CN112007176A - Mesoporous silica nano composite carrier, drug-loaded composite, application and pharmaceutical composition - Google Patents
Mesoporous silica nano composite carrier, drug-loaded composite, application and pharmaceutical composition Download PDFInfo
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- CN112007176A CN112007176A CN202010936439.0A CN202010936439A CN112007176A CN 112007176 A CN112007176 A CN 112007176A CN 202010936439 A CN202010936439 A CN 202010936439A CN 112007176 A CN112007176 A CN 112007176A
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 title claims abstract description 263
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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Abstract
The invention relates to the technical field of medicines, in particular to a mesoporous silica nano composite carrier, a medicine carrying compound, application and a medicine composition. The mesoporous silica nano composite carrier comprises a nano-cluster core with the characteristic of magnetic imaging and an organic mesoporous silica shell wrapping the nano-cluster core, wherein the surface of the organic mesoporous silica shell is modified with optical imaging molecules. The mesoporous silica nano composite carrier can effectively load active drugs, has a good treatment effect on liver tumors, can be deposited at a high concentration in local tumor parts, continuously releases the loaded active drugs and kills tumor cells. Meanwhile, after the composite carrier loads the active drug and enters the body, the multi-modal imaging effect is achieved by utilizing the characteristics of magnetic resonance imaging and optical imaging of the composite carrier, and then the release, the drug effect, the mechanism and the like of the drug are effectively detected, so that the composite carrier has important clinical identification and research significance.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a mesoporous silica nano composite carrier, a medicine carrying compound, application and a medicine composition.
Background
Tumor imaging and targeted therapy based on nanotechnology are important components of tumor basic and clinical therapy. The traditional transcatheter arterial chemoembolization treatment of liver tumor mainly utilizes an emulsifier which is used for delivering chemotherapeutics and iodized oil through artery to realize local chemotherapy and transcatheter arterial embolization treatment on liver cancer. The medicine is supplied through the artery supplying blood to reach the aim of local high medicine concentration and blocking blood supply to tumor. However, the medicament of the chemotherapeutics-the iodized oil emulsifier is released quickly, so that the local medicament of the tumor circulates and empties quickly along with blood, and the effective medicament concentration in the tumor lasts for a short time. Therefore, the development of a treatment method which is simple in preparation, high in tumor local enrichment concentration, long in duration and good in treatment effect and is suitable for the liver cancer transarterial perfusion chemotherapy is urgently needed.
The mesoporous organic silica nanoparticles have uniform particle size, large specific surface area and uniformly distributed mesopores, so that the mesoporous organic silica nanoparticles have good biocompatibility, abundant surface modification groups and good drug loading function, and thus, good drug delivery and image evaluation functions are exerted. At present, the nano medical mesoporous silicon has been developed into a large class of drug delivery carriers. The mesoporous silicon is used as a carrier to overcome the defects of low bioavailability, unstable blood circulation and the like of a pure chemotherapeutic medicament and realize the anti-tumor effect of the mesoporous silicon. However, the mesoporous silicon nanometer is used as a chemotherapeutic drug carrier and is not reported to be used for the treatment of liver tumor by the arterial chemoembolization.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a mesoporous silica nano composite carrier, a drug-loaded composite, application and a pharmaceutical composition. The mesoporous silica nano composite carrier can effectively load active drugs, has a good treatment effect on liver tumors, particularly has a good effect in the treatment of the liver tumors through arterial chemoembolization, can be deposited at a high concentration in local tumors, continuously releases the loaded active drugs, and further kills tumor cells.
The invention is realized by the following steps:
in a first aspect, an embodiment of the present invention provides a mesoporous silica nanocomposite carrier, which includes a nanocluster core having a magnetic imaging characteristic and an organic mesoporous silica shell wrapping the nanocluster core, wherein the surface of the organic mesoporous silica shell is modified with optical imaging molecules. The mesoporous silica nano composite carrier can load active drugs, and the organic mesoporous silica shell is mainly used for loading the active drugs.
In an alternative embodiment, the nanocluster core is formed of a compound having magnetic imaging characteristics;
preferably, the compound having magnetic imaging characteristics comprises ferroferric oxide;
preferably, the optical imaging molecule is modified on the surface of the organic mesoporous silica shell through a sulfydryl group;
preferably, the optical imaging molecule comprises Cy5.5.
In alternative embodiments, it comprises Fe3O4Nanocluster core and encapsulating said Fe3O4The nano-cluster core is an organic mesoporous silica shell, and Cy5.5 is modified on the surface of the organic mesoporous silica shell through sulfydryl;
preferably, the average particle diameter of the mesoporous silica nanocomposite support is 362.21 ± 20.71 nm.
In a second aspect, an embodiment of the present invention provides a method for preparing a mesoporous silica nanocomposite support according to any one of the previous embodiments, including: the organic mesoporous silica shell is wrapped on the nano-cluster core, and then optical imaging molecules are grafted on the surface of the organic mesoporous silica shell.
