Silicon dioxide-metal organic framework composite material with Janus structure as well as preparation method and application of silicon dioxide-metal organic framework composite material

Abstract

The invention provides a silicon dioxide-metal organic framework composite material with a Janus structure as well as a preparation method and application of the silicon dioxide-metal organic framework composite material. The composite material comprises a metal organic framework and silicon dioxide, the composite material comprises a first surface and a second surface opposite to the first surface, the first surface and the second surface jointly form the surface of the composite material, the first surface is formed by silicon dioxide, and the second surface is formed by a metal organic framework. The composite material can be used as a drug carrying platform to realize directional movement and graded drug release; the composite material also has the functions of microwave thermal therapy and microwave power therapy, and can realize collaborative therapy on tumors. The composite material has a Janus structure, namely has two drug loading ends with different properties, so that the selection of the drug loading ends is variable and can be designed, a nano drug loading platform for different tumor treatment can be customized and designed according to a treatment mode, and the application prospect of the nano drug loading platform is greatly expanded.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to a silica-metal organic framework composite material with a Janus structure, and a preparation method and application thereof. The composite material has the characteristics of directional movement, graded drug release, microwave thermal therapy, and microwave dynamic therapy, and can be used as a drug-carrying platform to achieve the purpose of synergistic tumor treatment. Background Art

[0002] The combined treatment of multiple drugs can achieve complementary therapeutic functions to achieve better therapeutic effects. Among them, the nano-drug delivery platform loaded with multiple drugs is the key to achieving multiple drugs targeting tumor sites. However, the current multi-drug nano-drug delivery platform lacks precise consideration of drug release time and release location. Studies have shown that breaking through the tumor barrier, controlling and programming the release of drugs in the nano-platform for spatiotemporal delivery are of great significance to improving the efficacy of cancer treatment. The interaction between drugs or the cycle specificity of the action of chemotherapeutic drugs leads to the inability to achieve 1+1>2 in drug treatment effects; in addition, the complex tumor environment faced by drug delivery (cell membrane barriers, high interstitial pressure, dense connective tissue, etc.) leads to uneven distribution of nano-drug delivery platforms in tumors, as well as insufficient enrichment of delivered drugs, resulting in insufficient concentration of chemotherapeutic drugs at the targeted location. Therefore, it is very important to improve the therapeutic effectiveness of chemotherapeutic drugs, and the key way to achieve this is to use a new drug delivery platform that can control drug release in both spatial and temporal dimensions.

[0003] Compared with the core-shell structure, the nano drug delivery platform with Janus structure has a more excellent directional movement effect in the process of tumor treatment. At present, the nano drug delivery platform with Janus structure is mainly realized by self-assembly of single-component materials or multi-component materials, which has high requirements for interface binding ability and special properties of the material itself, and the synthesis method is relatively cumbersome and the yield is low. In order to meet the application needs of constructing a multifunctional drug delivery platform to achieve effective tumor treatment, it is urgent to establish a nano drug delivery platform with Janus structure that has simple steps, convenient operation and high yield. Summary of the invention

[0004] In order to more accurately realize the spatiotemporal controlled release and functional integration of a nano drug delivery platform for a variety of different drugs, the present invention provides a silica-metal organic framework composite material with a Janus structure and a preparation method and application thereof, wherein the composite material can be used as a drug delivery platform to achieve directional movement and graded drug release; the composite material also has the functions of microwave thermal therapy and microwave dynamic therapy, and can achieve synergistic treatment of tumors. Since the composite material has a Janus structure, that is, it has two drug delivery ends with different properties, the choice of drug delivery ends is varied and designable, so the nano drug delivery platform for different tumor treatments can be customized and designed according to the treatment method, greatly expanding its application prospects.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] A silicon dioxide-metal organic framework composite material with a Janus structure, the composite material comprising a metal organic framework and silicon dioxide; the composite material comprising a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silicon dioxide, and the second surface is formed by the metal organic framework.

[0007] According to an embodiment of the present invention, the metal organic framework grows on a portion of the surface of silicon dioxide and forms more than one metal organic framework; or, the metal organic framework grows on a portion of the surface of silicon dioxide and forms a cluster consisting of multiple metal organic frameworks.

[0008] According to an embodiment of the present invention, the silica is selected from mesoporous silica and / or dendritic silica.

[0009] According to an embodiment of the present invention, the mass of silicon dioxide in the silicon dioxide-metal organic framework composite material having a Janus structure accounts for 65%-75% of the total mass of the silicon dioxide-metal organic framework composite material having a Janus structure.

[0010] According to an embodiment of the present invention, the mass of the metal organic framework in the silica-metal organic framework composite material with a Janus structure accounts for 25%-35% of the total mass of the silica-metal organic framework composite material with a Janus structure.

[0011] According to an embodiment of the present invention, the silica-metal organic framework composite material having a Janus structure further includes a first drug and a second drug.

[0012] According to an embodiment of the present invention, the first drug is loaded on the first surface; preferably, the first drug is loaded in the pores of silica.

[0013] According to an embodiment of the present invention, the first drug is selected from at least one of doxorubicin (DOX) and pentafluorouracil (5-FU).

[0014] According to an embodiment of the present invention, the second drug is loaded on the first surface and the second surface; preferably, the second drug is loaded on the surface of silica and the surface of the metal organic framework.

[0015] According to an embodiment of the present invention, the second drug is selected from at least one of 6-diazo-5-oxo-L-norleucine (DON) and apatinib (AP).

[0016] According to an embodiment of the present invention, the loading rate of the first drug is 3%-20%; the loading rate of the second drug is 5%-20%.

[0017] The present invention provides a drug-carrying platform, which comprises the above-mentioned silicon dioxide-metal organic framework composite material with Janus structure.

[0018] According to an embodiment of the present invention, the drug loading platform has a core-shell structure, which includes a core and an outer coating layer coated on the outer surface of the core; the core includes the above-mentioned silica-metal organic framework composite material with Janus structure.

[0019] According to an embodiment of the present invention, the outer coating layer includes at least one of menthol, myristyl alcohol, hyaluronic acid and polyethylene glycol.

[0020] According to an embodiment of the present invention, the outer coating layer includes a first outer coating layer and a second outer coating layer, the first outer coating layer is coated on the outer surface of the core, and the second outer coating layer is coated on the outer surface of the first outer coating layer; the first outer coating layer includes at least one of menthol and tetradecanol; the second outer coating layer includes at least one of hyaluronic acid and polyethylene glycol.

[0021] According to an embodiment of the present invention, the drug loading platform further comprises an inner coating layer, and the inner coating layer is coated on the outer surface of the silica-metal organic framework composite material with a Janus structure that carries the first drug.

[0022] According to an embodiment of the present invention, the second drug is loaded on the inner coating layer.

[0023] According to an embodiment of the present invention, the inner coating layer includes at least one of polydopamine and chitosan.

[0024] According to one embodiment of the present invention, the drug loading platform includes a silica-metal organic framework composite material with a Janus structure; the composite material includes a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by the metal organic framework.

[0025] According to one embodiment of the present invention, the drug loading platform includes a silica-metal organic framework composite material with a Janus structure; the composite material includes a first drug, a second drug, a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by a metal organic framework; the first drug is loaded on the first surface; the second drug is loaded on the first surface and the second surface.

[0026] Preferably, the first drug is loaded on silica; the second drug is loaded on silica and the metal organic framework. Also preferably, the first drug is loaded in the pores of silica; the second drug is loaded on the surface of silica and on the surface of the metal organic framework.

[0027] According to one embodiment of the present invention, the drug loading platform has a core-shell structure, which includes a core and an outer coating layer coated on the outer surface of the core; the core includes a silica-metal organic framework composite material with a Janus structure; the composite material includes a first drug, a second drug, a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by a metal organic framework; the first drug is loaded on the first surface; the second drug is loaded on the first surface and the second surface; the outer coating layer includes at least one of menthol, tetradecyl alcohol, hyaluronic acid and polyethylene glycol.

[0028] Preferably, the outer coating layer includes a first outer coating layer and a second outer coating layer, the first outer coating layer is coated on the outer surface of the core, and the second outer coating layer is coated on the outer surface of the first outer coating layer; the first outer coating layer includes at least one of menthol and tetradecanol; the second outer coating layer includes at least one of hyaluronic acid and polyethylene glycol.

[0029] According to one embodiment of the present invention, the drug loading platform includes a silica-metal organic framework composite material with a Janus structure and an inner coating layer; the composite material includes a first drug, a second drug, a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by a metal organic framework; the first drug is loaded on the first surface; the inner coating layer is coated on the outer surface of the silica-metal organic framework composite material with a Janus structure loaded with the first drug; the second drug is loaded on the inner coating layer; the inner coating layer includes at least one of polydopamine and chitosan.

[0030] According to one embodiment of the present invention, the drug loading platform has a core-shell structure, which includes a core and an outer coating layer coated on the outer surface of the core; the core includes a silica-metal organic framework composite material with a Janus structure and an inner coating layer; the composite material includes a first drug, a second drug, a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by a metal organic framework; the first drug is loaded on the first surface; the inner coating layer is coated on the outer surface of the silica-metal organic framework composite material with a Janus structure loaded with the first drug; the second drug is loaded on the inner coating layer; the outer coating layer includes at least one of menthol, tetradecanol, hyaluronic acid and polyethylene glycol; the inner coating layer includes at least one of polydopamine and chitosan.

[0031] The present invention also provides a method for preparing the above-mentioned silicon dioxide-metal organic framework composite material having a Janus structure, the method comprising the following steps:

[0032] Silica and a solution containing a metal salt are mixed, and the mixed system is separated after being evenly mixed to obtain a solid component; a solution containing an imidazole organic ligand is added to the solid component to react to prepare the silica-metal organic framework composite material with a Janus structure.

[0033] According to an embodiment of the present invention, the mass ratio of the silicon dioxide to the metal salt is 45-90:540; the mass ratio of the metal salt to the imidazole organic ligand is 1-2:2.

[0034] The present invention also provides a method for preparing the above-mentioned silicon dioxide-metal organic framework composite material having a Janus structure, the method comprising the following steps:

[0035] (1) mixing silica, a first drug, an alcohol solvent, ammonia water with or without addition, and tetraethyl orthosilicate with or without addition, and reacting the mixture to prepare silica loaded with the first drug;

[0036] (2) mixing the silica loaded with the first drug in step (1) and the solution containing the metal salt, and separating the mixed system after being evenly mixed to obtain a solid component; adding a solution containing an imidazole organic ligand to the solid component to react, and preparing a silica-metal organic framework composite material with a Janus structure loaded with the first drug;

[0037] (3) Mixing the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2), an alcohol solvent, and a second drug, and performing negative pressure suction after mixing evenly to prepare a silica-metal organic framework composite material with a Janus structure.

