Pharmaceutical composition containing dTRIM24 nanoparticles for treating arteriosclerosis and application of pharmaceutical composition

Abstract

The invention discloses an arteriosclerosis treatment pharmaceutical composition containing dTRI M24 nanoparticles and application of the arteriosclerosis treatment pharmaceutical composition, and belongs to the technical field of arteriosclerosis treatment. The arteriosclerosis treatment pharmaceutical composition containing dTRI M24 nano-particles comprises the following components in percentage by weight: 50-85% of a nano-carrier, 5-10% of dTRI M24 nano-particles, 5-10% of dTRI M24 nano-particles, 5-10% of dTRI 5%-10% of an active drug; 0.5%-20% of a stabilizer; and 1%-5% of a targeting ligand. The problems that in the prior art, lipid metabolism balance is possibly interfered, and the liver metabolism pressure is increased are solved, passive targeting aggregation of the medicine in tumor tissue is achieved by enhancing permeation and retention effects, targeting to arteriosclerosis plaques is enhanced, inflammatory response can be better inhibited, the liver metabolism pressure can be reduced, and the curative effect of the medicine is improved. The condition that transaminase is increased in a patient suffering from hepatic insufficiency is avoided, and the treatment effect is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of arteriosclerosis treatment, and particularly to an arteriosclerosis treatment pharmaceutical composition containing dTRIM24 nanoparticles and its application. Background Art

[0002] Arteriosclerosis is a general term for a state in which various substances deposit inside arteries, causing the inner walls of the arteries to thicken, harden, lose elasticity, and the inner cavity to narrow. Arteriosclerosis develops asymptomatically. When it reaches the onset of myocardial infarction, cerebral infarction, aortic aneurysm, etc., it is a serious disease that can be life-threatening.

[0003] Chinese Patent with publication number CN1681533A discloses a pharmaceutical composition for treating arteriosclerosis. The pharmaceutical composition is characterized in that an ADP receptor antagonist and an ACAT inhibitor are administered simultaneously or at different times. The pharmaceutical composition obtained by administering the ADP receptor antagonist and the ACAT inhibitor simultaneously or at different times can be used as a preventive or therapeutic drug (especially a therapeutic drug) for arteriosclerosis in warm-blooded animals (especially humans) or diseases caused by arteriosclerosis such as ischemic heart disease, ischemic encephalopathy, or peripheral circulatory insufficiency.

[0004] In the actual use of the above patent, since the ACAT inhibitor reduces the formation of arterial plaques by inhibiting cholesterol esterification, it may interfere with the lipid metabolism balance, and the ADP receptor antagonist needs to be metabolized by the liver. The combination of the two may increase the liver metabolism pressure. Especially in patients with liver insufficiency, it may induce elevated transaminases or drug accumulation. For this, we propose an arteriosclerosis treatment pharmaceutical composition containing dTRIM24 nanoparticles and its application. Summary of the Invention

[0005] The purpose of the present invention is to provide an arteriosclerosis treatment pharmaceutical composition containing dTRIM24 nanoparticles and its application, which can provide sustained release and stability, reduce the dosing frequency and maintain a stable blood drug concentration, avoid direct contact between the drug and the external environment, significantly improve the chemical stability and storage period of the drug, and achieve passive targeting aggregation of the drug in tumor tissues through enhanced permeability and retention effects, and enhance the targeting to arteriosclerotic plaques, can better inhibit the inflammatory response, improve the targeting by adding a targeting ligand, can reduce the liver metabolism pressure, avoid the situation of elevated transaminases in patients with liver insufficiency, and improve the treatment effect, thus solving the problems raised in the above background art.

[0006] To achieve the above purpose, the present invention provides the following technical solution: An arteriosclerosis treatment pharmaceutical composition containing dTRIM24 nanoparticles, the composition contains components with the following weight percentages respectively:

[0007] Nanocarrier, 50% - 85%;

[0008] Active drug, 5% - 10%;

[0009] Stabilizer, 0.5% - 20%;

[0010] Targeting ligand, 1% - 5%.

