CN113184861A - Mesoporous silica, carboxylated mesoporous silica, drug-loading system, and preparation method and application thereof - Google Patents
Mesoporous silica, carboxylated mesoporous silica, drug-loading system, and preparation method and application thereof Download PDFInfo
- Publication number
- CN113184861A CN113184861A CN202110473105.9A CN202110473105A CN113184861A CN 113184861 A CN113184861 A CN 113184861A CN 202110473105 A CN202110473105 A CN 202110473105A CN 113184861 A CN113184861 A CN 113184861A
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- China
- Prior art keywords
- mesoporous silica
- preparation
- carboxylated
- drug
- curcumin
- Prior art date
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- Granted
Links
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- 239000000377 silicon dioxide Substances 0.000 title claims abstract description 160
- 238000002360 preparation method Methods 0.000 title claims abstract description 51
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 105
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- 229940079593 drug Drugs 0.000 claims abstract description 25
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- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims abstract description 20
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- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B33/00—Silicon; Compounds thereof
- C01B33/113—Silicon oxides; Hydrates thereof
- C01B33/12—Silica; Hydrates thereof, e.g. lepidoic silicic acid
- C01B33/18—Preparation of finely divided silica neither in sol nor in gel form; After-treatment thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
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- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/01—Particle morphology depicted by an image
- C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
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- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
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- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
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- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
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- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
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- Organic Chemistry (AREA)
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides mesoporous silica, carboxylated mesoporous silica, a drug loading system, a preparation method and application thereof, and relates to the technical field of nano drug loading materials. The preparation method of the mesoporous silica provided by the invention adopts a sol-gel method, takes a silicon source as a silicon precursor, takes cetyl trimethyl ammonium bromide as a template agent, takes ammonia water as a pH regulator and a catalyst, takes ethanol and water as a solvent, and realizes the adjustment of the pore volume and the pore diameter of MSN by controlling the proportion of the raw materials and taking micelle self-assembly as the template in the reaction process, and then the silicon precursor is deposited on the surface of the template to form a silicon shell, so that the adjustment of the particle size of the MSN is realized, and the template is removed by calcination, thereby realizing the adjustment of the particle size, the specific surface area, the pore volume and the pore diameter of the mesoporous silica; and triethanolamine does not need to be added in the preparation process, the preparation process is safe and environment-friendly, the production cost is low, and the large-scale production can be realized.
Description
Technical Field
The invention relates to the technical field of nano drug-loaded materials, in particular to mesoporous silica, carboxylated mesoporous silica, a drug-loaded system, and a preparation method and application thereof.
Background
A clinically common cancer treatment is the use of chemotherapeutic agents, such as: cisplatin, adriamycin, camptothecin, amlodipine, etoposide and teniposide. However, these chemotherapeutic agents have a large side effect on the human body and have only limited killing power of tumor cells. Curcumin is a relatively non-toxic natural product isolated from turmeric and has been widely used as a flavor and colorant in food products. Curcumin has strong antioxidant, anti-inflammatory and anti-tumor activities, and especially can promote the healing of skin wounds. In addition, curcumin has phototoxic effects on bacteria and tumor cells, and can be used as a photosensitizer for photodynamic therapy (PDT). Curcumin, which has many advantages, is a powerful candidate for the prevention and treatment of a variety of diseases. But the extremely low water solubility of curcumin in the microenvironment significantly reduces bioavailability and has not been approved for use as a therapeutic drug.
The utilization of nano drug-loaded systems for load transportation of curcumin is an effective method for enhancing the bioavailability of curcumin for anticancer therapy. For example, in the prior art, "preparation of curcumin mesoporous silica nanoparticle drug delivery system and drug loading performance thereof" (see lina et al, preparation of curcumin mesoporous silica nanoparticle drug delivery system and drug loading performance thereof [ J ]. university of fujian medicine, 2018,52(1):19-23), a curcumin mesoporous silica nanoparticle drug delivery system is disclosed, and hydrogen bonding adsorption is performed on curcumin by using MSN-rich silicon hydroxyl. However, in the prior art, hydrogen bonds are used for adsorbing curcumin, and in the ethanol washing or water washing process of the drug delivery system, curcumin can be rapidly separated from mesoporous silica due to the extremely weak hydrogen bond effect, cannot play a slow release role, and cannot reach a tumor, so that the practical application value of curcumin is limited.
"Multifunctional mesoporous silica nanoparticles for pH controlled drug release and functional imaging" (see j. mater.chem.,2011,21,16869-16872) discloses a Multifunctional mesoporous silica nanocomposite nanoparticle Doxorubicin (DOX) -loaded drug delivery system, wherein after mesoporous silica is connected with DOX through a hydrazone bond, the mesoporous silica becomes white powder without DOX loading after being washed by ethanol and water for multiple times, and after the mesoporous silica is connected with DOX through the hydrazone bond, the mesoporous silica can be washed by ethanol and water for multiple times, and the washed mesoporous silica is still brown yellow powder loaded with DOX. However, the drug delivery system releases hydrazone bonds while releasing drugs slowly, and the hydrazone bonds have high toxicity to cells.
Disclosure of Invention
In view of the above, the invention aims to provide mesoporous silica, carboxylated mesoporous silica, a drug-loading system, a preparation method and an application thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of mesoporous silica, which comprises the following steps:
the preparation method comprises the following steps of firstly mixing hexadecyl trimethyl ammonium bromide, ethanol and water, adjusting the pH value to 10-11 by using ammonia water, then adding a silicon source for second mixing, and carrying out nucleophilic substitution-polymerization reaction to obtain a precursor;
calcining the precursor to obtain mesoporous silica;
the volume ratio of the water to the ethanol is 8: (1-6).
