CN113750245A - Double-cavity type nano-scale drug carrier, drug loading system, preparation method and application thereof - Google Patents

Double-cavity type nano-scale drug carrier, drug loading system, preparation method and application thereof Download PDF

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CN113750245A
CN113750245A CN202111175965.0A CN202111175965A CN113750245A CN 113750245 A CN113750245 A CN 113750245A CN 202111175965 A CN202111175965 A CN 202111175965A CN 113750245 A CN113750245 A CN 113750245A
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drug
mesoporous silica
cavity
double
scale
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李健
张晴
栗坤
石明
刘志伟
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Yanshan University
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Abstract

A double-cavity type nano-scale drug carrier, a drug carrying system, a preparation method and application thereof belong to the technical field of anti-tumor drugs. The invention provides a double-cavity type nano-scale drug carrier, which comprises a mesoporous silicon dioxide inner cavity wrapped by a polydopamine coating and a sulfhydryl-modified beta-cyclodextrin inner cavity bonded outside the polydopamine coating. A double-cavity type nano-scale drug delivery system containing a double-cavity type nano-scale drug carrier further comprises a drug A loaded in an inner cavity of mesoporous silica and a drug B loaded in an inner cavity of beta-cyclodextrin modified by sulfydryl. The drug carrier provided by the invention can load the hydrophobic drug through the cavity of the mesoporous silica pore channel loaded with the hydrophilic drug and the beta-cyclodextrin, so that the hydrophobic drug and the hydrophilic drug are respectively positioned in two independent spaces, the effects of the hydrophobic drug and the hydrophilic drug are respectively exerted, the interaction between the hydrophobic drug and the hydrophilic drug is avoided, and the effect of sequential release can be achieved in time.

Description

Double-cavity type nano-scale drug carrier, drug loading system, preparation method and application thereof
Technical Field
The invention belongs to the technical field of antitumor drugs, and particularly relates to a double-cavity type nano-scale drug carrier, a drug delivery system, and a preparation method and application thereof.
Background
Cancer is a persistent disease seriously harming human health, and a chemically synthesized single anti-cancer drug has the disadvantages of large toxic and side effects, low curative effect and weak targeting effect. In recent years, in order to reduce the toxic and side effects of chemotherapy drugs and improve the drug concentration of targeted parts, people prepare antitumor drugs into targeted preparations, thereby solving the problem of low drug treatment efficiency to a greater extent.
A single chemotherapeutic drug has a single mechanism of action and cannot achieve the desired anticancer effect, so in order to enhance the tumor treatment effect, multiple drugs are loaded and combined with multiple treatment mechanisms, such as photodynamic therapy, photothermal therapy, chemodynamic therapy, gene therapy, hunger therapy and the like, to achieve the synergistic treatment effect. The mesoporous silica is used as an anti-tumor drug carrier, and the application of the mesoporous silica in cancer treatment is receiving more and more attention. The mesoporous silica can not only remarkably improve the bioavailability of the drug and realize the effective delivery of the drug, but also improve the targeting property of the drug to tumor cells and realize the specific on-demand release of the drug. The novel nano-carrier has very wide application prospect in cancer treatment.
The double-cavity nano-scale drug carrier is used as a novel nano-carrier, and the co-loading of the hydrophilic drug and the hydrophobic drug can be realized by combining two independent drug loading spaces of a mesoporous silica inner cavity and a beta-cyclodextrin inner cavity. Therefore, the interaction among drug molecules is avoided, the treatment effect of the drug is reduced, meanwhile, the loading capacity of the drug is increased by the double-cavity type nano-scale drug carrier, and the synergistic treatment effect of the three treatment modes of photodynamic treatment, photothermal treatment and chemotherapy of the drug on the tumor is promoted.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to design and provide a double-cavity type nano-scale drug carrier, a drug carrying system, a preparation method and application thereof. The two medicines are separated by utilizing the double-cavity type medicine carrier, the hydrophilic medicine is loaded in the inner cavity of the mesoporous silicon dioxide, and the hydrophobic medicine is adsorbed by the cavity of the beta-cyclodextrin. The sequential release of the medicaments in time is realized, and the influence on the synergistic treatment effect of two or more medicaments due to the interaction between different hydrophilic medicaments and hydrophobic medicaments in the common carrier is avoided.
A double-cavity type nano-scale drug carrier is characterized in that the double-cavity type nano-scale drug carrier comprises a mesoporous silica inner cavity wrapped by a polydopamine coating and a mercapto-modified beta-cyclodextrin inner cavity bonded outside the polydopamine coating.
The double-cavity type nano-scale drug carrier is characterized in that the mass ratio of mesoporous silica, polydopamine and sulfydryl modified beta-cyclodextrin in the inner cavity of the mesoporous silica wrapped by the polydopamine coating is 1-10:1: 0.2-1.
