Preparation method of targeted composite nano-drug-loaded particles and application thereof

Abstract

The application relates to the technical field of medicines, and particularly discloses a preparation method of a targeted composite nano drug-loaded particle and application thereof, wherein the targeted composite nano drug-loaded particle is formed by compounding starch and PEG-b-PMAA micelles modified by hyaluronic acid. Since CD44 receptors are highly expressed in inflammatory macrophages or synoviocytes, the CD44 receptors are specifically recognized by introducing hyaluronic acid, so that the problems of passive targeting and low enrichment efficiency of the nano drug-loaded particle are solved. The physical compounding of the starch and the polymer micelles realizes high drug loading and high stability. The micelles have good stability, high bioavailability and excellent slow-release performance, can improve the efficiency of preventing and treating gouty arthritis, reduce the systemic toxicity of drugs, and have a wide application prospect in the preparation of medicines for resisting gouty arthritis.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a method for preparing targeted composite drug-carrying nanoparticles and their applications. Background Technology

[0002] Gouty arthritis (GA) is a chronic metabolic inflammatory disease driven by persistent hyperuricemia, characterized by the deposition of monosodium urate (MSU) crystals in and around joints. In recent years, the global prevalence of gout has been steadily increasing, reaching 1%–6% in adults. Although uric acid-lowering drugs are widely used clinically, existing formulations exhibit significant fluctuations in blood drug concentrations, and these drugs generally have hepatotoxicity and nephrotoxicity. Conventional formulations cannot achieve stable drug release. There is an urgent clinical need for a drug delivery system that can stabilize blood drug concentrations, reduce drug toxicity, and target the lesion.

[0003] Berberine (BBR) is a natural benzylisoquinoline alkaloid, and its potential value in the treatment of gout has received increasing attention in recent years. Berberine can inhibit uric acid reabsorption and promote uric acid excretion at the uric acid metabolism level; it can also synergistically alleviate gouty inflammation and kidney damage through multiple mechanisms, including activating the Nrf2 antioxidant pathway, inhibiting the JAK2 / STAT3 signaling pathway, and regulating gut microbiota. However, berberine's self-aggregation under acidic conditions leads to poor solubility, low intestinal permeability, and extensive enterohepatic metabolism. This severely limits the exposure concentration of berberine at the target sites of gout, making it difficult to achieve an effective anti-inflammatory therapeutic window at the joint under conventional administration conditions.

[0004] Starch, a naturally abundant, biocompatible, and biodegradable high-molecular-weight polysaccharide, is mainly composed of two components: amylose and amylopectin. In the field of drug delivery, it plays multiple roles, ranging from a traditional excipient to a high-end intelligent carrier. Studies have shown that the abundant hydroxyl groups on the starch molecule provide ample active sites for chemical modification. Modification methods such as carboxymethylation, phosphorylation, and acetylation can introduce negative charges, alter hydrophilicity, and introduce cross-linking groups. Modification not only changes the physicochemical properties of starch but also affects its nanoparticle formation mechanism and stability. Furthermore, starch-based carriers can be progressively degraded into glucose units in vivo by α-amylase and glucosidase. The degradation products are non-toxic and can be cleared through normal metabolic pathways, leading to their widespread application in drug sustained-release. Moreover, due to the fact that starch does not cause adverse reactions with most drugs, it has a natural advantage in reducing carrier-related toxicity and simplifying regulatory evaluation.

[0005] Hyaluronic acid (HA) is widely distributed in human extracellular matrix, synovial fluid, cartilage, and skin, exhibiting excellent biocompatibility, biodegradability, and non-immunogenicity. It has been widely applied in drug delivery systems and tissue engineering. More importantly, HA is a natural ligand for the CD44 receptor on cell surfaces, enabling it to specifically recognize and bind to CD44. During acute gouty arthritis attacks, CD44 expression is significantly increased on the surfaces of synovial cells, infiltrating macrophages, and neutrophils, providing a biological basis for hyaluronic acid-mediated active targeted drug delivery. Through the specific recognition of CD44 by hyaluronic acid, selective accumulation and endocytosis of drug carriers at the site of joint inflammation can be promoted, increasing local drug concentration and reducing systemic exposure, thus potentially enhancing anti-inflammatory efficacy while reducing toxic side effects.