Preferably, the mass ratio of the silicon source to the hexadecyl trimethyl ammonium bromide is (1-2): (0.3 to 0.6);
the second mixed raw material also comprises a pore-expanding agent;
the pore-expanding agent comprises n-decane and/or 1,3, 5-trimethylbenzene;
the mass ratio of the silicon source to the pore-expanding agent is (1-2): (0 to 10.5).
The invention provides the mesoporous silica prepared by the preparation method in the technical scheme, the particle size of the mesoporous silica is 20-600 nm, and the specific surface area of the mesoporous silica is 850-1300 m2The pore diameter is 2-10 nm, and the pore volume is 0.6-3.5 cm3/g。
The invention provides carboxylated mesoporous silica, which comprises the mesoporous silica in the technical scheme and 3- (triethoxysilyl) propyl succinic acid connected with the mesoporous silica through a silica bond.
The invention provides a preparation method of carboxylated mesoporous silica in the technical scheme, which comprises the following steps:
mixing 3- (triethoxysilyl) propyl succinic anhydride with alcohol, and carrying out alcoholysis reaction to obtain 3- (triethoxysilyl) propyl succinic acid solution;
mixing the 3- (triethoxysilyl) propyl succinic acid solution, the mesoporous silica according to claim 3 and an amide solvent, and carrying out esterification reaction to obtain the carboxylated mesoporous silica.
The invention provides application of the carboxylated mesoporous silica or the carboxylated mesoporous silica prepared by the preparation method in the technical scheme as a drug carrier.
The invention provides a drug-loading system, which comprises carboxylated mesoporous silica and curcumin connected with the carboxylated mesoporous silica through ester bonds;
the carboxylated mesoporous silica is the carboxylated mesoporous silica according to the technical scheme or the carboxylated mesoporous silica prepared by the preparation method according to the technical scheme.
The invention provides a preparation method of the medicine carrying system in the technical scheme, which comprises the following steps:
mixing carboxylated mesoporous silica, N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, 4- (dimethylamino) pyridine, curcumin and an amide solvent, and carrying out esterification reaction to obtain a drug-carrying system.
Preferably, the mass ratio of the carboxylated mesoporous silica to the N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride to the 4- (dimethylamino) pyridine to the curcumin is (50-200): (10-300): (50-500): (50-500).
The invention also provides the application of the drug-carrying system in the technical scheme or the drug-carrying system prepared by the preparation method in the technical scheme in drug release in non-disease treatment or preparation of anti-cancer drugs.
The invention provides a preparation method of mesoporous silica, which comprises the following steps: firstly mixing hexadecyl trimethyl ammonium bromide, ethanol and water, adjusting the pH value to 10-11 by using ammonia water, then secondly mixing with a silicon source, and carrying out nucleophilic substitution-polymerization reaction to obtain a precursor; calcining the precursor to obtain mesoporous silica; the volume ratio of the water to the ethanol is 8: (1-6). The method adopts a sol-gel method, takes a silicon source as a silicon precursor, takes cetyl trimethyl ammonium bromide as a template agent, takes ammonia water as a pH regulator and a catalyst, takes ethanol and water as solvents, and takes the micelles of the cetyl trimethyl ammonium bromide as the template in the nucleophilic substitution-polymerization reaction process, thereby realizing the regulation of the pore volume and the pore diameter of the MSN; and triethanolamine does not need to be added in the preparation process, the preparation process is safe and environment-friendly, the production cost is low, and the large-scale production can be realized.
The invention provides the mesoporous silica prepared by the preparation method in the technical scheme. The mesoporous silicon dioxide provided by the invention has good biocompatibility and stability; the surface of the mesoporous silica has silicon hydroxyl which can be modified by functional groups and biological targets; in addition, the polymer has high specific surface area, large pore volume and adjustable pore diameter, is favorable for high loading rate and controllable release of small molecules, and can be used as a drug carrier.
The invention provides carboxylated mesoporous silica, which is obtained by modifying the mesoporous silica by 3- (triethoxysilyl) propyl succinic anhydride. The carboxylated mesoporous silica provided by the invention is modified by carboxyl, can be connected with curcumin containing phenolic hydroxyl through ester bonds, and the ester bonds can be hydrolyzed under the acidic, neutral and alkaline conditions, so that the carboxylated mesoporous silica provided by the invention and the curcumin can be hydrolyzed under the acidic, neutral and alkaline conditions to release the curcumin and the basically nontoxic carboxylated mesoporous silica after being connected through the ester bonds, and therefore, the carboxylated mesoporous silica prepared by the invention can be used as a curcumin carrier.
The invention provides a preparation method of carboxylated mesoporous silica, which comprises the following steps: mixing 3- (triethoxysilyl) propyl succinic anhydride (TPSA) and alcohol, and carrying out alcoholysis reaction to obtain a 3- (triethoxysilyl) propyl succinic acid (TPSA-COOH) solution; and mixing the 3- (triethoxysilyl) propyl succinic acid solution, the mesoporous silica and an amide solvent, and carrying out esterification reaction to obtain the carboxylated mesoporous silica. In the invention, acid anhydride in the TPSA reacts with alcohol to release carboxylic acid to obtain TPSA-COOH, and the TPSA-COOH is coupled with silicon hydroxyl in the mesoporous silica to convert the silicon hydroxyl of the mesoporous silica into carboxyl; the preparation method is simple to operate, low in production cost and suitable for industrial production.
The invention provides a drug loading system which comprises carboxylated mesoporous silica and curcumin connected with the carboxylated mesoporous silica through ester bonds. In the drug loading system provided by the invention, curcumin is connected with carboxylated mesoporous silica in a covalent bond ester bond form, and compared with the condition that curcumin is adsorbed on the surface of silica by a hydrogen bond, the covalent bond ester bond can be better washed by ethanol or water for multiple times, so that the loading rate and bioavailability of curcumin can be improved; compared with curcumin which is connected to the surface of silicon dioxide by a hydrazone bond, the ester bond has no toxicity; moreover, as the ester bond can be hydrolyzed under acidic, neutral or alkaline conditions, the drug-loading system provided by the invention can realize the release of curcumin by hydrolyzing the ester bond in an acidic or alkaline environment; the hydrolysate of the drug-loaded system, namely the carboxylated mesoporous silica, is relatively nontoxic to Hela cells; therefore, the drug carrier system provided by the invention has excellent drug slow release function and anticancer effect, and can be used for drug slow release or preparation of anticancer drugs.