The double-cavity type nano-scale drug carrier is characterized in that the average particle size of the double-cavity type nano-scale drug carrier is 150-220 nm, preferably 180-200 nm, the particle size of the mesoporous silica is 40-60 nm, preferably 45-52 nm, and the specific surface area is 600-1000 m2Preferably 700 to 900 m/g2Per g, pore volume of 1-1.5 cm3Preferably 1 to 1.3 cm/g3The pore diameter is 3-6 nm, preferably 4.6-5.8 nm, and the nano-grade mesoporous silica wrapped by the polydopamine coatingThe thickness of the rice grains is 80-160 nm, preferably 100-130 nm.
The double-cavity type nano-scale drug delivery system containing the double-cavity type nano-scale drug carrier is characterized by further comprising a drug A loaded in the inner cavity of the mesoporous silica and a drug B loaded in the inner cavity of the mercapto-modified beta-cyclodextrin.
The double-cavity type nano-scale drug delivery system is characterized in that the drug A is a water-soluble drug, the water-soluble drug comprises docetaxel, adriamycin or methotrexate, preferably adriamycin, the drug B comprises a fat-soluble drug, the fat-soluble drug comprises hydroxycamptothecin, paclitaxel, a photosensitizer Ce6 or beta-lapachone, and preferably the photosensitizer Ce 6. The drugs A and B both comprise anti-cancer drugs.
The double-cavity type nano-scale drug delivery system is characterized in that the mass ratio of the drug A to the mesoporous silica is 1-5: 10-20, preferably 1-2: 10-15, and the mass ratio of the drug B to the mercapto-modified beta-cyclodextrin is 1-10:1, preferably 3-10: 1.
A preparation method of a double-cavity type nano-scale drug delivery system is characterized by comprising the following steps:
(1) preparing mesoporous silicon dioxide;
(2) mixing the mesoporous silica obtained in the step (1), a drug A and a first solvent for reaction, performing ultrasonic treatment, and performing turnover incubation to obtain a mesoporous silica primary drug-loading system loaded with the drug A;
(3) mixing the mesoporous silica primary drug-loading system loaded with the drug A obtained in the step (2) with dopamine, isopropanol and a second solvent, magnetically stirring, carrying out autopolymerization reaction, and centrifuging to obtain mesoporous silica coated by a polydopamine coating; (4) and (4) mixing the mesoporous silica coated by the polydopamine coating obtained in the step (3) with beta-cyclodextrin modified by sulfydryl, a drug B and a third solvent, performing rotary incubation and then performing dialysis treatment to obtain the double-cavity type nano-scale drug delivery system.
The preparation method of the double-cavity type nano-scale drug delivery system is characterized in that the preparation method of the mesoporous silica in the step (1) comprises the following steps: cetyl trimethyl ammonium bromide is used as a liquid crystal template, an amphiphilic active agent is adopted to be converted into a periodic liquid crystal mesophase when a spherical micelle is formed by molecular self-assembly at the critical micelle concentration, a water-soluble silicon dioxide precursor is adopted to be assembled around the surfactant micelle to form a hybrid nano composite material, then the surfactant template is removed by extraction or calcination to obtain mesoporous silicon dioxide, and the extraction conditions are as follows: controlling the condensation reflux temperature to be 60-70 ℃, controlling the condensation reflux time to be 48-72 h, controlling the centrifugal rotation speed to be 10000-14000 r/min, preferably 12000-13800 r/min, and controlling the centrifugal time to be 10-20 min, preferably 15-18 min;
in the step (2), the first solvent comprises a phosphate solution, the pH value of the phosphate solution is 7.2-7.6, the volume ratio of the mass of the mesoporous silica to the first solvent is 10-30: 5-20 mg/mL, preferably 15-25 mg: 5-15 mg/mL, the mass ratio of the drug A to the mesoporous silica is 1-5: 10-20, the temperature of the mixing reaction is 24-28 ℃, preferably 25 ℃, and the ultrasonic treatment conditions are as follows: the ultrasonic power is 250-400W, the ultrasonic time is 15-20 min, and the conditions of overturning incubation are as follows: the rotating speed is 20-40 r/min, preferably 25-35 r/min, the temperature is room temperature, and the time is 8-12 h, preferably 10 h.
The preparation method of the double-cavity type nano-scale drug delivery system is characterized in that the second solvent in the step (3) comprises a Tris-HCl buffer solution, the pH value of the Tris-HCl buffer solution is 8.5-10.5, preferably 9-10, the volume ratio of the added mass of the mesoporous silica in the step (2) to the second solvent is 20-40: 10-30 mg/mL, preferably 20-40: 15-25 mg/mL, the volume ratio of the added mass of the mesoporous silica in the step (2) to isopropanol is 20-40: 2-6 mg/mL, preferably 20-40: 3-4 mg/mL, the mass ratio of the added mass of dopamine to the added mass of the mesoporous silica in the step (2) is 1: 1-10, the magnetic stirring time is 8-12 h, preferably 10h, the rotating speed is 100-200 r/min, preferably 150-180 r/min, the temperature is room temperature, preferably 24-26 ℃, the rotating speed of the centrifugation is 10000-14000 r/min, preferably 12000-13800 r/min, the time is 10-20 min, preferably 15-18 min;
in the step (4), the third solvent comprises a phosphate solution, the pH value of the third solvent is 7.2-7.6, the mass ratio of the sulfhydryl-modified beta-cyclodextrin to the drug B is 1-10:1, preferably 3-10: 1, and the conditions of rotary incubation are as follows: the rotating speed is 20-40 r/min, preferably 25-35 r/min, the temperature is room temperature, preferably 24-26 ℃, the time is 3-6 h, preferably 4h, the dialysis time is 12-24 h, and the aperture of the dialysis bag for dialysis is 3500-14000 meshes.