In an alternative embodiment, the step of preparing the nanocluster core comprises: mixing metal salt and weak acid and strong base salt to carry out hydrothermal reaction;
preferably, the step of preparing the nanocluster core comprises: mixing and dissolving iron salt, sodium acetate and trisodium citrate, and reacting for 8-12 hours at the temperature of 180 ℃ and 220 ℃;
preferably, the iron salt is ferric chloride;
preferably, the mass ratio of the ferric trichloride to the sodium acetate to the trisodium citrate is 1:1.5-2.0: 0.2-0.5;
preferably, the step of preparing the nanocluster core comprises: cooling, solid-liquid separation and washing are sequentially carried out after the reaction;
preferably, the step of coating the organic mesoporous silica shell on the nanocluster core comprises: mixing a structure directing agent, a nanocluster core and a silicon source for reaction;
preferably, the step of coating the organic mesoporous silica shell on the nanocluster core comprises: in a water-ethanol/n-hexane two-phase system, a structure directing agent, a nano-cluster core, an organic silicon source and an inorganic silicon source are mixed for reaction;
preferably, the step of coating the organic mesoporous silica shell on the nanocluster core comprises: mixing the structure directing agent, ethanol, water and an alkaline substance, adding the mixture into the nano-cluster core, performing ultrasonic treatment, adding n-hexane, standing, adding the inorganic silicon source and the organic silicon source, reacting to form an organic mesoporous silica shell, and wrapping the organic mesoporous silica shell outside the nano-cluster core;
preferably, the structure directing agent is cetyltrimethylammonium bromide; the inorganic silicon source is tetraethoxysilane; the organic silicon source is 1, 2-bis (triethoxysilyl) ethane, the alkaline substance is ammonia water, and the ammonia water with the mass concentration of 25-28% is preferred;
preferably, the mass ratio of the cetyltrimethylammonium bromide to the nanocluster core is 15-17: 1, adding 0.2-0.3 ml of the tetraethoxysilane and 0.2-0.3 ml of the 1, 2-bis (triethoxysilyl) ethane per 10mg of the nanocluster core;
preferably, the step of coating the organic mesoporous silica shell on the nanocluster core comprises: removing the structure directing agent after the reaction is finished;
preferably, the step of removing the structure directing agent comprises: extracting a reaction mixed solution formed after the reaction is finished, and removing the structure directing agent;
preferably, the step of grafting comprises: modifying sulfydryl on the organic mesoporous silica shell, and then reacting the sulfydryl with an optical imaging raw material to modify the optical imaging molecule on the surface of the organic mesoporous silica shell;
preferably, the step of grafting comprises: mixing nanoparticles formed by wrapping an organic mesoporous silica shell on a nano-cluster core with a compound containing sulfydryl for reaction, and then reacting with an optical imaging raw material;
preferably, the step of grafting comprises: dispersing the nano particles in a mixed solution of an alcohol solvent and 3-mercaptopropyltriethoxysilane, then reacting for 10-14 hours at 55-70 ℃ to form mercapto-modified nano particles, then dispersing the nano particles in water, and then reacting with an amide compound and Cy5.5-maleimide.
In a third aspect, the present invention provides a drug-loaded composite, which includes an active drug and the mesoporous silica nanocomposite carrier according to any one of the foregoing embodiments or the mesoporous silica nanocomposite carrier prepared by the method according to any one of the foregoing embodiments, where the mesoporous silica nanocomposite carrier loads the active drug;
preferably, the active drug is loaded in the mesopores of the organic mesoporous silica shell of the mesoporous silica nanocomposite carrier;
preferably, the active drug is an anti-tumor compound;
preferably, the drug loading of the active drug is 270-280 mu g mg-1. Drug loading means that 270-280 micrograms of active drug per mg of drug-loaded complex.
In an alternative embodiment, the method comprises the following steps: loading an active drug on the mesoporous silica nano composite carrier or the mesoporous silica nano composite carrier prepared by the preparation method of the mesoporous silica nano composite carrier;
preferably, the step of loading comprises: mixing the mesoporous silica nano composite carrier with the active drug for reaction, so that the active drug is loaded on the organic mesoporous silica shell;
preferably, the reaction conditions are: stirring for 20-24 hours in the dark.
In a fourth aspect, embodiments of the present invention provide a pharmaceutical composition comprising iodized oil and a drug-loaded complex of the foregoing embodiments or a method of preparing a drug-loaded complex of the foregoing embodiments.
In a fifth aspect, the present invention provides a mesoporous silica nanocomposite carrier according to any one of the foregoing embodiments, a mesoporous silica nanocomposite carrier prepared by a method for preparing a mesoporous silica nanocomposite carrier according to any one of the foregoing embodiments, a drug-loaded composite according to any one of the foregoing embodiments, or a drug-loaded composite according to a method for preparing a drug-loaded composite according to any one of the foregoing embodiments, and an application of the drug-loaded composite in magnetic resonance imaging and/or optical imaging, which is not intended for diagnosis and treatment of diseases, and which can be used for studying drug release, whether to target corresponding tissues, and a mechanism of action of a drug.
In a sixth aspect, the present invention provides a use of the mesoporous silica nanocomposite carrier according to any one of the foregoing embodiments, the mesoporous silica nanocomposite carrier prepared by the method for preparing the mesoporous silica nanocomposite carrier according to any one of the foregoing embodiments, the drug-loaded composite according to the method for preparing the drug-loaded composite according to the foregoing embodiments, or the pharmaceutical composition according to the foregoing embodiments in preparing a drug for treating liver tumor;
preferably, the medicine is a medicine capable of being directly perfused into tumor bodies;
preferably, the drug is a drug that undergoes transcatheter chemoembolization;
preferably, the drug is a drug that is perfused into the liver tumor through the artery.
The invention has the following beneficial effects: the embodiment of the invention provides a mesoporous silica nano composite carrier, which can effectively load active drugs, has the characteristics of magnetic imaging and optical imaging, has a good treatment effect on liver tumors, particularly has a good effect on the liver tumors in the treatment of arterial chemoembolization, can be deposited at a high concentration in local tumors, continuously releases the loaded active drugs and kills tumor cells. Meanwhile, after the composite carrier loads the active drug and enters the body, the multi-modal imaging effect is achieved by utilizing the characteristics of magnetic resonance imaging and optical imaging of the composite carrier, and then the release, the drug effect, the mechanism and the like of the drug are effectively detected, so that the composite carrier has important clinical identification and research significance.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a graph of the results of characterization of an embodiment of the present invention;
FIG. 2 is a graph showing the results of detection in Experimental example 1 of the present invention;
FIG. 3 is a graph showing the results of detection in Experimental example 2 of the present invention;
FIG. 4 shows Fe of the present invention3O4The process chart of treating liver tumor by @ PMOs-Cy5.5-Dox under the guidance of DSA through hepatic artery perfusion and combined with iodized oil embolism;
FIG. 5 is Fe3O4The magnetic resonance imaging evaluation graph of the @ PMOs-Cy5.5 treated liver tumor by arterial infusion and combined iodized oil treated liver tumor by arterial infusion and the magnetic resonance imaging evaluation graph of each set of control treated liver tumor by arterial infusion are set;
FIG. 6 is Fe3O4The curve of the volume analysis after treatment and pathological picture of each control group such as @ PMOs-Cy5.5 were treated by arterial infusion and combination with iodized oil.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The features and properties of the present invention are described in further detail below with reference to examples.
