Tetrandrine and folic acid co-loaded nanoparticles as well as preparation method and application thereof
By using lyophilized nanoparticles containing tetrandrine, folic acid co-loaded nanoliposomes and hyaluronidase layers, the problem of insufficient efficacy of tetrandrine in the lungs was solved, achieving better pulmonary fibrosis inhibition and enhancing drug delivery and penetration into the lungs.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ANHUI UNIV OF SCI & TECH
- Filing Date
- 2026-03-13
- Publication Date
- 2026-05-12
AI Technical Summary
In the existing technology, tetrandrine has limited efficacy in treating pneumoconiosis fibrosis and is difficult to act directly on the lungs, which affects its efficacy.
A nanoparticle lyophilized powder was prepared by co-loading tetrandrine and folic acid with nanoliposomes and coating them with a hyaluronidase layer, combined with chitosan quaternary ammonium salt. The nanoparticles were then prepared into nanoparticles suitable for lung inhalation through electrostatic adsorption and lyophilization technology, thereby achieving effective drug delivery.
It enhances the inhibitory effect of tetrandrine and folic acid on pulmonary fibrosis, promotes drug penetration into the interstitial fibrosis by the hyaluronidase layer, and improves mucosal adhesion and permeability by chitosan quaternary ammonium salt, thereby enhancing the drug's effect on the lungs.
Smart Images
Figure CN122005497A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pulmonary fibrosis treatment technology, and in particular to a tetrandrine and folic acid co-loaded nanoparticle, its preparation method, and its application. Background Technology
[0002] Pneumoconiosis is a disease caused by long-term inhalation of inorganic mineral dust, characterized by diffuse nodular or reticular fibrosis of the lung tissue. The cause is often attributed to occupational or environmental factors, such as silica dust, asbestos dust, or carbon black dust. Pneumoconiosis is classified into many types, such as silicosis, coal worker's pneumoconiosis, graphite pneumoconiosis, and asbestosis. The causative factors are related to dust particle size, dust concentration, and exposure time.
[0003] Initially, patients may have no obvious symptoms, but as the disease progresses, the main symptoms include cough, sputum production, and shortness of breath. Complications include tuberculosis, pulmonary heart disease, and acute respiratory failure. The main treatments for pneumoconiosis include symptomatic treatment, medication, and removal from dusty work environments. Pulmonary rehabilitation is highly beneficial for relieving symptoms and improving quality of life. Patients with end-stage pneumoconiosis may require a lung transplant.
[0004] Tetrandrine has a clear effect in delaying the progression of fibrosis in pneumoconiosis, but the effect of using tetrandrine alone still needs to be improved; and currently, tetrandrine is mostly prepared in tablets or injections, which cannot act directly on the lungs, thus affecting its efficacy. Summary of the Invention
[0005] Based on the technical problems existing in the background technology, the present invention proposes a nanoparticle co-loaded with tetrandrine and folic acid, its preparation method and application. The freeze-dried powder of nanoparticles containing tetrandrine and folic acid described in the present invention has a good inhibitory effect on pulmonary fibrosis.
[0006] This invention proposes a nanoparticle comprising: tetrandrine, folic acid co-loaded nanoliposomes, and a hyaluronidase layer coated on the surface of the co-loaded nanoliposomes.
[0007] Preferably, the co-loaded nanoliposomes contain 1-6 wt% tetrandrine and 0.2-1.2 wt% folic acid.
[0008] Preferably, the carrier for the tetrandrine and folic acid co-loaded nanoliposomes is composed of lecithin, cationic lipids and cholesterol.
[0009] Preferably, the cationic lipid is at least one of (2,3-dioleopropyl)trimethylammonium chloride, dioleoylphosphatidylethanolamine, and dioleoyloxypropyldimethylammonium chloride.
[0010] Preferably, the molar ratio of lecithin, cationic lipids, and cholesterol is 1.5-2:1.5-2:1.
[0011] Preferably, tetrandrine and folic acid co-loaded nanoliposomes are prepared by thin-film dispersion method.