[0006] In particular, for targeted composite drug-loaded nanoparticles, the hydrophobic core of the drug-loaded micelles can efficiently encapsulate hydrophobic drugs such as berberine, while its hydrophilic shell endows the micelles with good colloidal stability and long-term circulation capability, thereby fundamentally improving the solubility and in vivo delivery efficiency of berberine. Furthermore, since hyaluronic acid's natural affinity for the CD44 receptor constitutes the core molecular basis for active targeted drug delivery, hyaluronic acid is both a key effector molecule in gout inflammation and an ideal target for precise targeted intervention. Moreover, the cavities created after high-amylose gelatinization can load drugs; by combining them with hyaluronic acid-modified drug-loaded micelles, the drug loading capacity can be significantly increased, and the sustained-release effect prolonged. Therefore, it is still necessary to develop a structurally well-defined, controllable, CD44 receptor-targeting composite delivery system, and to realize the efficient delivery of berberine and its application in the treatment of gouty arthritis based on this material. Summary of the Invention

[0007] To address the problems existing in the prior art, this invention provides a method for preparing targeted composite drug-loaded nanoparticles and their applications. The targeted composite drug-loaded nanoparticles are formed by combining starch and HA-modified drug-loaded micelles. Hyaluronic acid serves as a targeting shell, enabling precise drug delivery to gouty arthritis via a hyaluronic acid-guided composite delivery system. Furthermore, starch is introduced to increase the drug loading capacity of the composite drug-loaded nanoparticles. Unlike conventional modified materials in the prior art, the targeted composite delivery system constructed in this invention possesses stability, high drug loading capacity, self-assembly capability, and targeted delivery capability to the inflammatory factor CD44. This system can improve the efficiency of preventing and treating gouty arthritis and reduce systemic toxicity, showing broad application prospects in the preparation of drugs for treating gouty arthritis.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solutions.

[0009] This invention discloses a method for preparing targeted composite drug-loaded nanoparticles and their applications. The method is characterized in that the targeting is the precise recognition of CD44 receptor by hyaluronic acid, and the composite drug-loaded nanoparticles are formed by the physical combination of starch and drug-loaded micelles.

[0010] Furthermore, the targeted composite delivery system is formed by a combination of starch and polymer micelles modified with targeting ligands.

[0011] Furthermore, the targeted ligand-modified polymer micelles are HA-PEG-b-PMAA micelles, which are assembled from the polymer HA-PEG-b-PMAA by a thin-film hydration method. The PEG ends have amino groups, and the PMAA chains are rich in carboxyl groups.

[0012] Furthermore, the target ligand is hyaluronic acid, which is coupled with NH2-PEG-b-PMAA. That is, the carboxyl group of hyaluronic acid and the terminal amino group of PEG are condensed by EDC / NHS to form an amide bond, thus obtaining HA-PEG-b-PMAA.

[0013] Furthermore, the drug-loaded starch-polymer micelles are obtained by gelatinizing and regenerating starch and then assembling them with drug-loaded micelles.

[0014] Furthermore, the mass ratio of the high amylose starch to the hyaluronic acid-modified amphiphilic polymer micelles is 1~20:1.

[0015] The present invention also provides a method for preparing targeted composite drug-loaded nanoparticles and their applications, comprising the following steps: (1) Dissolve sodium hyaluronate in deionized water, adjust the pH to 4.5, add EDC and NHS, and activate at room temperature for 10-60 min by stirring. (2) Dissolve NH2-PEG-b-PMAA in a small amount of PBS (pH 7.4) and add it dropwise to the product of step (1) above. Adjust the pH to 7.4 and stir the reaction at room temperature for 24 h. (3) Collect the product obtained in step (2) and freeze-dry it to obtain freeze-dried HA-PEG-b-PMAA; (4) Dissolve the product obtained in step (3) in an organic solvent with berberine at a mass ratio of 1 to 30:1, then remove the solvent by rotary evaporation to form a thin film, and then dry under vacuum. (5) Add PBS to the product obtained in step (4), hydrate and sonicate, collect and filter to obtain HA-PEG-b-PMAA drug-loaded micelles, and store at 4 °C in the dark. (6) Add the gelatinized starch dropwise to the HA-PEG-b-PMAA drug-loaded micelle solution obtained in step (5) and stir for 15~60 min. (7) Remove the residual organic solvent and excess raw material from the product obtained in step (6) by dialysis, then filter it through a filter membrane and collect the filtrate to obtain targeted composite nanoparticles.