[0011] Preferably, the nanocarrier comprises components with the following weight percentages respectively:

[0012] Poly(lactic - co - glycolic acid) copolymer nanospheres, 5% - 10%;

[0013] Liposome suspension, 45% - 75%.

[0014] Preferably, the active drug comprises components with the following weight percentages respectively:

[0015] dTRI M24 molecule, 4% - 15%;

[0016] Small molecule inhibitor, 1% - 5%.

[0017] Preferably, the stabilizer comprises components with the following weight percentages respectively:

[0018] Surfactant, 0.1% - 15%;

[0019] pH regulator, 0.1% - 5%.

[0020] Preferably, the surfactant is DSPE - PEG2000 or poloxamer 188, and the pH regulator is phosphate or histidine buffer solution.

[0021] Preferably, the targeting ligand comprises components with the following weight percentages respectively

[0022] Anti - CD36 monoclonal antibody, 0.5% - 2%;

[0023] Surface - conjugated antibody, 0.3% - 2%;

[0024] Peptide ligand, 0.1% - 1%.

[0025] Preferably, the preparation of the liposome suspension specifically includes: dissolving 10% lecithin and 20% cholesterol in chloroform, rotary evaporating to form a uniform lipid film, adding an aqueous buffer solution containing dTRI M24 nanoparticles, and dispersing to form a liposome suspension.

[0026] Preferably, the preparation of the poly(lactic - co - glycolic acid) copolymer nanospheres specifically includes:

[0027] Using dichloromethane and ethanol as a mixed solvent, prepare a poly(lactic-co-glycolic acid) copolymer solution;

[0028] Dropwise add the poly(lactic-co-glycolic acid) copolymer solution into an aqueous solution of polyvinyl alcohol and vortex at high speed, and perform ultrasonic emulsification to obtain an emulsion;

[0029] Stir the emulsion until the organic solvent completely evaporates, solidify and form the nano-microspheres, and centrifuge to obtain poly(lactic-co-glycolic acid) copolymer nano-microspheres.

[0030] Preferably, the preparation of the nano-carrier specifically includes:

[0031] Coat the surface of the poly(lactic-co-glycolic acid) copolymer with a metal-organic framework shell formed by the coordination of zinc ions and epigallocatechin gallate;

[0032] Mix the poly(lactic-co-glycolic acid) copolymer nano-microspheres with a liposome suspension containing a metal-organic framework shell;

[0033] Through physical adsorption, the liposome suspension is coated on the surface of the poly(lactic-co-glycolic acid) copolymer nano-microspheres to form a core-shell structure. After removing unencapsulated drugs and small molecule impurities, a nano-carrier is formed.

[0034] Preferably, the arteriosclerosis treatment drug composition containing dTRI M24 nanoparticles is a drug composition for treating arteriosclerosis.

[0035] Compared with the prior art, the beneficial effects of the present invention are:

[0036] The present invention uses poly(lactic-co-glycolic acid) copolymer as the inner core of the carrier, encapsulates dTRI M24 and auxiliary drugs, can provide slow release and stability, reduce the dosing frequency and maintain a stable blood drug concentration, is particularly suitable for scenarios such as anti-tumor drugs and vaccines that require long-term treatment, avoids direct contact between the drug and the external environment, significantly improves the chemical stability and storage period of the drug, and realizes passive targeting aggregation of the drug in tumor tissues through the enhanced permeability and retention effect, and enhances the targeting to atherosclerotic plaques, can better inhibit the inflammatory response, improves the targeting by adding a targeting ligand, can reduce the liver metabolism pressure, avoid the situation of inducing elevated transaminases in patients with liver insufficiency, and improves the treatment effect. Description of the Drawings

[0037] Figure 1 It is a flowchart for preparing a drug composition for treating arteriosclerosis containing dTRI M24 nanoparticles according to the present invention. Detailed Embodiments