[0012] The specific steps of the above-mentioned thin film dispersion method include: dissolving tetrandrine, lecithin, cationic lipids, and cholesterol in an organic solvent and evaporating them to form a film; adding folic acid buffer solution for hydration to obtain a suspension; sonicating, homogenizing and passing through a membrane; and dialysis with water to obtain an aqueous dispersion of tetrandrine and folic acid co-loaded nanoliposomes.
[0013] The above-mentioned tetrandrine and folic acid co-loaded nanoliposomes can be stored in solution for later use.
[0014] The ratio of the total weight of the above-mentioned lecithin, cationic lipids and cholesterol to the weight of tetrandrine is 17-53:1.
[0015] The organic solvents mentioned above can be ethanol, chloroform, etc., and the lecithin mentioned above can be soybean lecithin, etc.
[0016] The above evaporation is vacuum rotary evaporation; the preferred evaporation temperature is 40-45℃, the preferred evaporation speed is 80-120 rpm, and the preferred evaporation time is 2-4 hours.
[0017] The solvent for the above-mentioned folic acid buffer solution is phosphate buffer, and its pH is preferably 7.3-7.5.
[0018] The preferred ratio of the above-mentioned folic acid buffer solution to lecithin is 10 ml: 0.75-1.5 mmol.
[0019] The preferred hydration temperature is 40-45℃, and the preferred hydration time is 1-1.5h. Stirring is performed simultaneously during hydration, with a preferred stirring speed of 300-500 rpm; the preferred ultrasonication time is 10-20min.
[0020] The molecular weight cutoff of the dialysis bag is 3500; the dialysis time is 8-12 hours, and the water is changed every 4 hours.
[0021] Preferably, the co-loaded nanoliposomes and the hyaluronidase layer are coated through electrostatic interaction.
[0022] Preferably, the particle size of the nanoparticles is 100-300 nm.
[0023] The present invention also proposes a method for preparing the above-mentioned nanoparticles, comprising the following steps: mixing tetrandrine, folic acid co-loaded nanoliposome aqueous dispersion and hyaluronidase aqueous solution, electrostatic adsorption, solid-liquid separation, and obtaining nanoparticles.
[0024] Preferably, the mass fraction of the hyaluronidase aqueous solution is 0.05-0.15 wt%.
[0025] Preferably, the mass fraction of tetrandrine and folic acid co-loaded nanoliposomes in the aqueous dispersion is 2-3 wt%.
[0026] Preferably, the volume ratio of tetrandrine, folic acid co-loaded nanoliposome aqueous dispersion and hyaluronidase aqueous solution is 1:0.8-1.
[0027] Preferably, electrostatic adsorption is performed at room temperature for 0.5-1 h.
[0028] The present invention also proposes a lyophilized nanoparticle powder comprising: the above-mentioned nanoparticles and chitosan quaternary ammonium salt.
[0029] Preferably, the weight ratio of nanoparticles to chitosan quaternary ammonium salt is 1:0.8-1.2.
[0030] Preferably, the chitosan quaternary ammonium salt is N-(2-hydroxy)propyl-3-methylammonium chloride chitosan, abbreviated as HTCC.
[0031] The present invention also proposes a method for preparing the above-mentioned lyophilized nanoparticle powder, comprising the following steps: dispersing nanoparticles in water, adding chitosan quaternary ammonium salt and mixing, electrostatic adsorption, and lyophilizing to obtain lyophilized nanoparticle powder.
[0032] The electrostatic adsorption conditions were as follows: electrostatic adsorption at room temperature for 0.5 h.
[0033] In the aforementioned lyophilized nanoparticle powder, the content of tetrandrine can be 0.8-2.6 wt%, and the content of folic acid can be 0.15-0.55 wt%. The aforementioned lyophilized nanoparticle powder can also be uniformly dispersed in physiological saline or PBS buffer, and then placed in a suitable nebulizer to achieve nebulized drug delivery.
[0034] A small amount of surfactant can also be added to prevent agglomeration and improve atomization efficiency.