[0016] Further, in step (1), the volume of deionized water is 1-20 ml, the molar ratio of carboxyl groups:EDC:NHS (repeating units) of sodium hyaluronate is 1:2:2, the pH adjustment solvent is 0.1 M HCl, and the molecular weight of the sodium hyaluronate is 5 × 10⁻⁶. 4 ~2×10 6 Da.

[0017] Furthermore, in step (2), the PBS is pH 7.4, the pH-adjusting solvent is 0.1 M NaOH, and the reaction is carried out at room temperature with stirring for 12-24 h.

[0018] Further, the organic solvent in step (4) is one or a mixture of methanol, ethanol, and acetone; the volume-to-mass ratio of the organic solvent to the HA-PEG-b-PMAA is 1-10 mL: 20 mg.

[0019] Furthermore, in step (5), the pH of PBS is 7.4, the volume of PBS is 1~20ml, hydration is performed at 60℃ for 15~60min; sonication is performed in an ice bath for 1~10min, and filtration is performed using a 0.45 μm microporous membrane.

[0020] Furthermore, in step (6), the mass fraction of gelatinized high amylose is 1% to 20%; the solvent for gelatinized starch includes water, DMSO, alkaline solution, concentrated salt solution, and ionic liquid.

[0021] Furthermore, in step (7), the dialysis solvent is pure water or physiological saline, and the dialysis is performed for 24 hours, with the dialysis solvent being changed every 4 hours.

[0022] The present invention also provides a drug encapsulated in the core of a targeted composite nanoparticle; the drug is selected from at least one of berberine, colchicine, curcumin, baicalin, artemisinin, kaempferol, and luteolin.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows.

[0024] The targeted composite drug-carrying nanoparticles provided by this invention physically combine the hollow structure of gelatinized high-amylose starch with hyaluronic acid-modified polymer micelles to form a targeted composite delivery system. This system enables high drug loading, efficient recognition of the inflammatory environment, and stable sustained release. Due to the high expression of CD44 in the pathological microenvironment of gouty arthritis, and the natural affinity of hyaluronic acid for the CD44 receptor, it constitutes an ideal target for precise targeted intervention, significantly enhancing the active targeted recognition and accumulation of drugs at the arthritic site.

[0025] Therefore, this invention provides a method for preparing targeted composite drug-loaded nanoparticles and their applications. These targeted composite drug-loaded nanoparticles possess advantages such as stable self-assembly, high-efficiency loading, and CD44-targeted delivery, and can serve as a novel formulation material basis for the treatment of gouty arthritis. Detailed Implementation

[0026] The present invention will be further described in detail below with reference to specific embodiments. However, this should not be construed as limiting the scope of the above-described subject matter of the present invention to the following embodiments; all technologies implemented based on the content of the present invention fall within the scope of the present invention.

[0027] Unless otherwise specified, all reagents and materials used in this invention are commercially available.

[0028] Example 1: Preparation of targeted composite drug-carrying nanoparticles

[0029] (1) Preparation of HA-PEG-b-PMAA

[0030] Accurately weigh sodium hyaluronate (5×10) 4 100 mg of HA-PEG-b-PMAA was dissolved in 10 mL of deionized water, and the pH was adjusted to 4.5 with 0.1 M HCl. 96 mg of EDC and 57 mg of NHS (molar ratio of carboxyl group: EDC: NHS (repeating unit) = 1:2:2) were added, and the mixture was stirred at room temperature for 30 min to obtain an activated hyaluronic acid solution. 1.5 eq of NH2-PEG-b-PMAA was dissolved in 2 mL of PBS (pH 7.4) and added dropwise to the activated hyaluronic acid solution. The pH was adjusted to 7.4 with 0.1 M NaOH, and the reaction was stirred at room temperature for 24 h. The mixture was then dialyzed against deionized water for 48 h, and finally freeze-dried to obtain HA-PEG-b-PMAA.