[0038] According to an embodiment of the present invention, in step (1), the mass ratio of the silica to the first drug is 1-3:1; the mass ratio of the silica to the alcohol solvent is 1-3:2; the mass ratio of the silica to aqueous ammonia is 1-3:0.02; the mass ratio of the silica to tetraethyl orthosilicate is 1-3:0.08.

[0039] According to an embodiment of the present invention, in step (1), silica, a first drug and an alcohol solvent are first mixed, and then ammonia water and tetraethyl orthosilicate are added to the mixed solution to react to prepare silica loaded with the first drug.

[0040] According to an embodiment of the present invention, in step (2), the mass ratio of the silica loaded with the first drug and the metal salt in step (1) is 45-90:540; the mass ratio of the metal salt and the imidazole organic ligand is 1-2:2.

[0041] According to an embodiment of the present invention, in step (3), the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the alcohol solvent is 3-15:1; the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the second drug is 3-15:1.

[0042] The present invention also provides a method for preparing a drug-carrying platform, the method comprising the following steps:

[0043] (1) mixing silica, a first drug, an alcohol solvent, ammonia water with or without addition, and tetraethyl orthosilicate with or without addition, and reacting the mixture to prepare silica loaded with the first drug;

[0044] (2) mixing the silica loaded with the first drug in step (1) and the solution containing the metal salt, and separating the mixed system after being evenly mixed to obtain a solid component; adding a solution containing an imidazole organic ligand to the solid component to react, and preparing a silica-metal organic framework composite material with a Janus structure loaded with the first drug;

[0045] (3') mixing the silica-metal organic framework composite material with a Janus structure carrying the first drug in step (2), ammonia water, a substance forming an inner coating layer and an alcohol solvent, and reacting them, adding the second drug after the reaction is completed, mixing them evenly and performing negative pressure suction to prepare the drug loading platform; or,

[0046] (3") mixing the silica-metal organic framework composite material with a Janus structure carrying the first drug in step (2), the second drug and the material forming the outer coating layer, and performing negative pressure suction and / or dispersion to prepare the drug loading platform; or,

[0047] (3') mixing the silica-metal organic framework composite material with a Janus structure loaded with the first drug of step (2), ammonia water, a substance forming an inner coating layer, and an alcohol solvent, and reacting them. After the reaction is completed, adding the second drug and a substance forming an outer coating layer, and performing negative pressure suction and / or dispersion to prepare the drug loading platform.

[0048] According to an embodiment of the present invention, in step (1), the mass ratio of the silica to the first drug is 1-3:1; the mass ratio of the silica to the alcohol solvent is 1-3:2; the mass ratio of the silica to aqueous ammonia is 1-3:0.02; the mass ratio of the silica to tetraethyl orthosilicate is 1-3:0.08.

[0049] According to an embodiment of the present invention, in step (1), silica, a first drug and an alcohol solvent are first mixed, and then ammonia water and tetraethyl orthosilicate are added to the mixed solution to react to prepare silica loaded with the first drug.

[0050] According to an embodiment of the present invention, in step (2), the mass ratio of the silica loaded with the first drug and the metal salt in step (1) is 45-90:540; the mass ratio of the metal salt and the imidazole organic ligand is 1-2:2.

[0051] According to an embodiment of the present invention, in step (3') and step (3'"), the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the second drug is 3-15:1.

[0052] According to an embodiment of the present invention, in step (3"), the silica-metal organic framework composite material with a Janus structure carrying the first drug of step (2), the second drug and the substance forming the first outer coating layer are mixed, and negative pressure suction is performed, and the solid component obtained after suction is dispersed in a solution containing the substance forming the second outer coating layer to prepare the drug loading platform.

[0053] According to an embodiment of the present invention, in step (3"), the silica-metal organic framework composite material with a Janus structure loaded with the first drug, the second drug and part of the material forming the first outer coating layer of step (2) are subjected to negative pressure suction, and after the negative pressure suction is completed, part of the material forming the first outer coating layer is added for negative pressure suction.

[0054] According to an embodiment of the present invention, in step (3'"), after the reaction is completed, the second drug and the substance forming the first outer coating layer are added and mixed, and negative pressure suction is performed. The solid component obtained after the suction is dispersed in a solution containing the substance forming the second outer coating layer to prepare the drug loading platform.

[0055] According to an embodiment of the present invention, in step (3'"), after the reaction is completed, the second drug and part of the material forming the first outer coating layer are added for negative pressure suction, and after the negative pressure suction is completed, part of the material forming the first outer coating layer is added for negative pressure suction.

[0056] The present invention also provides application of the silicon dioxide-metal organic framework composite material with Janus structure and the drug-carrying platform in drug delivery.

[0057] The present invention also provides the use of the silicon dioxide-metal organic framework composite material with Janus structure and the drug-carrying platform in the preparation of drugs for treating tumors.

[0058] The present invention also provides a method for drug delivery, in particular a method for chemotherapy drug delivery, which comprises using the above-mentioned silica-metal organic framework composite material or drug-carrying platform with Janus structure.

[0059] Beneficial effects of the present invention:

[0060] (1) The present invention provides a silica-metal organic framework composite material with a Janus structure. The silica-metal organic framework composite material with a Janus structure has the ability of directional movement, achieving penetration of tumor cells, and controlled release of drugs with graded drug release, and can achieve the release of a first drug (such as a chemotherapy drug, an immune drug, a gene drug, etc.) at a more appropriate time and location, enhance the endocytosis of the composite material by tumor cells, and improve the therapeutic effect of chemotherapy drugs, and has good clinical application prospects. The silica-metal organic framework composite material with a Janus structure also has the functions of microwave hyperthermia and microwave dynamic response to achieve synergistic treatment of tumors. Since the composite material has a Janus structure, that is, it has two drug-carrying ends with different properties, the choice of the drug-carrying end is varied and designable, so that a nano drug-carrying platform for different tumor treatments can be customized and designed according to the treatment method, which greatly expands its application prospects.

[0061] (2) The method for preparing the silica-metal organic framework composite material with Janus structure provided by the present invention provides a new idea for the synthesis of Janus nanomaterials. The present invention combines silica with a metal organic framework and controls the synthesis by means of a local adsorption method. The preparation steps of the composite material are simple, the operation is convenient, and the yield is high.

[0062] (3) The silica-metal organic framework composite material with Janus structure of the present invention has good biocompatibility and controllable size. It can be targeted to the tumor area through the high permeability and retention effect of solid tumors, enhance the production of reactive oxygen species, regulate the high redox characteristics of the tumor microenvironment, produce oxygen and reactive oxygen species under high hydrogen peroxide conditions, improve the hypoxic environment, and further promote the synergistic treatment of microwave thermotherapy and microwave power therapy. The microwave responsive tumor diagnosis and treatment preparation finally obtained has good clinical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 This is a transmission electron microscope characterization image of the dendritic silica (DMSNs) prepared in Example 1.

[0064] Figure 2 This is a transmission electron microscope characterization image of the silica-metal organic framework composite material with a Janus structure prepared in Example 7.

[0065] Figure 3 This is a transmission electron microscopy characterization image of the drug loading platform prepared in Example 13, which includes a silica-metal organic framework composite material with a Janus structure.

[0066] Figure 4This is a preparation route for the drug delivery platform comprising a silica-metal organic framework composite material having a Janus structure prepared in Example 13.

[0067] Figure 5 Schematic diagram of the oxygen generation effect of the silicon dioxide-metal organic framework composite material with Janus structure prepared in Example 7.

[0068] Figure 6 This is a schematic diagram for comparing the kinetic diffusion coefficients of the silica-metal organic framework composite material with a Janus structure prepared in Example 7.

[0069] Figure 7 This is a schematic diagram showing a comparison of the mean square displacement of the silicon dioxide-metal organic framework composite material with a Janus structure obtained in Example 7.

[0070] Figure 8 Schematic diagram of the microwave heating curve of the silica-metal organic framework composite material with Janus structure prepared in Example 7 in physiological saline.

[0071] Fig. 9 Schematic diagram for characterizing the microwave dynamic performance of the materials prepared in Example 1 and Example 7.

[0072] Fig.10 The drug release of the drug-loading platform comprising the silica-metal organic framework composite material having a Janus structure prepared in Example 13 was carried out under acidic phosphate buffer solution conditions. DETAILED DESCRIPTION

[0073] <Silica-metal organic framework composites with Janus structure>

[0074] As mentioned above, the present invention provides a silica-metal organic framework composite material with a Janus structure, wherein the composite material includes a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by the metal organic framework.

[0075] According to an embodiment of the present invention, the Janus structure is a double-sided structure. In the present invention, the Janus structure is formed by a metal organic framework and silicon dioxide.

[0076] According to an embodiment of the present invention, the metal organic framework grows on a portion of the surface of silicon dioxide to form a silicon dioxide-metal organic framework composite material having a Janus structure.

[0077] According to an embodiment of the present invention, the metal organic framework grows on a portion of the surface of silicon dioxide and forms more than one metal organic framework; or, the metal organic framework grows on a portion of the surface of silicon dioxide and forms a cluster consisting of multiple metal organic frameworks.

[0078] According to an embodiment of the present invention, the metal organic framework grows on a part of the surface of silicon dioxide and obtains 1-5 metal organic frameworks, for example, 1, 2, 3, 4 or 5 metal organic frameworks.

[0079] According to an embodiment of the present invention, the first surface is at a negative potential, that is, the surface of the silicon dioxide is at a negative potential.

[0080] According to an embodiment of the present invention, the second surface has a positive potential, that is, the surface of the metal organic framework has a positive potential.

[0081] According to an embodiment of the present invention, the longest diameter of the silica-metal organic framework composite material having a Janus structure is 150-330 nm, for example, 150 nm, 180 nm, 200 nm, 220 nm, 240 nm, 250 nm, 260 nm, 280 nm, 300 nm, 320 nm or 330 nm.

[0082] <Silicon Dioxide>

[0083] According to an embodiment of the present invention, the type, structure and size of the silicon dioxide can be controlled.

[0084] According to an embodiment of the present invention, the silica is selected from mesoporous silica and / or dendritic silica; preferably, the silica is selected from dendritic silica.

[0085] According to an embodiment of the present invention, the pore structure of the mesoporous silica is in a grid shape, and the pore size of the mesoporous silica is 2-20 nm, for example, 5 nm, 8 nm, 10 nm, 12 nm, 15 nm or 18 nm.