The invention provides a preparation method of the medicine carrying system in the technical scheme, which comprises the following steps: mixing carboxylated mesoporous silica, N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, 4- (dimethylamino) pyridine, curcumin and an amide solvent, and carrying out esterification reaction to obtain a drug-carrying system. The preparation method provided by the invention is simple to operate and suitable for industrial production.
Drawings
FIG. 1 is an SEM image of mesoporous silica prepared in examples 1-7;
FIG. 2 is a TEM image of mesoporous silica prepared in examples 1 to 7;
FIG. 3 is a nitrogen adsorption/desorption isotherm curve of the mesoporous silica prepared in examples 1 to 7, wherein an interpolated graph is a pore size distribution curve;
FIG. 4 is a small-angle XRD (X-ray diffraction) spectrum of mesoporous silica prepared in examples 1-7;
fig. 5 is an SEM image of SG129 prepared in example 9;
fig. 6 is a TEM image of SG129 prepared in example 9;
fig. 7 is an SEM image of SG133 prepared in example 10;
fig. 8 is a TEM image of SG133 prepared in example 10;
FIG. 9 is a hydrogen spectrum of curcumin, TPSA, SG129 prepared in example 9, SG129-COOH prepared in example 11 and SG129-CUR prepared in example 13;
FIG. 10 is a hydrogen spectrum of SG129-CUR prepared in example 14;
FIG. 11 is a graph of the UV absorption spectrum of SG129-CUR at different test times;
FIG. 12 is a graph of curcumin release at different test times;
in FIGS. 1-4, a is example 1, b is example 2, c is example 3, d is example 4, e is example 5, f is example 6, g is example 7, and h is example 8.
Detailed Description
The invention provides a preparation method of mesoporous silica, which comprises the following steps:
the preparation method comprises the following steps of firstly mixing hexadecyl trimethyl ammonium bromide, ethanol and water, adjusting the pH value to 10-11 by using ammonia water, then adding a silicon source for second mixing, and carrying out nucleophilic substitution-polymerization reaction to obtain a precursor;
calcining the precursor to obtain Mesoporous Silica (MSN);
the volume ratio of the water to the ethanol is 8: (1-6).
In the present invention, all the raw material components are commercially available products well known to those skilled in the art unless otherwise specified.
The preparation method comprises the steps of mixing cetyl trimethyl ammonium bromide, ethanol and water firstly, adjusting the pH value to 10-11 by using ammonia water, adding a silicon source for mixing secondly, and carrying out nucleophilic substitution-polymerization reaction to obtain a precursor.
In the present invention, the volume ratio of water to ethanol is 8: (1 to 6), preferably 8: (2-5), more preferably 8: (3-4). In the present invention, the silicon source preferably includes tetramethyl orthosilicate and/or tetrabutyl orthosilicate. In the invention, the mass ratio of the silicon source to the hexadecyl trimethyl ammonium bromide is preferably (1-2): (0.3 to 0.6), more preferably (1.2 to 1.8): (0.35-0.55), most preferably (1.4-1.5): (0.4-0.5). In the invention, the mass ratio of the silicon source to the water is (1-2): and 16, more preferably (1.2 to 1.8): 16, most preferably (1.4-1.5): 16. in the invention, the concentration of the ammonia water is preferably 25-28 wt%, and more preferably 26-27 wt%; the using amount of the ammonia water is not particularly limited, and the pH value can be adjusted to 10-11, and is preferably 10.5; in the embodiment of the invention, the volume ratio of the mass of the silicon source to the ammonia water is preferably (1-2) g: (0.5 to 1) mL, more preferably (1.2 to 1.8) g: (0.6-0.9), mL, most preferably (1.5-1.6) g: (0.7-0.8) mL. The invention controls the raw material proportion in the range, and prepares the series mesoporous silicon dioxide with adjustable particle size, specific surface area, pore diameter and pore volume.
In the invention, cetyl trimethyl ammonium bromide, ethanol and water are firstly mixed, ammonia water is used for adjusting the pH value to 10-11, then a silicon source is added for second mixing, preferably, cetyl trimethyl ammonium bromide, ethanol and water are firstly mixed, and a water-ethanol-CTAB mixed solution is obtained; adding ammonia water into the water-ethanol-CTAB mixed solution, and performing ultrasonic dispersion to obtain a dispersion; dropwise adding a silicon source into the dispersion for second mixing; the first mixing and the second mixing are preferably stirring mixing, and the speed of the first mixing and the second mixing is not particularly limited in the invention, and the raw materials can be uniformly mixed; the ultrasonic dispersion time is preferably 30-60 min, and more preferably 40-50 min; the temperature of the second mixing is preferably room temperature; the dropping speed is not specially limited, and the dropping can be carried out at a constant speed.
In the present invention, the second mixed raw material preferably further comprises a pore-expanding agent; the pore-expanding agent preferably comprises n-decane and/or 1,3, 5-Trimethylbenzene (TMB); the mass ratio of the silicon source to the pore-expanding agent is preferably (1-2): (0 to 10.5), more preferably (1.2 to 1.8): (2-8), most preferably (1.4-1.5): (5-6). In the invention, when the pore-expanding agent is n-decane and 1,3, 5-trimethylbenzene, the volume ratio of the n-decane to the 1,3, 5-trimethylbenzene is preferably (0-8.5): (0 to 4.5), more preferably (1 to 7): (1-4), most preferably (3-5): (2-3); the n-decane and TMB have synergistic effect to enlarge the aperture and pore volume of the mesoporous silica. In the invention, the pore-expanding agent is preferably added at the same time as the silicon source; when the second mixed raw material comprises the pore-expanding agent, the second mixing temperature is preferably 60-100 ℃, and more preferably 70-80 ℃.
