group, HFFD group, ASD group, and CPB@ASD NPs group after treatment, respectively.

[0026] Fig.13 A and 13B are the glucose tolerance and insulin tolerance tests of mice in each group after treatment, respectively. DETAILED DESCRIPTION

[0027] The preparation method of the nanoparticles based on the conjugate of pB and ASD comprises the following steps:

[0028] (1) Synthesis of phenylboronic acid derivative monomer B;

[0029] (2) Synthesizing phenylboronic acid polymer pB by reversible addition-fragmentation chain transfer polymerization (RAFT), the main chain of which contains phenylboronic acid groups;

[0030] (3) pB and ASD are connected by forming a phenylboronic acid ester bond with the sugar ring on ASD to form a pB-ASD conjugate. Due to its amphiphilicity, pB-ASD self-assembles to form nanoparticles PB@ASD NPs.

[0031] (4) PEG aqueous solution was added to PB@ASD NPs to modify the PEG coating through electrostatic interaction to obtain the final nanoparticles CPB@ASD NPs, where ASD is Akebia saponin D.

[0032] The CPB@ASD NPs of the present invention have a narrow and adjustable particle size distribution, high ASD loading efficiency and stability, can efficiently cross the gastrointestinal barrier, increase intestinal absorption, protect the activity of ASD during circulation and transportation to target organs or tissues, reduce toxic side effects, and improve drug delivery efficiency. In a mouse metabolic-related fatty liver disease model, compared with the same dose of small molecule ASD, CPB@ASD NPs showed significantly enhanced therapeutic effects on metabolic-related fatty liver disease and obesity, and can significantly improve dyslipidemia, impaired glucose tolerance and insulin resistance.

[0033] Preferably, in step (1), 1.50 g of 3-aminophenylboronic acid is weighed and added to 15 mL of deionized water, and stirred thoroughly to promote dissolution; 4 mol / L sodium hydroxide solution is slowly added dropwise thereto, the pH value is adjusted to 10.5, and the mixture is stirred until fully dissolved, and the system is placed in an ice bath; 1.19 g of acryloyl chloride is weighed and slowly added dropwise to 3-aminophenylboronic acid, stirring while adding dropwise, and sodium hydroxide solution is added dropwise to maintain the pH value at 10.5; the mixture is reacted in an ice bath for 30 minutes and then continued to react at room temperature for 4 hours; the pH value of the reaction solution is adjusted to 3 with 2 mol / L hydrochloric acid, and the mixture is extracted 3 times with ethyl acetate, and the organic phase is collected; anhydrous sodium sulfate is added to remove moisture, and the boronic acid monomer B is obtained after suction filtration, rotary evaporation, and vacuum drying.

[0034] Preferably, in step (2), the RAFT synthesis of phenylboronic acid polymer comprises: weighing 3.8 mg of DDMAT, 0.4 mg of AIBN and 100 mg of 3-acrylamidophenylboronic acid into a flask, adding dimethyl sulfoxide, stirring to dissolve; introducing nitrogen into the flask to remove oxygen in the system, placing the flask at 65 o C oil bath for 24 hours; collect the solution in the flask, place it in a dialysis bag with a molecular weight of 3500 and dialyze it for 48 hours, collect the solution in the dialysis bag, and dry it to obtain phenylboronic acid polymer pB. DDMAT is 2-(dodecyl trithiocarbonate)-2-methylpropionic acid. AIBN is azobisisobutyronitrile.

[0035] Preferably, in step (3), 5 mg pB and 15 mg ASD are weighed into a sample bottle, 1 mL dimethyl sulfoxide is added to dissolve, and the mixture is stirred and reacted at room temperature for 4 hours to obtain a pB and ASD conjugate pB-ASD.