[0031] (2) Preparation of HA-PEG-b-PMAA targeted drug-loaded micelles

[0032] Accurately weigh 20 mg of HA-PEG-b-PMAA and 2 mg of berberine, dissolve them in 2 mL of methanol, remove the solvent by rotary evaporation at 40 °C to form a thin film, and vacuum dry overnight. Add 5 mL of PBS to the film, hydrate at 60 °C for 20 min, sonicate at 40 W on ice for 4 min, collect and filter through a 0.45 μm filter membrane to obtain drug-loaded micelles, and store at 4 °C protected from light.

[0033] (3) Preparation of HA-PEG-b-PMAA-HAS targeted composite nanoparticles

[0034] Dissolve 0.5g of starch in 25ml of DMSO and gelatinize at 90℃ for 10min. Add berberine and stir for 5min. Cool to 40℃ and, while stirring, add dropwise the HA-PEG-b-PMAA targeted drug-loaded micelles. Continue stirring for 15min after addition. Dialyze the prepared sample in a dialysis bag (3000DA) for 48h, changing the water every 2 hours to remove impurities, obtaining targeted composite drug-loaded nanoparticles.

[0035] Example 2: Preparation of targeted composite drug-carrying nanoparticles

[0036] (1) Preparation of HA-PEG-b-PMAA

[0037] Accurately weigh sodium hyaluronate (5×10) 5 80 mg of HA-PEG-b-PMAA was dissolved in 5 mL of deionized water, and the pH was adjusted to 4.5 with 0.1 M HCl. 96 mg of EDC and 57 mg of NHS (molar ratio of carboxyl group: EDC: NHS (repeating unit) = 1:2:2) were added, and the mixture was stirred at room temperature for 40 min to obtain an activated hyaluronic acid solution. 1.5 eq of NH2-PEG-b-PMAA was dissolved in 2 mL of PBS (pH 7.4) and added dropwise to the activated hyaluronic acid solution. The pH was adjusted to 7.4 with 0.1 M NaOH, and the reaction was stirred at room temperature for 12 h. The mixture was then dialyzed against deionized water for 48 h, and finally freeze-dried to obtain HA-PEG-b-PMAA.

[0038] (2) Preparation of HA-PEG-b-PMAA targeted drug-loaded micelles

[0039] Accurately weigh 40 mg of HA-PEG-b-PMAA and 2 mg of curcumin, dissolve them in 2 mL of ethanol, remove the solvent by rotary evaporation at 40 °C to form a thin film, and vacuum dry overnight. Add 10 mL of PBS to the film, hydrate at 60 °C for 30 min, sonicate at 40 W on ice for 6 min, collect and filter through a 0.45 μm filter membrane to obtain drug-loaded micelles, and store at 4 °C protected from light.

[0040] (3) Preparation of HA-PEG-b-PMAA-HAS targeted composite drug-carrying nanoparticles

[0041] Dissolve 0.4 g of starch in 25 ml of DMSO and gelatinize at 90 °C for 20 min. Add curcumin and stir for 5 min. Cool to 40 °C and, while stirring, add dropwise the HA-PEG-b-PMAA targeted drug-loaded micelles. Continue stirring for 30 min after addition. Place the prepared sample in a dialysis bag (3000 DA) and dialyze for 24 h, changing the water every 4 hours to remove impurities, obtaining targeted composite drug-loaded nanoparticles.