The application of a double-cavity nano-scale drug carrier and a drug-loading system in the synergistic treatment of diseases by two or more drugs.
The invention has the following beneficial effects:
the invention provides a double-cavity type nano-scale drug carrier, which comprises sulfhydryl modified beta-cyclodextrin, a polydopamine carrying system coating bonded with the sulfhydryl modified beta-cyclodextrin and a mesoporous silicon dioxide inner cavity wrapped by the polydopamine coating. In the invention, the mesoporous silica pore canal is loaded with hydrophilic drugs and the cavity of beta-cyclodextrin is loaded with hydrophobic drugs, and the double-cavity drug carrier ensures that the two drugs are respectively in independent spaces and are not influenced by intermolecular force and other chemical bonds.
The mesoporous silica, polydopamine and beta-cyclodextrin in the drug-loading system have no toxic or side effect on normal cells and have good biocompatibility. The carrier not only increases the loading of the drug, but also improves the drug release rate, and strengthens the synergistic treatment effect of three treatment mechanisms of photodynamic treatment, photothermal treatment and chemotherapy on the tumor. The sequential release of the medicaments in time is realized, and the influence on the synergistic treatment effect of two or more medicaments due to the interaction between different hydrophilic medicaments and hydrophobic medicaments in the common carrier is avoided.
Drawings
FIG. 1 is a TEM image of mesoporous silica of example 1;
FIG. 2 is a TEM image of mesoporous silica nanoparticles coated with polydopamine coating in example 1;
FIG. 3 is a TEM image of mesoporous silica of example 2;
fig. 4 is a TEM image of mesoporous silica nanoparticles coated with polydopamine coating in example 3.
Detailed Description
The invention will be further explained with reference to the drawings and examples.
The invention provides a double-cavity type nano-scale drug carrier, which comprises a mesoporous silicon dioxide inner cavity wrapped by a polydopamine coating and a sulfhydryl-modified beta-cyclodextrin inner cavity bonded outside the polydopamine coating. All starting materials are conventional commercial products unless otherwise specified.
The particle size of the mesoporous silica is preferably 40-60 nm, and more preferably 45-52 nm; the specific surface area is preferably 600-1000 m2(iv)/g, more preferably 700 to 900m2(ii)/g; the pore volume is preferably 1-1.5 cm3A concentration of 1 to 1.3cm3(ii)/g; the pore diameter is preferably 3 to 6nm, and more preferably 4.6 to 5.8 nm. The pore diameter of the sulfhydryl modified beta-cyclodextrin is 0.8nm, and the depth of a cavity is 0.7-0.8 nm.
In the invention, the drug carrier also comprises a polydopamine layer wrapped on the surface of the mesoporous silica. The thickness of the mesoporous silica nanoparticles wrapped by the polydopamine coating is 80-160 nm, and more preferably 100-130 nm. The mass ratio of the mesoporous silica to the polydopamine is 1-10:1, and preferably 2: 1. The polydopamine plays a role in encapsulating the mesoporous silica. The drug carrier also comprises beta-cyclodextrin which is connected to the surface of the polydopamine and is modified by sulfydryl. The mass ratio of polydopamine to sulfhydryl-modified beta-cyclodextrin is 1:0.2-1, preferably 3: 1. the mesoporous silica, the polydopamine and the mercapto-modified beta-cyclodextrin have no toxic or side effect on normal cells and have good biocompatibility.
The drug carrier provided by the invention can load the hydrophobic drug through the cavity of the mesoporous silica pore channel loaded with the hydrophilic drug and the beta-cyclodextrin, so that the hydrophobic drug and the hydrophilic drug are respectively positioned in two independent spaces to respectively exert the effects of the drugs, the interaction between the drugs is avoided, and the three mechanisms of photodynamic therapy, photothermal therapy and chemotherapy are synergistic to achieve more remarkable treatment effects.
The invention also provides a medicine carrying system, which comprises a medicine carrier and a medicine loaded in the medicine carrier; the drug carrier is the drug carrier of the technical scheme, the hydrophilic drug is loaded in a mesoporous silica pore channel, and the hydrophobic drug is loaded in a cavity of the mercapto-modified beta-cyclodextrin. The particle size of the drug delivery system is preferably 150-220 nm, and more preferably 180-200 nm. The hydrophilic drug loaded in the mesoporous silica pore channel preferably comprises docetaxel, adriamycin or methotrexate, and more preferably adriamycin. The mass ratio of the adriamycin to the mesoporous silica is 1-5: 10-20, and more preferably 1-2: 10-15. The hydrophobic drug loaded in the cavity of the sulfhydryl-modified beta-cyclodextrin preferably comprises hydroxycamptothecin, paclitaxel, a photosensitizer Ce6 or beta-lapachone, and more preferably a photosensitizer Ce 6. The mass ratio of the sulfhydryl-modified beta-cyclodextrin to the drug is preferably 1-10:1, and more preferably 3-10: 1.