In the invention, the temperature of the nucleophilic substitution-polymerization reaction is preferably 30-70 ℃, and more preferably 40-60 ℃; the time of the nucleophilic substitution-polymerization reaction is preferably 1-10 h, and more preferably 2-5 h; the nucleophilic substitution-polymerization reaction includes a nucleophilic reaction (formula (1)), an alcohol condensation reaction (formula (2)), a water condensation reaction (formula (3)), and a polymerization reaction (formula (4)), wherein R represents an alkyl group:
after the nucleophilic substitution-polymerization reaction, the method preferably further comprises the steps of carrying out solid-liquid separation on the reaction liquid of the nucleophilic substitution-polymerization reaction, and sequentially carrying out alcohol washing, drying and grinding on the obtained solid product to obtain the precursor. The solid-liquid separation method of the present invention is not particularly limited, and a solid-liquid separation method known to those skilled in the art, specifically, centrifugal separation, may be employed. In the invention, the alcohol washing is preferably ethanol washing, the number of times of ethanol washing is preferably 3-5 times, and more preferably 4 times, and the purpose of the ethanol washing is to remove the pore-expanding agent and the template agent. In the present invention, the drying is preferably performed by air drying; the drying stability is preferably 60-120 ℃, and more preferably 80-100 ℃; in the present invention, the drying time is not particularly limited, and the drying time may be set to a constant weight. In the present invention, the grinding is preferably performed in an agate mortar, and the particle size of the precursor after grinding is preferably 30 to 500nm, and more preferably 50 to 300 nm.
After the precursor is obtained, the precursor is calcined to obtain the mesoporous silica. In the invention, the calcination temperature is preferably 500-600 ℃, more preferably 520-580 ℃, and most preferably 550-560 ℃; the heating rate of the temperature rising to the calcining temperature is preferably 1-10 ℃/min, more preferably 2-8 ℃/min, and most preferably 4-5 ℃/min; starting timing when the temperature is increased to the calcining temperature, wherein the calcining time is preferably 5-10 h, more preferably 6-9 h, and most preferably 7-8 h; the calcination is preferably carried out in a muffle furnace; the atmosphere for the calcination is preferably air. In the invention, hexadecyl trimethyl ammonium bromide is decomposed by combustion in the calcining process; when the preparation raw materials comprise the pore-expanding agent, the pore-expanding agent acts on the CTAB, the occupied area of the CTAB is enlarged, and the pore-expanding agent and the CTAB are combusted and decomposed in the calcining process, so that the pore diameter and the pore volume of the mesoporous silica are larger, and the framework of the mesoporous silica is wider. After the calcination, the invention preferably further comprises grinding the calcined product to obtain mesoporous silica; the invention is not particularly limited to the grinding, and the particle size of the obtained mesoporous silica can be controlled to be 20-600 nm.
The invention provides the mesoporous silica prepared by the preparation method in the technical scheme. In the invention, the particle size of the mesoporous silica is 20-600 nm, preferably 30-500 nm, more preferably 100-400 nm, and most preferably 200-300 nm; the specific surface area of the mesoporous silica is 850-1300 m2Preferably 900 to 1250 m/g2(iv)/g, more preferably 950～1200m2The most preferable range is 1000 to 1100m2(ii)/g; the aperture of the mesoporous silica is 2-10 nm, preferably 3-9 nm, more preferably 4-8 nm, and most preferably 5-6 nm; the pore volume of the mesoporous silica is 0.6-3.5 cm3Preferably 1 to 3 cm/g3A concentration of 1.5 to 2.5cm3(iv) g, most preferably 2 to 2.5cm3/g。
The invention provides carboxylated mesoporous silica (abbreviated as MSN-COOH) which comprises the mesoporous silica as claimed in claim 3 and 3- (triethoxysilyl) propyl succinic acid bonded with the mesoporous silica through a silica bond.
In the invention, the load of the 3- (triethoxysilyl) propylsuccinic acid is preferably 20-60%, more preferably 30-50%, and most preferably 35-47%.
In the present invention, the particle size, specific surface area, pore size and pore volume of the carboxylated mesoporous silica are preferably the same as those of the mesoporous silica, and are not described herein again.
The invention provides application of the mesoporous silica as a drug carrier in the technical scheme. The mesoporous silicon dioxide provided by the invention has good biocompatibility and stability; the surface of the mesoporous silica has silicon hydroxyl which can react with a silane coupling agent and can be modified by functional groups and biological targets; moreover, the nano-particles have high specific surface area, large pore volume, adjustable pore diameter and good particle size uniformity, are favorable for high loading rate and controllable release of small molecules, and can be used as a drug carrier.
The invention provides a preparation method of the carboxylated mesoporous silica, which comprises the following steps:
mixing 3- (triethoxysilyl) propyl succinic anhydride with alcohol, and carrying out alcoholysis reaction to obtain 3- (triethoxysilyl) propyl succinic acid solution;
and mixing the 3- (triethoxysilyl) propyl succinic acid solution, the mesoporous silica and the amide solvent in the technical scheme, and performing esterification reaction to obtain carboxylated mesoporous silica (MSN-COOH).
According to the invention, 3- (triethoxysilyl) propyl succinic anhydride (TPSA) and alcohol are mixed for alcoholysis reaction to obtain 3- (triethoxysilyl) propyl succinic acid (TPSA-COOH) solution. In the present invention, the alcohol preferably comprises ethanol and/or methanol; the volume ratio of the 3- (triethoxysilyl) propyl succinic anhydride to the alcohol is preferably (0.5-50): (1-100), more preferably (10-40): (10-80), most preferably (20-30): (30-50).