[0042] Example 3: Preparation of targeted composite drug-carrying nanoparticles

[0043] (1) Preparation of HA-PEG-b-PMAA

[0044] Accurately weigh sodium hyaluronate (2×10⁻⁶) 6 60 mg of HA-PEG-b-PMAA was dissolved in 15 mL of deionized water, and the pH was adjusted to 4.5 with 0.1 M HCl. 96 mg of EDC and 57 mg of NHS (molar ratio of carboxyl group: EDC: NHS (repeating unit) = 1:2:2) were added, and the mixture was stirred at room temperature for 50 min to obtain an activated hyaluronic acid solution. 1.5 eq of NH2-PEG-b-PMAA was dissolved in 2 mL of PBS (pH 7.4) and added dropwise to the activated hyaluronic acid solution. The pH was adjusted to 7.4 with 0.1 M NaOH, and the reaction was stirred at room temperature for 12 h. The mixture was then dialyzed against deionized water for 48 h, and finally freeze-dried to obtain HA-PEG-b-PMAA.

[0045] (2) Preparation of HA-PEG-b-PMAA targeted drug-loaded micelles

[0046] Accurately weigh 60 mg of HA-PEG-b-PMAA and 2 mg of berberine, dissolve them in 15 mL of methanol, remove the solvent by rotary evaporation at 40 °C to form a thin film, and vacuum dry overnight. Add 15 mL of PBS to the film, hydrate at 60 °C for 40 min, sonicate at 40 W on ice for 8 min, collect and filter through a 0.45 μm filter membrane to obtain drug-loaded micelles, and store at 4 °C protected from light.

[0047] (3) Preparation of HA-PEG-b-PMAA-HAS targeted composite drug-carrying nanoparticles

[0048] Dissolve 0.2 g of starch in 25 ml of DMSO and gelatinize at 90 °C for 40 min. Add berberine and stir for 5 min. Cool to 40 °C and, while stirring, add dropwise the HA-PEG-b-PMAA targeted drug-loaded micelles. Continue stirring for 45 min after addition. Dialyze the prepared sample in a dialysis bag (3000 DA) for 24 h, changing the water every 4 hours to remove impurities, thus obtaining targeted composite drug-loaded nanoparticles.

[0049] Example 4: Preparation of targeted composite drug-carrying nanoparticles

[0050] (1) Preparation of HA-PEG-b-PMAA

[0051] Accurately weigh sodium hyaluronate (5×10) 440 mg of HA-PEG-b-PMAA was dissolved in 20 mL of deionized water, and the pH was adjusted to 4.5 with 0.1 M HCl. 96 mg of EDC and 57 mg of NHS (molar ratio of carboxyl group: EDC: NHS (repeating unit) = 1:2:2) were added, and the mixture was stirred at room temperature for 60 min to obtain an activated hyaluronic acid solution. 1.5 eq of NH2-PEG-b-PMAA was dissolved in 2 mL of PBS (pH 7.4) and added dropwise to the activated hyaluronic acid solution. The pH was adjusted to 7.4 with 0.1 M NaOH, and the reaction was stirred at room temperature for 24 h. The mixture was then dialyzed against deionized water for 48 h, and finally freeze-dried to obtain HA-PEG-b-PMAA.

[0052] (2) Preparation of HA-PEG-b-PMAA targeted drug-loaded micelles

[0053] Accurately weigh 10 mg of HA-PEG-b-PMAA and 2 mg of colchicine, dissolve them in 5 mL of ethanol, remove the solvent by rotary evaporation at 40 °C to form a thin film, and vacuum dry overnight. Add 10 mL of PBS to the film, hydrate at 60 °C for 60 min, sonicate at 40 W on ice for 10 min, collect and filter through a 0.45 μm filter membrane to obtain drug-loaded micelles, and store at 4 °C protected from light.

[0054] (3) Preparation of HA-PEG-b-PMAA-HAS targeted composite drug-carrying nanoparticles

[0055] Dissolve 0.1 g of starch in 25 ml of DMSO and gelatinize at 90 °C for 60 min. Add colchicine and stir for 5 min. Cool to 40 °C. While stirring, add the HA-PEG-b-PMAA targeted drug-loaded micelles dropwise. Continue stirring for 60 min after addition. Dialyze the prepared sample in a dialysis bag (3000 DA) for 24 h, changing the water every 4 hours to remove impurities, obtaining targeted composite drug-loaded nanoparticles.

[0056] Comparative Example 1

[0057] In this comparative example, no composite drug-loaded nanoparticles were formed; instead, HA-PEG-b-PMAA micelles were used directly for drug loading, omitting step (3).