[0086] According to an embodiment of the present invention, the pore structure of the dendritic silica is a tree-like pore, and the pore size of the dendritic silica is 25-50 nm, for example, 25 nm, 28 nm, 30 nm, 35 nm, 40 nm, 45 nm or 50 nm.

[0087] According to an embodiment of the present invention, the median particle size of the silica is 150-250 nm, for example, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 210 nm, 220 nm, 230 nm, 240 nm or 250 nm.

[0088] According to an embodiment of the present invention, the mesoporous silica can be prepared by a method known in the art; illustratively, the mesoporous silica is prepared by the following method:

[0089] (i) adding hexadecyltrimethylammonium bromide and ammonia water into water, and then adding ethyl orthosilicate to carry out reaction. After the reaction is completed, washing away the template, and preparing the mesoporous silica.

[0090] According to an embodiment of the present invention, the dendritic silica may be prepared by a method known in the art; illustratively, the dendritic silica may be prepared by the following method:

[0091] (ii) triethanolamine is added to water, and after being evenly dispersed, hexadecyltrimethylammonium bromide and sodium salicylate are added, and then silane is added to react. After the reaction is completed, the template is washed away with acid to prepare the dendritic silica.

[0092] According to an embodiment of the present invention, in step (ii), the silane is selected from at least one of tetraethyl orthosilicate and bis[3-(triethoxysilyl)propyl]-tetrasulfide.

[0093] According to an embodiment of the present invention, the mass of silicon dioxide in the silicon dioxide-metal organic framework composite material with a Janus structure accounts for 65%-75% of the total mass of the silicon dioxide-metal organic framework composite material with a Janus structure, for example, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 71%, 73%, 74% or 75%.

[0094] According to an embodiment of the present invention, the silica can achieve loading of a first drug and a second drug, wherein the first drug and the second drug are defined as described above.

[0095] <Metal-organic frameworks>

[0096] According to an embodiment of the present invention, the type, structure and size of the metal organic framework can be controlled.

[0097] According to an embodiment of the present invention, the metal organic framework is selected from at least one of a cobalt-based metal organic framework material, a zinc-based metal organic framework material, a copper-based metal organic framework material, and a manganese-based metal organic framework material.

[0098] According to an embodiment of the present invention, the organic ligand of the metal organic framework is selected from imidazole organic ligands, such as imidazole (IM), 2-methylimidazole (MIM), 2-ethylimidazole (EIM), 2-nitroimidazole (NIM), 4-chloroimidazole (CIM), 4-bromoimidazole (BRIM), 4-nitroimidazole (NIM), 4,5-dichloroimidazole (DCIM), benzimidazole (BIM), 3-azabenzimidazole (ABIM), 5-chlorobenzimidazole (CBIM), 5,6-dimethylbenzimidazole (DMBIM), 5-bromobenzimidazole (BRBIM), 5-nitrobenzimidazole (NBIM), 5-azabenzimidazole (ABIM), 4-cyanoimidazole (CNIM), imidazole-2-carboxaldehyde (2-ICA) and purine (PUR).

[0099] According to an embodiment of the present invention, the metal organic framework is selected from ZIF-67 formed by metal cobalt salt and 2-methylimidazole (MIM) or ZIF-90 formed by metal zinc salt and imidazole-2-carboxaldehyde.

[0100] According to an embodiment of the present invention, the median particle size of the metal organic framework is 30-80 nm, for example, 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm or 80 nm.

[0101] According to an embodiment of the present invention, the mass of the metal organic framework in the silica-metal organic framework composite material with a Janus structure accounts for 25%-35% of the total mass of the silica-metal organic framework composite material with a Janus structure, for example, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34% or 35%.

[0102] According to an embodiment of the present invention, the metal organic framework can realize the loading of a second drug, and the definition of the second drug is as described above.

[0103] <First drug and second drug>

[0104] According to an embodiment of the present invention, the silica-metal organic framework composite material having a Janus structure further includes a first drug and a second drug.

[0105] According to an embodiment of the present invention, the difference in release time of the first drug and the second drug is achieved by loading the first drug and the second drug at different positions of the silica-metal organic framework composite material having a Janus structure. This is mainly because the degradation rate of the metal organic framework is much greater than the degradation rate of silica, resulting in the rapid release of the second drug loaded on the metal organic framework, while the first drug loaded on silica is slowly released due to the encapsulation of silica and the slow degradation of silica.

[0106] According to an embodiment of the present invention, the first drug is loaded on the first surface; preferably, the first drug is loaded in the pores of silica.

[0107] According to an embodiment of the present invention, the first drug is selected from drugs with good alcohol solubility and chemotherapeutic effect. Preferably, the first drug is selected from at least one of doxorubicin (DOX) and pentafluorouracil (5-FU).

[0108] According to an embodiment of the present invention, the second drug is loaded on the first surface and the second surface; preferably, the second drug is loaded on the surface of silica and the surface of the metal organic framework.

[0109] According to an embodiment of the present invention, the second drug is selected from drugs with good alcohol solubility or water solubility and tumor microenvironment improvement effect. Preferably, the second drug is selected from at least one of 6-diazo-5-oxo-L-norleucine (DON) and apatinib (AP).

[0110] According to an embodiment of the present invention, the loading rate of the first drug is 3%-20%, preferably 5%-17%, for example 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%. The loading rate of the first drug refers to the percentage of the mass of the first drug to the total mass of the silica-metal organic framework composite material with a Janus structure.

[0111] According to an embodiment of the present invention, the loading rate of the second drug is 5%-20%, preferably 7-14%, for example, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%. The loading rate of the second drug refers to the percentage of the mass of the second drug to the total mass of the silica-metal organic framework composite material with a Janus structure.

[0112] <Characteristics of Silica-MOF Composites with Janus Structure>

[0113] According to an embodiment of the present invention, the silica-metal organic framework composite material with a Janus structure has the characteristics of directional movement, graded drug release, microwave thermal therapy, and microwave dynamic therapy.

[0114] According to an embodiment of the present invention, the silica-metal organic framework composite material with a Janus structure has a good directional motion effect and has the ability of graded drug release, can break through the tumor barrier (high interstitial pressure, cell membrane, etc.), and achieve the difference in drug release time at the tumor site. Specifically, the silica-metal organic framework composite material with a Janus structure can generate gas (such as oxygen) as a power, and can show an excellent directional motion effect; the silica-metal organic framework composite material with a Janus structure has good drug loading performance and drug delivery performance, can improve drug loading capacity, and also has a drug release control function, that is, it has the characteristics of graded drug release.

[0115] According to an embodiment of the present invention, the silica-metal organic framework composite material with a Janus structure has a good microwave thermal therapy effect, has good microwave heat conversion performance under microwave irradiation, is a good microwave thermal sensitizer, and can effectively kill tumor cells.

[0116] According to an embodiment of the present invention, the silica-metal organic framework composite material with a Janus structure has a good microwave power therapy effect. It can promote electron and energy transfer under microwave irradiation, and catalyze hydrogen peroxide to produce oxygen, thereby releasing reactive oxygen, which is beneficial to alleviate hypoxia in the tumor microenvironment, cascade enhance the generation of reactive oxygen, and induce tumor cell apoptosis. It is a good microwave power sensitizer and can cooperate with microwave hyperthermia to specifically kill tumor cells.

[0117] <Drug loading platform>

[0118] As mentioned above, the present invention provides a drug-carrying platform, which includes the above-mentioned silica-metal organic framework composite material with Janus structure.

[0119] According to an embodiment of the present invention, the drug loading platform has a core-shell structure, which includes a core and an outer coating layer coated on the outer surface of the core; the core includes the above-mentioned silica-metal organic framework composite material with Janus structure.

[0120] According to an embodiment of the present invention, the outer coating layer includes at least one of menthol, myristyl alcohol, hyaluronic acid and polyethylene glycol.

[0121] According to an embodiment of the present invention, the outer coating layer includes a first outer coating layer and a second outer coating layer, the first outer coating layer is coated on the outer surface of the core, and the second outer coating layer is coated on the outer surface of the first outer coating layer; the first outer coating layer includes at least one of menthol and tetradecanol; the second outer coating layer includes at least one of hyaluronic acid and polyethylene glycol.

[0122] According to an embodiment of the present invention, the thickness of the outer coating layer is 2-10nm, for example, 2nm, 3nm, 4nm, 5nm, 6nm, 8nm or 10nm. Preferably, the thickness of the first outer coating layer is 2-8nm, and the thickness of the second outer coating layer is 2-8nm.

[0123] According to an embodiment of the present invention, the introduction of the outer coating layer can play a role of temperature-sensitive control and can be used as a release switch for the second drug and a microwave-sensitizing switch; the introduction of the outer coating layer can improve the drug loading capacity of the drug loading platform; the introduction of the outer coating layer can improve the biocompatibility, safety, passive targeting and long-circulation performance of the drug loading platform in the body.

[0124] According to an embodiment of the present invention, the menthol and / or tetradecanol can play a role of temperature-sensitive control and can be used as a release switch and microwave-sensitized switch for the second drug; specifically, the menthol and / or tetradecanol can be liquefied at a specific temperature to achieve the release of the second drug; that is, when microwaves are applied to the drug-carrying platform, the menthol and / or tetradecanol can be liquefied to achieve the release of the second drug. The menthol and / or tetradecanol can increase the drug loading rate of the second drug through physical encapsulation. Since the degradation rate of the metal organic framework is fast, the release speed of the second drug is fast, and the menthol and / or tetradecanol can also control the release time of the second drug to give full play to its role.

[0125] According to an embodiment of the present invention, the introduction of polyethylene glycol and / or hyaluronic acid can improve the biocompatibility, safety, passive targeting and long-circulation performance of the drug-carrying platform in vivo.

[0126] According to an embodiment of the present invention, the drug loading platform further comprises an inner coating layer, and the inner coating layer is coated on the outer surface of the silica-metal organic framework composite material with a Janus structure that carries the first drug.

[0127] According to an embodiment of the present invention, the second drug is loaded on the inner coating layer.

[0128] According to an embodiment of the present invention, the inner coating layer includes at least one of polydopamine and chitosan.

[0129] According to an embodiment of the present invention, the thickness of the inner coating layer is 2-10 nm, for example, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 8 nm or 10 nm.

[0130] According to an embodiment of the present invention, the introduction of the inner coating layer can improve the biocompatibility of the carrier platform.

[0131] <Structure and composition of drug delivery platform>

[0132] According to one embodiment of the present invention, the drug loading platform includes a silica-metal organic framework composite material with a Janus structure; the composite material includes a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by the metal organic framework.