[0035] The present invention also proposes the application of the above-mentioned nanoparticles and the above-mentioned lyophilized nanoparticle powder in the preparation of drugs for inhibiting and / or treating pulmonary fibrosis.
[0036] Preferably, pulmonary fibrosis is pneumoconiosis; more preferably, pulmonary fibrosis is silicosis.
[0037] Beneficial effects
[0038] This invention uses tetrandrine and folic acid in combination to enhance the effect of inhibiting pulmonary fibrosis; and prepares them into nanoparticles and lyophilized powder, which can be directly applied to the lungs to further improve efficacy.
[0039] Since tetrandrine is insoluble in water while folic acid is readily soluble in water, this invention uses lecithin, cationic lipids, and cholesterol as carriers to prepare co-loaded nanoliposomes, achieving co-loading of tetrandrine and folic acid. Furthermore, the co-loaded nanoliposomes carry a positive charge, which electrostatically adsorbs with a negatively charged aqueous solution of hyaluronidase, causing hyaluronidase to be coated on the surface of the tetrandrine and folic acid co-loaded nanoliposomes, thus obtaining nanoparticles.
[0040] The combination of tetrandrine and folic acid in the nanoparticles can enhance the inhibitory effect on pulmonary fibrosis. Furthermore, the hyaluronidase layer can decompose hyaluronic acid and digest the extracellular matrix. It can effectively digest hyaluronic acid in pulmonary fibrosis foci, penetrate the intercellular matrix, promote the effective delivery of tetrandrine and folic acid, and improve the efficacy.
[0041] Negatively charged nanoparticles are mixed with positively charged chitosan quaternary ammonium salt, and electrostatic adsorption occurs, allowing the chitosan quaternary ammonium salt to coat the nanoparticles. After lyophilization, the chitosan quaternary ammonium salt can achieve a particle size of 1-3 μm for the lyophilized nanoparticle powder, meeting the particle size requirements for inhaled lung formulations. Furthermore, the chitosan quaternary ammonium salt exhibits good biocompatibility, biodegradability, mucosal adhesion, and permeability enhancement. In conjunction with hyaluronidase, it further promotes the effective delivery of tetrandrine and folic acid, thereby improving drug efficacy. Attached Figure Description
[0042] Figure 1 These are typical images of HE staining of mouse lung tissue in each group. AF represents the normal control group, silicosis group, Example 1 group, Comparative Example 1 group, Comparative Example 2 group, and Comparative Example 3 group, in that order.
[0043] Figure 2 Typical images of Masson staining of lung tissue from mice in each group are shown. AF represents the normal control group, silicosis group, Example 1 group, Comparative Example 1 group, Comparative Example 2 group, and Comparative Example 3 group, respectively. Detailed Implementation
[0044] The technical solution of the present invention will be described in detail below through specific embodiments. However, it should be clearly stated that these embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention.
[0045] Example 1 A method for preparing nanoparticles includes the following steps: 0.2 g of tetrandrine, 2.2741 g (0.003 mol) of soybean lecithin, 2.2321 g (0.003 mol) of dioleoylphosphatidylethanolamine, and 0.7733 g (0.002 mol) of cholesterol were dissolved in ethanol and evaporated under reduced pressure at 40 °C for 4 h to form a film. The evaporation speed was 80 rpm. 40 ml of a phosphate buffer solution (pH=7.4) containing 0.04 g of folic acid was added, and the mixture was then evaporated at 40 °C for 400 h. The mixture was stirred at rpm for 1.5 h to obtain a suspension; it was sonicated for 20 min, homogenized and passed through a membrane, and then placed in a dialysis bag with a molecular weight cutoff of 3500. Dialysis was performed with water for 12 h, with the water changed every 4 h to adjust the solid content, resulting in an aqueous dispersion of tetrandrine and folic acid co-loaded nanoliposomes with a mass fraction of 2.5 wt% (in the co-loaded nanoliposomes, the encapsulation rate of tetrandrine was 96.3% and the content was 3.5 wt%, and the encapsulation rate of folic acid was 97.3% and the content was 0.70 wt%). The above-mentioned tetrandrine, folic acid co-loaded nanoliposome aqueous dispersion and 0.1 wt% hyaluronidase aqueous solution were mixed in equal volumes, electrostatically adsorbed at room temperature for 0.5 h, centrifuged, and washed with water to obtain nanoparticles with an average particle size of 189 nm.