[0038] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0039] In order to solve the problem that in the existing technology during use, since ACAT inhibitors reduce the formation of arterial plaques by inhibiting cholesterol esterification, they may interfere with the lipid metabolism balance, and ADP receptor antagonists need to be metabolized by the liver, and the combination of the two may increase the liver metabolism pressure, especially in patients with liver insufficiency, which may induce elevated transaminases or drug accumulation. Please refer to Figure 1 , the following technical solutions are provided in this embodiment:

[0040] Example 1: An arteriosclerosis treatment pharmaceutical composition containing dTRI M24 nanoparticles, which contains the following components by weight percentage:

[0041] Nanocarrier, 85%;

[0042] Active drug, 8%;

[0043] Stabilizer, 4%;

[0044] Targeting ligand, 3%.

[0045] The nanocarrier contains the following components by weight percentage:

[0046] Poly(lactic-co-glycolic acid) copolymer nanospheres, 10%;

[0047] Liposome suspension, 75%.

[0048] Liposome suspension can improve the encapsulation efficiency and enhance cell uptake. Using poly (lactic - co - glycolic acid) as the carrier core, it encapsulates dTRI M24 and auxiliary drugs, and is coated with a targeting modification layer on the surface, which can provide sustained release and stability. Poly (lactic - co - glycolic acid) is composed of lactic acid and glycolic acid, and its degradation products are water and carbon dioxide, which have no toxic side effects on the human body, have excellent biocompatibility, can precisely control the material degradation rate to meet the needs of different drug release cycles, and the degradation time ranges from several weeks to several months. Poly (lactic - co - glycolic acid) can form a stable nanoparticle structure and slowly release the encapsulated drugs through hydrolysis, reducing the dosing frequency and maintaining a stable blood drug concentration, which is especially suitable for scenarios such as anti - tumor drugs and vaccines that require long - term treatment. As a hydrophobic core, poly (lactic - co - glycolic acid) can effectively encapsulate hydrophobic drugs, avoid direct contact between the drugs and the external environment, and significantly improve the chemical stability and storage period of the drugs. Combined with targeted molecular modification, the poly (lactic - co - glycolic acid) carrier can extend the in - vivo circulation time and achieve passive targeted accumulation of drugs in tumor tissues through the enhanced permeability and retention effect.

[0049] The active drug contains components with the following weight percentages respectively:

[0050] dTRI M24 molecule, 8%;

[0051] Small molecule inhibitor, 1%.

[0052] The stabilizer contains components with the following weight percentages respectively:

[0053] Surfactant, 2.5%;

[0054] pH regulator, 0.5%.

[0055] The surfactant is DSPE - PEG2000 or poloxamer 188, and the surfactant can prevent nanoparticle aggregation. The pH regulator is phosphate or histidine buffer, and the pH regulator can maintain the physiological compatibility of the preparation.

[0056] The targeting ligand contains components with the following weight percentages respectively

[0057] Anti - CD36 monoclonal antibody, 1.5%;

[0058] Surface - conjugated antibody, 1%;

[0059] Peptide ligand, 0.5%.

[0060] The preparation of liposome suspension specifically includes: dissolving 10% lecithin and 20% cholesterol in chloroform, rotary evaporating to form a uniform lipid film, and adding an aqueous buffer solution containing dTRI M24 nanoparticles to disperse and form liposome suspension.

[0061] Preparation of poly(lactic-co-glycolic acid) nanoparticles specifically includes the following steps:

[0062] Using dichloromethane and ethanol as a mixed solvent, prepare a poly(lactic-co-glycolic acid) copolymer solution;

[0063] Dropwise add the poly(lactic-co-glycolic acid) copolymer solution into an aqueous solution of polyvinyl alcohol and vortex at high speed, followed by ultrasonic emulsification to obtain an emulsion;

[0064] Stir the emulsion until the organic solvent completely evaporates, solidify and shape the nanoparticles, and centrifuge to obtain poly(lactic-co-glycolic acid) nanoparticles.