[0036] Preferably, in step (4), 10 mL of deionized water is slowly added dropwise to pB-ASD while stirring. After the addition is completed, stirring is continued at room temperature for 30 minutes to obtain pB-ASD conjugate nanoparticles PB@ASD NPs; 4 mL of PB@ASD NPs is taken and 1 mg / mL of NH 2 -PEG-NH 2 4 mL of aqueous solution was added dropwise while stirring. After the addition was completed, stirring was continued at room temperature for 30 minutes. The obtained emulsion was placed in a dialysis bag and dialyzed in deionized water for 48 hours. The emulsion in the dialysis bag was collected to obtain the final nanoparticles CPB@ASD NPs.

[0037] Preferably, the phenylboronic acid derivative monomer B is 3-acrylamidophenylboronic acid, 2-aminophenylboronic acid, p-aminophenylboronic acid, or 4-boron-L-phenylalanine.

[0038] Preferably, the molar ratio of monomer B and DDMAT is 30-200:1, the mass ratio of pB and ASD is 1:0.2-50, and PEG is NH 2 -PEG-NH 2 or PEG-NH 2 , molecular weight is 1000-100000.

[0039] Preferably, the molar ratio of monomer B to DDMAT is 50:1.

[0040] Also provided is an application of nanoparticles based on the pB and ASD conjugate, which is used in preparing drugs for treating metabolism-related fatty liver disease and obesity.

[0041] Also provided is an application of nanoparticles based on the pB and ASD conjugate, which is used in preparing drugs for improving dyslipidemia, impaired glucose tolerance or insulin resistance.

[0042] The embodiments of the present invention are described in detail below.

[0043] Figure 1 The synthetic route of 3-acrylamide phenylboronic acid monomer B is as follows. Weigh 1.50 g of 3-aminophenylboronic acid (10.95 mmol) and add it to 15 mL of deionized water. Stir thoroughly to promote dissolution. Slowly add sodium hydroxide solution (4 mol / L) to adjust the pH value to about 10.5, stir thoroughly until fully dissolved, and place the system in an ice bath. Weigh 1.2 times the equivalent of acryloyl chloride (1.19 g, 13.15 mmol) and slowly add it to 3-aminophenylboronic acid. Stir while adding, and add sodium hydroxide solution to maintain the pH value at about 10.5. After 30 minutes of ice bath reaction, continue to react at room temperature for 4 hours. Use hydrochloric acid (2 mol / L) to adjust the pH value of the above reaction solution to about 3, extract with ethyl acetate 3 times, and collect the organic phase. Add anhydrous sodium sulfate to remove moisture, and obtain (3-acrylamide phenyl) boronic acid monomer (B) after suction filtration, rotary evaporation, and vacuum drying.

[0044] Figure 2The synthetic route of phenylboronic acid polymer pB (4-((3-borylphenyl)amino)-3-((((dodecylthio)carbonylthio)methyl)-2,2-dimethyl-4-oxobutanoic acid). The phenylboronic acid polymer was synthesized by reversible addition-fragmentation chain transfer polymerization (RAFT). 3.8 mg of 2-(dodecyltrithiocarbonate)-2-methylpropionic acid (DDMAT), 0.4 mg of azobisisobutyronitrile (AIBN) and 100 mg of (3-acrylamidophenyl)boronic acid were weighed into a flask, and dimethyl sulfoxide was added and stirred to dissolve. Nitrogen was introduced into the flask to remove oxygen in the system. The flask was placed at 65 o C oil bath for 24 hours. Collect the solution in the flask, place it in a dialysis bag with a molecular weight of 3500 for 48 hours, collect the solution in the dialysis bag, and dry it to obtain phenylboronic acid polymer (pB). The molar ratio of monomer B and DDMAT can be 30-200:1. In this case, the molar ratio of monomer B and DDMAT is 50:1.

[0045] Figure 3 The synthetic route of the conjugate of phenylboronic acid polymer and akebia saponin D is as follows. 5 mg pB and 15 mg ASD are weighed into a sample bottle, 1 mL dimethyl sulfoxide is added to dissolve, and the mixture is stirred and reacted for 4 hours at room temperature to obtain a conjugate of pB and ASD (pB-ASD). The mass ratio of pB to ASD is preferably, but not limited to, 1:3.