[0133] According to one embodiment of the present invention, the drug loading platform includes a silica-metal organic framework composite material with a Janus structure; the composite material includes a first drug, a second drug, a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by a metal organic framework; the first drug is loaded on the first surface; the second drug is loaded on the first surface and the second surface.

[0134] Preferably, the first drug is loaded on silica; the second drug is loaded on silica and the metal organic framework. Also preferably, the first drug is loaded in the pores of silica; the second drug is loaded on the surface of silica and on the surface of the metal organic framework.

[0135] According to one embodiment of the present invention, the drug loading platform has a core-shell structure, which includes a core and an outer coating layer coated on the outer surface of the core; the core includes a silica-metal organic framework composite material with a Janus structure; the composite material includes a first drug, a second drug, a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by a metal organic framework; the first drug is loaded on the first surface; the second drug is loaded on the first surface and the second surface; the outer coating layer includes at least one of menthol, tetradecyl alcohol, hyaluronic acid and polyethylene glycol.

[0136] Preferably, the outer coating layer includes a first outer coating layer and a second outer coating layer, the first outer coating layer is coated on the outer surface of the core, and the second outer coating layer is coated on the outer surface of the first outer coating layer; the first outer coating layer includes at least one of menthol and tetradecanol; the second outer coating layer includes at least one of hyaluronic acid and polyethylene glycol.

[0137] According to one embodiment of the present invention, the drug loading platform includes a silica-metal organic framework composite material with a Janus structure and an inner coating layer; the composite material includes a first drug, a second drug, a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by a metal organic framework; the first drug is loaded on the first surface; the inner coating layer is coated on the outer surface of the silica-metal organic framework composite material with a Janus structure loaded with the first drug; the second drug is loaded on the inner coating layer; the inner coating layer includes at least one of polydopamine and chitosan.

[0138] According to one embodiment of the present invention, the drug loading platform has a core-shell structure, which includes a core and an outer coating layer coated on the outer surface of the core; the core includes a silica-metal organic framework composite material with a Janus structure and an inner coating layer; the composite material includes a first drug, a second drug, a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by a metal organic framework; the first drug is loaded on the first surface; the inner coating layer is coated on the outer surface of the silica-metal organic framework composite material with a Janus structure loaded with the first drug; the second drug is loaded on the inner coating layer; the outer coating layer includes at least one of menthol, tetradecanol, hyaluronic acid and polyethylene glycol; the inner coating layer includes at least one of polydopamine and chitosan.

[0139] <Method for preparing silica-metal organic framework composite material with Janus structure>

[0140] As mentioned above, the present invention also provides a method for preparing the above-mentioned silicon dioxide-metal organic framework composite material having a Janus structure, the method comprising the following steps:

[0141] Silica and a solution containing a metal salt are mixed, and the mixed system is separated after being evenly mixed to obtain a solid component; a solution containing an imidazole organic ligand is added to the solid component to react to prepare the silica-metal organic framework composite material with a Janus structure.

[0142] According to an embodiment of the present invention, the mixing time is 5-15 min, such as 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min or 15 min.

[0143] According to an embodiment of the present invention, the mixing is performed under ultrasonic conditions. The power of the ultrasonic is 400-500W.

[0144] According to an embodiment of the present invention, the mass ratio of the silica to the metal salt is 45-90:540; the mass ratio of the metal salt to the imidazole organic ligand is 1-2:2; the concentration of the solution containing the metal salt is 100-200 mg / mL, such as 100 mg / mL, 150 mg / mL or 200 mg / mL; the concentration of the solution containing the imidazole organic ligand is 25-50 mg / mL, such as 25 mg / mL, 37.5 mg / mL or 50 mg / mL.

[0145] According to an embodiment of the present invention, the reaction time is 0.5-2h; the reaction temperature is room temperature.

[0146] According to an embodiment of the present invention, the solution containing metal salt is an organic solution containing metal salt, and the solution containing imidazole organic ligand is an organic solution containing imidazole organic ligand. The organic solvent in the organic solution includes at least one of ethanol, methanol, dimethyl sulfoxide and N,N-dimethylformamide.

[0147] According to an embodiment of the present invention, the purpose of the mixing is to allow the silicon dioxide and the metal ions to fully contact each other, and to ensure that the silicon dioxide surface adsorbs sufficient metal ions. The separation is centrifugal separation; the purpose of the centrifugal separation is to remove free and unadsorbed metal ions, thereby achieving the preparation of a silicon dioxide-metal organic framework composite material with a Janus structure, while also avoiding the generation of a free metal organic framework.

[0148] <Method for preparing silica-metal organic framework composite material with Janus structure>

[0149] The present invention also provides a method for preparing the above-mentioned silicon dioxide-metal organic framework composite material having a Janus structure, the method comprising the following steps:

[0150] (1) mixing silica, a first drug, an alcohol solvent, ammonia water with or without addition, and tetraethyl orthosilicate with or without addition, and reacting the mixture to prepare silica loaded with the first drug;

[0151] (2) mixing the silica loaded with the first drug in step (1) and the solution containing the metal salt, and separating the mixed system after being evenly mixed to obtain a solid component; adding a solution containing an imidazole organic ligand to the solid component to react, and preparing a silica-metal organic framework composite material with a Janus structure loaded with the first drug;

[0152] (3) Mixing the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2), an alcohol solvent, and a second drug, and performing negative pressure suction after mixing evenly to prepare a silica-metal organic framework composite material with a Janus structure.

[0153] According to an embodiment of the present invention, in step (1), the tetraethyl orthosilicate is hydrolyzed under alkaline conditions to generate small particles of silica and coated on the surface of the silica, so that the first drug that has entered the pores of the silica is accumulated in the pores by these small particles of silica, thereby achieving encapsulation of the first drug, that is, encapsulating the first drug in the pores of the silica, increasing the loading amount of the first drug, and at the same time controlling the slow release of the first drug.

[0154] According to an embodiment of the present invention, in step (1), the alcohol solvent is selected from ethanol and / or methanol.

[0155] According to an embodiment of the present invention, in step (1), the reaction temperature is 75-85°C, such as 75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C or 85°C, and the reaction time is 4-6 hours.

[0156] According to an embodiment of the present invention, in step (1), the reaction is carried out under stirring conditions.

[0157] According to an embodiment of the present invention, in step (1), the mass ratio of the silica to the first drug is 1-3:1; the mass ratio of the silica to the alcohol solvent is 1-3:2; the mass ratio of the silica to aqueous ammonia is 1-3:0.02; the mass ratio of the silica to tetraethyl orthosilicate is 1-3:0.08.

[0158] According to an embodiment of the present invention, in step (1), silica, a first drug and an alcohol solvent are first mixed, and then ammonia water and tetraethyl orthosilicate are added to the mixed solution to react to prepare silica loaded with the first drug.

[0159] According to an embodiment of the present invention, in step (2), the mixing time is 5-15 min, such as 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min or 15 min. The mixing temperature is room temperature. When the mixing time is within the above range, the reduction in the loading amount of the first drug caused by mixing will not be reduced.

[0160] According to an embodiment of the present invention, in step (2), the mixing is performed under ultrasonic conditions with a power of 400-500W.

[0161] According to an embodiment of the present invention, in step (2), the mass ratio of the silica loaded with the first drug and the metal salt in step (1) is 45-90:540; the mass ratio of the metal salt and the imidazole organic ligand is 1-2:2; the concentration of the solution containing the metal salt is 100-200 mg / mL, such as 100 mg / mL, 150 mg / mL or 200 mg / mL; the concentration of the solution containing the imidazole organic ligand is 25-50 mg / mL, such as 25 mg / mL, 37.5 mg / mL or 50 mg / mL.

[0162] According to an embodiment of the present invention, in step (2), the solution containing metal salt is an organic solution containing metal salt, and the solution containing imidazole organic ligand is an organic solution containing imidazole organic ligand.

[0163] According to an embodiment of the present invention, in step (2), the reaction time is 0.5-2h; and the reaction temperature is room temperature.

[0164] According to an embodiment of the present invention, in step (2), the alcohol solution is at least one of methanol and ethanol.

[0165] According to an embodiment of the present invention, in step (2), the purpose of the mixing is to allow the silicon dioxide and the metal ions to fully contact each other, and to ensure that the silicon dioxide surface adsorbs sufficient metal ions. The separation is centrifugal separation; the purpose of the centrifugal separation is to remove free and unadsorbed metal ions, thereby achieving the preparation of a silicon dioxide-metal organic framework composite material with a Janus structure, while also avoiding the generation of a free metal organic framework.

[0166] According to an embodiment of the present invention, in step (3), the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the alcohol solvent is 3-15:1; the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the second drug is 3-15:1.

[0167] According to an embodiment of the present invention, in step (3), the mixing is carried out under stirring conditions.

[0168] According to an embodiment of the present invention, in step (3), the loading of the second drug can be achieved by the negative pressure suction method.

[0169] According to an embodiment of the present invention, in step (3), the alcohol solvent is selected from ethanol and / or methanol.

[0170] <Method for preparing drug loading platform>

[0171] As mentioned above, the present invention also provides a method for preparing a drug loading platform, the method comprising the following steps:

[0172] (1) mixing silica, a first drug, an alcohol solvent, ammonia water with or without addition, and tetraethyl orthosilicate with or without addition, and reacting the mixture to prepare silica loaded with the first drug;

[0173] (2) mixing the silica loaded with the first drug in step (1) and the solution containing the metal salt, and separating the mixed system after being evenly mixed to obtain a solid component; adding a solution containing an imidazole organic ligand to the solid component to react, and preparing a silica-metal organic framework composite material with a Janus structure loaded with the first drug;

[0174] (3') mixing the silica-metal organic framework composite material with a Janus structure carrying the first drug in step (2), ammonia water, a substance forming an inner coating layer and an alcohol solvent, and reacting them, adding the second drug after the reaction is completed, mixing them evenly and performing negative pressure suction to prepare the drug loading platform; or,

[0175] (3") mixing the silica-metal organic framework composite material with a Janus structure carrying the first drug in step (2), the second drug and the material forming the outer coating layer, and performing negative pressure suction and / or dispersion to prepare the drug loading platform; or,

[0176] (3') mixing the silica-metal organic framework composite material with a Janus structure loaded with the first drug of step (2), ammonia water, a substance forming an inner coating layer, and an alcohol solvent, and reacting them. After the reaction is completed, adding the second drug and a substance forming an outer coating layer, and performing negative pressure suction and / or dispersion to prepare the drug loading platform.

[0177] According to an embodiment of the present invention, in step (1), silicon dioxide, the first drug and an alcohol solvent are first mixed, and then ammonia water and tetraethyl orthosilicate are added under stirring to carry out a reaction.