[0065] Preparation of the nanocarrier specifically includes the following steps:

[0066] Coat the surface of the poly(lactic-co-glycolic acid) copolymer with a metal-organic framework shell formed by the coordination of zinc ions and epigallocatechin gallate to enhance the stability of the carrier and endow antioxidant and anti-inflammatory functions;

[0067] Mix the poly(lactic-co-glycolic acid) nanoparticles with a lipidosome suspension;

[0068] Through physical adsorption, the lipidosome suspension is coated on the surface of the poly(lactic-co-glycolic acid) nanoparticles to form a core-shell structure. After removing unencapsulated drugs and small molecule impurities, a nanocarrier is formed.

[0069] To achieve the sustained-release effect of the drug, the lipidosome suspension can further encapsulate hydrophilic drugs (such as the anti-inflammatory molecule RvD1) to enhance the targeting to atherosclerotic plaques. A cholesterol efflux promoter can be integrated into the lipidosome suspension layer to accelerate lipid metabolism. The added epigallocatechin gallate can reduce the oxidative stress in the plaque microenvironment and simultaneously release anti-inflammatory drugs to inhibit the inflammatory response.

[0070] A pharmaceutical composition for treating atherosclerosis containing dTRIM24 nanoparticles is a pharmaceutical composition for treating atherosclerosis.

[0071] dTRIM24 can regulate the NF-κB or NLRP3 inflammasome pathway, reduce macrophage polarization (M1 type) and the release of inflammatory factors, inhibit the abnormal proliferation of smooth muscle cells, promote collagen synthesis, reduce the risk of plaque rupture, and accelerate reverse cholesterol transport (such as enhancing ABCA1 expression)

[0072] A method for preparing a pharmaceutical composition for treating atherosclerosis containing dTRIM24 nanoparticles includes the following steps:

[0073] Step 1: Prepare poly(lactic-co-glycolic acid) (PLGA) nanoparticles and liposome suspension. The PLGA nanoparticles and liposome suspension are made into nanocarriers with a particle size of 50 - 200 nm. Among them, the content of PLGA nanoparticles is 10%, and the content of liposome suspension is 75%.

[0074] Step 2: Coating stabilizers on the surface of the nanocarriers to improve the stability of the colloid, modifying targeting ligands on the surface of the nanocarriers, and achieving plaque targeting function through physical coating. Among them, the content of nanocarriers is 85%, the content of targeting ligands is 3%, and the content of stabilizers is 3%.

[0075] Step 3: Load dTRIM24 molecules and small molecule inhibitors onto the surface of the nanocarriers by covalent bonding, and control the drug encapsulation efficiency and drug loading. Among them, the content of dTRIM24 molecules is 8%, and the content of small molecule inhibitors is 1%.

[0076] Step 4: Use ultrafiltration to remove unencapsulated drugs and free reagents, measure the particle size and Zeta potential by dynamic light scattering, observe the morphology by transmission electron microscopy, and analyze the drug loading and release curve using ultraviolet-visible spectroscopy.

[0077] Analyzing the drug loading and release curve using ultraviolet-visible spectroscopy specifically includes:

[0078] Dissolve the arteriosclerosis treatment drug composition containing dTRIM24 nanoparticles in an appropriate solvent to prepare a series of standard solutions with different concentrations.

[0079] Use an ultraviolet-visible spectrophotometer, set the maximum absorption wavelength. Usually, the specific absorption peak wavelength of the drug will be selected as the measurement wavelength, and use a reference solution for calibration to ensure the accuracy of the instrument.

[0080] Put the standard solution and the test solution into cuvettes respectively, record their absorbances. The concentration and absorbance data of the standard will be used to plot the standard curve.

[0081] Taking the concentration of the standard as the abscissa and the absorbance as the ordinate, use Excel or other software to calculate the regression equation and ensure that the correlation coefficient reaches above 0.999 to ensure a good linear relationship.

[0082] According to the standard curve, the concentration of the test sample can be calculated through its absorbance, thereby determining the drug loading.

[0083] Sampling at different time points, recording the absorbance at each time point, correlating the absorbance data with time, plotting the release curve, and analyzing the drug release behavior.