The invention also provides a preparation method of the medicine carrying system in the technical scheme, which comprises the following steps:
cetyl trimethyl ammonium bromide is used as a liquid crystal template, an amphiphilic active agent is converted into a periodic liquid crystal intermediate phase when a spherical micelle is formed by molecular self-assembly at critical micelle concentration, a water-soluble silicon dioxide precursor such as tetraethyl silicate is assembled around the surfactant micelle to form a hybrid nano composite material, and then the surfactant template is removed by extraction or calcination to obtain the mesoporous silicon dioxide material. The template is removed through condensation and reflux by an extraction method, and the temperature of the magnetic stirrer is adjusted, wherein the condensation and reflux temperature is controlled to be 60-70 ℃, and the condensation and reflux time is preferably 48-72 hours.
Standing and centrifuging the condensed and refluxed mesoporous silica suspension, wherein the rotation speed of the centrifugation is preferably 10000-14000 r/min, and more preferably 12000-13800 r/min; the time is preferably 10 to 20min, and more preferably 15 to 18 min. And drying and grinding the product obtained after centrifugation to obtain the mesoporous silica material required by the subsequent experiment.
Mixing the prepared mesoporous silica, the drug and the first solvent for reaction to obtain the primary drug-loading system of the mesoporous silica loaded with the drug.
The first solvent is phosphate solution which is prepared by dissolving potassium dihydrogen phosphate, disodium hydrogen phosphate dodecahydrate, sodium chloride and potassium chloride in deionized water, and the pH value of the phosphate solution is preferably 7.4. The mass ratio of the drug to the mesoporous silica is preferably 1-5: 10-20, and more preferably 1-2: 10-15. In the invention, the ratio of the mass of the mesoporous silica to the volume of the first solvent is preferably 10-30 mg: 5-20 mL, more preferably 25-25 mg: 5-15 mL. The mesoporous silica, the drug and the first solvent are mixed and then subjected to ultrasonic treatment. In the invention, the power of the ultrasonic wave is 250-400W, and the time is 15-20 min. The temperature of the mixed suspension is preferably 24-28 ℃, and more preferably 25 ℃. The drug loading is carried out under the condition of overturning incubation, and whether the light shielding treatment is carried out or not is selected according to the drug requirement. The rotating speed of the overturning is 20-40 r/min, and preferably 25-35 r/min. The temperature is room temperature, the time is 8-12 h, and the preferable time is 10 h. After loading the drug, the loaded product is centrifuged. In the invention, the rotation speed of the centrifugation is preferably 10000-14000 r/min, more preferably 12000-13800 r/min; the time is preferably 10 to 20min, and more preferably 15 to 18 min. And centrifuging to obtain the mesoporous silica primary drug-loading system loaded with the drug.
And mixing the mesoporous silica primary drug-loading system loaded with the drug, dopamine, isopropanol and a second solvent, magnetically stirring, and carrying out a self-polymerization reaction to obtain the mesoporous silica material encapsulated by the polydopamine layer.
Firstly, mixing the mesoporous silica material loaded with the drug with a second solvent, and uniformly dispersing the mesoporous silica loaded with the drug in the second solvent; in the invention, the second solvent is Tris-HCl buffer solution, and the pH value is preferably 8-10.5, and more preferably 9-10. In the invention, the mass of the mesoporous silica and the volume ratio of the second solvent are preferably 20-40 mg: 10-30 mL, more preferably 20-40 mg: 15-25 mL.
And mixing the mixed suspension with dopamine, wherein the mass ratio of the mesoporous silica to the dopamine is preferably 20-40: 10-20, and more preferably 20: 10-15.
And in the mixing process, slowly dropwise adding isopropanol into the suspension, and controlling the reaction rate of dopamine during self polymerization. The preferred mass ratio of the mesoporous silica to the isopropanol is 20-40 mg: 2-6 mL, and the more preferred mass ratio of the mesoporous silica to the isopropanol is 20-40 mg: 3-4 mL. The dripping speed is preferably 10-30 drops/min, and more preferably 15-20 drops/min.
The reaction is stirred by magnetic force to generate self-polymerization reaction, so that dopamine forms polydopamine and wraps the surface of mesoporous calcium dioxide loaded with the drug to obtain the mesoporous silicon dioxide material wrapped by the polydopamine layer.
In the invention, the self-polymerization reaction is preferably carried out under the condition of stirring, and the rotation speed of the stirring is preferably 100-200 r/min, and more preferably 150-180 r/min. The temperature is preferably room temperature, and more preferably 24 to 26 ℃. The time is preferably 8-12 h, and more preferably 10 h. After the self-polymerization reaction is finished, the self-polymerization reaction also needs to be subjected to centrifugal treatment. In the invention, the rotation speed of the centrifugation is preferably 10000-14000 r/min, more preferably 12000-13800 r/min; the time is preferably 10 to 20min, and more preferably 15 to 18 min. And centrifuging to obtain the mesoporous silica material encapsulated by the polydopamine layer.