[0178] According to an embodiment of the present invention, in step (1), the tetraethyl orthosilicate is hydrolyzed under alkaline conditions to generate small particles of silica and coated on the surface of the silica, so that the first drug that has entered the pores of the silica is accumulated in the pores by these small particles of silica, thereby achieving encapsulation of the first drug, that is, encapsulating the first drug in the pores of the silica, increasing the loading amount of the first drug, and at the same time controlling the slow release of the first drug.

[0179] According to an embodiment of the present invention, in step (1), the alcohol solvent is selected from ethanol and / or methanol.

[0180] According to an embodiment of the present invention, in step (1), the reaction temperature is 75-85°C, such as 75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C or 85°C, and the reaction time is 4-6 hours.

[0181] According to an embodiment of the present invention, in step (1), the reaction is carried out under stirring conditions.

[0182] According to an embodiment of the present invention, in step (1), the mass ratio of the silica to the first drug is 1-3:1; the mass ratio of the silica to the alcohol solvent is 1-3:2; the mass ratio of the silica to aqueous ammonia is 1-3:0.02; the mass ratio of the silica to tetraethyl orthosilicate is 1-3:0.08.

[0183] According to an embodiment of the present invention, in step (1), silica, a first drug and an alcohol solvent are first mixed, and then ammonia water and tetraethyl orthosilicate are added to the mixed solution to react to prepare silica loaded with the first drug.

[0184] According to an embodiment of the present invention, in step (2), the mixing time is 5-15 min, such as 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min or 15 min. The mixing temperature is room temperature. When the mixing time is within the above range, the reduction in the loading amount of the first drug caused by mixing will not be reduced.

[0185] According to an embodiment of the present invention, in step (2), the mixing is performed under ultrasonic conditions with a power of 400-500W.

[0186] According to an embodiment of the present invention, in step (2), the mass ratio of the silica loaded with the first drug and the metal salt in step (1) is 45-90:540; the mass ratio of the metal salt and the imidazole organic ligand is 1-2:2; the concentration of the solution containing the metal salt is 100-200 mg / mL, such as 100 mg / mL, 150 mg / mL or 200 mg / mL; the concentration of the solution containing the imidazole organic ligand is 25-50 mg / mL, such as 25 mg / mL, 37.5 mg / mL or 50 mg / mL.

[0187] According to an embodiment of the present invention, in step (2), the solution containing metal salt is an organic solution containing metal salt, and the solution containing imidazole organic ligand is an organic solution containing imidazole organic ligand.

[0188] According to an embodiment of the present invention, in step (2), the reaction time is 0.5-2h; and the reaction temperature is room temperature.

[0189] According to an embodiment of the present invention, in step (2), the alcohol solution is at least one of methanol and ethanol.

[0190] According to an embodiment of the present invention, in step (2), the purpose of the mixing is to allow the silicon dioxide and the metal ions to fully contact each other, and to ensure that the silicon dioxide surface adsorbs sufficient metal ions. The separation is centrifugal separation; the purpose of the centrifugal separation is to remove free and unadsorbed metal ions, thereby achieving the preparation of a silicon dioxide-metal organic framework composite material with a Janus structure, while also avoiding the generation of a free metal organic framework.

[0191] According to an embodiment of the present invention, in step (3') and step (3''), the substance forming the inner coating layer includes at least one of dopamine and chitosan. The alcohol solvent is selected from ethanol and / or methanol.

[0192] According to an embodiment of the present invention, in step (3') and step (3'"), the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to ammonia water is 7.5-30:0.02. The mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the substance forming the inner coating layer is 7.5-30:0.8. The mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the alcohol solvent is 7.5-30:1.

[0193] According to an embodiment of the present invention, in step (3') and step (3'"), the mixing is performed under stirring conditions.

[0194] According to an embodiment of the present invention, in step (3') and step (3'"), the reaction time is 0.2-2h; the reaction temperature is room temperature. During the reaction, the substance forming the inner coating layer can form a coating layer under alkaline conditions and coat the outer surface of the silica-metal organic framework composite material with a Janus structure carrying the first drug.

[0195] According to an embodiment of the present invention, in step (3'), the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the second drug is 3-15:1.

[0196] According to an embodiment of the present invention, in step (3') and step (3'"), the loading of the second drug is achieved by negative pressure suction, and the coating of the outer coating layer can also be achieved; preferably, the second drug is loaded onto the inner coating layer by negative pressure suction, and the silica-metal organic framework composite material with a Janus structure loaded with the first drug and the second drug is coated at the same time.

[0197] According to an embodiment of the present invention, in step (3") and step (3'"), the substance forming the outer coating layer includes at least one of menthol, tetradecanol, hyaluronic acid and polyethylene glycol.

[0198] According to an embodiment of the present invention, in step (3") and step (3"'), the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug and the second drug in step (2) is 3-15:1. The mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) and the substance forming the outer coating layer is 1-4:2, for example, 1:2, 2:2, 3:2 or 4:2.

[0199] According to an embodiment of the present invention, in step (3"), the silica-metal organic framework composite material with a Janus structure carrying the first drug of step (2), the second drug and the substance forming the first outer coating layer are mixed, and negative pressure suction is performed, and the solid component obtained after suction is dispersed in a solution containing the substance forming the second outer coating layer to prepare the drug loading platform.

[0200] According to an embodiment of the present invention, in step (3"), the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the substance forming the first outer coating layer is 7.5-30:0.8; the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the substance forming the second outer coating layer is 1-2:1.

[0201] According to an embodiment of the present invention, in step (3"), the substance forming the first outer coating layer is added to the reaction system in batches for multiple times; illustratively, the silica-metal organic framework composite material with a Janus structure loaded with the first drug, the second drug and part of the substance forming the first outer coating layer in step (2) are subjected to negative pressure suction, and after the negative pressure suction is completed, part of the substance forming the first outer coating layer is added for negative pressure suction; research has found that the method of adding the substance forming the first outer coating layer to the reaction system in batches for multiple times is conducive to increasing the loading amount of the second drug.

[0202] According to an embodiment of the present invention, in step (3''), after the reaction is completed, the second drug and the substance forming the first outer coating layer are added and mixed, and negative pressure suction is performed, and the solid component obtained after suction is dispersed in a solution containing the substance forming the second outer coating layer to prepare the drug loading platform

[0203] According to an embodiment of the present invention, in step (3'), the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the substance forming the first outer coating layer is 7.5-30:0.8; the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the substance forming the second outer coating layer is 1-2:1.

[0204] According to an embodiment of the present invention, in step (3'), the substance forming the first outer coating layer is added to the reaction system in batches for multiple times; illustratively, after the reaction is completed, the second drug and part of the substance forming the first outer coating layer are added for negative pressure suction, and after the negative pressure suction is completed, part of the substance forming the first outer coating layer is added for negative pressure suction; research has found that the method of adding the substance forming the first outer coating layer to the reaction system in batches for multiple times is beneficial to increasing the loading amount of the second drug.

[0205] According to an embodiment of the present invention, in step (3") and step (3'"), the dispersion is carried out by shaking.

[0206] According to an embodiment of the present invention, in step (3") and step (3'"), the dispersion time is 0.5-2h.

[0207] <Application of Silica-Metal Organic Framework Composites with Janus Structure>

[0208] The present invention also provides application of the silicon dioxide-metal organic framework composite material with Janus structure and the drug-carrying platform in drug delivery.

[0209] According to an embodiment of the present invention, the silica-metal organic framework composite material or drug-carrying platform having a Janus structure is dispersed in deionized water, observed under a 60k dark field microscope with or without hydrogen peroxide, and the movement of the silica-metal organic framework composite material or drug-carrying platform having a Janus structure is recorded, and the diffusion coefficient and mean square displacement are statistically calculated. This method can prove that the silica-metal organic framework composite material or drug-carrying platform having a Janus structure has the ability to deliver drugs.

[0210] <Application of Silica-Metal Organic Framework Composites with Janus Structure and Drug Delivery Platform>

[0211] The present invention also provides the use of the silicon dioxide-metal organic framework composite material with Janus structure and the drug-carrying platform in the preparation of drugs for treating tumors.

[0212] According to the embodiment of the present invention, the silica-metal organic framework composite material or drug loading platform with Janus structure has the characteristics of directional movement, which can break through the tumor barrier (high interstitial pressure, cell membrane, etc.) and achieve the purpose of releasing the drug deep into the tumor. Because of the different release rates of drugs, for example, the second drug that can improve the microenvironment is first released in the microenvironment, and the first drug loaded on silica that can act on the cell nucleus is released slowly and continuously, and the cell uptake is increased based on movement, which can achieve controlled release of the drug's action site, that is, the silica-metal organic framework composite material or drug loading platform with Janus structure of the present invention can realize the release of two drugs at different positions and different times according to demand, and ensure that the first drug has a deeper release position, thereby improving the cell uptake rate.

[0213] According to an embodiment of the present invention, a silica-metal organic framework composite material or a drug-carrying platform having a Janus structure is dispersed in physiological saline, and a dispersion liquid with a concentration of 0-5 mg / mL (such as 0 mg / mL, 2.5 mg / mL or 5 mg / mL) is prepared, and the temperature change of the dispersion liquid with different concentrations is recorded under microwave irradiation conditions. This method can prove that the silica-metal organic framework composite material or drug-carrying platform having a Janus structure can be used to prepare drugs for microwave hyperthermia treatment of tumors.

[0214] According to an embodiment of the present invention, the silica-metal organic framework composite material with a Janus structure and the drug loading platform are used in the preparation of drugs for microwave hyperthermia treatment of tumors.

[0215] According to an embodiment of the present invention, the silica-metal organic framework composite material with a Janus structure and the drug loading platform are used in the preparation of drugs for chemotherapy treatment of tumors.

[0216] According to an embodiment of the present invention, the silica-metal organic framework composite material with a Janus structure and the drug loading platform are used in the preparation of drugs for microwave power therapy of tumors.

[0217] According to an embodiment of the present invention, a silica-metal organic framework composite material or a drug-carrying platform having a Janus structure is dispersed in a buffer solution, a dispersion solution having a concentration of 0-5 mg / mL (such as 0 mg / mL, 2.5 mg / mL or 5 mg / mL) is prepared, a detection indicator is added in the presence of hydrogen peroxide, and the microwave irradiation is allowed to stand for 60 minutes to detect the level of reactive oxygen generated. This method can prove that the silica-metal organic framework composite material and the drug-carrying platform having a Janus structure can be used to prepare drugs for microwave power therapy of tumors.

