Targeting nano composite material based on manganese dioxide growing on surface of mesoporous silicon dioxide as well as preparation and application of targeting nano composite material
By growing manganese dioxide on the surface of mesoporous silica and modifying WYRGRL polypeptides to form targeted nanocomposites, the limitations of the binding of median porous silica and manganese dioxide in the prior art are solved, and the drug is efficiently loaded, anti-inflammatory and chondrocyte targeting is achieved, providing a highly effective drug delivery vehicle suitable for osteoarthritis treatment.
Patent Information
- Application Number
- CN202411920137.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-25
- Publication Date
- 2025-03-28
AI Technical Summary
The prior art has not yet effectively combined mesoporous silica with manganese dioxide, and has not fully utilized the advantages of both, especially in applications in drug delivery systems.
By growing manganese dioxide on the mesoporous silica surface and modifying the WYRGRL polypeptide on its surface, the targeted nanocomposite material is enhanced, thereby enhancing its role in drug delivery systems.
This targeted nanocomposite not only can effectively load drugs and exert anti-inflammatory effects, but also has chondrocyte targeting, providing an efficient drug delivery vehicle suitable for the treatment of osteoarthritis.
Smart Images
Figure CN119701009A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of composite materials, and relates to a targeted nano composite material based on mesoporous silicon dioxide surface-grown manganese dioxide, and the preparation and application thereof. Background Art
[0002] Due to the unique structural properties of mesoporous particles, such as uniform pore size and long-range ordered pore structure, these porous structures are widely used in different fields such as catalysis, adsorption, separation, sensing and biomedicine. Among various mesoporous materials, mesoporous silica nanoparticles (MSNs) are a promising class of porous materials with excellent surface properties, including high specific surface area and pore size. MSNs are submicron-sized structures with a large number of pores in the nanostructure to load various molecules. In addition, they have good biocompatibility, controllable size, and easy surface modification.
[0003] In addition, manganese dioxide (MnO2) nanoparticles themselves can be used not only as nanocarriers for drug delivery, but also as therapeutic drugs. MnO2 nanomaterials have enzyme-like activity (such as catalytic reaction on H2O2), redox activity (such as unique reaction with GSH), high sensitivity to pH, and degradation into Mn 2+ Due to its properties such as rapid clearance from the body, it has been widely used in the construction of biosensors, imaging and disease treatment.
[0004] However, there is no literature report on organically combining MSNs and MnO2 to overcome the limitations of the two materials. The present invention is proposed based on this. Summary of the invention
[0005] The purpose of the present invention is to overcome the defects of the above-mentioned prior art and to provide a targeted nanocomposite material based on manganese dioxide grown on the surface of mesoporous silica and its preparation and application, which can overcome the limitations of simple MSNs nanoparticles and MnO2, and can also combine the advantages of the two to enhance its role in drug delivery systems.
[0006] The purpose of the present invention can be achieved by the following technical solutions:
[0007] In a first aspect, the present invention provides a targeted nanocomposite material based on manganese dioxide grown on the surface of mesoporous silica, which is obtained by sequentially modifying the surface of mesoporous silica with manganese dioxide and a WYRGRL polypeptide.
[0008] Furthermore, the particle size of the targeted nanocomposite material is 140-180 nm, preferably about 160 nm, the thickness of the surface-modified manganese dioxide is 10-35 nm, preferably about 20 nm, the mesopores are evenly distributed, and the specific surface area is large.
[0009] In the second aspect, the present invention provides a method for preparing a targeted nanocomposite material based on the growth of manganese dioxide on the surface of mesoporous silica, wherein manganese dioxide is first grown on the surface of mesoporous silica to obtain a MnO2@MSNs nanocomposite, and then PAH( 4-aminohippuric acid ) and PAA (polyacrylic acid), and finally connected with the amino group in the WYRGRL polypeptide to obtain a WYRGRL polypeptide-modified composite material, which is the target product.