[0084] According to the data of the standard curve and the release curve, the release efficiency and stability of the drug are evaluated by comparing the release curves under different conditions.

[0085] Step Five: Evaluate the colloidal stability and drug retention rate of the nanoparticles in physiological environments such as PBS, plasma, etc.

[0086] Example Two: An arteriosclerosis treatment drug composition containing dTRIM24 nanoparticles, which comprises the following components in weight percentages:

[0087] Nanocarrier, 73%;

[0088] Active drug, 10%

[0089] Stabilizer, 13%;

[0090] Targeting ligand, 4%.

[0091] The nanocarrier comprises the following components in weight percentages:

[0092] Poly(lactic-co-glycolic acid) copolymer nanospheres, 8%;

[0093] Liposome suspension, 65%.

[0094] The active drug comprises the following components in weight percentages:

[0095] dTRI M24 molecule, 6%;

[0096] Small molecule inhibitor, 4%.

[0097] The stabilizer comprises the following components in weight percentages:

[0098] Surfactant, 10%;

[0099] pH regulator, 3%.

[0100] The targeting ligand comprises the following components in weight percentages

[0101] Anti-CD36 monoclonal antibody, 2%;

[0102] Surface-conjugated antibody, 1%;

[0103] Peptide ligand, 1%.

[0104] A method for preparing an arteriosclerosis treatment drug composition containing dTRIM24 nanoparticles, comprising the following steps:

[0105] Step 1: Prepare poly(lactic-co-glycolic acid) (PLGA) nanoparticles and liposome suspension. The PLGA nanoparticles and liposome suspension are made into nanocarriers with a particle size of 150 nm. Among them, the content of PLGA nanoparticles is 8%, and the content of liposome suspension is 65%.

[0106] Step 2: Coating stabilizers on the surface of the nanocarriers to improve the stability of the colloid, modifying targeting ligands on the surface of the nanocarriers, and achieving plaque targeting function through physical coating. Among them, the content of nanocarriers is 73%, the content of targeting ligands is 4%, and the content of stabilizers is 13%.

[0107] Step 3: Load dTRIM24 molecules and small molecule inhibitors onto the surface of the nanocarriers by covalent bonding, and control the drug encapsulation efficiency and drug loading. Among them, the content of dTRIM24 molecules is 6%, and the content of small molecule inhibitors is 4%.

[0108] Step 4: Use ultrafiltration to remove unencapsulated drugs and free reagents, measure the particle size and Zeta potential by dynamic light scattering, observe the morphology by transmission electron microscopy, and analyze the drug loading and release curve using ultraviolet-visible spectroscopy.

[0109] Step 5: Evaluate the colloidal stability and drug retention rate of the nanoparticles in the physiological environment, such as PBS, plasma, etc.

[0110] Example 3: An arteriosclerosis treatment drug composition containing dTRIM24 nanoparticles, and the components thereof contain the following weight percentages respectively:

[0111] Nanocarriers, 65%;

[0112] Active drug, 10%;

[0113] Stabilizer, 20%;

[0114] Targeting ligand, 5%.

[0115] Nanocarriers contain the following components with the following weight percentages respectively:

[0116] Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, 10%;

[0117] Liposome suspension, 55%.

[0118] Active drug contains the following components with the following weight percentages respectively:

[0119] dTRIM24 molecules, 8%;

[0120] Small molecule inhibitors, 2%.

[0121] A stabilizer, comprising components with the following weight percentages respectively:

[0122] Surfactant, 15%;

[0123] pH regulator, 5%.

[0124] A targeting ligand, comprising components with the following weight percentages respectively

[0125] Anti-CD36 monoclonal antibody, 2%;

[0126] Surface-coupled antibody, 2%;

[0127] Peptide ligand, 1%.