[0046] Slowly add 10 mL of deionized water to the pB-ASD and stir while adding. After the addition is completed, continue stirring at room temperature for 30 minutes to obtain pB-ASD conjugate nanoparticles (PB@ASD NPs). Take 4 mL of pB-ASD conjugate nanoparticles and slowly add 4 mL of NH 2 -PEG-NH 2 (MW: 2000, 1 mg / mL) aqueous solution was added dropwise while stirring. After the addition was completed, stirring was continued at room temperature for 30 minutes. Finally, the obtained emulsion was placed in a dialysis bag and dialyzed in deionized water for 48 hours. The emulsion in the dialysis bag was collected to obtain the final nanoparticles (CPB@ASD NPs). The particle size and potential were characterized by dynamic light scattering (DLS).

[0047] The following describes the oral administration of nanoparticles to treat mice with metabolic-associated fatty liver disease.

[0048] (1) Construction of a mouse model of metabolic-associated fatty liver disease: C57BL / 6 mice were used as experimental subjects. After acclimatization to the environment in an SPF-level standardized animal center for one week, the mice were fed a high-fat and high-sugar diet (D12492 high-fat feed; 5% fructose in drinking water) for 8 weeks to construct a mouse model of metabolic-associated fatty liver disease.

[0049] (2) Oral administration of nanoparticles: CPB@ASD NPs were administered by oral gavage, with a dose of 75 mg / kg of akebia saponin D, once a day for 12 weeks. The control group was given an equal dose of akebia saponin D and saline at the same time.

[0050] (3) Evaluation method: The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to test the glucose tolerance and insulin resistance of mice. After the treatment cycle, the mice in each group were weighed. The mice were euthanized and the blood and liver of the mice were separated. The liver was weighed and stained with hematoxylin-eosin (H&E). The plasma of the mouse blood was separated and blood biochemical tests were performed, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), low-density lipoprotein cholesterol (LDL), triglycerides (TG) and total cholesterol (CHO).

[0051] The H NMR spectrum of B is Figure 4 As shown. The peaks at δ = 5.73–5.75, 6.27–6.43, 6.43–6.45 are respectively attributed to the peaks of the three hydrogen protons in the double bond of the acryloyl group. δ = 7.29-7.30, 7.50-7.51, 7.82,7.83 are respectively attributed to the peaks of the four hydrogen protons in the benzene ring. δ = 7.89-8.09 is attributed to the peaks of the two hydrogen protons in phenylboronic acid. δ = 10.07-10.12 is attributed to the peaks of the hydrogen protons in the imino group. The above results indicate the successful synthesis of B.

[0052] The H NMR spectrum of pB is as follows Figure 5 As shown. The three packets in the range of δ = 7.04-7.67 belong to the peaks of hydrogen protons in the benzene ring, the peak at δ = 8.62 belongs to the peak of hydrogen protons in phenylboronic acid, and the peak at δ = 9.61 belongs to the peak of hydrogen protons in the imino group. The above results indicate the successful synthesis of pB. After calculation, the degree of polymerization of B is about 30.

[0053] Figure 6 The particle size, potential and polydispersity index (PDI) of the nanoparticles are shown. DLS results show that the particle size of CPB@ASD NPs is about 280.0 nm, the potential is about -17.0 mV, and the PDI is about 0.06. Compared with PB@ASD NPs, the particle size of CPB@ASD NPs is significantly increased, and the potential and PDI do not change significantly.

[0054] Figure 7 The standard curve of ASD and the drug loading rate of ASD in CPB@ASD NPs. The standard curve of ASD determined by high performance liquid chromatography (HPLC) is y = 4.213*X+30.78, R2 =0.9997, with a good linear relationship. The drug loading rate of ASD in CPB@ASD NPs was calculated to be 32.6%.