[0046] A method for preparing a lyophilized nanoparticle powder includes the following steps: 0.3g of the above-mentioned nanoparticles are dispersed in 30ml of water, 0.3g of N-(2-hydroxy)propyl-3-methylammonium chloride chitosan is added, the mixture is stirred and mixed, electrostatic adsorption is performed at room temperature for 0.5h, and then lyophilized to obtain the lyophilized nanoparticle powder (the content of tetrandrine in the lyophilized nanoparticle powder is 1.68wt% and the content of folic acid is 0.34wt%). The aggregates formed by the obtained lyophilized powder have a particle size of 1-3μm, which meets the particle size requirements for inhaled lung preparations.
[0047] Example 2 A method for preparing nanoparticles includes the following steps: 0.1 g of tetrandrine, 2.2741 g (0.003 mol) of soybean lecithin, 2.2321 g (0.003 mol) of dioleoylphosphatidylethanolamine, and 0.7733 g (0.002 mol) of cholesterol were dissolved in ethanol and evaporated under reduced pressure at 45 °C for 2 h to form a film. The evaporation speed was 120 rpm. 20 ml of a phosphate buffer solution (pH=7.4) containing 0.02 g of folic acid was added, and the mixture was then evaporated at 45 °C for 400 h. The mixture was stirred at rpm for 1 hour to obtain a suspension; it was sonicated for 20 minutes, homogenized and passed through a membrane, and then placed in a dialysis bag with a molecular weight cutoff of 3500. Dialysis was performed with water for 8 hours, with the water changed every 4 hours to adjust the solid content, resulting in an aqueous dispersion of tetrandrine and folic acid co-loaded nanoliposomes with a mass fraction of 2.5 wt% (in the co-loaded nanoliposomes, the encapsulation rate of tetrandrine was 96.8% and the content was 1.8 wt%, and the encapsulation rate of folic acid was 97.9% and the content was 0.36 wt%). The above-mentioned tetrandrine, folic acid co-loaded nanoliposome aqueous dispersion and 0.1 wt% hyaluronidase aqueous solution were mixed in equal volumes, electrostatically adsorbed at room temperature for 0.5 h, centrifuged, and washed with water to obtain nanoparticles.
[0048] A method for preparing a lyophilized nanoparticle powder includes the following steps: 0.3g of the above nanoparticles are dispersed in 30ml of water, 0.3g of N-(2-hydroxy)propyl-3-methylammonium chloride chitosan is added, the mixture is stirred and mixed, electrostatic adsorption is performed at room temperature for 0.5h, and then lyophilized to obtain the lyophilized nanoparticle powder (the content of tetrandrine in the lyophilized nanoparticle powder is 0.87wt% and the content of folic acid is 0.17wt%).
[0049] Example 3 A method for preparing nanoparticles includes the following steps: 0.3 g of tetrandrine, 2.2741 g (0.003 mol) of soybean lecithin, 2.0958 g (0.003 mol) of (2,3-dioleoxypropyl)trimethylammonium chloride, and 0.7733 g (0.002 g) of cholesterol were dissolved in ethanol and evaporated under reduced pressure at 40 °C for 4 h to form a film. The evaporation speed was 100 rpm. 40 ml of a phosphate buffer solution (pH=7.4) containing 0.06 g of folic acid was added, and the mixture was then evaporated at 40 °C for 400 h. The mixture was stirred at rpm for 1.5 h to obtain a suspension; it was sonicated for 20 min, homogenized and passed through a membrane, and then placed in a dialysis bag with a molecular weight cutoff of 3500. Dialysis was performed with water for 12 h, with the water changed every 4 h to adjust the solid content, resulting in an aqueous dispersion of tetrandrine and folic acid co-loaded nanoliposomes with a mass fraction of 2.5 wt% (in the co-loaded nanoliposomes, the encapsulation rate of tetrandrine was 96.0% and the content was 5.3 wt%, and the encapsulation rate of folic acid was 97.1% and the content was 1.1 wt%). The above-mentioned tetrandrine, folic acid co-loaded nanoliposome aqueous dispersion and 0.1 wt% hyaluronidase aqueous solution were mixed in equal volumes, electrostatically adsorbed at room temperature for 0.5 h, centrifuged, and washed with water to obtain nanoparticles.