The embodiment of the invention provides a mesoporous silica nano composite carrier, which comprises a nanocluster core with a magnetic imaging characteristic and an organic mesoporous silica shell wrapping the nanocluster core, wherein optical imaging molecules are modified on the surface of the organic mesoporous silica shell, and the organic mesoporous silica shell can be loaded with active drugs. The composite carrier can effectively load active drugs, has a good treatment effect on liver tumors, particularly has a good effect in the treatment of the liver tumors through arterial chemoembolization, can be deposited at high concentration in local tumors, continuously releases the loaded active drugs and kills tumor cells. Meanwhile, the composite carrier has the characteristics of magnetic imaging and optical imaging, and can be applied to magnetic resonance imaging and optical imaging.
Meanwhile, the mesoporous silica nano composite carrier has uniform size and morphology, and has good dispersibility and biocompatibility.
Further, the nanocluster core is formed of a compound having magnetic imaging characteristics; the compound with the magnetic imaging characteristic comprises ferroferric oxide; the optical imaging molecule is modified on the surface of the organic mesoporous silica shell through sulfydryl; the optical imaging molecule comprises Cy5.5.
It should be noted that although the embodiments of the present invention only provide the formation of the nanocluster core with magnetic imaging characteristics by ferroferric oxide, other compounds with magnetic imaging characteristics in the prior art are also within the scope of the present invention. Similarly, the embodiment of the invention only provides cy5.5 as an optical imaging molecule, and other optical imaging molecules capable of being grafted to the surface of the organic mesoporous silica shell in the prior art are also within the protection scope of the embodiment of the invention.
Specifically, the mesoporous silica nanocomposite carrier comprises Fe3O4Nanocluster core and encasing said Fe3O4The nano-cluster core is an organic mesoporous silica shell, and Cy5.5 is modified on the surface of the organic mesoporous silica shell through sulfydryl; the average grain diameter of the mesoporous silicon oxide nano composite carrier is 362.21 +/-20.71 nm.
Further, an embodiment of the present invention further provides a preparation method of the mesoporous silica nanocomposite carrier, including:
s1, preparing a nanocluster core;
mixing metal salt and weak acid and strong base salt to carry out hydrothermal reaction; specifically, mixing and dissolving iron salt, sodium acetate and trisodium citrate, and reacting for 8-12 hours at the temperature of 180-220 ℃; wherein the ferric salt is ferric trichloride; the mass ratio of the ferric trichloride to the sodium acetate to the trisodium citrate is 1:1.5-2.0: 0.2-0.5. The adoption of the substances and the proportion can be beneficial to the formation of a nano-cluster core and the formation of a subsequent composite carrier, and the arrangement of the weak acid and strong base salts such as sodium acetate, trisodium citrate and the like can prevent the formed nano-cluster core from being aggregated, so that the formed nano-cluster core is dispersed, and the efficacy of the subsequent composite carrier is improved.
And after the reaction is finished, sequentially carrying out cooling, solid-liquid separation and washing to obtain the nano-cluster core.
The further specific process is as follows: dissolving ferric trichloride hexahydrate in ethylene glycol, observing the state of the solution, adding sodium acetate and trisodium citrate, and performing magnetic stirring and ultrasonic treatment to obtain a mixed solution. Transferring the obtained mixed solution into a stainless steel high-pressure steam kettle with polytetrafluoroethylene as a lining, heating and reacting at a reaction temperature to obtain Fe3O4A nanocluster core.
S2, wrapping a nano-cluster core by an organic mesoporous silica shell;
mixing a structure directing agent, a nanocluster core and a silicon source for reaction; specifically, the structure directing agent, ethanol, water and alkaline substances are mixed and then added into the nano-cluster core for ultrasonic treatment, then n-hexane is added, then the mixture is kept stand, and after the inorganic silicon source and the organic silicon source are added for reaction, an organic mesoporous silica shell is formed and wraps the nano-cluster core. The reaction is carried out in a water-ethanol/normal hexane two-phase system, which is beneficial to the formation of a shell layer and the formation of a subsequent composite carrier.
Wherein the guiding agent is Cetyl Trimethyl Ammonium Bromide (CTAB); the inorganic silicon source is Tetraethoxysilane (TEOS); the organic silicon source is 1, 2-bis (triethoxysilyl) ethane (BTSE), the alkaline substance is ammonia water, preferably ammonia water with the mass concentration of 25-28%, and the mass ratio of the hexadecyl trimethyl ammonium bromide to the nano cluster core is 15-17: 1, adding 0.2-0.3 ml of the ethyl orthosilicate and 0.2-0.3 ml of the 1, 2-bis (triethoxysilyl) ethane per 10mg of the nanocluster core.
The combination of the organic silicon source and the inorganic silicon source in the embodiment of the invention can improve the biocompatibility. After CTAB and the silicon dioxide oligomer monomer are combined, because thermodynamic stability is maintained, the combined monomers grow into larger particles through the covalent bond of silicon-oxygen-silicon, then slowly grow into a shell, and finally form the organic mesoporous silicon dioxide shell. Meanwhile, when the silica layer is coated, the added CTAB is an amphiphilic substance and can be adsorbed by a nanometer surface interface to provide a template for the growth of the silica layer, and then the silica layer grows on the CTAB.
Further, after the reaction is finished, CTAB needs to be removed, that is, the reaction mixture formed after the reaction is finished is extracted to remove the structure directing agent. The specific operation is as follows: extracting the prepared material in ethanol at 60-70 ℃ for 3-6h, finally washing with ethanol for 3 times, and carrying out vacuum drying overnight to finally obtain the nano-particles with the nano-cluster cores coated by the organic mesoporous silica shells and the CTAB removed.
S3, modifying optical imaging molecules;
grafting optical imaging molecules on the surface of the organic mesoporous silica shell, specifically, modifying sulfydryl on the organic mesoporous silica shell, then mercapto reacts with optical imaging raw materials to enable the surface of the organic mesoporous silica shell to be modified with the optical imaging molecules, more specifically, the organic mesoporous silica shell is wrapped in nano particles formed by a nano cluster core and dispersed in a mixed solution of alcohol solvent and 3-mercaptopropyltriethoxysilane, then reacting for 10-14 hours at the temperature of 55-70 ℃ to form sulfydryl modified nano particles, then dispersing the nano particles in water, mixing with amide compounds and Cy5.5-maleimide, and oscillating the mixture to react at room temperature (generally about 25 ℃), centrifuging the mixture, and centrifuging the mixture to obtain the required composite carrier.