[0128] A method for preparing an arteriosclerosis treatment pharmaceutical composition containing dTRIM24 nanoparticles, comprising the following steps:

[0129] Step 1: Prepare poly(lactic-co-glycolic acid) copolymer nanospheres and liposome suspension, and make the poly(lactic-co-glycolic acid) copolymer nanospheres and liposome suspension into a nanocarrier with a particle size of 200 nm. Among them, the content of poly(lactic-co-glycolic acid) copolymer nanospheres is 25%, and the content of liposome suspension is 40%;

[0130] Step 2: Coating a stabilizer on the surface of the nanocarrier to improve the stability of the colloid, and modifying a targeting ligand on the surface of the nanocarrier to achieve plaque targeting function through physical coating. Among them, the content of the nanocarrier is 65%, the content of the targeting ligand is 5%, and the content of the stabilizer is 20%;

[0131] Step 3: Load dTRIM24 molecules and small molecule inhibitors onto the surface of the nanocarrier by covalent bonding, and control the drug encapsulation efficiency and drug loading amount. Among them, the content of dTRIM24 molecules is 8%, and the content of small molecule inhibitors is 2%;

[0132] Step 4: Use ultrafiltration to remove unencapsulated drugs and free reagents, measure the particle size and Zeta potential by dynamic light scattering, observe the morphology by transmission electron microscopy, and analyze the drug loading amount and release curve using ultraviolet-visible spectroscopy;

[0133] Step 5: Evaluate the colloidal stability and drug retention rate of the nanoparticles in the physiological environment, such as PBS, plasma, etc.

[0134] Comparative Example 1: An arteriosclerosis treatment pharmaceutical composition containing dTRIM24 nanoparticles, said composition comprising components with the following weight percentages respectively:

[0135] Nanocarrier, 65%;

[0136] Active drug, 10%

[0137] Stabilizer, 20%;

[0138] Targeting ligand, 5%.

[0139] Preparation of the nanocarrier specifically includes:

[0140] Mix the poly(lactic-co-glycolic acid) copolymer nanospheres with the liposome suspension;

[0141] Through physical adsorption, the liposome suspension is wrapped on the surface of the poly(lactic-co-glycolic acid) copolymer nanospheres to form a core-shell structure. After removing the unencapsulated drugs and small molecule impurities, the nanocarrier is formed.

[0142] Comparative Example 2: An arteriosclerosis treatment pharmaceutical composition containing dTRI M24 nanoparticles, and the components thereof contain the following weight percentages respectively:

[0143] Nanocarrier, 65%;

[0144] Stabilizer, 20%;

[0145] Targeting ligand, 5%.

[0146] A method for preparing an arteriosclerosis treatment pharmaceutical composition containing dTRI M24 nanoparticles includes the following steps:

[0147] Step 1: Prepare poly(lactic-co-glycolic acid) copolymer nanospheres and liposome suspension. The poly(lactic-co-glycolic acid) copolymer nanospheres and the liposome suspension are made into a nanocarrier with a particle size of 150 nm. Among them, the content of the poly(lactic-co-glycolic acid) copolymer nanospheres is 8%, and the content of the liposome suspension is 65%;

[0148] Step 2: Coating the stabilizer on the surface of the nanocarrier to improve the colloidal stability, and modifying the targeting ligand on the surface of the nanocarrier to achieve the plaque targeting function through physical coating. Among them, the content of the nanocarrier is 73%, the content of the targeting ligand is 4%, and the content of the stabilizer is 13%;

[0149] Step 3: Use ultrafiltration to remove the unencapsulated drugs and free reagents, measure the particle size and Zeta potential by dynamic light scattering, observe the morphology by transmission electron microscopy, and analyze the drug loading and release curve by ultraviolet-visible spectroscopy.

[0150] Step 4: Evaluate the colloidal stability and drug retention rate of the nanoparticles in the physiological environment, such as PBS, plasma, etc.