[0050] A method for preparing a lyophilized nanoparticle powder includes the following steps: 0.3g of the above nanoparticles are dispersed in 30ml of water, 0.3g of N-(2-hydroxy)propyl-3-methylammonium chloride chitosan is added, the mixture is stirred and mixed, electrostatic adsorption is performed at room temperature for 0.5h, and then lyophilized to obtain the lyophilized nanoparticle powder (the content of tetrandrine in the lyophilized nanoparticle powder is 2.55wt% and the content of folic acid is 0.53wt%).
[0051] Comparative Example 1 Without adding folic acid, the process was the same as in Example 1, and the resulting lyophilized nanoparticle powder was obtained.
[0052] Comparative Example 2 Take 0.3g of the nanoparticles prepared in Example 1 and disperse them in 30ml of water. Add 0.3g of glucose, stir and mix well, and freeze dry to obtain freeze-dried nanoparticle powder.
[0053] Comparative Example 3 Take 12 ml of the aqueous dispersion of tetrandrine and folic acid co-loaded nanoliposomes prepared in Example 1 with a mass fraction of 2.5 wt%, add 0.3 g of N-(2-hydroxy)propyl-3-methylammonium chloride chitosan, stir and mix well, freeze dry to obtain freeze-dried nanoparticle powder.
[0054] A mouse model of silicosis fibrosis was established using silica suspension. The therapeutic effects of the lyophilized nanoparticles obtained in Example 1 and Comparative Examples 1-3 on silicosis fibrosis were investigated. The specific steps are as follows: Forty-eight male C57BL / 6 mice weighing 18-20g were randomly divided into six groups (n=8) after one week of acclimatization feeding: normal control group, silicosis group, Example 1 group, Comparative Example 1 group, Comparative Example 2 group, and Comparative Example 3 group. Except for the normal control group, the mice in the other groups were anesthetized by isoflurane inhalation and then slowly instilled 50 μL of 50 mg / mL silica suspension into the nasal cavity (3 times / day, for 28 consecutive days).
[0055] Treatment began the day after successful model establishment (referred to as Day 1) and continued for 28 consecutive days. The lyophilized nanoparticles from Example 1 and Comparative Examples 1-3 were uniformly dispersed in physiological saline and administered to mice in each group via nebulization in a closed induction chamber. The dosage was 50 mg / kg body weight, calculated based on the drug component tetrandrine. The silicosis group received an equal volume of physiological saline via nebulization. The normal control group received no treatment. On day 28 after the last administration, all mice were sacrificed, and the following tests were performed: General indicators: Weigh the mouse's body weight and lung wet weight, and calculate the lung coefficient = (lung wet weight / body weight × 100%).
[0056] Bronchoalveolar lavage fluid (BALF) analysis: BALF was collected and the contents of hydroxyproline (HYP), transforming growth factor β1 (TGF-β1), interleukin-1β (IL-1β), interleukin-18 (IL-18), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were detected by enzyme-linked immunosorbent assay.
[0057] Pathological analysis of lung tissue: Lung tissue was taken, fixed, dehydrated, embedded, and sectioned, and then stained with HE and Masson staining, respectively. The pathological changes of inflammation and fibrosis in the lung tissue were observed under an optical microscope.