According to the embodiment of the invention, a compound containing sulfydryl, such as 3-mercaptopropyltriethoxysilane, is used firstly, and then sulfydryl is introduced into the organic mesoporous silica shell, so that the subsequent optical imaging molecules in the optical imaging raw material can conveniently react with sulfydryl, and then the optical imaging molecules are grafted on the surface of the organic mesoporous silica shell, and the optical imaging molecules are modified on the surface of the organic mesoporous silica shell.
It should be noted that, the embodiment of the present invention only provides 3-mercaptopropyltriethoxysilane and cy5.5-maleimide as the thiol-containing compound and the optical imaging raw material, but other thiol-containing compounds capable of simultaneously reacting with the organic mesoporous silica shell and cy5.5 in the prior art are within the scope of the present invention. Similarly, other optical imaging materials that can react Cy5.5 with thiol groups are also within the scope of embodiments of the present invention.
The alcohol solvent is ethanol, and the amide compound can be dimethylformamide.
The preparation method provided by the embodiment of the invention has the characteristics of simple preparation process, easiness in operation, good repeatability, high yield, low cost and environmental friendliness.
The embodiment of the invention also provides a drug-loaded compound, which comprises an active drug and the mesoporous silica nano-composite carrier, wherein the mesoporous silica nano-composite carrier loads the active drug, specifically, the mesoporous of the organic mesoporous silica shell loads the active drug surface, that is, the active drug is positioned in the mesoporous of the organic mesoporous silica shell. Wherein the active drug is an anti-tumor compound; for example, doxorubicin and the like, which have anti-tumor effectsA compound with tumor efficacy. The drug loading rate of the active drug is 270--1。
The drug-loaded compound has good treatment effect on liver tumor, can be deposited at high concentration in the local tumor, and then continuously releases the loaded active drug, and finally kills tumor cells.
The embodiment of the invention also provides a pharmaceutical composition which comprises iodized oil and the drug-loaded compound, and the two drugs can play a synergistic role in cooperation and can improve the treatment effect of liver tumor in the process of transcatheter arterial chemoembolization.
The embodiment of the invention also provides application of the mesoporous silica nano composite carrier and the drug-loaded composite in magnetic resonance imaging and/or optical imaging, so that a multi-modal imaging effect can be achieved, and the treatment effect of the drug-loaded composite can be detected through near-infrared optical imaging and magnetic resonance imaging.
The embodiment of the invention also provides an application of the mesoporous silica nano composite carrier and the drug-loaded composite in preparing the anti-liver tumor drug; wherein, the medicine can be directly poured into tumor bodies; the medicine is a medicine for transcatheter arterial chemoembolization, and the medicine is a medicine perfused into liver tumor via artery. The medicine formed by the medicine-carrying compound or the composite carrier can be directly poured into a tumor body, so that the local high-concentration nano particles of the tumor are promoted to be enriched, the local medicine concentration of the tumor is increased, the whole-body chemotherapy reaction is reduced, and the high-concentration chemotherapy medicine kills tumor cells. Or the medicine formed by the medicine-carrying compound or the compound carrier is used for the treatment of liver tumor by arterial chemoembolization.
Example 1
The embodiment provides a preparation method of a mesoporous silica nano composite carrier, which comprises the following steps:
s1, nanocluster core:
0.8125g of ferric chloride hexahydrate was dissolved in 25ml of ethylene glycol for 30 minutes, and then the state of the solution was observed. Then 1.5g sodium acetate and 0.325g trisodium citrate were added to the above solution, magnetically stirred for 1h and then sonicated for 1 h. After thatThe obtained mixed solution is transferred into a stainless steel high-pressure steam kettle with a polytetrafluoroethylene lining, heated to 200 ℃ and continuously reacted for 10 hours. Cooling to room temperature and taking out to obtain Fe3O4The nanoclusters were washed three times with ethanol.
S2, wrapping the organic mesoporous silica shell on the nano-cluster core;
0.16g CTAB was dissolved in a mixed solution of 30mL of ethanol, 75mL of water and 1mL of an aqueous ammonia solution (mass concentration: 25%). Simultaneously adding 10.4mg of the above synthesized Fe3O4A nanocluster. Sonicate for 5min, stir at 500rpm for 1h at 20 ℃, and slowly pour into 25mL of n-hexane along the bottle wall. The water-ethanol/n-hexane two-phase solution is placed in a water bath at about 20 ℃ for 10 minutes without stirring. Then, a mixture of TEOS (0.25mL) and BTSE (0.25mL) was added dropwise to the above mixed solution, and the reaction was continued in a water bath. After 72h, centrifuge at 9000rpm for 10min and wash with ethanol 3 times. To remove CTAB template, the above reaction solution was extracted in 200mL of ethanol at 60 deg.C for 3h, finally washed with 500mL of ethanol for 3 times, vacuum dried overnight to obtain CTAB template-removed Fe3O4@ PMOs composite nanoparticles.
S3, modifying optical imaging molecules;
fe to be synthesized3O4@ PMOs composite nanoparticles (10mg) were dispersed in a mixed solution of ethanol (40mL) and 3-mercaptopropyltriethoxysilane (20. mu.L). Then, stirring was carried out at a speed of 200rpm at 60 ℃ for 12 hours to obtain mercapto-modified Fe3O4@ PMOs nanoparticles, washing Fe with ethanol3O4@ PMOs nanoparticles were centrifuged three times at 9000rpm for 10min to remove thiol-modified Fe3O4@ PMOs nanoparticles were dispersed in a mixed solution of water (2mL), dimethylformamide (2mL) and Cy5.5-maleimide (0.2 mg). Oscillating at room temperature for 12h, centrifuging, and washing to obtain mesoporous silica nano composite carrier (Fe)3O4@PMOs-Cy5.5)。
The embodiment also provides a preparation method of the drug-loaded compound, which comprises the following steps:
5mg of the mesoporous silica nano-particles prepared in the exampleComposite carrier (Fe)3O4@ PMOs-Cy5.5) and 5mg Dox were mixed with 10mL of PBS (pH 7.4) solution, and then, after stirring at room temperature for 24 hours in the dark, centrifuged at 9000rpm for 10 minutes to obtain Dox-loaded Fe3O4@ PMOs-cy5.5, drug-loaded complexes (Fe)3O4@PMOs@cy5.5-Dox)。
To remove free Dox, Fe was further washed with PBS3O4@ PMOs-Cy5.5-Dox three times.