[0010] Furthermore, the mesoporous silica has a perfect spherical structure and a particle size of 100-120 nm, and is prepared by the following method:
[0011] After the hexadecyltrimethylammonium chloride, triethanolamine and water are uniformly mixed, the mixture is stirred in an oil bath, and then the tetraethyl orthosilicate-cyclohexane solution is added, and the stirring is continued. The obtained product is centrifuged and washed to obtain mesoporous silica;
[0012] The ratio of the addition amount of hexadecyltrimethylammonium chloride, triethanolamine, and tetraethyl orthosilicate-cyclohexane solution is 9 g:300 mL:100 mL, and the concentration of the tetraethyl orthosilicate-cyclohexane solution is 10%;
[0013] The temperature of the oil bath stirring is 50-70°C and the time is 1.5-2.5h;
[0014] The stirring temperature is continued to be 50-70°C for 1.5-2.5 days.
[0015] Furthermore, the growth process of the manganese dioxide is specifically as follows:
[0016] Manganese acetate tetrahydrate and ammonium chloride are added to the dispersion of mesoporous silica, and then potassium permanganate solution is added while stirring, followed by ammonia solution, and stirring is continued. The obtained precipitate is washed and dried to obtain a MnO2@MSNs nanocomposite.
[0017] The ratio of the added amounts of manganese acetate tetrahydrate, ammonium chloride, mesoporous silica, potassium permanganate solution, and ammonia solution is 7 mg: 10 mg: 5 mg: 3 mg: 10 μL;
[0018] The concentration of the potassium permanganate solution was 10 mg / mL, and the concentration of the ammonia solution was 28%.
[0019] Further, the process of modifying the WYRGRL polypeptide is specifically as follows:
[0020] The PAH solution and the MnO2@MSNs nanocomplex are mixed for a primary reaction. The primary reaction product is washed and then added to the PAA solution for a secondary reaction. The secondary reaction product is washed and then added to the WYRGRL polypeptide solution for a tertiary reaction. The mixture is centrifuged to obtain the WYRGRL polypeptide-coupled MnO2@MSNs nanoparticles, which are the target product.
[0021] The ratio of the addition amount of PAH solution, MnO2@MSNs nanocomposite, PAA solution, and WYRGRL polypeptide solution is (8-12) mg: (45-55) mg: (45-55) mg: 3 mg, preferably 10 mg: 50 mg: 50 mg: 3 mg;
[0022] The concentrations of the PAH solution, PAA solution, and WYRGRL polypeptide solution are (4-6) mg / mL, (4-6) mg / mL, and (2.5-3.5) mg / mL, respectively, preferably 5 mg / mL, 5 mg / mL, and 3 mg / mL, respectively. Furthermore, the PAH is polyallylamine hydrochloride, and PAA is polyacrylic acid.
[0023] In a third aspect, the present invention provides a targeted nanocomposite material based on manganese dioxide grown on the surface of mesoporous silica for use in the preparation of drug delivery. When used, the targeted nanocomposite material of the present invention can not only efficiently load drugs but also exert anti-inflammatory effects and has chondrocyte targeting.
[0024] In a fourth aspect, the present invention provides a drug delivery complex, comprising a STING inhibitor and a targeted nanocomposite material based on manganese dioxide grown on the surface of mesoporous silica as described above, wherein the drug content is about 3.8%.
[0025] Furthermore, the STING inhibitor is C-178.
[0026] In a fifth aspect, the present invention provides a use of a drug delivery complex in the preparation of a joint cavity targeted delivery system for the treatment of osteoarthritis.
[0027] Compared with the prior art, the present invention has the following advantages:
[0028] (1) By modifying the surface of mesoporous silica with manganese dioxide, it can not only efficiently load drugs but also exert anti-inflammatory effects. By surface-modifying WYRGRL peptide, it has chondrocyte targeting.
[0029] (2) The particle size of the nanocomposite material is about 160 nm, the surface manganese dioxide thickness is about 20 nm, the mesopore distribution is uniform, and the specific surface area is large.
[0030] (3) In addition, the nanocomposite material has catalytic enzyme activity and ROS response; it can efficiently load drugs and simultaneously release them slowly. This highly efficient drug delivery carrier can provide a targeted delivery system for intra-articular administration in the treatment of osteoarthritis. BRIEF DESCRIPTION OF THE DRAWINGS
[0031] Figure 1 The scanning electron microscope image and the transmission electron microscope image of the MSNs nanoparticles in Example 1 of the present invention are shown;
[0032] Figure 2 The scanning electron microscope image and the transmission electron microscope image of the MnO2@MSNs nanoparticles in Example 2 of the present invention;
[0033] Figure 3 This is a graph showing the release of C-178 by the C-178@mSMW nanomaterial in Example 4 of the present invention;
[0034] Figure 4 This is a diagram showing the uptake of mSMW nanomaterials by chondrocytes in Example 5. DETAILED DESCRIPTION
[0035] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.