[0058] (1) Preparation of HA-PEG-b-PMAA Accurately weigh 40 mg of sodium hyaluronate and dissolve it in 10 mL of deionized water. Adjust the pH to 4.5 with 0.1 M HCl. Add 96 mg of EDC and 57 mg of NHS (molar ratio of carboxyl group: EDC: NHS (repeating unit) = 1:2:2). Stir at room temperature for 60 min to activate the solution and obtain activated hyaluronic acid. Dissolve 1.5 eq of NH2-PEG-b-PMAA in a small amount of PBS (pH 7.4) and add it dropwise to the activated hyaluronic acid solution. Adjust the pH to 7.4 with 0.1 M NaOH. Stir at room temperature for 24 h, then dialyze with deionized water for 48 h. Finally, freeze-dry to obtain HA-PEG-b-PMAA.

[0059] (2) Preparation of HA-PEG-b-PMAA targeted drug-loaded micelles Accurately weigh 10 mg of HA-PEG-b-PMAA and 5 mg of berberine, dissolve them in 5 mL of methanol, remove the solvent by rotary evaporation at 40 °C to form a thin film, and vacuum dry overnight. Add 2 mL of PBS to the film, hydrate at 60 °C for 60 min, sonicate at 40 W on ice for 5 min, collect and filter through a 0.45 μm filter membrane to obtain drug-loaded micelles, and store at 4 °C protected from light.

[0060] Comparative Example 2

[0061] This comparative example is basically the same as Example 1, except that the high amylose is replaced with an equal mass of ordinary corn starch.

[0062] (1) Preparation of HA-PEG-b-PMAA

[0063] Accurately weigh 100 mg of sodium hyaluronate and dissolve it in 10 mL of deionized water. Adjust the pH to 4.5 with 0.1 M HCl. Add 96 mg of EDC and 57 mg of NHS (molar ratio of carboxyl group: EDC: NHS (repeating unit) = 1:2:2). Stir at room temperature for 30 min to activate the solution and obtain activated hyaluronic acid. Dissolve 1.5 eq of NH2-PEG-b-PMAA in a small amount of PBS (pH 7.4) and add it dropwise to the activated hyaluronic acid solution. Adjust the pH to 7.4 with 0.1 M NaOH and stir at room temperature for 24 h. Then dialyze with deionized water for 48 h and finally freeze-dry to obtain HA-PEG-b-PMAA.

[0064] (2) Preparation of HA-PEG-b-PMAA targeted drug-loaded micelles

[0065] Accurately weigh 10 mg of HA-PEG-b-PMAA and 1 mg of berberine, dissolve them in 2 mL of methanol, remove the solvent by rotary evaporation at 40 °C to form a thin film, and vacuum dry overnight. Add 2 mL of PBS to the film, hydrate at 60 °C for 20 min, sonicate at 40 W on ice for 5 min, collect and filter through a 0.45 μm filter membrane to obtain drug-loaded micelles, and store at 4 °C protected from light.

[0066] Preparation of HA-PEG-b-PMAA-HAS targeted composite drug-carrying nanoparticles

[0067] Dissolve 0.5g of starch in 25ml of DMSO and gelatinize at 90℃ for 10min. Add berberine and stir for 5min. Cool to 40℃ and, while stirring, add dropwise the HA-PEG-b-PMAA targeted drug-loaded micelles. Continue stirring for 15min after addition. Dialyze the prepared sample in a dialysis bag (3000DA) for 48h, changing the water every 2 hours to remove impurities, obtaining targeted composite drug-loaded nanoparticles.

[0068] The drug loading and encapsulation efficiency of Examples 1-4 and Comparative Examples 1 and 2 were tested according to the above method, and the results are shown in Table 1.

[0069] Table 1. Drug loading and encapsulation efficiency tests sample Average particle size (nm) Encapsulation rate % Drug loading % Example 1 327 71.4 26.3 Example 2 339 77.7 28.0 Example 3 298 97.8 32.8 Example 4 314 91.3 31.4 Comparative Example 1 192 73.8 12.9 Comparative Example 2 627 91.6 19.4

[0070] This invention limits the scope of the patent. Various modifications and variations can be made to this invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this invention should be included within the scope of protection of this invention.

