CN110801441A - Capsaicin and adriamycin combined dual-pH-value-response intelligent nano drug delivery system and preparation method and application thereof - Google Patents
Capsaicin and adriamycin combined dual-pH-value-response intelligent nano drug delivery system and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system and a preparation method and application thereof.A sol-gel method is used for synthesizing amino mesoporous silica nanospheres, and capsaicin is loaded in pore channels of the amino mesoporous silica nanospheres; secondly, coating chitosan on the surface of the mesoporous silica nanospheres, and then modifying the surface of the mesoporous silica nanospheres coated with the chitosan with 4-formylphenylboronic acid; finally, the adriamycin is reversibly combined with phenylboronic acid through a boron ester bond to prepare the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system. The mesoporous silica nanospheres are used as drug carriers, so that good dispersibility and biological safety are ensured; chitosan coating is carried out on the mesoporous silicon dioxide nanospheres loaded with capsaicin, so that the surface functional groups of the mesoporous silicon dioxide nanospheres are enriched while the medicine is prevented from being leaked in advance. The capsaicin and the adriamycin are used together, so that the cell drug resistance generated by single adriamycin treatment can be reduced, and the cytotoxicity of the adriamycin is enhanced synergistically.
Description
Technical Field
The invention relates to the technical fields of nano materials, drug combination, drug loading, characteristic response and the like, in particular to a capsaicin and adriamycin combined drug dual pH response intelligent nano drug delivery system and preparation and application thereof.
Background
Chitosan is a non-toxic, biocompatible polymer, and is a biodegradable material that has been approved by the Food and Drug Administration (FDA) for use in humans. Each structural unit of the chitosan contains a primary amino group, and the chitosan is active chemically and can provide reactive sites for various groups. In addition, chitosan is insoluble in water under neutral and alkaline pH conditions, but becomes a water-soluble cationic polyelectrolyte when the pH is low. Therefore, the chitosan is used for encapsulating the drug, so that the leakage of the drug under the physiological pH condition is reduced. However, when the acidic pH conditions of lysosomes are reached, chitosan will dissolve, thereby achieving pH-responsive release of the drug. In addition, the chitosan can be finally degraded in vivo and discharged out of the body, and has very good biological safety.
Phenylboronic acid (PBA) and derivatives thereof can be reversibly combined with an ortho-diol or meta-diol structural compound under an alkaline condition to form a five-membered/six-membered lactone ring (boroester bond); the formed boroester bond is broken in a low pH environment. Therefore, the release regulation can be realized through the reversible combination property of PBA and the diol compound, and the pH response release of the drug can be realized. The common anticancer drug adriamycin has a vicinal diol structure, so that the adriamycin can be reversibly combined with a surface modified PBA material to realize drug loading; the drug delivery system reaches normal cells, and the boron ester bond cannot be disconnected due to the high pH value of the physiological environment, so that the damage to the normal cells is avoided; after the drug delivery system enters tumor cells, the boroester bond is broken under the acidic pH condition of lysosomes, thereby realizing the pH response release of the drug. The intelligent response type drug release can improve the treatment effect of the tumor while reducing the damage of the drug to normal cells.
The mesoporous silica is a mesoporous material with wide application, has good biocompatibility, can load drugs with large specific surface area and pore volume, is easy to modify chemical bonds, and is an ideal drug carrier. Compared with the traditional medicine carrying system (such as liposome and organic polymer), the aperture of the silicon dioxide can be regulated within the range of 2-50 nm, and the adsorption and release of medicine molecules are facilitated. On the other hand, the surface of the silicon dioxide contains abundant silicon hydroxyl, and the silicon dioxide can be subjected to surface modification by a chemical grafting method, so that the effect of the silicon dioxide on drug molecules is increased, the slow release of the drug is favorably realized, and the aim of long-acting drug delivery is fulfilled.
In tumor treatment, when a single drug is used, a large amount of drug is required, large toxic and side effects may be generated, and long-term and repeated use of the same drug can generate cell drug resistance, thereby reducing the treatment effect. The combined medication refers to that several medicines are used simultaneously or sequentially in the treatment process, and compared with single-medicine treatment, the combined medication can reduce the possibility of the occurrence of drug resistance of cells, improve the treatment effect and reduce the damage to normal cells. Tumor cell resistance is primarily due to the overexpression of ABC transporters in the cell membrane, which excrete chemotherapeutic drugs outside the cell, resulting in cell resistance, the most typical efflux transmembrane protein being P-glycoprotein. Capsaicin (Cap) is an active ingredient of capsicum, and has analgesic, antioxidant and antiinflammatory effects, and also has antitumor effect. In addition, capsaicin can also be used as a substrate of P-glycoprotein, can be used as a competitive inhibitor to inhibit the activity of P-glycoprotein and reduce the drug resistance of tumor cells, and is used together with adriamycin (DOX) to reduce the adriamycin discharged outside cells and increase the concentration of the adriamycin in the cells, so that the efficacy of the adriamycin is improved, and the cytotoxicity of the adriamycin is synergistically increased. However, capsaicin has strong irritativeness and stimulates mucous membranes to cause a series of symptoms such as nasal discharge, sneezing, and coughing, and thus has limited clinical applications.