In the present invention, the mixing method is preferably stirring mixing, and the speed and time of stirring mixing are not particularly limited in the present invention, and the raw materials may be uniformly mixed. In the invention, the temperature of the alcoholysis reaction is preferably 15-70 ℃, more preferably 20-60 ℃, and most preferably 40 ℃; the alcoholysis reaction time is preferably 10-24 h, more preferably 12-22 h, and most preferably 15-20 h; the reaction occurring during the alcoholysis reaction is as shown in formula (5):
after the 3- (triethoxysilyl) propyl succinic acid solution is obtained, the 3- (triethoxysilyl) propyl succinic acid solution, the mesoporous silica and the amide solvent are mixed according to the technical scheme for esterification reaction, and the carboxylated mesoporous silica is obtained.
In the present invention, the ratio of the volume of the 3- (triethoxysilyl) propylsuccinic anhydride to the mass of the mesoporous silica is preferably (0.5 to 50) mL: (0.1-20) g, more preferably (10-40) mL: (1-15) g, most preferably (20-30) mL: (5-10) g. In the present invention, the mixing manner is preferably stirring mixing, and the stirring mixing speed is not particularly limited, and the raw materials can be uniformly mixed; the mixing order is preferably to disperse the mesoporous silica in an amide solvent to obtain a silica dispersion; mixing the 3- (triethoxysilyl) propyl succinic acid solution and the silica dispersion with stirring; the mixing temperature of the 3- (triethoxysilyl) propyl succinic acid solution and the silicon dioxide dispersion is preferably 100-200 ℃, and more preferably 120-150 ℃; the amide-based solvent preferably includes N, N-Dimethylformamide (DMF) or N, N-dimethylacetamide.
In the invention, the temperature of the esterification reaction is preferably 100-200 ℃, more preferably 120-180 ℃, and most preferably 150-160 ℃; the esterification reaction time is preferably 2-8 h, more preferably 4-6 h, and most preferably 5-6 h; the reaction occurring during the esterification reaction is represented by the formula (6):
wherein,
the mesoporous silica is represented, and the carboxylated mesoporous silica prepared by the invention is a mixture of two products.
After the esterification reaction, the method preferably further comprises the steps of carrying out solid-liquid separation on the reaction liquid of the esterification reaction, and sequentially carrying out alcohol washing and drying on the obtained solid product to obtain the carboxylated mesoporous silica. The solid-liquid separation method of the present invention is not particularly limited, and a solid-liquid separation method known to those skilled in the art, specifically, centrifugal separation, may be employed. In the present invention, the alcohol washing is preferably ethanol washing, the number of times of ethanol washing is preferably 3 to 5 times, and more preferably 4 times, and the purpose of the ethanol washing is to remove unreacted raw materials and impurities. In the present invention, the drying is preferably performed by air drying; the drying stability is preferably 60-120 ℃, and more preferably 80-100 ℃; in the present invention, the drying time is not particularly limited, and the drying time may be set to a constant weight.
The invention provides application of the carboxylated mesoporous silica serving as a drug carrier in the technical scheme. The surface of the carboxylated mesoporous silica provided by the invention is modified by carboxyl, the carboxylated mesoporous silica can be connected with curcumin containing phenolic hydroxyl through ester bonds, and the ester bonds can be hydrolyzed under acidic, neutral and alkaline conditions to release the curcumin and the basically non-toxic carboxylated mesoporous silica, so that the carboxylated mesoporous silica prepared by the invention can be used as a carrier of a medicament.
The invention provides a drug-loading system, which comprises carboxylated mesoporous silica and curcumin connected with the carboxylated mesoporous silica through ester bonds;
the carboxylated mesoporous silica is the carboxylated mesoporous silica according to the technical scheme or the carboxylated mesoporous silica prepared by the preparation method according to the technical scheme.
In the invention, the loading amount of the curcumin is preferably 3-10 wt%, more preferably 4-9 wt%, and most preferably 6-8 wt%. In the invention, the particle size of the drug-carrying system is preferably 20-600 nm, more preferably 30-500 nm, further preferably 100-400 nm, and most preferably 200-300 nm.
The invention provides a preparation method of a medicine carrying system in the technical scheme, which comprises the following steps:
mixing carboxylated mesoporous silica, N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, 4- (dimethylamino) pyridine, curcumin and an amide solvent, and carrying out esterification reaction to obtain a drug-loaded system (MSN-CUR).
In the invention, the mass ratio of the carboxylated mesoporous silica to the N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride to the 4- (dimethylamino) pyridine to the curcumin is preferably (50-200): (10-300): (50-500): (50-500), more preferably (80-180): (50-250): (100-400): (100-500), most preferably (100-150): (100-200): (200-300): (200-300).
In the invention, the structural formula of the curcumin (abbreviated as Cur) is shown as
In the invention, the mixing mode of the carboxylated mesoporous silica, the N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, the 4- (dimethylamino) pyridine, the curcumin and the amide solvent is preferably stirring mixing, the speed and the time of stirring and mixing are not particularly limited, and the raw materials can be uniformly mixed; the mixing order is preferably to disperse the carboxylated mesoporous silica in the amide solvent, and then to add the N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (EDC), the 4- (dimethylamino) pyridine (DMA) and the curcumin in sequence. In the present invention, the EDC functions as an activating agent for carboxyl groups; the DMAP acts as a catalyst.