[0151] Treat mice with the arteriosclerosis treatment pharmaceutical compositions containing dTRI M24 nanoparticles prepared in Examples 1-3 and Comparative Examples 1-2:

[0152] Twenty-five ApoE gene knockout mice induced by a high-fat diet were selected to simulate the characteristics of human cardiovascular diseases;

[0153] The twenty-five ApoE gene knockout mice induced by a high-fat diet were divided into 5 groups, with 5 mice in each group. Among them, three groups were respectively treated with the arteriosclerosis treatment drug compositions containing dTRIM24 nanoparticles prepared in Examples 1 to 3, the low / high dose groups of dTRIM24 nanoparticles, and the other two groups were respectively treated with the arteriosclerosis treatment drug compositions prepared in Comparative Example 1 and Comparative Example 2;

[0154] After 20 days, the lipid core area as a proportion of the total plaque volume was quantified by aortic tissue section, and the levels of inflammatory factors such as IL-6, TNF-α, and IL-1β in the plaques were measured by ELISA. The treatment results are shown in Table 1:

[0155] Lipid core occupies the total volume of plaque area Inflammatory factor level Example 1 30％～33％ -0.3～0.1 Example 2 34％～36％ 0.1～0.13 Example 3 37％～38％ 0.13～0.2 Comparative Example 1 39％～40％ 0.2～0.24 Comparative Example 2 >40％ >0.24

[0156] Table 1

[0157] As can be seen from the above table, in Examples 1 to 3, although the arteriosclerosis treatment drug compositions containing dTRIM24 nanoparticles were prepared using the same materials, due to the amounts of the materials used, the particle sizes of the prepared nanocarriers were inconsistent, which in turn led to differences in the treatment effects. The materials and amounts used in Comparative Example 1 were the same as those in Example 3, but when preparing the nanocarrier, a metal-organic framework shell formed by the coordination of zinc ions and epigallocatechin gallate was not coated on the surface of the poly(lactic-co-glycolic acid), resulting in differences in the treatment effects. Compared with Comparative Example 1, in the preparation of the arteriosclerosis treatment drug composition in Comparative Example 2, no active drug was added, resulting in an insignificant treatment effect.

[0158] In summary, a pharmaceutical composition for treating arteriosclerosis containing dTRI M24 nanoparticles of the present invention uses a poly(lactic-co-glycolic acid) copolymer as a carrier core, encapsulates dTRI M24 and auxiliary drugs, and is coated with a targeting modification layer on the surface, which can provide sustained release and stability. The poly(lactic-co-glycolic acid) copolymer is composed of lactic acid and glycolic acid, and its degradation products are water and carbon dioxide, which have no toxic and side effects on the human body, have excellent biocompatibility, can precisely control the material degradation rate, meet the requirements of different drug release cycles, and the degradation time ranges from several weeks to several months. The poly(lactic-co-glycolic acid) copolymer can form a stable nanoparticle structure, slowly release the encapsulated drug through hydrolysis, reduce the dosing frequency and maintain a stable blood drug concentration, and is particularly suitable for scenarios such as anti-tumor drugs and vaccines that require long-term treatment. As a hydrophobic core, the poly(lactic-co-glycolic acid) copolymer can effectively encapsulate hydrophobic drugs, avoid direct contact between the drug and the external environment, and significantly improve the chemical stability and storage period of the drug. Combined with targeted molecular modification, the poly(lactic-co-glycolic acid) copolymer carrier can extend the in vivo circulation time and achieve passive targeting accumulation of the drug in tumor tissues through the enhanced permeability and retention effect, and enhance the targeting to atherosclerotic plaques. Cholesterol efflux promoters can be integrated into the liposome suspension layer to accelerate lipid metabolism. The added epigallocatechin gallate can reduce the oxidative stress in the plaque microenvironment, and at the same time release anti-inflammatory drugs to inhibit the inflammatory response. The nanocarrier with a particle size of 50 nm helps to penetrate the vascular endothelial barrier. In particular, there may be vascular endothelial damage in the atherosclerotic plaque area, and smaller nanoparticles are more likely to penetrate into the lesion site. At the same time, the small particle size can enhance the retention ability of the nanocarrier in the blood vessel wall, and the treatment effect is better.

[0159] It should be noted that in this article, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variant thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements not only includes those elements, but also includes other elements not expressly listed, or also includes elements inherent to such process, method, article or device.