And mixing the mesoporous silica material encapsulated by the polydopamine layer, beta-cyclodextrin modified by sulfydryl, a medicament and a third solvent, carrying out rotary incubation, and reacting to obtain the double-cavity type nano-scale medicament carrying system.
In the invention, the mesoporous silica material encapsulated by the polydopamine layer, the beta-cyclodextrin modified by sulfydryl and a third solvent are mixed. In the invention, the mass ratio of the sulfhydryl modified beta-cyclodextrin to the polydopamine is 0.2-1: 1, preferably 0.2-0.8: 1. In the present invention, the third solvent is a phosphate solution prepared by dissolving potassium dihydrogen phosphate, disodium hydrogen phosphate dodecahydrate, sodium chloride and potassium chloride in deionized water, and the pH value of the phosphate solution is preferably 7.4. The mixing is not particularly limited in the present invention as long as it can be mixed uniformly.
In the invention, the reaction solution is subjected to rotary incubation to obtain the sulfhydryl modified beta-cyclodextrin, the polydopamine coating bonded with the sulfhydryl modified beta-cyclodextrin and the mesoporous silica inner cavity drug carrier wrapped by the polydopamine coating. In the invention, the rotating speed is 20-40 r/min, preferably 25-35 r/min. The temperature is preferably room temperature, and more preferably 24-26 ℃. The time is preferably 3-6 h, and more preferably 4 h.
And after the complete drug carrier is obtained, loading the drug, wherein the drug loading is carried out under the rotary incubation condition. In the invention, the mass ratio of the sulfhydryl-modified beta-cyclodextrin to the drug is preferably 1-10:1, and more preferably 3-10: 1. In the invention, the rotating speed is 20-40 r/min, preferably 25-35 r/min. The temperature is preferably room temperature, and more preferably 24-26 ℃. The time is preferably 3-6 h, and more preferably 4 h.
In the present invention, after drug loading, the product is centrifuged. In the invention, the rotation speed of the centrifugation is preferably 10000-14000 r/min, more preferably 12000-13800 r/min; the time is preferably 10 to 20min, and more preferably 15 to 18 min. And centrifuging to obtain the double-cavity type nano-scale drug loading system loaded with the drug.
In the invention, the preparation method of the drug carrier is prepared according to the preparation method of a drug-carrying system, and the difference is that no drug is added. The drug-carrying system in the technical scheme or the drug-carrying system prepared by the preparation method in the technical scheme can be applied to the anti-tumor aspect.
The drug carrier provided by the invention can load the hydrophobic drug through the cavity of the mesoporous silica pore channel loaded with the hydrophilic drug and the beta-cyclodextrin, so that the hydrophobic drug and the hydrophilic drug are respectively positioned in two independent spaces, the functions of the drugs are respectively exerted, the interaction between the drugs is avoided, and the effect of sequential release can be achieved in time, the photosensitizer Ce6 loaded in the cavity of the beta-cyclodextrin can play a role in photodynamic therapy, the drug resistance of cells is reduced, the killing effect of adriamycin on tumors is enhanced, and the synergistic treatment effect of photodynamic therapy and chemotherapy is promoted.
Example 1:
(1) dissolving 0.5g of hexadecyl trimethyl ammonium bromide serving as a liquid crystal template in 200mL of deionized water, adding 0.14g of sodium hydroxide, performing ultrasonic treatment until the solution is completely dissolved, heating to 80 ℃, stirring at high temperature, and keeping the stirring speed at 300 r/min. After 15min, adding 2.4mL of water-soluble silicon dioxide precursor tetraethyl silicate, mixing and stirring for 2h, standing for precipitation, removing supernatant, and centrifuging. Then, the template is removed by condensation reflux through an extraction method, the temperature of the magnetic stirrer is adjusted to 65 ℃, and the condensation reflux time is 72. And standing and centrifuging the condensed and refluxed mesoporous silica suspension. The centrifugal speed is 13000r/min, and the centrifugal time is 16 min. And drying and grinding the product obtained after centrifugation to obtain the mesoporous silica material.
The mesoporous silica material is subjected to transmission electron microscope detection to obtain a transmission electron microscope image, as shown in fig. 1, the mesoporous silica has a particle size of 40nm, and the surface of the mesoporous silica has fingerprint-like patterns, which indicates that the mesoporous silica material has a mesoporous structure.