[0218] <Method of drug delivery>

[0219] The present invention also provides a method for drug delivery, in particular a method for chemotherapy drug delivery, which comprises using the above-mentioned silica-metal organic framework composite material or drug-carrying platform with Janus structure.

[0220] The preparation method of the present invention will be described in further detail below in conjunction with specific examples. It should be understood that the following examples are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0221] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0222] Example 1

[0223] (1) At 80°C, 68 mg of triethanolamine was added dropwise to 30 mL of deionized water, and after stirring evenly, 380 mg of hexadecyltrimethylammonium bromide (CTAB) and 168 mg of sodium salicylate (NaSal) were added. After stirring for 1 hour, 4 mL of tetraethyl orthosilicate (TEOS) was slowly and uniformly added dropwise. After stirring for 4 hours, the precipitate was centrifuged to obtain a precipitate. 30 mL of 4% hydrochloric acid was added to the precipitate, and the precipitate was stirred for 6 hours and centrifuged to obtain a precipitate. The precipitate was washed with water 3 times to prepare dendritic silica.

[0224] like Figure 1 As shown, the dendritic silica prepared in Example 1 was characterized by transmission electron microscopy, and the particle size observed by transmission electron microscopy was 203 nm.

[0225] Example 2

[0226] (1) At 80°C, 68 mg of triethanolamine was added dropwise to 30 mL of deionized water, and after stirring evenly, 380 mg of hexadecyltrimethylammonium bromide (CTAB) and 168 mg of sodium salicylate (NaSal) were added. After stirring for 1 hour, 4 mL of tetraethyl orthosilicate (TEOS) was slowly and uniformly added dropwise. After stirring for 6 hours, the precipitate was centrifuged to obtain a precipitate. 30 mL of 4% hydrochloric acid was added to the precipitate, and the precipitate was stirred for 6 hours and centrifuged to obtain a precipitate. The precipitate was washed with water 3 times to prepare dendritic silica.

[0227] The dendritic silica prepared in Example 2 was characterized by transmission electron microscopy, and the particle size observed by transmission electron microscopy was 215 nm.

[0228] Example 3

[0229] (1) At 80°C, 68 mg of triethanolamine was added dropwise to 30 mL of deionized water, and after stirring evenly, 570 mg of hexadecyltrimethylammonium bromide (CTAB) and 252 mg of sodium salicylate (NaSal) were added. After stirring for 1 hour, 8 mL of tetraethyl orthosilicate (TEOS) was slowly and uniformly added dropwise. After stirring for 4 hours, the precipitate was centrifuged to obtain a precipitate. 30 mL of 4% hydrochloric acid was added to the precipitate, and the precipitate was stirred for 6 hours and centrifuged to obtain a precipitate. The precipitate was washed with water 3 times to prepare dendritic silica.

[0230] The dendritic silica prepared in Example 3 was characterized by transmission electron microscopy, and the particle size observed by transmission electron microscopy was 226 nm.

[0231] Example 4

[0232] (1) Same as Example 1.

[0233] (2) At room temperature, 2.5 mg of the dendritic silica obtained in step (1) and 20 μL of aqueous ammonia were added to anhydrous ethanol solution. After stirring for 30 min, 80 μL of a 1:1 mixed solution of tetraethyl orthosilicate (TEOS) and ethanol was added. After stirring for 2 hours, the precipitate was centrifuged and washed three times with water to obtain silica without drug loading.

[0234] After synthesis, the hydrophilicity of the material becomes better and its dispersibility in water is better.

[0235] Example 5

[0236] (1) Same as Example 1.

[0237] (2) At room temperature, 2.5 mg of the dendritic silica obtained in step (1), 20 μL of ammonia water and 1 mg of doxorubicin (DOX) were added to anhydrous ethanol solution. After stirring for 30 min, 80 μL of a 1:1 mixed solution of tetraethyl orthosilicate (TEOS) and ethanol was added. After stirring for 2 hours, the precipitate was centrifuged and washed with water three times to prepare silica loaded with DOX drug.

[0238] After synthesis, the hydrophilicity of the material improved and its dispersibility in water was better. Meanwhile, successful loading of DOX was detected by UV spectrophotometer, and the synthetic material was reddish brown.

[0239] Example 6

[0240] (1) Same as Example 1.

[0241] (2) At room temperature, 2.5 mg of the dendritic silica obtained in step (1), 20 μL of ammonia water and 1 mg of pentafluorouracil (5-FU) were added to anhydrous ethanol solution. After stirring for 30 min, 80 μL of a 1:1 mixed solution of tetraethyl orthosilicate (TEOS) and ethanol was added. After stirring for 2 hours, the precipitate was centrifuged and washed with water three times to prepare silica loaded with 5-FU drug.

[0242] After synthesis, the hydrophilicity of the material improved and its dispersibility in water was better. At the same time, the successful loading of 5-FU was detected by UV spectrophotometer, and the synthetic material was light yellow.

[0243] Example 7

[0244] (1) Same as Example 4.

[0245] (2) Same as Example 4.

[0246] (3) 100 mg of the drug-free silica prepared in step (2) was mixed with 5.4 ml of a 100 mg / mL ethanol solution of cobalt nitrate hexahydrate and ultrasonicated for 10 min. After centrifugation, 21.6 mL of an ethanol solution was added and stirred. Then, 21.6 mL of an ethanol solution containing 25 mg / mL dimethylimidazole ligand was added and stirred. After the reaction was completed, the mixture was washed with ethanol and centrifuged.

[0247] like Figure 2 As shown, the silica-metal organic framework composite material with a Janus structure prepared in Example 7 was characterized by transmission electron microscopy and had an obvious Janus structural morphology. XRD detection showed that the product had the same characteristic peaks as ZIF-67, proving the successful preparation of the silica-metal organic framework composite material with a Janus structure.

[0248] Example 8

[0249] (1) Same as Example 5.

[0250] (2) Same as Example 5.

[0251] (3) 100 mg of the DOX-loaded silica prepared in step (2) was mixed with 5.4 ml of a 100 mg / mL ethanol solution of cobalt nitrate hexahydrate and ultrasonicated for 10 min. After centrifugation, 21.6 mL of an ethanol solution was added and stirred. 21.6 mL of an ethanol solution containing 25 mg / mL dimethylimidazole ligand was added and stirred. After the reaction was completed, the mixture was washed with ethanol and centrifuged.

[0252] like Figure 3As shown, the silica-metal organic framework composite material with a Janus structure loaded with DOX prepared in Example 8 was characterized by transmission electron microscopy, which showed that it had an obvious Janus structural morphology, which was consistent with the structure synthesized in Example 7. XRD detection showed that the product had the same characteristic peaks as ZIF-67, proving the successful preparation of the silica-metal organic framework composite material with a Janus structure loaded with DOX.

[0253] Example 9

[0254] (1) Same as Example 5.

[0255] (2) Same as Example 5.

[0256] (3) 100 mg of the DOX-loaded silica prepared in step (2) was mixed with 5.4 ml of a 100 mg / mL ethanol solution of cobalt nitrate hexahydrate and ultrasonicated for 15 min. After centrifugation, 21.6 mL of an ethanol solution was added and stirred. 21.6 mL of an ethanol solution containing 25 mg / mL dimethylimidazole ligand was added and stirred. After the reaction was completed, the mixture was washed with ethanol and centrifuged.

[0257] The silica-metal organic framework composite material with a Janus structure and loaded with DOX drug prepared in Example 9 was characterized by transmission electron microscopy, and still had a clear Janus structural morphology, with no significant difference from Example 7, proving that the ultrasonic time would not have a significant effect on the special morphology of the silica-metal organic framework with a Janus structure within a controllable range.

[0258] Example 10

[0259] (1) Same as Example 5.

[0260] (2) Same as Example 5.

[0261] (3) 100 mg of the DOX-loaded silica prepared in step (2) was mixed with 5.4 ml of a 200 mg / mL ethanol solution of cobalt nitrate hexahydrate and ultrasonicated for 10 min. After centrifugation, 21.6 mL of an ethanol solution was added and stirred. Then, 21.6 mL of an ethanol solution containing 50 mg / mL dimethylimidazole ligand was added and stirred. After the reaction was completed, the mixture was washed with ethanol and centrifuged.

[0262] The silica-metal organic framework composite material with a Janus structure and loaded with DOX drug prepared in Example 10 was characterized by transmission electron microscopy, and still had an obvious Janus structural morphology, with no obvious difference from Example 7, proving that the concentration of the organic ligand solution would not have a significant effect on the special morphology of the silica-metal organic framework composite material with a Janus structure within a controllable range.

[0263] Embodiment 11

[0264] (1) Same as Example 5.

[0265] (2) Same as Example 5.

[0266] (3) 100 mg of silica loaded with DOX drug prepared in step (2) was mixed with 5.4 ml of 100 mg / mL zinc acetate ethanol solution and ultrasonicated for 10 min. After centrifugation, 21.6 mL of N,N-dimethylformamide solution was added and stirred. 21.6 mL of dimethyl sulfoxide solution containing 25 mg / mL imidazole-2-carboxaldehyde ligand was added and stirred. After the reaction was completed, the mixture was washed with ethanol and centrifuged.

[0267] Characterization by transmission electron microscopy confirmed the successful synthesis of ZIF-90 as a metal-organic framework in a silica-metal-organic framework with a Janus structure.

[0268] Example 12

[0269] (1) Same as Example 8.

[0270] (2) Same as Example 8.

[0271] (3) Same as Example 8.

[0272] (4) 15 mg of the silica-metal organic framework composite material with a Janus structure loaded with DOX drug in step (3) was dispersed in 2 mL of ethanol solution, stirred with 40 μL of ammonia water and 0.8 mg of dopamine, and then 0.1 mg of DON and 15 mg of tetradecanol were added for negative pressure suction, and then placed in an aqueous solution containing 2 ml of 15 mg / mL polyethylene glycol for shaking to obtain a drug loading platform including a silica-metal organic framework composite material with a Janus structure.

[0273] The drug loading platform including the silica-metal organic framework composite material with Janus structure prepared in Example 12 was characterized by transmission electron microscopy. The Janus structure morphology was not destroyed and the structural characteristics were obvious. The introduction of the outer coating layer improved the stability and biocompatibility of the drug loading platform, making it more suitable for biological related experiments. The drug loading rate was 5.17% when tested by ultraviolet spectrophotometer.

[0274] Example 13

[0275] (1) Same as Example 8.

[0276] (2) Same as Example 8.

[0277] (3) Same as Example 8.