Claims

1. A method for preparing targeted composite drug-loaded nanoparticles and its application, characterized in that, The targeted composite delivery system is formed by a combination of starch and polymer micelles modified with targeting ligands.

2. The method for preparing targeted composite drug-carrying nanoparticles according to claim 1 and its application, characterized in that, The target ligand is hyaluronic acid. The carboxyl group of hyaluronic acid and the terminal amino group of PEG are condensed by EDC / NHS to form an amide bond, resulting in HA-PEG-b-PMAA.

3. The method for preparing targeted composite drug-loaded nanoparticles according to claim 1 and its application, characterized in that, The targeted ligand-modified polymer micelles are HA-PEG-b-PMAA micelles, which are formed by coupling NH2-PEG-b-PMAA with hyaluronic acid and then assembling them by thin-film hydration.

4. The method for preparing targeted composite drug-carrying nanoparticles according to claim 1 and its application, characterized in that, The targeted composite drug-loaded nanoparticles are polymer drug-loaded micelles modified with starch and targeted ligands. Specifically, the targeted composite drug-loaded nanoparticles are obtained by loading HA-PEG-b-PMAA drug-loaded micelles through structural changes caused by starch gelatinization and retrogradation.

5. The method for preparing targeted composite drug-carrying nanoparticles according to claim 1 and its application, characterized in that, The drug-loaded substance is selected from at least one of berberine, colchicine, curcumin, baicalin, artemisinin, kaempferol, and luteolin.

6. A method for preparing targeted composite drug-carrying nanoparticles according to any one of claims 1-5 and its application, characterized in that, Includes the following steps: (1) Dissolve sodium hyaluronate in deionized water, adjust the pH to 4.5, add EDC and NHS, and activate by stirring at room temperature; (2) Dissolve NH2-PEG-b-PMAA in a small amount of PBS (pH 7.4) and add it dropwise to the product of step (1) above. Adjust the pH to 7.4, stir the reaction at room temperature for 24 h, and then freeze dry to obtain HA-PEG-b-PMAA. (3) Dissolve the product obtained in step (2) in an organic solvent with the drug at a mass ratio of 1 to 30:1, then remove the solvent by rotary evaporation to form a thin film, dry under vacuum, add PBS, hydrate and sonicate, collect and filter to obtain HA-PEG-b-PMAA drug-loaded micelles, and store at 4 °C in the dark. (4) Add the gelatinized starch dropwise to the HA-PEG-b-PMAA drug-loaded micelle solution obtained in step (3), stir, dialyze to remove impurities, filter through a filter membrane, collect the filtrate, and obtain the targeted composite nano-drug-loaded particles.

7. The preparation method according to claim 6, characterized in that, In step (1), the volume of deionized water is 1-20 ml, the molar ratio of carboxyl group:EDC:NHS (repeating unit) of sodium hyaluronate is 1:2:2, the pH adjustment solvent is 0.1 M HCl, the activation conditions are stirring at room temperature for 10-60 min, and the molecular weight of the sodium hyaluronate is 5×10⁻⁶. 4 ~2×10 6 Da.

8. The preparation method according to claim 6, characterized in that, In step (2), the solvent for adjusting the pH is 0.1 M NaOH, and the reaction is carried out at room temperature with stirring for 12-24 h.

9. The preparation method according to claim 6, characterized in that, The organic solvent in step (3) is one or a mixture of methanol, ethanol, and acetone; the volume-to-mass ratio of the organic solvent to the HA-PEG-b-PMAA is 1-10 mL: 20 mg; the PBS volume is 1-20 mL. The hydration temperature is 60 °C, the hydration time is 15-60 min; the ice bath sonication time is 1-10 min; and filtration is performed using a 0.45 μm microporous membrane.

10. The preparation method according to claim 6, characterized in that, In step (4), the mass fraction of gelatinized starch is 1% to 20%; the solvents for gelatinized starch include water, DMSO, alkaline solution, concentrated salt solution, and ionic liquid; the dialysis solvent is pure water or physiological saline.