(2) 20mg of the powder with the particle size of 40nm and the specific surface area of 800m2Per g, pore volume 1.2cm3Mixing/g of mesoporous silica with the pore diameter of 5.4nm and 5mg of adriamycin, dissolving the mixture in 10ml of phosphate solution with the pH value of 7.4, and performing ultrasonic treatment after mixing to uniformly disperse the mixture, wherein the ultrasonic power is 300W, the time is 20min, and the temperature is 25 ℃. Mixing to obtain a suspension, loading the medicine under the condition of overturning incubation, wherein the medicine needs to be protected from light, overturning incubation is carried out on the suspension, the overturning rotation speed is 38r/min, the room temperature is the room temperature condition, the time is 10h, after the medicine is loaded, centrifugal treatment needs to be carried out on the loaded product, and the centrifugal rotation speed is 13000 r/min; the time is 16 min. And centrifuging to obtain the mesoporous silica primary drug-loading system loaded with the drug.
(3) Mixing the mesoporous silica material loaded with the drug with a Tris-HCl buffer solution with the pH value of 14 mLof 10, and mixing the mixed solution with 30mg of dopamine to obtain a suspension; and (3) dropwise adding 6mL of isopropanol into the suspension at a dropping rate of 20 drops/min, and carrying out self-polymerization reaction by magnetic stirring at a rotation speed of 150r/min and a temperature of 25 ℃ for 12 hours. And (3) after the self-polymerization is finished, carrying out centrifugation on the suspension for 15min at the rotating speed of 13000r/min to obtain the mesoporous silica material wrapped with the polydopamine layer.
(4) And mixing the mesoporous silica material encapsulated by the polydopamine layer with 5mg of sulfydryl modified beta-cyclodextrin, dissolving the mixture in 10ml of phosphate solution with the pH value of 7.4, and uniformly mixing the mixture. And rotationally incubating the mixed solution for 4 hours at the rotating speed of 35r/min, and connecting the sulfhydryl modified beta-cyclodextrin to the polydopamine layer. After the reaction, 1mgCe6 was added to the mixture, and the mixture was again incubated for 4 hours at 35r/min at room temperature. After drug loading, the product was centrifuged. The rotating speed is 13000r/min during centrifugation; the time is 16min, and the double-cavity type nano drug-carrying system carrying the drug is obtained after centrifugation.
And (2) carrying out transmission electron microscope detection on the double-cavity type nano-scale drug carrying system loaded with the drug to obtain a transmission electron microscope picture, wherein the particle size of the double-cavity type nano-scale drug carrying system is 200nm, compared with the picture 1, the picture 2 is in a regular spherical shape, the inner part is mesoporous silica, the outer layer is a polydopamine layer and mercapto-modified beta-cyclodextrin connected with the polydopamine layer, the color is darker, the particle size is larger, fingerprint patterns on the surface disappear, and the result shows that the surface of the mesoporous silica is completely covered by the polydopamine layer.
Example 2:
(1) dissolving 0.5g of hexadecyl trimethyl ammonium bromide serving as a liquid crystal template in 200mL of deionized water, adding 0.14g of sodium hydroxide, performing ultrasonic treatment until the solution is completely dissolved, heating to 80 ℃, stirring at high temperature, and keeping the stirring speed at 300 r/min. Adding 2.4mL water-soluble silicon dioxide precursor such as tetraethyl silicate after 15min, mixing and stirring for 2h, standing for precipitation, discarding supernatant, and centrifuging. Then, the template is removed by condensation reflux through an extraction method, the temperature of the magnetic stirrer is adjusted to 65 ℃, and the condensation reflux time is 60 hours. And standing and centrifuging the condensed and refluxed mesoporous silica suspension. The centrifugal speed is 13000r/min, and the centrifugal time is 16 min. And drying and grinding the product obtained after centrifugation to obtain the mesoporous silica material.
The mesoporous silica material is subjected to transmission electron microscope detection to obtain a transmission electron microscope image, as shown in fig. 3, the mesoporous silica has a particle size of 70nm, and the surface has fingerprint-like patterns, which indicates that the material has a mesoporous structure.
(2) 20mg of the powder with the particle size of 70nm and the specific surface area of 600m2Per g, pore volume 1.3cm3Mixing/g of mesoporous silica with the pore diameter of 5.2nm and 5mg of adriamycin, dissolving the mixture in 10ml of phosphate solution with the pH value of 7.4, and performing ultrasonic treatment after mixing to uniformly disperse the mixture, wherein the ultrasonic power is 300W, the time is 20min, and the temperature is 25 ℃. Mixing to obtain a suspension, loading the medicine under the condition of overturning incubation, wherein the medicine needs to be protected from light, overturning incubation is carried out on the suspension, the overturning rotation speed is 38r/min, the room temperature is the room temperature condition, the time is 10h, after the medicine is loaded, centrifugal treatment needs to be carried out on the loaded product, and the centrifugal rotation speed is 13000 r/min; the time is 16 min. And centrifuging to obtain the mesoporous silica primary drug-loading system loaded with the drug.
(3) Mixing the mesoporous silica material loaded with the drug with a Tris-HCl buffer solution with the pH value of 16 mLof 10, and mixing the mixed solution with 10mg of dopamine to obtain a suspension; dropwise adding 4mL of isopropanol into the suspension at a dropping rate of 20 drops/min, and carrying out self-polymerization reaction by magnetic stirring at a rotation speed of 150r/min and a temperature of 25 ℃ for 12 h. And (3) after the self-polymerization is finished, carrying out centrifugation on the suspension for 15min at the rotating speed of 13000r/min to obtain the mesoporous silica material wrapped with the polydopamine layer.