[0058] HYP (hypoallergenic amino acid) is a unique and characteristic amino acid component of collagen fibers, serving as a core, specific, and sensitive biochemical indicator reflecting the progression and severity of organ fibrosis. In the pathological process of silicosis, inhaled silica dust continuously induces lung inflammation and tissue damage, ultimately leading to irreversible fibrotic lesions characterized by excessive and abnormal deposition of collagen in the pulmonary interstitium and structural disorder. Quantitative analysis of HYP content in lung tissue allows for an objective and precise quantification of the degree of fibrosis.
[0059] TGF-β1 is a recognized key factor in promoting fibrosis, playing a crucial role as both a "master switch" and an "engine" in the pathogenesis of silicosis. During the progression of silicosis, the phagocytosis of silica dust by macrophages induces a persistent inflammatory response and cell damage. In this process, a large number of cells (such as activated macrophages, epithelial cells, and fibroblasts) are activated and secrete and release TGF-β1. Elevated TGF-β1 levels in bronchoalveolar lavage fluid (BALF) reflect the activation of a key upstream pathway in silicosis fibrosis, marking the progression of the disease from a simple inflammatory response to a fibrosis-driven stage characterized by tissue remodeling and collagen deposition. Many antifibrotic drugs target the TGF-β1 signaling pathway directly or indirectly. A decrease in TGF-β1 levels signifies successful inhibition of the pro-fibrotic "master switch," indicating that downstream processes such as fibroblast activation and excessive collagen synthesis will be suppressed, ultimately leading to a reduction in HYP levels and improvement in fibrotic lesions.
[0060] In a mouse model of silicosis, the combined detection of the dynamic levels of IL-1β, IL-18, TNF-α, and IL-6 is a key strategy for systematically elucidating the molecular mechanisms of silica-induced lung injury, accurately assessing disease progression, and screening potential therapeutic targets. These four cytokines constitute the core regulatory network of silicosis from the initiation of acute inflammation to the evolution of chronic fibrosis: IL-1β and IL-18, as marker effector molecules of NLRP3 inflammasome activation, show a synchronous increase that is direct evidence of pyroptosis of alveolar macrophages after silica stimulation, and can keenly reflect the degree of early lung tissue damage before pathological changes appear; TNF-α, as an upstream pro-inflammatory core factor, accelerates neutrophil recruitment by amplifying the inflammatory cascade, and its level changes are directly related to the intensity of the acute inflammatory storm; while IL-6, as a key mediator with both pro-inflammatory and pro-fibrotic functions, not only participates in the acute immune response, but also directly promotes myofibroblast transformation and collagen deposition by mediating signal transduction and activation of the STAT3 (STAT3) pathway, and is an important hub for the transformation of inflammation into fibrosis. This composite index is highly correlated with decreased lung function, collagen content, and pathological scores, providing a standardized bridge for clinical translational research and offering indispensable experimental evidence for early diagnosis, risk stratification, and targeted drug development of silicosis.
[0061] The results are as follows Figure 1-2 As shown in Table 1.
[0062] Figure 1 These are typical images of HE staining of mouse lung tissue in each group. AF represents the normal control group, silicosis group, Example 1 group, Comparative Example 1 group, Comparative Example 2 group, and Comparative Example 3 group, in that order.
[0063] Figure 2 Typical images of Masson staining of lung tissue from mice in each group are shown. AF represents the normal control group, silicosis group, Example 1 group, Comparative Example 1 group, Comparative Example 2 group, and Comparative Example 3 group, respectively.
[0064] Table 1 Test Results
[0065] Note: Compared with the normal control group, ## P <0.01; compared with the silicosis group, Compared with Example 1, △△ P <0.01, △ P <0.05; compared with Comparative Example 1, ○○ P <0.01, ○ P <0.05.
[0066] From Table 1 and Figure 1-2 It can be seen that although the lung coefficient, HYP content, TGF-β1 content, IL-1β content, IL-18 content, TNF-α content, and IL-6 content of Example 1 were higher than those of the normal control group, they were much lower than those of the silicosis group and Comparative Examples 1-3, indicating that the lyophilized nanoparticle powder of the present invention has a good inhibitory effect on silicosis fibrosis. Compared with Comparative Example 1, Example 1 has a better inhibitory effect on silicosis fibrosis through the synergistic effect of tetrandrine and folic acid. Compared with Comparative Examples 2-3, Example 1 has a better inhibitory effect on silicosis fibrosis through the synergistic effect of hyaluronidase and chitosan quaternary ammonium salt.