[0055] After treatment, the mouse livers were isolated, photographed, weighed, and the liver index was calculated ( Figure 8 , Fig. 9 ). The results showed that compared with mice on a normal diet (Control), the livers of mice in the HFFD group were significantly enlarged, fatty liver was severe, and liver weight, mouse body weight, and liver index increased significantly. After treatment with ASD and CPB@ASD NPs, the livers of mice were significantly reduced, the body weight was significantly reduced, and fatty liver was significantly improved. Compared with the small molecule ASD group, the various indicators of mice in the CPB@ASD NPs group were also significantly improved. This shows that CPB@ASD NPs can significantly enhance the ability of ASD to treat metabolic-related fatty liver disease, obesity, and other metabolic diseases.

[0056] Hematoxylin-eosin (H&E) staining images of the livers of mice in each group are shown in Figure 2. Fig.10 As shown. The results showed that compared with mice on a normal diet (Control), the fat vacuoles in the liver of mice in the HFFD group increased significantly, and lipid damage was severe. After treatment with the ASD group and CPB@ASD NPs, the fat vacuoles in the liver of mice were significantly reduced, and lipid damage was significantly reduced. The treatment effect of the CPB@ASD NPs group was significantly better than that of the small molecule ASD group.

[0057] like Fig.11 As shown in the figure, compared with mice on a normal diet (Control), the liver function-related indicators ALT, AST and LDH in the blood of mice in the HFFD group were significantly decreased after treatment with the ASD group and CPB@ASD NPs, and the treatment effect of the CPB@ASD NPs group was significantly better than that of the small molecule ASD group. This shows that CPB@ASD NPs can significantly enhance the ability of ASD to improve the liver function of mice.

[0058] like Fig.12 As shown in the figure, compared with mice on a normal diet (Control), the levels of blood lipid-related indicators in the HFFD group mice increased significantly. After treatment with the ASD group and CPB@ASD NPs, the levels of these indicators in the blood of mice decreased significantly, and the treatment effect of the CPB@ASDNPs group was significantly better than that of the small molecule ASD group. This shows that CPB@ASD NPs can significantly enhance the ability of ASD to improve dyslipidemia in mice.

[0059] like Fig.13As shown in the figure, compared with mice fed a normal diet (Control), the glucose tolerance and insulin resistance of mice in the HFFD group became worse. After treatment with the ASD group and CPB@ASD NPs, the glucose tolerance and insulin resistance of mice were significantly improved, and the treatment effect of the CPB@ASD NPs group was better than that of the small molecule ASD group. This shows that CPB@ASD NPs can significantly improve the ability of ASD to improve glucose tolerance and insulin resistance in mice.

[0060] The above results show that compared with the therapeutic effect of the same dose of small molecule ASD, the therapeutic effect of CPB@ASD NPs on metabolic disease mice is significantly enhanced, which is manifested in improving the ability of ASD to treat metabolic-related fatty liver disease and obesity, improving the ability of ASD to improve dyslipidemia, and improving the ability of ASD to improve impaired glucose tolerance and insulin resistance. This shows that CPB@ASDNPs can significantly improve the therapeutic efficiency of ASD for metabolic-related fatty liver disease, obesity and other metabolic diseases by improving the bioavailability of ASD.

[0061] The advantages of the present invention are as follows:

[0062] 1. The synthesized phenylboronic acid polymer pB has a high density of phenylboronic acid groups, which is covalently linked with Akebia saponin D to form amphiphilic pB-ASD. pB-ASD is amphiphilic and can self-assemble to form nanoparticles with high stability and drug loading rate.

[0063] 2. By combining the PEG coating with electrostatic interaction, the ability of nanoparticles to break through the intestinal barrier is enhanced, thereby enhancing intestinal absorption and improving the bioavailability and therapeutic efficiency of ASD.