In the invention, the temperature of the esterification reaction is preferably 40-80 ℃, more preferably 50-70 ℃, and most preferably 60 ℃, and the time of the esterification reaction is preferably 1-10 hours, more preferably 2-8 hours, and most preferably 4-6 hours; in the esterification reaction process, under the combined action of EDC (activating reagent of carboxyl) and DMAP (catalyst), curcumin containing phenolic hydroxyl is connected to carboxylated mesoporous silica in a covalent bond ester bond form, compared with a conventional hydrogen bond adsorption means, the covalent bond ester bond can be more subjected to multiple times of washing by ethanol and water, the loading rate and bioavailability of the curcumin can be improved, and the reaction generated in the esterification reaction process is as shown in formula (7):
after the esterification reaction, the method preferably further comprises the steps of carrying out solid-liquid separation on reaction liquid of the esterification reaction, and sequentially carrying out alcohol washing and drying on obtained solid products to obtain a drug-carrying system. The solid-liquid separation method of the present invention is not particularly limited, and a solid-liquid separation method known to those skilled in the art, specifically, centrifugal separation, may be employed. In the present invention, the alcohol washing is preferably ethanol washing, the number of times of ethanol washing is preferably 3 to 5 times, and more preferably 4 times, and the purpose of the ethanol washing is to remove unreacted raw materials and impurities. In the present invention, the drying is preferably performed by air drying; the drying stability is preferably 60-120 ℃, and more preferably 80-100 ℃; in the present invention, the drying time is not particularly limited, and the drying time may be set to a constant weight.
The invention provides the application of the drug-carrying system in the technical scheme or the drug-carrying system prepared by the preparation method in the technical scheme in drug release in non-disease treatment or preparation of anti-cancer drugs.
In the invention, ester bonds connecting curcumin and carboxylated silica can be hydrolyzed under acidic, alkaline or neutral conditions of the drug-carrying system, wherein the hydrolysis route under acidic conditions is shown as formula (8), and carboxylated mesoporous silica (MSN-COOH) and curcumin are subjected to esterification reaction under the action of EDC and DMAP to obtain the drug-carrying system (MSN-CUR); under the acidic condition, ester bonds in the MSN-CUR are hydrolyzed to release curcumin and MSN-COOH.
In the drug loading system provided by the invention, curcumin is connected to carboxylated mesoporous silica in a covalent bond ester bond form, and compared with the condition that curcumin is adsorbed on the surface of silica by a hydrogen bond, the covalent bond ester bond can withstand multiple times of washing with ethanol and water, so that the loading rate and bioavailability of curcumin are really improved; compared with curcumin linked to the silica surface with a hydrazone bond, toxicity is low. The drug-loading system provided by the invention has excellent drug slow-release function and anticancer effect, and can be used for drug slow release or preparation of anticancer drugs.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Mixing 16mL of deionized water, 2mL of ethanol and 0.6g of CTAB, adding 27 wt% ammonia water to adjust the pH value to 10, and performing ultrasonic treatment for 30min to obtain a dispersion; dropwise adding 2ml of TEOS into the dispersion under the conditions of room temperature and magnetic stirring, reacting for 2h under the condition of room temperature, centrifugally separating, washing the obtained solid product with ethanol for 3 times, then air-drying at 60 ℃ to constant weight, and grinding with an agate mortar until the particle size is 30-500 nm to obtain a precursor; and (3) placing the precursor in a muffle furnace, heating the precursor from room temperature to 550 ℃ at the heating rate of 1 ℃/min, and calcining for 5h to obtain mesoporous silica (marked as MSN), wherein the structural parameters of the mesoporous silica are shown in Table 1.
Examples 2 to 7
Mesoporous silica was prepared according to the method of example 1, preparation conditions and structural parameters (particle size, specific surface area S) of the productBETPore volume VPAnd an aperture DP) As shown in table 1.
FIG. 1 is an SEM image of mesoporous silica prepared in examples 1 to 7, as shown in FIG. 1, a TEM image is as shown in FIG. 2, a nitrogen adsorption/desorption isotherm is as shown in FIG. 3 (an interpolation graph in FIG. 3 is a pore size distribution curve), a small-angle XRD spectrum is as shown in FIG. 4, and in FIGS. 1 to 4, a is example 1, b is example 2, c is example 3, d is example 4, e is example 5, f is example 6, g is example 7, and h is example 8.
Comparative examples 1 to 3
Mesoporous silica was prepared according to the difference of example 1 from example 1 in that ammonia water was replaced with triethylamine, the preparation conditions of comparative examples 1 to 3, and the structural parameters (particle size, specific surface area S) of the productBETPore volume VPAnd an aperture DP) As shown in table 1.
TABLE 1 preparation conditions of examples 1 to 7 and structural parameters of the prepared mesoporous silica
From FIGS. 1 to 3 and Table 1According to the invention, ammonia water is used as a pH regulator and a catalyst, and the dosage ratio of water to ethanol is controlled to prepare the catalyst with the average pore diameter of 30-500 nm and the specific surface area of 1130-1315 m2Per g, pore volume of 0.6-2.5 cm3(ii) mesoporous silica having a pore diameter of 2 to 2.6 nm; the triethylamine is used as a pH regulator and a catalyst, and the mesoporous silica prepared under the same conditions has large particle size, small specific surface area, small pore volume and small pore diameter; the particle size, specific surface area, pore volume and pore diameter of the mesoporous silica can be adjusted by adjusting the dosage ratio of water and ethanol.
Fig. 4 demonstrates the existence of mesopores in the mesoporous silica prepared by the present invention.
Example 9
Mixing 16mL of deionized water, 4mL of ethanol, 0.6g of CTAB and 0.5mL of 25 wt% ammonia water, and performing ultrasonic treatment for 30min to obtain a dispersion; under the condition of magnetic stirring at 60 ℃, sequentially adding 2.14mL of n-decane, 1.14mL of TMB and 2mL of TEOS into the dispersion, reacting for 2h, carrying out centrifugal separation, washing the obtained solid product with ethanol for 3 times, then air-drying the solid product to constant weight at 60 ℃, grinding the solid product into powder by using an agate mortar, putting the powder into a muffle furnace, heating to 550 ℃ at the heating rate of 1 ℃/min, and then calcining for 5h to obtain mesoporous silicon dioxide (white powder, marked as SG 129).