(4) And mixing the mesoporous silica material encapsulated by the polydopamine layer with 5mg of sulfydryl modified beta-cyclodextrin, dissolving the mixture in 10ml of phosphate solution with the pH value of 7.4, and uniformly mixing the mixture. And rotationally incubating the mixed solution for 4 hours at the rotating speed of 35r/min, and connecting the sulfhydryl modified beta-cyclodextrin to the polydopamine layer. After the reaction, 1mgCe6 was added to the mixture, and the mixture was again incubated for 4 hours at 35r/min at room temperature. After drug loading, the product was centrifuged. The rotating speed is 13000r/min during centrifugation; the time is 16min, and the double-cavity type nano-scale drug-loaded system is obtained after centrifugation. The particle size of the double-cavity type nano-scale drug delivery system is 240nm through observation of a transmission electron microscope, and the particle size is shown in figure 3.
Example 3:
(1) the mesoporous silica was synthesized in the same manner as in example 1.
(2) 30mg of the powder with the particle size of 40nm and the specific surface area of 800m2Per g, pore volume 1.2cm3Mixing/g of mesoporous silica with the pore diameter of 5.4nm and 5mg of adriamycin, dissolving the mixture in 10ml of phosphate solution with the pH value of 7.4, and performing ultrasonic treatment after mixing to uniformly disperse the mixture, wherein the ultrasonic power is 300W, the time is 20min, and the temperature is 25 ℃. Mixing to obtain a suspension, loading the medicine under the condition of overturning incubation, wherein the medicine needs to be protected from light, overturning incubation is carried out on the suspension, the overturning rotation speed is 38r/min, the room temperature is the room temperature condition, the time is 10h, after the medicine is loaded, centrifugal treatment needs to be carried out on the loaded product, and the centrifugal rotation speed is 13000 r/min; the time is 16 min. And centrifuging to obtain the mesoporous silica primary drug-loading system loaded with the drug.
(3) Mixing the mesoporous silica material loaded with the drug with a Tris-HCl buffer solution with the pH value of 21 mLof 10, and mixing the mixed solution with 20mg of dopamine to obtain a suspension; and (3) dropwise adding 9mL of isopropanol into the suspension at a dropping rate of 20 drops/min, and carrying out self-polymerization reaction by magnetic stirring at a rotation speed of 150r/min and a temperature of 25 ℃ for 12 hours. And (3) after the self-polymerization is finished, carrying out centrifugation on the suspension for 15min at the rotating speed of 13000r/min to obtain the mesoporous silica material wrapped with the polydopamine layer.
(4) And mixing the mesoporous silica material encapsulated by the polydopamine layer with 5mg of sulfydryl modified beta-cyclodextrin, dissolving the mixture in 10ml of phosphate solution with the pH value of 7.4, and uniformly mixing the mixture. And rotationally incubating the mixed solution for 4 hours at the rotating speed of 35r/min, and connecting the sulfhydryl modified beta-cyclodextrin to the polydopamine layer. After the reaction, 1mgCe6 was added to the mixture, and the mixture was again incubated for 4 hours at 35r/min at room temperature. After drug loading, the product was centrifuged. The rotating speed is 13000r/min during centrifugation; the time is 16min, and the double-cavity type nano-scale drug-loaded system is obtained after centrifugation. Through transmission electron microscope observation, the shape of the example 3 is not obviously different from the examples 1 and 2, the particle size is slightly different, the particle size of the double-cavity type nano-scale drug carrying system is 180nm, and the transmission electron microscope result is shown in figure 4.
Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.

Claims (10)

1. A double-cavity type nano-scale drug carrier is characterized in that the double-cavity type nano-scale drug carrier comprises a mesoporous silica inner cavity wrapped by a polydopamine coating and a mercapto-modified beta-cyclodextrin inner cavity bonded outside the polydopamine coating.
2. The double-cavity type nano-scale drug carrier according to claim 1, wherein the mass ratio of the mesoporous silica in the inner cavity of the mesoporous silica wrapped by the polydopamine coating to the polydopamine to the mercapto-modified beta-cyclodextrin is 1-10:1: 0.2-1.
3. The dual-cavity nanoscale drug carrier according to claim 1, wherein the average particle size of the dual-cavity nanoscale drug carrier is 150-220 nm, preferably 180-200 nm, the particle size of the mesoporous silica is 40-60 nm, preferably 45-52 nm, and the specific surface area is 600-1000 m2Preferably 700 to 900 m/g2Per g, pore volume of 1-1.5 cm3Preferably 1 to 1.3 cm/g3The particle size is 3-6 nm, the preferable particle size is 4.6-5.8 nm, and the thickness of the nano-particle of the mesoporous silica wrapped by the polydopamine coating is 80-160 nm, and the preferable particle size is 100-130 nm.