[0278] (4) 15 mg of the Janus-structured silica-metal organic framework loaded with DOX drug from step (3) was dispersed in 2 mL of ethanol solution and stirred with 40 μL of ammonia water and 0.8 mg of dopamine. Then, 0.1 mg of DON and 7.5 mg of tetradecanol were added for negative pressure suction. Then, 7.5 mg of tetradecanol was added for negative pressure suction and the mixture was placed in an aqueous solution containing 2 mL of 15 mg / mL polyethylene glycol and shaken to obtain a drug-carrying platform comprising a silica-metal organic framework composite material having a Janus structure.

[0279] like Figure 4 As shown, the drug loading platform including the silica-metal organic framework composite material with a Janus structure prepared in Example 13 was characterized by transmission electron microscopy, and there was no obvious difference from the drug loading platform prepared in Example 12, proving that the gradual addition of tetradecanol would not affect the drug loading platform including the silica-metal organic framework composite material with a Janus structure, but the drug loading rate became 9.34%, indicating that the introduction of tetradecanol helps to load DON and improve the drug loading rate.

[0280] Embodiment 14

[0281] (1) Same as Example 8.

[0282] (2) Same as Example 8.

[0283] (3) Same as Example 8.

[0284] (4) 15 mg of the silica-metal organic framework with a Janus structure loaded with DOX drug in step (3) was dispersed in 2 mL of ethanol solution and stirred with 40 μL of ammonia water and 2.4 mg of dopamine, and then 0.1 mg of DON and 7.5 mg of tetradecanol were added for negative pressure suction, and then 7.5 mg of tetradecanol was added for negative pressure suction, and then placed in an aqueous solution containing 2 ml of 15 mg / mL polyethylene glycol and shaken to obtain a drug loading platform including a silica-metal organic framework composite material with a Janus structure.

[0285] The drug delivery platform including the silica-metal organic framework composite material with a Janus structure prepared in Example 14 was characterized by transmission electron microscopy. There was no obvious difference from the drug delivery platform prepared in Example 12, but the effect of oxygen production was reduced. This was because the dopamine coating layer was too thick, which blocked the contact between the metal organic framework and hydrogen peroxide, reducing the microwave effect. The metal organic framework improved the constrained inelastic collision of ions through the ion domain effect, reduced ion collisions, and obtained a higher molecular weight heating efficiency, resulting in poor oxygen production and microwave temperature rise effects.

[0286] Embodiment 15

[0287] (1) Same as Example 8.

[0288] (2) Same as Example 8.

[0289] (3) Same as Example 8.

[0290] (4) 15 mg of the Janus-structured silica-metal organic framework loaded with DOX drug from step (3) was dispersed in 2 mL of ethanol solution and stirred with 40 μL of ammonia water and 0.8 mg of dopamine. Then, 0.1 mg of apatinib (AP) and 7.5 mg of tetradecanol were added for negative pressure suction. Then, 7.5 mg of tetradecanol was added for negative pressure suction and the mixture was placed in an aqueous solution containing 2 mL of 15 mg / mL polyethylene glycol and shaken to obtain a drug-carrying platform comprising a silica-metal organic framework composite material having a Janus structure.

[0291] The drug delivery platform including the silica-metal organic framework composite material with a Janus structure prepared in Example 15 was characterized by transmission electron microscopy, and there was no obvious difference from the drug delivery platform prepared in Example 12. The successful loading of AP was confirmed by ultraviolet detection.

[0292] Test Example 1

[0293] The materials prepared in Example 1 and Example 7 were tested for in vitro power (oxygen) generation performance. The specific experimental method is as follows:

[0294] (1) The materials prepared in Example 1 and Example 7 were added to PBS respectively;

[0295] (2) placing the probe of the dissolved oxygen meter in the solution obtained in (1) and recording the change in the reading of the dissolved oxygen meter;

[0296] Test Example 1 proves that the dendritic silica material (DMSNs+H 2 O 2) has no effect of generating oxygen under hydrogen peroxide conditions, while the silica-metal organic framework composite material with a Janus structure prepared in Example 7 has the effect of generating oxygen under hydrogen peroxide conditions.

[0297] Figure 5 Schematic diagram of oxygen generation effect of the silicon dioxide-metal organic framework composite material with Janus structure prepared in Example 7, Figure 5 It can be seen that the silica-metal organic framework composite material (DS-Z+H 2 O 2 ) has obvious gas production performance.

[0298] Test Example 2

[0299] The material prepared in Example 7 was tested for its sports performance. The specific experimental method is as follows:

[0300] (1) The material prepared in Example 7 was dispersed in water or a 10 mM hydrogen peroxide solution;

[0301] (2) placing the solution of (1) in a custom-made small-well glass slide;

[0302] (3) Use a dark-field microscope to observe and record the motion trajectory.

[0303] Test Example 2 demonstrates the movement of the material prepared in Example 7 in the presence or absence of hydrogen peroxide, thereby indicating that the silica-metal organic framework composite material with a Janus structure has obvious directional movement performance.

[0304] Figure 6 Schematic diagram of the comparison of the kinematic diffusion coefficients of the silicon dioxide-metal organic framework composite material with Janus structure obtained in Example 7. Figure 6 It can be seen that the prepared silica-metal organic framework composite material with Janus structure is 2 O 2 ) is significantly higher than that of (DS-Z) under the condition without hydrogen peroxide.

[0305] Figure 7 Schematic diagram of the comparison of the mean square displacement of the silicon dioxide-metal organic framework composite material with Janus structure obtained in Example 7. Figure 7 It can be seen that the prepared silica-metal organic framework composite material with Janus structure is 2 O 2) is significantly higher than that in the absence of hydrogen peroxide (DS-Z).

[0306] Test Example 3

[0307] The material prepared in Example 7 was tested for its in vitro microwave heat conversion performance. The specific experimental method is as follows:

[0308] (1) Disperse sodium chloride in deionized water to prepare normal saline (0.9% NaCl);

[0309] (2) The materials prepared in Example 7 were added to normal saline to prepare solutions with concentrations of 0, 2.5 mg / mL, and 5 mg / mL, respectively;

[0310] (3) The solution of (2) was irradiated with microwaves at a power of 0.9 W and an irradiation time of 5 min, and the temperature of the solution was monitored in real time using a near-infrared thermal imager.

[0311] Figure 8 Schematic diagram of microwave heating curve of the silicon dioxide-metal organic framework composite material with Janus structure prepared in Example 7 in physiological saline, Figure 8 It can be seen that the material prepared in Example 7 has a heating effect under microwave conditions that is significantly different from that of physiological saline, and as the concentration increases, the heating rate accelerates, showing obvious concentration dependence.

[0312] Test Example 4

[0313] The materials prepared in Example 1 and Example 7 were tested for in vitro microwave dynamic performance. The specific experimental method is as follows:

[0314] (1) The materials prepared in Example 1 and Example 7 were added to phosphate buffered saline to prepare solutions with concentrations of 0.5 mg / mL and 1 mg / mL, respectively;

[0315] (2) Add 10 μM reactive oxygen species detection probe DCFH-DA to the solution;

[0316] (3) irradiating the solution with 0.9 W microwave for 5 min;

[0317] (4) Keep the mixture away from light for 2 h, then centrifuge and collect the supernatant;

[0318] (5) Under excitation at a wavelength of 480 nm, the fluorescence intensity at 520 nm was detected.

[0319] Test Example 4 proves that the material (DS) prepared in Example 1 does not have microwave power properties; the material (DS-Z) prepared in Example 7 has microwave power properties; under microwave stimulation, it can promote the transfer of electrons and energy, further improve the efficiency of generating reactive oxygen species, and can be used for the synergistic diagnosis and treatment of microdynamic therapy of tumors in vivo.

[0320] Fig. 9 Schematic diagram of characterization of microwave power performance of materials obtained in Example 1 and Example 7. Fig. 9 It can be seen that the material prepared in Example 7 has an active oxygen generation effect that is significantly different from that of physiological saline under microwave conditions, and as the concentration increases, the amount of active oxygen generated in the same time is higher, with obvious concentration dependence. At the same time, the dendritic silica prepared in Example 1 also has no obvious active oxygen generation effect. Therefore, the silica-metal organic framework composite material with a Janus structure can promote the transfer of electrons and energy under microwave stimulation, further improve the efficiency of generating active oxygen, and can be used for the coordinated diagnosis and treatment of microwave thermal-dynamic therapy of tumors in vivo. It can be seen from this that the silica-metal organic framework composite material with a Janus structure of the present invention has the ability to generate active oxygen in vitro and has the potential for microwave dynamic therapy.

[0321] Test Example 5

[0322] The material prepared in Example 13 was subjected to an in vitro drug release test. The specific experimental method is as follows:

[0323] (1) The material prepared in Example 13 was added to a phosphate buffered saline solution to obtain solutions with concentrations of 0.5 mg / mL and 1 mg / mL;

[0324] (2) irradiating the solution with 0.9 W microwave for 5 min;

[0325] (3) removing the upper solution at 0.5, 3, 6, 12, 24, and 48 h;

[0326] (4) Use ultraviolet light to detect drug release.

[0327] Test Example 5 demonstrates that the drug-loading platform of Example 13 has the effect of drug release, and the drug release occurs in a graded manner, which has the potential to improve chemotherapy treatment.

[0328] Fig.10The drug release of the drug-carrying platform comprising a silica-metal organic framework composite material having a Janus structure prepared in Example 13 under acidic phosphate buffer solution conditions. Specifically, the release of the drug is detected by using an ultraviolet-visible spectrophotometer (UV). Since the chemotherapy drug DOX and the tumor microenvironment improving drug DON have different absorbance positions, rapid and simultaneous detection of drug release can be achieved, wherein DON has an obvious absorption peak at 273nm and DOX has an obvious absorption peak at 480nm. The drug loading rates of DON and DOX of the drug-carrying platform comprising a silica-metal organic framework composite material having a Janus structure prepared in Example 13 are 9.34% and 4.86%, respectively.

[0329] The drug-carrying platform of Example 13 was irradiated under microwave conditions for 5 minutes and then maintained at 37°C for drug release experiments. Under acidic conditions, the release rate and release amount of DON and DOX were faster than those in a neutral environment, especially the release difference of DON was more obvious. In phosphate buffered saline, the DON release rate reached 77.6% of the dose within 6 hours, while DOX was continuously released for a long time, and there was still a release trend after 48 hours. This proves the ability of the drug-carrying platform to successfully achieve the expected designed graded release, combined with the proven directional movement ability, using the characteristics of directional movement, stimulating the drug-carrying platform to quickly release DON to improve the tumor environment, and DOX can break through multiple barriers of the tumor and improve the effect of chemotherapy treatment.

[0330] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A silica-metal organic framework composite material with a Janus structure, the composite material comprising a metal organic framework and silica; the composite material comprising a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by the metal organic framework.