The drug-loading rate of DOX in the drug-loaded compound is 1.38 mg.
Example 2 to example 3
The preparation methods of the mesoporous silica nanocomposite carriers provided in examples 2 to 3 are substantially the same as the preparation method of the mesoporous silica nanocomposite carrier provided in example 1, except that the operation conditions are different, specifically as follows:
example 2:
s1, preparing a nanocluster core;
the mass ratio of ferric trichloride to sodium acetate to trisodium citrate is 1:1.5:0.2, the reaction temperature is 180 ℃, and the reaction time is 8 hours.
S2, wrapping the organic mesoporous silica shell on the nano-cluster core;
the mass concentration of ammonia water is 25%, the mass ratio of hexadecyl trimethyl ammonium bromide to the nano cluster core is 15:1, 0.2 ml of tetraethoxysilane and 0.2 ml of 1, 2-bis (triethoxysilyl) ethane are correspondingly added into each 10mg of the nano cluster core, the extraction temperature is 60 ℃ when CTAB is removed, and the extraction time is 3 hours.
S3, modifying optical imaging molecules;
the temperature of grafting mercapto group is 55 deg.C, and the time is 10 h.
Example 3:
s1, preparing a nanocluster core;
the mass ratio of ferric trichloride to sodium acetate to trisodium citrate is 1:2.0:0.5, the reaction temperature is 220, and the reaction time is 12 hours.
S2, wrapping the organic mesoporous silica shell on the nano-cluster core;
the mass concentration of ammonia water is 28%, the mass ratio of hexadecyl trimethyl ammonium bromide to the nano cluster core is 17:1, 0.3 ml of tetraethoxysilane and 0.3 ml of 1, 2-bis (triethoxysilyl) ethane are correspondingly added into each 10mg of the nano cluster core, the extraction temperature is 70 ℃ when CTAB is removed, and the extraction time is 6 hours.
S3, modifying optical imaging molecules;
the temperature of grafting mercapto group is 70 deg.C, and the time is 14 h.
Characterization of
For Fe prepared in example 13O4Nanoclusters and Fe3O4The @ PMOs composite nano particles are subjected to transmission electron microscope detection to detect Fe3O4The @ PMOs composite nanoparticles were subjected to infrared and nitrogen adsorption, mesoporous pore size distribution, and hydrodynamic size detection, and the Fe prepared in example 1 was subjected to3O4Nanocluster, Fe3O4@ PMOs composite nanoparticles, Fe3O4@ PMOs-Cy5.5 and Fe3O4@ PMOs @ cy5.5-Dox Zeta potential was measured.
The detection result is shown in figure 1, wherein a-b in figure 1 are different magnifications Fe3O4The transmission electron microscope detection result graph of the nanoclusters shows that the Fe prepared by the embodiment of the invention3O4The nanoclusters are uniform spheres, have good dispersibility and have a diameter of about 180 nm.
In FIG. 1, c-f are different magnifications Fe3O4A transmission electron microscope detection result graph of the @ PMOs composite nano particles; from this, it can be seen that Fe prepared in the examples of the present invention3O4The @ PMOs composite nano-particles are uniform spheres, have good dispersibility and are about 362nm in diameter. And as can be seen from f in fig. 1, the thickness of the mesoporous silica layer wrapped by the outer layer is 90nm, that is, the thickness of the organic mesoporous silica shell is 90 nm.
In FIG. 1, g is Fe3O4Infrared detection of @ PMOs composite nanoparticles, 1396cm-1And 2981cm-1Is in the form of-CH3-CH3C-H bending and stretching vibration bands in the radical, indicatingThe framework is added with an ethane group.
In FIG. 1, h-i is Fe3O4The nitrogen adsorption pattern and mesoporous size distribution of the @ PMOs composite nanoparticles according to IUPAC nomenclature, Fe3O4The nitrogen adsorption isotherms for the @ PMOs composite nanoparticles are in a typical type iv curve, indicating a typical mesoporous structure. The specific surface area of PMOs is 539m2g-1Pore volume of 0.694cm3 g-1The mesopore size was 2.9 nm.
In FIG. 1, j is Fe3O4Nanoclusters and Fe3O4A hydrodynamic size plot of @ PMOs composite nanoparticles; thus, Fe3O4Nanoclusters and Fe3O4The hydrodynamic diameters of the @ PMOs composite nanoparticles were 210nm and 406nm, respectively.
In FIG. 1, k is a Zeta potential result chart. As can be seen from k in FIG. 1, Fe3O4Nanocluster, Fe3O4@ PMOs composite nanoparticles, Fe3O4@ PMOs-Cy5.5 and Fe3O4The zeta potentials of @ PMOs-Cy5.5-Dox in distilled water were-22.6, -31.4, -35.9, and-24.9 mV, respectively, which also confirmed the successful Dox loading.
Experimental example 1
For Fe prepared in example 13O4@ PMOs-Cy5.5-Dox was subjected to in vitro phagocytosis assay, and the phagocytosis of the nanomaterial by cells was observed by monitoring Cy5.5 fluorescence.
The specific operation is as follows:
HepG-2 cells (1X 10 per well)5Individual cells) were placed in 2mL DMEM covered glass-bottom culture dishes containing 10% fetal bovine serum and placed at 37 ℃ with 5% CO2Culturing in a humidified atmosphere. After overnight incubation, the cells were washed with PBS and 0.05mg mL-1Fe3O4@ PMO-Cy5.5-Dox (0.5 mL). 1. After 3, 6, 24h, cells were washed 3 times with PBS. 4% Paraformaldehyde PBS for 30min, and DAPI stained the nuclei (1.5. mu.g mL)-1PBS solution), staining for 10 min. Then, a confocal laser scanning microscope (FV1000, Olympus, Germany) was usedNation) was performed with a Confocal Laser Scanning Microscope (CLSM) of HepG-2 cells, using blue fluorescence (405 fluorescent irradiation) and green fluorescence (673 fluorescent irradiation).
The results are shown in FIG. 2, wherein a in FIG. 2 is Confocal Laser Scanning Microscope (CLSM) showing that HepG2 cells are in Fe3O4Results of incubation in @ PMOs-Cy5.5-Dox for 1, 3, 6 and 24 hours at 37 ℃. The CLSM images of DAPI and cy5.5 were taken at a blue fluorescence filter (from blue to 405nm) and a green fluorescence filter (from green to 673nm), respectively. In FIG. 2, a shows DAPI stained nuclei and fluorescence of Cy5.5 in cytoplasm, and it can be seen from fused image MERGE that the drug-loaded complex enters into cells.