4. A dual-cavity nano-scale drug delivery system comprising the dual-cavity nano-scale drug carrier of claim 1, further comprising a drug a loaded in the inner cavity of the mesoporous silica and a drug B loaded in the inner cavity of the mercapto-modified β -cyclodextrin.
5. The dual-cavity nano-scale drug delivery system of claim 4, wherein the drug A is a water-soluble drug comprising docetaxel, doxorubicin or methotrexate, preferably doxorubicin, and the drug B comprises a fat-soluble drug comprising hydroxycamptothecin, paclitaxel, photosensitizer Ce6 or beta-lapachone, preferably photosensitizer Ce 6.
6. The double-cavity type nano-scale drug delivery system of claim 4, wherein the mass ratio of the drug A to the mesoporous silica is 1-5: 10-20, preferably 1-2: 10-15, and the mass ratio of the drug B to the sulfhydryl-modified beta-cyclodextrin is 1-10:1, preferably 3-10: 1.
7. A preparation method of a double-cavity type nano-scale drug delivery system is characterized by comprising the following steps:
(1) preparing mesoporous silicon dioxide;
(2) mixing the mesoporous silica obtained in the step (1), a drug A and a first solvent for reaction, performing ultrasonic treatment, and performing turnover incubation to obtain a mesoporous silica primary drug-loading system loaded with the drug A;
(3) mixing the mesoporous silica primary drug-loading system loaded with the drug A obtained in the step (2) with dopamine, isopropanol and a second solvent, magnetically stirring, carrying out autopolymerization reaction, and centrifuging to obtain mesoporous silica coated by a polydopamine coating;
(4) and (4) mixing the mesoporous silica coated by the polydopamine coating obtained in the step (3) with beta-cyclodextrin modified by sulfydryl, a drug B and a third solvent, performing rotary incubation and then performing dialysis treatment to obtain the double-cavity type nano-scale drug delivery system.
8. The method of claim 7, wherein the mesoporous silica of step (1) is prepared by: cetyl trimethyl ammonium bromide is used as a liquid crystal template, an amphiphilic active agent is adopted to be converted into a periodic liquid crystal mesophase when a spherical micelle is formed by molecular self-assembly at the critical micelle concentration, a water-soluble silicon dioxide precursor is adopted to be assembled around the surfactant micelle to form a hybrid nano composite material, then the surfactant template is removed by extraction or calcination to obtain mesoporous silicon dioxide, and the extraction conditions are as follows: controlling the condensation reflux temperature to be 60-70 ℃, controlling the condensation reflux time to be 48-72 h, controlling the centrifugal rotation speed to be 10000-14000 r/min, preferably 12000-13800 r/min, and controlling the centrifugal time to be 10-20 min, preferably 15-18 min;
in the step (2), the first solvent comprises a phosphate solution, the pH value of the phosphate solution is 7.2-7.6, the volume ratio of the mass of the mesoporous silica to the first solvent is 10-30: 5-20 mg/mL, preferably 15-25 mg: 5-15 mg/mL, the mass ratio of the drug A to the mesoporous silica is 1-5: 10-20, the temperature of the mixing reaction is 24-28 ℃, preferably 25 ℃, and the ultrasonic treatment conditions are as follows: the ultrasonic power is 250-400W, the ultrasonic time is 15-20 min, and the conditions of overturning incubation are as follows: the rotating speed is 20-40 r/min, preferably 25-35 r/min, the temperature is room temperature, and the time is 8-12 h, preferably 10 h.
9. The preparation method of the double-cavity type nano-scale drug delivery system according to claim 7, wherein the second solvent in the step (3) comprises Tris-HCl buffer solution, the pH value of the Tris-HCl buffer solution is 8.5-10.5, preferably 9-10, the volume ratio of the added mass of the mesoporous silica in the step (2) to the second solvent is 20-40: 10-30 mg/mL, preferably 20-40: 15-25 mg/mL, the volume ratio of the added mass of the mesoporous silica in the step (2) to isopropanol is 20-40: 2-6 mg/mL, preferably 20-40: 3-4 mg/mL, the mass ratio of dopamine to the added mass of the added amount of the mesoporous silica in the step (2) is 1: 1-10, the magnetic stirring time is 8-12 h, preferably 10h, and the rotation speed is 100-200 r/min, preferably 150-180 r/min, the temperature is room temperature, preferably 24-26 ℃, the rotating speed of the centrifugation is 10000-14000 r/min, preferably 12000-13800 r/min, the time is 10-20 min, preferably 15-18 min;
in the step (4), the third solvent comprises a phosphate solution, the pH value of the third solvent is 7.2-7.6, the mass ratio of the sulfhydryl-modified beta-cyclodextrin to the drug B is 1-10:1, preferably 3-10: 1, and the conditions of rotary incubation are as follows: the rotating speed is 20-40 r/min, preferably 25-35 r/min, the temperature is room temperature, preferably 24-26 ℃, the time is 3-6 h, preferably 4h, the dialysis time is 12-24 h, and the aperture of the dialysis bag for dialysis is 3500-14000 meshes.
10. The application of a double-cavity nano-scale drug carrier and a drug-loading system in the synergistic treatment of diseases by two or more drugs.
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