2. The composite material according to claim 1, wherein The metal organic framework grows on a part of the surface of silicon dioxide and forms more than one metal organic framework; or, the metal organic framework grows on a part of the surface of silicon dioxide and forms a cluster consisting of a plurality of metal organic frameworks. Preferably, the silica is selected from mesoporous silica and / or dendritic silica. Preferably, the mass of silicon dioxide in the silicon dioxide-metal organic framework composite material with a Janus structure accounts for 65%-75% of the total mass of the silicon dioxide-metal organic framework composite material with a Janus structure; the mass of the metal organic framework in the silicon dioxide-metal organic framework composite material with a Janus structure accounts for 25%-35% of the total mass of the silicon dioxide-metal organic framework composite material with a Janus structure.

3. The composite material according to claim 1 or 2, wherein: The silica-metal organic framework composite material with a Janus structure further includes a first drug and a second drug, wherein the first drug is loaded on the first surface, and the second drug is loaded on the first surface and the second surface. Preferably, the first drug is loaded in the pores of silica, and the second drug is loaded on the surface of silica and on the surface of the metal organic framework. Preferably, the first drug is selected from at least one of doxorubicin (DOX) and pentafluorouracil (5-FU); the second drug is selected from at least one of 6-diazo-5-oxo-L-norleucine (DON) and apatinib (AP). Preferably, the loading rate of the first drug is 3%-20%; The loading rate of the second drug is 5%-20%.

4. A drug loading platform, comprising the silica-metal organic framework composite material with a Janus structure according to any one of claims 1 to 3. Preferably, the drug-carrying platform has a core-shell structure, which includes a core and an outer coating layer coated on the outer surface of the core; the core includes the above-mentioned silica-metal organic framework composite material with a Janus structure. Preferably, the outer coating layer comprises at least one of menthol, tetradecanol, hyaluronic acid and polyethylene glycol. Preferably, the outer coating layer includes a first outer coating layer and a second outer coating layer, the first outer coating layer is coated on the outer surface of the core, and the second outer coating layer is coated on the outer surface of the first outer coating layer; the first outer coating layer includes at least one of menthol and tetradecanol; the second outer coating layer includes at least one of hyaluronic acid and polyethylene glycol. Preferably, the drug loading platform further comprises an inner coating layer, wherein the inner coating layer is coated on the outer surface of the silica-metal organic framework composite material with a Janus structure loaded with the first drug. Preferably, the second drug is loaded on the inner coating layer. Preferably, the inner coating layer comprises at least one of polydopamine and chitosan.

5. The drug loading platform according to claim 4, wherein: The drug loading platform comprises a silica-metal organic framework composite material having a Janus structure; the composite material comprises a metal organic framework and silica; the composite material comprises a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by the metal organic framework; or, The drug loading platform comprises a silica-metal organic framework composite material having a Janus structure; the composite material comprises a first drug, a second drug, a metal organic framework and silica; the composite material comprises a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by the metal organic framework; the first drug is loaded on the first surface; the second drug is loaded on the first surface and the second surface; or, The drug-carrying platform has a core-shell structure, which includes a core and an outer coating layer coated on the outer surface of the core; the core includes a silica-metal organic framework composite material with a Janus structure; the composite material includes a first drug, a second drug, a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by a metal organic framework; the first drug is loaded on the first surface; the second drug is loaded on the first surface and the second surface; the outer coating layer includes at least one of menthol, tetradecanol, hyaluronic acid and polyethylene glycol; or, The drug-carrying platform comprises a silica-metal organic framework composite material with a Janus structure and an inner coating layer; the composite material comprises a first drug, a second drug, a metal organic framework and silica; the composite material comprises a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by a metal organic framework; the first drug is loaded on the first surface; the inner coating layer is coated on the outer surface of the silica-metal organic framework composite material with a Janus structure loaded with the first drug; The second drug is loaded on the inner coating layer; the inner coating layer comprises at least one of polydopamine and chitosan; or, The drug loading platform has a core-shell structure, which includes a core and an outer coating layer coated on the outer surface of the core; the core includes a silica-metal organic framework composite material with a Janus structure and an inner coating layer; the composite material includes a first drug, a second drug, a metal organic framework and silica; the composite material includes a first surface and a second surface opposite to the first surface, the first surface and the second surface together constitute the surface of the composite material, the first surface is formed by silica, and the second surface is formed by a metal organic framework; the first drug is loaded on the first surface; the inner coating layer is coated on the outer surface of the silica-metal organic framework composite material with a Janus structure loaded with the first drug; the second drug is loaded on the inner coating layer; the outer coating layer includes at least one of menthol, tetradecanol, hyaluronic acid and polyethylene glycol; the inner coating layer includes at least one of polydopamine and chitosan.

6. The method for preparing the silicon dioxide-metal organic framework composite material having a Janus structure according to claim 1, the method comprising the following steps: Mixing silicon dioxide and a solution containing a metal salt, and separating the uniformly mixed system to obtain a solid component; A solution containing imidazole organic ligands is added to the solid component to carry out a reaction, thereby preparing the silicon dioxide-metal organic framework composite material with a Janus structure. Preferably, the mass ratio of the silicon dioxide to the metal salt is 45-90:540; the mass ratio of the metal salt to the imidazole organic ligand is 1-2:

2.

7. A method for preparing a silicon dioxide-metal organic framework composite material having a Janus structure according to claim 2 or 3, the method comprising the following steps: (1) mixing silica, a first drug, an alcohol solvent, ammonia water with or without addition, and tetraethyl orthosilicate with or without addition, and reacting the mixture to prepare silica loaded with the first drug; (2) mixing the silica loaded with the first drug in step (1) and the solution containing the metal salt, and separating the mixed system after being evenly mixed to obtain a solid component; adding a solution containing an imidazole organic ligand to the solid component to react, and preparing a silica-metal organic framework composite material with a Janus structure loaded with the first drug; (3) Mixing the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2), an alcohol solvent, and a second drug, and performing negative pressure suction after mixing evenly to prepare a silica-metal organic framework composite material with a Janus structure. Preferably, in step (1), the mass ratio of the silica to the first drug is 1-3:1; the mass ratio of the silica to the alcohol solvent is 1-3:2; the mass ratio of the silica to aqueous ammonia is 1-3:0.02; the mass ratio of the silica to tetraethyl orthosilicate is 1-3:0.

08. Preferably, in step (1), silica, the first drug and an alcohol solvent are first mixed, and then ammonia water and tetraethyl orthosilicate are added to the mixed solution to react to prepare silica loaded with the first drug. Preferably, in step (2), the mass ratio of the first drug-loaded silica and the metal salt in step (1) is 45-90:540; and the mass ratio of the metal salt and the imidazole organic ligand is 1-2:

2. Preferably, in step (3), the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the alcohol solvent is 3-15:1; the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the second drug is 3-15:

1.

8. A method for preparing the drug-carrying platform according to claim 4 or 5, the method comprising the following steps: (1) mixing silica, a first drug, an alcohol solvent, ammonia water with or without addition, and tetraethyl orthosilicate with or without addition, and reacting the mixture to prepare silica loaded with the first drug; (2) mixing the silica loaded with the first drug in step (1) and the solution containing the metal salt, and separating the mixed system after being evenly mixed to obtain a solid component; adding a solution containing an imidazole organic ligand to the solid component to react, and preparing a silica-metal organic framework composite material with a Janus structure loaded with the first drug; (3') mixing the silica-metal organic framework composite material with a Janus structure carrying the first drug in step (2), ammonia water, a substance forming an inner coating layer and an alcohol solvent, and reacting them, adding the second drug after the reaction is completed, mixing them evenly and performing negative pressure suction to prepare the drug loading platform; or, (3") mixing the silica-metal organic framework composite material with a Janus structure carrying the first drug in step (2), the second drug and the material forming the outer coating layer, and performing negative pressure suction and / or dispersion to prepare the drug loading platform; or, (3') mixing the silica-metal organic framework composite material with a Janus structure loaded with the first drug of step (2), ammonia water, a substance forming an inner coating layer, and an alcohol solvent, and reacting them. After the reaction is completed, adding the second drug and a substance forming an outer coating layer, and performing negative pressure suction and / or dispersion to prepare the drug loading platform. Preferably, in step (1), the mass ratio of the silica to the first drug is 1-3:1; the mass ratio of the silica to the alcohol solvent is 1-3:2; the mass ratio of the silica to aqueous ammonia is 1-3:0.02; the mass ratio of the silica to tetraethyl orthosilicate is 1-3:0.

08. Preferably, in step (1), silica, the first drug and an alcohol solvent are first mixed, and then ammonia water and tetraethyl orthosilicate are added to the mixed solution to react to prepare silica loaded with the first drug. Preferably, in step (2), the mass ratio of the first drug-loaded silica and the metal salt in step (1) is 45-90:540; and the mass ratio of the metal salt and the imidazole organic ligand is 1-2:

2. Preferably, in step (3') and step (3'"), the mass ratio of the silica-metal organic framework composite material with a Janus structure loaded with the first drug in step (2) to the second drug is 3-15:

1. Preferably, in step (3”), the silica-metal organic framework composite material with a Janus structure carrying the first drug of step (2), the second drug and the substance forming the first outer coating layer are mixed, and negative pressure suction is performed, and the solid component obtained after the suction is dispersed in a solution containing the substance forming the second outer coating layer to prepare the drug loading platform. Preferably, in step (3"), the silica-metal organic framework composite material with a Janus structure carrying the first drug, the second drug and part of the substance forming the first outer coating layer of step (2) are subjected to negative pressure suction, and after the negative pressure suction is completed, part of the substance forming the first outer coating layer is added for negative pressure suction. Preferably, in step (3'"), after the reaction is completed, the second drug and the substance forming the first outer coating layer are added and mixed, and negative pressure suction is performed. The solid component obtained after suction is dispersed in a solution containing the substance forming the second outer coating layer to prepare the drug loading platform. Preferably, in step (3'"), after the reaction is completed, the second drug and part of the material forming the first outer coating layer are added for negative pressure suction, and after the negative pressure suction is completed, part of the material forming the first outer coating layer is added for negative pressure suction.

9. Use of the silica-metal organic framework composite material with a Janus structure according to any one of claims 1 to 3 and the drug-carrying platform according to claim 4 or 5 in drug delivery or in the preparation of drugs for treating tumors.

10. A method for drug delivery, in particular a method for chemotherapy drug delivery, the method comprising using the silica-metal organic framework composite material with a Janus structure according to any one of claims 1 to 3, or the drug loading platform according to claim 4 or 5.

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