The SEM image of SG129 prepared in this example is shown in fig. 5, and the TEM image is shown in fig. 6. As can be seen from FIGS. 5 to 6, the SG129 prepared in this example has an average particle size of 50nm, a relatively narrow particle size distribution, and a BET specific surface area of about 1000m2A pore diameter of about 10.1nm and a pore volume of about 3.5 cm/g3/g
Example 10
Mixing 16mL of deionized water, 5mL of ethanol, 0.6g of CTAB and 0.5mL of 28 wt% ammonia water, and performing ultrasonic treatment for 30min to obtain a dispersion; under the condition of magnetic stirring at 60 ℃, 3.21mL of n-decane, 1.71mL of TMB and 2mL of TEOS are sequentially added into the dispersion for reaction for 2h, centrifugal separation is carried out, the obtained solid product is washed by ethanol for 3 times, then the solid product is air-dried to constant weight at 60 ℃, an agate mortar is used for grinding into powder, the powder is placed into a muffle furnace, the temperature is raised to 550 ℃ at the heating rate of 1 ℃/min, and then the powder is calcined for 5h, so that mesoporous silicon dioxide (white powder, marked as SG133) is obtained.
The SEM image of SG133 prepared in this example is shown in fig. 7, and the TEM image is shown in fig. 8. As can be seen from FIGS. 7 to 8, the SG133 prepared in this example has an average particle size of 80nm, a relatively narrow particle size distribution, and a BET specific surface area of about 900m2A pore diameter of about 8.6nm and a pore volume of about 2.0 cm/g3/g
Example 11
Mixing 0.8mL of TPPSA with 10mL of ethanol, and carrying out alcoholysis reaction for 15h at 40 ℃ under the condition of magnetic stirring to obtain a TPSA-COOH solution; dispersing 0.5g of SG129 in 100mL of DMF solution to obtain SG129 dispersion; adding the TPSA-COOH solution into SG129 dispersoid under the condition of magnetic stirring at the temperature of 120 ℃, reacting for 4h, centrifugally separating, washing the obtained solid product with ethanol for 3 times, and air-drying at the temperature of 60 ℃ to constant weight to obtain the carboxylated mesoporous silica (marked as SG129-COOH, the particle size is 50 +/-10 nm).
Example 12
Mixing 0.8mL of TPPSA with 10mL of ethanol, and carrying out alcoholysis reaction for 15h at 40 ℃ under the condition of magnetic stirring to obtain a TPSA-COOH solution; dispersing 0.5g of SG129 in 100mL of DMF solution to obtain SG133 dispersion; adding the TPSA-COOH solution into SG133 dispersoid under the condition of magnetic stirring at 120 ℃, reacting for 4h, centrifugally separating, washing the obtained solid product with ethanol for 3 times, and air-drying at 60 ℃ to constant weight to obtain the carboxylated mesoporous silica (marked as SG133-COOH, the particle size is 50 +/-10 nm).
Example 13
Dispersing 90mg of SG129-COOH prepared in example 11 in 9mL of DMF solution, sequentially adding 150mg of EDC, 200mg of DMAP and 130mg of curcumin, uniformly mixing, carrying out esterification reaction for 2h under the condition of magnetic stirring at 60 ℃, carrying out centrifugal separation, washing the obtained solid product with ethanol for 3 times, and carrying out air drying at 60 ℃ to constant weight to obtain a drug-loaded system (marked as SG129-CUR, wherein the particle size is 80 +/-20 nm), wherein the loading rate of the curcumin is 100 mu g of curcumin/1.0 mg of SG 129-CUR.
Example 14
Dispersing 90mg of SG133-COOH prepared in example 12 in 9mL of DMF solution, sequentially adding 150mg of EDC, 200mg of DMAP and 130mg of curcumin, uniformly mixing, carrying out esterification reaction for 2h under the condition of magnetic stirring at 60 ℃, carrying out centrifugal separation, washing the obtained solid product with ethanol for 3 times, and carrying out air drying at 60 ℃ to constant weight to obtain a drug-loaded system (marked as SG133-CUR, wherein the particle size is 80 +/-20 nm), wherein the loading rate of the curcumin is 100 mu g of curcumin/1.0 mg of SG 133-CUR.
The hydrogen spectrums of curcumin, TPSA, SG129 prepared in example 9, SG129-COOH prepared in example 11 and SG129-CUR prepared in example 13 are shown in FIG. 9, the hydrogen spectrum of SG129-CUR prepared in example 13 is shown in FIG. 10, and it can be seen from FIGS. 9-10 that curcumin is bonded to the surface of the carboxylated mesoporous silica in the form of covalent bond ester bonds.
Application example 1
8mg of SG129-CUR prepared in example 13 was dispersed in 4ml pbs buffer (10mM, pH 6.0) to obtain a dispersion; centrifuging the dispersion at intervals, testing the ultraviolet absorption spectrum of the supernatant, determining the release amount of curcumin according to the ultraviolet absorption spectrum, and supplementing 4mL of fresh PBS buffer solution into the precipitate to continuously monitor the curcumin release behavior; wherein 5% (w/v) SDS (sodium dodecyl sulfate) is added into PBS buffer solution to increase the solubility of the slowly released curcumin in the solution, and the lambda is 430nm in the ultraviolet absorption spectrum test process.
The UV absorption spectrum of SG129-CUR at different test times is shown in FIG. 11, and the release amount of curcumin is shown in FIG. 12. As can be seen from the graphs in FIGS. 11 to 12, the curcumin is successfully loaded on SG129-COOH, and the release amount of the curcumin is less than 35% in a 70h monitoring period, so that the drug-loaded system provided by the invention shows a sustained and slow curcumin release behavior.