[0036] In the following examples, PAH solution and WYRGRL polypeptide were purchased from Sigma-Aldrich (USA).
[0037] The rest of the raw materials or processing techniques, unless otherwise specified, are conventional commercially available raw materials or conventional processing techniques in the art.
[0038] Embodiment 1:
[0039] Preparation of MSNs:
[0040] First, 12 mL of hexadecyltrimethylammonium chloride, 0.36 g of triethanolamine, and 108 mL of water were mixed and stirred in an oil bath at 60 °C for 120 min. Then, 40 mL of 10 wt% ethyl orthosilicate-cyclohexane solution was added to the mixture and stirred in an oil bath at 60 °C for 2 d. Finally, the MSNs were washed by centrifugation with pure water and ethanol.
[0041] Figure 1 The scanning electron microscope and transmission electron microscope images of the synthesized MSNs nanoparticles clearly show that the prepared MSNs nanoparticles have a perfect spherical structure with a particle size of 100-120nm.
[0042] Embodiment 2:
[0043] Synthesis of MnO2@MSNs:
[0044] 70 mg of manganese acetate tetrahydrate and 100 mg of ammonium chloride were added to 20 mL of 2.5 mg of MSNs dispersion, and 3 mL of 10 mg / mL potassium permanganate solution was added while stirring at room temperature. Then 100 μL of ammonia solution was added and stirring was continued at room temperature for 12 h. The precipitate was then washed with ultrapure water and dried to obtain the MnO2@MSNs (mSM) nanocomposite.
[0045] Figure 2 The scanning electron microscope and transmission electron microscope images of the synthesized mSM nanoparticles show that the mSM nanoparticles have a pollen-like structure with uniform particle size and a particle size distribution of about 130 nm.
[0046] Embodiment 3:
[0047] MnO2@MSNs surface modified with WYRGRL peptide
[0048] First, 10 mL of 5 mg / mL PAH solution was added to 5 mL of 2 mg / mL MnO2@MSNs, and the reaction was continued at room temperature for 2 h, and the precipitate was washed with ultrapure water. Then, the precipitate was added to 10 mL of 5 mg / mL PAA solution, and the reaction was continued at room temperature for 2 h, and the precipitate was washed with ultrapure water. Finally, the precipitate was added to 1 mL of 3 mg / mL WYRGRL solution, and the reaction was continued at room temperature for 12 h. After centrifugation, WYRGRL peptide-coupled MnO2@MSNs (mSMW) nanoparticles were obtained.
[0049] Embodiment 4:
[0050] mSMW loading and releasing C-178
[0051] C-178 was added to the mSMW dispersion and stirred overnight in the dark. Then, C-178 was adsorbed into the pores using vacuum to obtain C-178@mSMW.
[0052] The release of C-178 was studied by dialysis. The C-178@mSMW solution was placed in a dialysis bag. The dialysis bag was placed on 0.01M PBS (50mL, pH 7.4) and stirred at 100rpm and 37°C. At predetermined time intervals, 1.0mL of release buffer was removed and 1.0mL of fresh PBS was added. The concentration of C-178 in the solution was determined and its release rate was calculated.
[0053] Figure 3The release of C-178 by nanomaterials shows that compared with MSNs, the release of C-178 by mSMW nanomaterials is slower, which is due to the delayed release of the drug after MnO2 coating.
[0054] Embodiment 5:
[0055] Uptake of mSMW nanomaterials by chondrocytes
[0056] Chondrocytes in the logarithmic growth phase were digested with trypsin, centrifuged, and inoculated into 6-well plates, which were then placed in an incubator for overnight culture. Then, different concentrations of FITC-labeled mSMW nanomaterial solutions were added and cultured for another 6 hours. DAPI was added for nucleus staining, and the cells were observed under a microscope and photographed.
[0057] Figure 4 This is the uptake of mSMW nanomaterials by chondrocytes. It can be seen from the figure that strong green fluorescence is present in chondrocytes, and the fluorescence intensity is dose-dependent.