In FIG. 2, b and c in FIG. 2, flow cytometry fluorescence quantification of HepG2 cells at 20. mu.g mL-1Fe (b) of3O4The fluorescence intensity results of Cy5.5 after incubation in the @ PMOs-Cy5.5-Dox solution for 1, 3 and 6h show that the fluorescence intensity is gradually increased along with the time, which indicates that the nano particles carry Cy5.5 fluorescence, and then the medicine-carrying compound in the cells is gradually increased along with the time.
Experimental example 2
(1) For Fe prepared in example 13O4@ PMOs @ cy5.5-Dox Loading and Release of chemotherapeutic drug Dox for detection.
The specific operation is as follows:
fe prepared as above3O4@ PMOs-Cy5.5-Dox (2.5mg) was dispersed in 10mL of PBS solution at pH 7.4 and pH 5.5, and shaken at 100rpm at 37. At regular intervals, 0.05mL of the mixture was centrifuged to give a clear supernatant, which was analyzed by UV-Vis spectroscopy at 482nm to calculate the free Dox content of the supernatant.
The detection result is shown in a in FIG. 3, and according to a in FIG. 3, Fe3O4The Dox loading in @ PMOs-Cy5.5 was found to be as high as 276.5 μ g mg-1. Drug delivery mechanism and Fe3O4The chemical and physical properties of @ PMOs-Cy5.5. Fe3O4@ PMOs-Cy5.5 has an open channel for the entry of drugs, and the channel is ordered, and the drug molecules are uniformly distributed. In addition, the first and second substrates are,surface properties are another important factor. Fe3O4The zeta potential of @ PMOs is negative and that of Dox is positive. Thus, Dox can be loaded into PMOs through electrostatic interactions. The drug release profile showed 16% cumulative doxorubicin release over 48 hours at pH 7.4, and up to 39% release at pH 5.5 (a in fig. 3). The results show that the acidic environment can accelerate the release rate of Dox. It is known that Dox can be loaded into PMOs by electrostatic interaction under neutral conditions. In an acidic environment, positively charged Dox exchanges with protons, which can reduce electrostatic interactions between Dox and PMOs. In addition, Dox molecules tend to be more hydrophilic at lower pH values. Thus, Fe3O4The Dox release process of @ PMOs-Cy5.5-Dox depends on pH value, and the pH value of the tumor microenvironment is lower than that of normal tissues, so that the pH sensitive drug release process is favorable for improving the drug release of tumor areas and reducing the toxicity to normal tissues.
(2) For Fe3O4Analysis of cytotoxicity and in vivo toxicity of @ PMOs-Cy5.5
The method comprises the following specific steps:
cytotoxicity assay: analysis of Fe by MTT method3O4The cytotoxicity of @ PMOs-Cy5.5 on HepG2 cells. In summary, cells were seeded in 96-well plates at a cell density of 1X 104Individual cells/37 ℃ at 5% CO2Content and 37 deg.C, and Fe of different concentrations3O4@PMOs-Cy5.5(0–2mg mL-1) And (5) hatching for 24 h. Then, the standard MTT method was performed to determine cell viability.
In vivo toxicity analysis: mixing Fe3O4@ PMO-Cy5.5 nanoparticles were injected via caudal vein into 4-week-old male ICR mice weighing 20g (n ═ 3 per group) at an injection dose of 25mg kg-1. To examine toxicity in vivo, the liver, spleen, heart, lung and kidney were excised 7 days after injection and fixed in 10% formalin solution. Paraffin embedding, sectioning, hematoxylin and eosin staining. The tissue sections were observed under an optical microscope (IX 71; Olympics mountain, Tokyo, Japan).
The detection results are shown in b and b in FIG. 3c, as can be seen in b of FIG. 3, the cytotoxicity results show, even in Fe3O4@ PMO-Cy5.5 concentration 2.0mg mL-1The relative survival rate of HepG2 cells remained above 89%.
Histological evaluation further investigated Fe3O4The toxicity of @ PMOs-Cy5.5. As can be seen from c in fig. 3, the analysis was performed on the obtained organ (heart, liver, lung, spleen, kidney) tissues. Cardiac tissue from cardiac samples was not edematous. Hepatocytes were normal, without inflammatory infiltrates and steatosis. Pulmonary fibrosis and inflammation are not seen in lung specimens. No obvious tissue injury, inflammation, pathological changes and necrosis are observed in other organs. These results clearly show that Fe3O4The @ PMOs-Cy5.5 nano-particles have good biocompatibility and have wide application prospect in the field of biomedicine.
(3)Fe3O4@ PMO-Cy5.5-Dox in vitro anti-HepG 2 cell Effect: HepG2 cells were plated at 1X 10 per well4The cells were seeded at a density of one cell in a 96-well plate for 24 hours, and the cells were cultured with 200. mu.l of a medium in which Fe is present3O4@ PMO-Cy5.5-Dox concentrations of 0, 0.0625, 0.125, 0.25, 0.5, 1mg mL-1At 5% CO2Incubating for 24h at 37 deg.C. Finally, the cell survival rate is calculated by using an MTT method.
The detection result is shown in d in fig. 3, and the cell survival rate is reduced along with the increase of the concentration of the drug-loaded complex as shown by the result of d in fig. 3. When the concentration increased to 1mg mL-1Of (i) Fe3O4@ PMO-Cy5.5-Dox killed 74.1% of HepG2 cells.
Experimental example 3
Arterial infusion therapy and combined iodol (Lipiodol) embolization treatment procedure and post-treatment efficacy assessment on rabbit VX2 liver carcinoma in situ model: an in situ tumor model of the liver of 18 rabbits VX2 was successfully constructed. All 18 rabbits meeting the standard were treated in groups, and randomly divided into 6 groups (n is 3), and the content of each group is as follows, and the group is a control group; a group of adriamycin; lipiodol group; fe3O4The @ PMOs + Lipiodol group; dox + Lipiodol group; fe3O4@ PMOs-Cy5.5-Dox + Lipidol group. For experimental animals, the menstruation was performed under general anesthesiaThe femoral artery was placed in a 3F catheter. Under DSA (GE, usa) guidance, groups of drugs were super-selectively injected into the hepatic tumor-supplying arteries. MRI examination was performed after 7 days and 14 days, respectively. Rabbits were sacrificed 1 month after treatment. We then dissect the liver tumor, measure and calculate the tumor volume.