Application example 2
And (3) testing the anti-tumor activity performance: the cytotoxic activity of the SG129-COOH, SG133-COOH, SG129-CUR and SG133-CUR samples prepared in examples 11-14 and pure curcumin on Hela is determined by an MTT method, and the specific steps are as follows:
tumor cells were inoculated in DMEM medium containing 10% Fetal Bovine Serum (FBS), 1% penicillin/streptomycin and 2.0g/L sodium bicarbonate, respectivelyPerforming the following steps; when the tumor cells grow to a logarithmic phase, the tumor cells are inoculated into a 96-well plate, and the inoculation amount is 6 multiplied by 103Individual cells/well; setting different concentration groups of each sample to be tested, setting 3 multiple wells in each group, taking dimethyl sulfoxide (DMSO) as blank control group, placing at 37 deg.C and 5 v/v% CO2Saturated humidity CO2The culture box is respectively aseptically cultured for 24h, 48h and 72h, MTT solution is absorbed and 100 mu LDMSO is added, and the average optical density (OD570) is read at the wavelength of 570nm by an automatic enzyme-labeled colorimeter after the precipitate is completely dissolved. Tumor cell survival (%) ═ aDrug group/A Blank space100%, A represents the average optical density at 570nm (OD570), and the test results are shown in Table 2.
TABLE 2 MTT assay conditions and test results
Under the action that the concentration of SG129-COOH and SG133-COOH is 1024 mu g/mL, the survival rates of Hela cells are still respectively 88.32 +/-9.9% and 88.30 +/-8.4% after 72h, which shows that the biological safety of MSN-COOH, namely the biological safety of residual skeleton after the MSN-CUR releases curcumin, is high. Under the action that the concentration of curcumin in SG129-CUR and SG133-CUR is 102.4 mu g/mL, the survival rate of Hela cells is reduced to 59.41 +/-2.0% and 57.25 +/-6.5% after 72 hours, which shows that the medicine carrying system MSN-CUR prepared by the invention has higher killing power for cancer cells, and the killing power comes from curcumin released by MSN, but not from MSN materials. Pure curcumin has low water solubility and bioavailability, but has good solubility in organic solvents such as ethanol and DMEM medium, so MTT control test can be carried out. Under the action that the concentration of the pure curcumin is 128 mu g/mL, the survival rate of Hela cells is reduced to 39.95 +/-5.5% after 72h, which cannot indicate that the pure curcumin has high cancer cell killing power, and indicates that the MSN-CUR has the cancer cell killing power equivalent to that of the pure curcumin. The carboxylated mesoporous silica (SG129-COOH, SG133-COOH) has little toxic and side effect and good biocompatibility; after curcumin containing phenolic hydroxyl groups is connected to the surface of the carboxylated mesoporous silica in a covalent bond ester bond form (SG129-CUR, SG133-CUR), the curcumin has good cancer cell killing power and has the toxicity on cancer cells equivalent to that of pure curcumin.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. The preparation method of the mesoporous silica is characterized by comprising the following steps:
the preparation method comprises the following steps of firstly mixing hexadecyl trimethyl ammonium bromide, ethanol and water, adjusting the pH value to 10-11 by using ammonia water, then adding a silicon source for second mixing, and carrying out nucleophilic substitution-polymerization reaction to obtain a precursor;
calcining the precursor to obtain mesoporous silica;
the volume ratio of the water to the ethanol is 8: (1-6).
2. The preparation method according to claim 1, wherein the mass ratio of the silicon source to the hexadecyl trimethyl ammonium bromide is (1-2): (0.3 to 0.6);
the second mixed raw material also comprises a pore-expanding agent;
the pore-expanding agent comprises n-decane and/or 1,3, 5-trimethylbenzene;
the mass ratio of the silicon source to the pore-expanding agent is (1-2): (0 to 10.5).
3. The mesoporous silica prepared by the preparation method of claim 1 or 2, wherein the mesoporous silica has a particle size of 20-600 nm and a specific surface area of 850-1300 m2The pore diameter is 2-10 nm, and the pore volume is 0.6-3.5 cm3/g。
4. A carboxylated mesoporous silica comprising the mesoporous silica as set forth in claim 3 and 3- (triethoxysilyl) propylsuccinic acid bonded to the mesoporous silica through a silica-oxygen bond.
5. The method for preparing the carboxylated mesoporous silica according to claim 4, comprising the following steps:
mixing 3- (triethoxysilyl) propyl succinic anhydride with alcohol, and carrying out alcoholysis reaction to obtain 3- (triethoxysilyl) propyl succinic acid solution;
mixing the 3- (triethoxysilyl) propyl succinic acid solution, the mesoporous silica according to claim 3 and an amide solvent, and carrying out esterification reaction to obtain the carboxylated mesoporous silica.
6. Use of the carboxylated mesoporous silica according to claim 4 or the carboxylated mesoporous silica prepared by the preparation method according to claim 5 as a drug carrier.
7. A drug-loading system is characterized by comprising carboxylated mesoporous silica and curcumin connected with the carboxylated mesoporous silica through ester bonds;
the carboxylated mesoporous silica is the carboxylated mesoporous silica according to claim 4 or the carboxylated mesoporous silica prepared by the preparation method according to any one of claims 5 to 6.
8. The method for preparing a drug delivery system of claim 7, comprising the steps of:
mixing carboxylated mesoporous silica, N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, 4- (dimethylamino) pyridine, curcumin and an amide solvent, and carrying out esterification reaction to obtain a drug-carrying system.
9. The preparation method according to claim 8, wherein the mass ratio of the carboxylated mesoporous silica to the N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride to the 4- (dimethylamino) pyridine to the curcumin is (50-200): (10-300): (50-500): (50-500).
10. The use of the drug-loaded system of claim 7 or the drug-loaded system prepared by the preparation method of any one of claims 8 to 9 for the sustained release of drugs in non-disease treatment or for the preparation of anti-cancer drugs.
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