[0058] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.
Claims
1. A targeted nanocomposite material based on manganese dioxide grown on the surface of mesoporous silica, characterized in that: It is obtained by sequentially modifying the surface of mesoporous silica with manganese dioxide and WYRGRL polypeptide.
2. The targeted nanocomposite material based on mesoporous silica surface-grown manganese dioxide according to claim 1, characterized in that: The particle size is 140-180 nm, and the thickness of the surface-modified manganese dioxide is 10-35 nm.
3. The method for preparing a targeted nanocomposite material based on mesoporous silica surface-grown manganese dioxide according to claim 1 or 2, characterized in that: First, manganese dioxide is grown on the surface of mesoporous silica to obtain a MnO2@MSNs nanocomposite, and then PAH and PAA are modified on the surface, and finally connected with the amino group in the WYRGRL polypeptide to obtain a WYRGRL polypeptide-modified composite material, which is the target product.
4. The method for preparing a targeted nanocomposite material based on mesoporous silica surface-grown manganese dioxide according to claim 3, characterized in that: The mesoporous silica has a perfect spherical structure and a particle size of 100-120 nm and is prepared by the following method: After the hexadecyltrimethylammonium chloride, triethanolamine and water are uniformly mixed, the mixture is stirred in an oil bath, and then the tetraethyl orthosilicate-cyclohexane solution is added, and the stirring is continued. The obtained product is centrifuged and washed to obtain mesoporous silica; The ratio of the addition amount of hexadecyltrimethylammonium chloride, triethanolamine, and tetraethyl orthosilicate-cyclohexane solution is 9 g:300 mL:100 mL, and the concentration of the tetraethyl orthosilicate-cyclohexane solution is 10%; The temperature of the oil bath stirring is 50-70°C and the time is 1.5-2.5h; The stirring temperature is continued to be 50-70°C for 1.5-2.5 days.
5. The method for preparing a targeted nanocomposite material based on mesoporous silica surface-grown manganese dioxide according to claim 3, characterized in that: The growth process of the manganese dioxide is specifically as follows: Manganese acetate tetrahydrate and ammonium chloride are added to the dispersion of mesoporous silica, and then potassium permanganate solution is added while stirring, followed by ammonia solution, and stirring is continued. The obtained precipitate is washed and dried to obtain a MnO2@MSNs nanocomposite. The ratio of the added amounts of manganese acetate tetrahydrate, ammonium chloride, mesoporous silica, potassium permanganate solution, and ammonia solution is 7 mg: 10 mg: 5 mg: 3 mg: 10 μL; The concentration of the potassium permanganate solution was 10 mg / mL, and the concentration of the ammonia solution was 28%.
6. The method for preparing a targeted nanocomposite material based on mesoporous silica surface-grown manganese dioxide according to claim 3, characterized in that: The process of modifying the WYRGRL polypeptide is as follows: The PAH solution and the MnO2@MSNs nanocomplex are mixed for a primary reaction. The primary reaction product is washed and then added to the PAA solution for a secondary reaction. The secondary reaction product is washed and then added to the WYRGRL polypeptide solution for a tertiary reaction. The mixture is centrifuged to obtain the WYRGRL polypeptide-coupled MnO2@MSNs nanoparticles, which are the target product. The mass ratio of PAH solution, MnO2@MSNs nanocomposite, PAA solution, and WYRGRL peptide solution is (8-12) mg: (45-55) mg: (45-55) mg: 3 mg; The concentrations of the PAH solution, PAA solution, and WYRGRL polypeptide solution are (4-6) mg / mL, (4-6) mg / mL, and (2.5-3.5) mg / mL, respectively.
7. Use of the targeted nanocomposite material based on mesoporous silica surface-grown manganese dioxide as claimed in claim 1 or 2 in the preparation of drug delivery.
8. A drug delivery complex, characterized in that It comprises a STING inhibitor and a targeted nanocomposite material based on manganese dioxide grown on the surface of mesoporous silica as claimed in claim 1 or 2, wherein the mass content of the STING inhibitor is 3.5-4%.
9. Use of the drug delivery complex as claimed in claim 8 in the preparation of a joint cavity targeted delivery system for the treatment of osteoarthritis.