The results of the above MRI evaluation during and after the treatment with the transarterial catheter infusion drug are shown in fig. 4-6. Wherein, FIG. 4 is Fe3O4The process chart of @ PMOs-Cy5.5-Dox for treating liver tumor by hepatic artery perfusion and combined iodized oil embolism under the guidance of DSA, and FIG. 5 is Fe3O4The evaluation graph of the magnetic resonance imaging of the @ PMOs-Cy5.5 after the liver tumor is treated by arterial infusion and the combined iodized oil after the liver tumor is treated by arterial infusion, and the evaluation graph of the magnetic resonance imaging of each group after the arterial infusion treatment are set; FIG. 6 is Fe3O4The curve of the volume analysis after treatment and pathological picture of each control group such as @ PMOs-Cy5.5 were treated by arterial infusion and combination with iodized oil.
As shown in fig. 4, the pre-treatment DSA images show the position of the arterial catheter, the position and gross morphology of the liver, and the distribution of blood vessels within the liver tumor (a in fig. 4). According to the specific position and distribution of the catheter and the angiography image of the liver tumor, the tip of the catheter is adjusted to the tumor supplying artery for injection of the drug to avoid the drug from being injected into other blood vessels in the liver outside the tumor, causing damage to the liver tissue. From fig. 4 a it can be seen that the catheter is fed to the opening of the tumor supply artery. Fe injection through arterial catheter3O4@ PMOs-Cy5.5-Dox nanoparticles and iodized oil. The DSA image after treatment shows that the blood vessels in the liver tumor area are developed and disappear, which indicates Fe3O4@ PMOs-Cy5.5-Dox nanoparticles have been successfully infused into liver tumors and chemoembolization of liver tumors was achieved in conjunction with Lipiodol injection (b in FIG. 4). Complete the in vivo trans-arterial Fe infusion3O4The process of treating liver cancer with @ PMOs-Cy5.5-Dox and treating liver cancer by artery combined with iodized oil embolism.
As can be seen in FIG. 5, the nano-platform was injected into the rabbit liver cancer model via hepatic artery, and Fe was studied3O4In vivo treatment of liver tumor by @ PMOs-Cy5.5-Dox nanoparticlesHas therapeutic effect. The curative effect of treating liver tumor by combining iodized oil embolism is further researched. Fe3O4@ PMOs-Cy5.5-Dox nanoparticles were locally accumulated in the tumor by hepatic arterial infusion. Magnetic Resonance Imaging (MRI) was used to assess the efficacy of liver cancer treatment (fig. 5). Liver tumors of each group were detected by MRI before treatment, and the results showed no significant difference in tumor size between groups. A significant increase in tumor volume was observed 7 days after MRI re-treatment in the control and doxorubicin groups, Lipiodol group, Lipiodol + Fe3O4The liver tumor volumes were slightly increased in the @ PMOs-Cy5.5 group and the Lipidodol + Adriamycin group, but in the Lipidodol + Fe group3O4The liver tumor volume was slightly decreased in the @ PMOs-Cy5.5-Dox group. MRI was performed again 14 days after the treatment, and the images showed significant increase in liver tumor volume in the control group and the doxorubicin group, Lipiodol + Fe3O4The liver tumor volumes of the three groups of @ PMOs-Cy5.5 and Adriamycin + Lipidol also continued to increase, but Lipidol + Fe3O4The liver tumor volume continued to decrease in the @ PMOs-Cy5.5-Dox group. It follows that treatment of liver tumors by Dox perfusion alone cannot effectively inhibit tumor progression, and that embolization with iodophor alone and treatment with Dox chemoembolization alone can only control tumor growth rate within 1 week. Iodized oil and nano composite carrier Fe3O4The combination of @ PMO-Cy5.5-Dox shows good effect on controlling the growth of liver tumor for a long time.
As can be seen from fig. 6, dynamic trend of liver tumor volume was analyzed by quantitative measurement of each group of tumor volume by MRI performed on MRI examination at 7 th and 14 th days after treatment (a in fig. 6). The results show that there is a significant difference in the growth rate of the tumor volume in each group. Among them, the liver tumor volume increased most rapidly in the control group and the Dox group. The tumor volume growth rate in the Dox group was similar to that in the control group. This further demonstrates that single Dox perfusion has no significant effect on liver cancer. And Lipiodol group, Lipiodol + Fe3O4The @ PMO-Cy5.5 group and the Lipiodol + Dox group have similar tumor volume growth speed, and the tumor volume growth speed is obviously lower than that of the control group and the Dox group. And Lipiodol + Fe3O4The @ PMO-Cy5.5-Dox group showed a distinct growth trend, with tumor volume continuing to shrink within 2 weeks after treatment. In addition, as can be seen from b in FIG. 6Two weeks post treatment tumor volume analysis showed Lipiodol + Fe3O4The @ PMO-Cy5.5-Dox group had the smallest tumor volume and was significantly different from the other groups. This result indicates that iodized oil embolism is combined with Fe3O4The @ PMO-Cy5.5-Dox infusion therapy has obvious effect on controlling liver tumor, and is superior to single iodized oil embolism and traditional iodized oil combined Dox chemoembolization. After 1 month of treatment, tumor tissues were taken for histopathological examination (c in fig. 6). Lipiodol + Fe3O4The @ PMO-Cy5.5-Dox group had a large number of necrotic structures in tumors, no significant residual tumor parenchymal components, and residual tumor parenchymal components in other groups. Fe3O4The effect of treating liver tumor by combining @ PMOs-Cy5.5-Dox with iodized oil chemoembolization is optimal.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The mesoporous silica nano composite carrier is characterized by comprising a nanocluster core with a magnetic imaging characteristic and an organic mesoporous silica shell wrapping the nanocluster core, wherein the surface of the organic mesoporous silica shell is modified with optical imaging molecules.
2. The mesoporous silica nanocomposite support according to claim 1, wherein the nanocluster core is formed of a compound having magnetic imaging characteristics;
preferably, the compound having magnetic imaging characteristics comprises ferroferric oxide;
preferably, the optical imaging molecule is modified on the surface of the organic mesoporous silica shell through a sulfydryl group;
preferably, the optical imaging molecule comprises Cy5.5.