[0067] In summary, this invention significantly enhances the inhibitory effect on pulmonary fibrosis through the synergistic effect of tetrandrine and folic acid. Furthermore, by combining hyaluronidase with chitosan quaternary ammonium salt, it effectively digests hyaluronic acid within pulmonary fibrosis foci, penetrating the interfibrotic matrix and promoting drug penetration. It also improves drug adhesion to the mucosa, preventing drug excretion and further enhancing drug permeability for effective drug delivery. This invention achieves a multi-faceted synergistic effect through the aforementioned substances, resulting in a superior inhibitory effect on silicosis fibrosis.
[0068] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.
Claims
1. A nanoparticle, characterized in that, include: Tetrandrine, folic acid co-loaded nanoliposomes and a hyaluronidase layer coated on the surface of the co-loaded nanoliposomes.
2. The nanoparticles according to claim 1, characterized in that, The co-loaded nanoliposomes contain 1-6 wt% tetrandrine and 0.2-1.2 wt% folic acid.
3. The nanoparticles according to claim 1 or 2, characterized in that, The carrier for the tetrandrine and folic acid co-loaded nanoliposomes is composed of lecithin, cationic lipids and cholesterol; preferably, the cationic lipid is at least one of (2,3-dioleopropyl)trimethylammonium chloride, dioleoylphosphatidylethanolamine, and dioleoyloxypropyldimethylammonium chloride; preferably, the molar ratio of lecithin, cationic lipids and cholesterol is 1.5-2:1.5-2:1; preferably, the tetrandrine and folic acid co-loaded nanoliposomes are prepared by thin film dispersion method.
4. The nanoparticles according to any one of claims 1-3, characterized in that, The co-loaded nanoliposomes and the hyaluronidase layer are coated by electrostatic interaction; preferably, the particle size of the nanoparticles is 100-300 nm.
5. A method for preparing nanoparticles as described in any one of claims 1-4, characterized in that, The process includes the following steps: mixing tetrandrine, folic acid co-loaded nanoliposome aqueous dispersion and hyaluronidase aqueous solution, electrostatic adsorption, solid-liquid separation, and obtaining nanoparticles.
6. The method for preparing nanoparticles according to claim 5, characterized in that, The mass fraction of the hyaluronidase aqueous solution is 0.05-0.15 wt%; preferably, the mass fraction of the tetrandrine and folic acid co-loaded nanoliposome aqueous dispersion is 2-3 wt%; preferably, the volume ratio of the tetrandrine and folic acid co-loaded nanoliposome aqueous dispersion to the hyaluronidase aqueous solution is 1:0.8-1; preferably, electrostatic adsorption is performed at room temperature for 0.5-1 h.
7. A lyophilized nanoparticle powder, characterized in that, include: The nanoparticles and chitosan quaternary ammonium salt according to any one of claims 1-4.
8. The lyophilized nanoparticle powder according to claim 7, characterized in that, The weight ratio of nanoparticles to chitosan quaternary ammonium salt is 1:0.8-1.2; preferably, the chitosan quaternary ammonium salt is N-(2-hydroxy)propyl-3-methylammonium chloride chitosan.
9. A method for preparing the lyophilized nanoparticle powder as described in claim 7 or 8, characterized in that, The process includes the following steps: dispersing nanoparticles in water, adding chitosan quaternary ammonium salt and mixing, electrostatic adsorption, and freeze-drying to obtain freeze-dried nanoparticle powder.
10. The use of the nanoparticles as described in any one of claims 1-4, or the lyophilized nanoparticle powder as described in claim 7 or 8, in the preparation of a drug for inhibiting and / or treating pulmonary fibrosis; preferably, the pulmonary fibrosis is pneumoconiosis fibrosis.