[0160] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made in these embodiments without departing from the principles and spirit of the present invention.

Claims

1. A pharmaceutical composition for treating arteriosclerosis comprising dTRIM24 nanoparticles, characterized in that: The components comprising the following weight percentages are respectively: Nanocarriers, 50% to 85%; Active drug, 5% to 10%; Stabilizer, 0.5% to 20%; Targeting ligand, 1% to 5%.

2. The pharmaceutical composition for treating arteriosclerosis comprising dTRIM24 nanoparticles according to claim 1, characterized in that: The nanocarrier comprises the following components in percentage by weight: Poly(lactic acid-glycolic acid) copolymer nanoparticles, 5% to 10%; Liposome suspension, 45% to 75%.

3. The pharmaceutical composition for treating arteriosclerosis comprising dTRIM24 nanoparticles according to claim 1, characterized in that: The active drug comprises the following components in percentage by weight: dTRIM24 molecules, 4% to 15%; Small molecule inhibitors, 1% to 5%.

4. The pharmaceutical composition for treating arteriosclerosis comprising dTRIM24 nanoparticles according to claim 1, characterized in that: The stabilizer comprises the following components in percentage by weight: Surfactant, 0.1% to 15%; pH adjuster, 0.1%~5%.

5. The pharmaceutical composition for treating arteriosclerosis comprising dTRIM24 nanoparticles according to claim 4, characterized in that: The surfactant is DSPE-PEG2000 or poloxamer 188, and the pH regulator is phosphate or histidine buffer.

6. The pharmaceutical composition for treating arteriosclerosis comprising dTRIM24 nanoparticles according to claim 1, characterized in that: The targeting ligand comprises the following components in weight percentage: anti-CD36 monoclonal antibody, 0.5% to 2%; Surface-coupled antibodies, 0.3% to 2%; Peptide ligands, 0.1% to 1%.

7. The pharmaceutical composition for treating arteriosclerosis comprising dTRIM24 nanoparticles according to claim 2, characterized in that: The preparation of the liposome suspension specifically includes: dissolving 10% lecithin and 20% cholesterol in chloroform, rotary evaporating to form a uniform lipid film, adding an aqueous buffer solution containing dTRIM24 nanoparticles, and dispersing to form a liposome suspension.

8. The pharmaceutical composition for treating arteriosclerosis comprising dTRIM24 nanoparticles according to claim 2, characterized in that: The preparation of the polylactic acid-glycolic acid copolymer nanoparticles specifically includes: Using dichloromethane and ethanol as a mixed solvent, a polylactic acid-glycolic acid copolymer solution was prepared; The polylactic acid-glycolic acid copolymer solution is added dropwise into the polyvinyl alcohol aqueous solution and vortexed at high speed for ultrasonic emulsification to obtain an emulsion; The emulsion is stirred until the organic solvent is completely volatilized, the nano-microspheres are solidified and formed, and the polylactic acid-glycolic acid copolymer nano-microspheres are obtained by centrifugation.

9. The pharmaceutical composition for treating arteriosclerosis comprising dTRIM24 nanoparticles according to claim 2, characterized in that: The preparation of the nanocarrier specifically includes: A metal organic framework shell formed by the coordination of zinc ions and epigallocatechin gallate is coated on the surface of poly(lactic-co-glycolic acid) copolymer; The poly(lactic-co-glycolic acid) nanospheres containing the metal organic framework shell are mixed with the liposome suspension; The liposome suspension is wrapped on the surface of polylactic acid-glycolic acid copolymer nanospheres through physical adsorption to form a core-shell structure, and the nanocarrier is formed after removing the unencapsulated drugs and small molecule impurities.

10. The use of a pharmaceutical composition for treating arteriosclerosis comprising dTRIM24 nanoparticles according to claim 9, characterized in that: The arteriosclerosis treatment pharmaceutical composition containing dTRIM24 nanoparticles is a pharmaceutical composition for treating arteriosclerosis.

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