[0064] 3. Compared with the same dose of small molecule ASD, CPB@ASD NPs showed significantly enhanced therapeutic effects on metabolic diseases such as metabolic-related fatty liver disease and obesity in mice.

[0065] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any simple modification, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention are still within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing nanoparticles based on a conjugate of pB and ASD, characterized in that: It includes the following steps: (1) Synthesis of phenylboronic acid derivative monomer B; In the step (1), 1.50 g of 3-aminophenylboronic acid is weighed and added to 15 mL of deionized water, and stirred thoroughly to promote dissolution; 4 mol / L sodium hydroxide solution is slowly added dropwise thereto, the pH value is adjusted to 10.5, and the mixture is stirred until fully dissolved, and the system is placed in an ice bath; 1.19 g of acryloyl chloride is weighed and slowly added dropwise to 3-aminophenylboronic acid, stirring while adding dropwise, and sodium hydroxide solution is added dropwise to maintain the pH value at 10.5; the mixture is reacted in an ice bath for 30 minutes and then continued to react at room temperature for 4 hours; the pH value of the reaction solution is adjusted to 3 with 2 mol / L hydrochloric acid, and the mixture is extracted three times with ethyl acetate, and the organic phase is collected; anhydrous sodium sulfate is added to remove moisture, and the mixture is filtered, rotary evaporated, and vacuum dried to obtain a phenylboronic acid derivative monomer B; (2) synthesizing phenylboronic acid polymer pB by reversible addition-fragmentation chain transfer polymerization (RAFT), the main chain of which contains phenylboronic acid groups; In the step (2), the RAFT method for synthesizing the phenylboronic acid polymer comprises: weighing 3.8 mg of DDMAT, 0.4 mg of AIBN and 100 mg of phenylboronic acid derivative monomer B into a flask, adding dimethyl sulfoxide, stirring and dissolving; introducing nitrogen into the flask to remove oxygen in the system, placing the flask at 65 o C oil bath for 24 hours; the solution in the flask was collected and placed in a dialysis bag with a molecular weight of 3500 for 48 hours, the solution in the dialysis bag was collected and dried to obtain phenylboronic acid polymer pB; (3) pB and ASD are connected by forming a phenylboronic acid ester bond with the sugar ring on ASD to form a pB-ASD conjugate. Due to its amphiphilicity, pB-ASD self-assembles to form nanoparticles PB@ASD NPs, where ASD is Akebia saponin D. In the step (3), 5 mg pB and 15 mg ASD were weighed into a sample bottle, 1 mL dimethyl sulfoxide was added to dissolve, and the mixture was stirred at room temperature for 4 hours to obtain a pB and ASD conjugate pB-ASD; (4) Add PEG aqueous solution to PB@ASD NPs to modify the PEG coating through electrostatic interaction to obtain the final nanoparticles CPB@ASD NPs; In the step (4), 10 mL of deionized water is slowly added dropwise to pB-ASD while stirring. After the addition is completed, stirring is continued at room temperature for 30 minutes to obtain pB-ASD conjugate nanoparticles PB@ASD NPs; 4 mL of PB@ASD NPs is taken, and 4 mL of an aqueous solution of NH2-PEG-NH2 with MW: 2000 and 1 mg / mL is slowly added dropwise thereto while stirring. After the addition is completed, stirring is continued at room temperature for 30 minutes; the obtained emulsion is placed in a dialysis bag and dialyzed in deionized water for 48 hours. The emulsion in the dialysis bag is collected to obtain the final nanoparticles CPB@ASD NPs.

2. The use of pB and ASD conjugate nanoparticles according to claim 1, characterized in that: The invention is used in preparing medicines for treating metabolism-related fatty liver disease and obesity.

3. The use of pB and ASD conjugate nanoparticles according to claim 1, characterized in that: The invention is used in preparing medicines for improving abnormal blood lipids, abnormal glucose tolerance or insulin resistance.

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