3. According to claim1 or 2, wherein the mesoporous silica nanocomposite support comprises Fe3O4Nanocluster core and encapsulating said Fe3O4The nano-cluster core is an organic mesoporous silica shell, and Cy5.5 is modified on the surface of the organic mesoporous silica shell through sulfydryl;
preferably, the average particle diameter of the mesoporous silica nanocomposite support is 362.21 ± 20.71 nm.
4. A method for preparing the mesoporous silica nanocomposite support according to any one of claims 1 to 3, comprising: the organic mesoporous silica shell is wrapped on the nano-cluster core, and then optical imaging molecules are grafted on the surface of the organic mesoporous silica shell.
5. The method of claim 4, wherein the step of preparing the nanocluster core includes: mixing metal salt and weak acid and strong base salt to carry out hydrothermal reaction;
preferably, the step of preparing the nanocluster core comprises: mixing and dissolving iron salt, sodium acetate and trisodium citrate, and reacting for 8-12 hours at the temperature of 180 ℃ and 220 ℃;
preferably, the iron salt is ferric chloride;
preferably, the mass ratio of the ferric trichloride to the sodium acetate to the trisodium citrate is 1:1.5-2.0: 0.2-0.5;
preferably, the step of preparing the nanocluster core comprises: cooling, solid-liquid separation and washing are sequentially carried out after the reaction;
preferably, the step of coating the organic mesoporous silica shell on the nanocluster core comprises: mixing a structure directing agent, a nanocluster core and a silicon source for reaction;
preferably, the step of coating the organic mesoporous silica shell on the nanocluster core comprises: in a water-ethanol/n-hexane two-phase system, a structure directing agent, a nano-cluster core, an organic silicon source and an inorganic silicon source are mixed for reaction;
preferably, the step of coating the organic mesoporous silica shell on the nanocluster core comprises: mixing the structure directing agent, ethanol, water and an alkaline substance, adding the mixture into the nano-cluster core, performing ultrasonic treatment, adding n-hexane, standing, adding the organic silicon source and the inorganic silicon source, reacting to form an organic mesoporous silica shell, and wrapping the organic mesoporous silica shell outside the nano-cluster core;
preferably, the structure directing agent is cetyltrimethylammonium bromide; the inorganic silicon source is tetraethoxysilane; the organic silicon source is 1, 2-bis (triethoxysilyl) ethane, the alkaline substance is ammonia water, and the ammonia water with the mass concentration of 25-28% is preferred;
preferably, the mass ratio of the cetyltrimethylammonium bromide to the nanocluster core is 15-17: 1, adding 0.2-0.3 ml of the tetraethoxysilane and 0.2-0.3 ml of the 1, 2-bis (triethoxysilyl) ethane per 10mg of the nanocluster core;
preferably, the step of coating the organic mesoporous silica shell on the nanocluster core comprises: removing the structure directing agent after the reaction is finished;
preferably, the step of removing the structure directing agent comprises: extracting a reaction mixed solution formed after the reaction is finished, and removing the structure directing agent;
preferably, the step of grafting comprises: modifying sulfydryl on the organic mesoporous silica shell, and then reacting the sulfydryl with an optical imaging raw material to modify the optical imaging molecule on the surface of the organic mesoporous silica shell;
preferably, the step of grafting comprises: mixing nanoparticles formed by wrapping an organic mesoporous silica shell on a nano-cluster core with a compound containing sulfydryl for reaction, and then reacting with an optical imaging raw material;
preferably, the step of grafting comprises: dispersing the nano particles in a mixed solution of an alcohol solvent and 3-mercaptopropyltriethoxysilane, then reacting for 10-14 hours at 55-70 ℃ to form mercapto-modified nano particles, then dispersing the nano particles in water, and then reacting with an amide compound and Cy5.5-maleimide.
6. A drug-loaded composite, which is characterized by comprising an active drug and the mesoporous silica nanocomposite carrier of any one of claims 1 to 3 or the mesoporous silica nanocomposite carrier prepared by the preparation method of the mesoporous silica nanocomposite carrier of any one of claims 4 or 5, wherein the mesoporous silica nanocomposite carrier loads the active drug;
preferably, the active drug is loaded in the mesopores of the organic mesoporous silica shell of the mesoporous silica nanocomposite carrier;
preferably, the active drug is an anti-tumor compound;
preferably, the drug loading of the active drug is 270-280 mu g mg-1。
7. A method for preparing a drug-loaded complex of claim 6, comprising: loading an active drug on the mesoporous silica nano composite carrier of any one of claims 1 to 3 or the mesoporous silica nano composite carrier prepared by the preparation method of the mesoporous silica nano composite carrier of claim 4 or 5;
preferably, the step of loading comprises: mixing the mesoporous silica nano composite carrier with the active drug for reaction, so that the active drug is loaded on the organic mesoporous silica shell;
preferably, the reaction conditions are: stirring for 20-24 hours in the dark.
8. A pharmaceutical composition comprising iodized oil and the drug-loaded complex of claim 6 or the method of preparation of a drug-loaded complex of claim 7.
9. Use of the mesoporous silica nanocomposite support according to any one of claims 1 to 3, the mesoporous silica nanocomposite support obtained by the method for preparing the mesoporous silica nanocomposite support according to claim 4 or 5, the drug-loaded complex according to claim 6, or the drug-loaded complex obtained by the method for preparing the drug-loaded complex according to claim 7 in magnetic resonance imaging and/or optical imaging, which is not aimed at diagnosis and treatment of diseases.
10. Use of the mesoporous silica nanocomposite carrier according to any one of claims 1 to 3, the mesoporous silica nanocomposite carrier prepared by the method for preparing the mesoporous silica nanocomposite carrier according to claim 4 or 5, the drug-loaded compound according to claim 6, the drug-loaded compound according to the method for preparing the drug-loaded compound according to claim 7, or the pharmaceutical composition according to claim 8 for preparing a medicament for treating liver tumor;
preferably, the medicine is a medicine capable of being directly perfused into tumor bodies;
preferably, the drug is a drug that undergoes transcatheter chemoembolization;
preferably, the drug is a drug that is perfused into the liver tumor through the artery.
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