Disclosure of Invention
The invention aims to provide a capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system, a preparation method and application thereof. The intelligent nano drug delivery system prepared by the method has the advantages of uniform particle size, good water solubility, good biological safety and dual pH responsiveness, can regulate and control the release of the drug through the change of pH, and can achieve better treatment effect by combined medication.
The invention is realized by the following technical scheme:
the invention discloses a preparation method of a capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system, which comprises the following steps:
(1) synthesizing mesoporous silica nanospheres with amino groups on the surfaces by a sol-gel method; secondly, loading capsaicin in the pore canal of the mesoporous silicon dioxide;
(2) coating chitosan on the surface of the drug-loaded mesoporous silica nanospheres treated in the step (1);
(3) modifying the surface of the mesoporous silica nanospheres coated with the chitosan processed in the step (3) by using 4-formylphenylboronic acid through Schiff base reaction, and combining adriamycin with phenylboronic acid through reversible boron ester bonds to realize drug loading;
(4) and (4) performing centrifugal treatment on the product prepared in the step (3) to realize separation of nano particles, and then washing and vacuum drying to prepare the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system.
Mixing polypropylene pyrrolidone, cetyl trimethyl ammonium bromide, methanol and water according to the weight ratio of (0.1-0.5): (0.3-1.5) g: (60-140) mL: (90-210) mL, and adjusting the pH value to 10.0-13.0;
adding 3-aminopropyltriethoxysilane and ethyl orthosilicate into the mixed system, magnetically stirring at room temperature for 2-5 hours, then placing the product into an ethanol solution of hydrochloric acid, stirring and refluxing at 70-85 ℃ for 12-24 hours, centrifugally separating, washing and vacuum drying the obtained reaction product to obtain mesoporous silica nanospheres with amino groups on the surface;
wherein the dosage ratio of ethanol solution of cetyl trimethyl ammonium bromide, 3-aminopropyl triethoxysilane, ethyl orthosilicate and hydrochloric acid is (0.3-1.5) g: (0.12-0.6) mL: (0.6-3) mL: (150-200) mL; the volume concentration of the hydrochloric acid in the ethanol solution of the hydrochloric acid is 2-4%.
Mixing mesoporous silica nanospheres with amino on the surface and a capsaicin ethanol solution with the concentration of 120-250 mug/mL according to the weight ratio of 10 mg: and after mixing the components in the dosage ratio of 20mL, shaking at room temperature for 60-180 min, separating out the supernatant through centrifugation, washing the centrifuged product, and drying in vacuum to obtain the capsaicin-loaded mesoporous silica nanospheres.
In the step (2), the chitosan, the glacial acetic acid and the drug-loaded mesoporous silica nanospheres are prepared according to the weight ratio of (90-300) mg: (30-100) mL: (100-400) mg, stirring at room temperature for 6-12 hours, and centrifugally separating, washing and vacuum drying a reaction product to obtain the chitosan-coated drug-loaded mesoporous silica nanosphere; wherein the volume concentration of the glacial acetic acid is 2-5%.
In the step (3), the drug-loaded mesoporous silica nanospheres coated with chitosan, 4-formylphenylboronic acid, sodium borohydride and methanol are mixed according to the weight ratio of (200-600) mg: (600-1800) mg: (700-2100) mg: (30-70) mL, reacting at room temperature for 24-36 h, and centrifuging to separate out solid polymers in the reaction solution to obtain the phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres.
In the step (4), the phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres and the adriamycin PBS buffer solution with the concentration of 240-400 mug/mL are mixed according to the weight ratio of 10 mg: and after mixing the components in the dosage ratio of 20mL, shaking for 2-5 h at room temperature, separating out the supernatant through centrifugation, washing the centrifuged product, and drying in vacuum to obtain the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system.
In the washing in the steps (1) to (4), the reaction product is washed to be neutral by adopting ultrapure water, and the vacuum drying is carried out for 4-10 h under the conditions of 30-60 ℃ and 0.04-0.06 MPa.
The invention also discloses a capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system obtained by the preparation method, which takes mesoporous silica nanospheres with the particle size of 100-150 nm as cores.
The invention also discloses a dual pH response intelligent nano drug delivery system for the combined drug of capsaicin and adriamycin, which can realize dual pH response drug release and combined drug.
In the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system, the combined drug delivery of capsaicin and adriamycin can reduce the drug resistance of tumor cells.
In the capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system, chitosan coated on the surface of a carrier is dissolved in an acidic environment, so that capsaicin is released in a tumor slightly acidic environment, and the irritation of capsaicin to normal tissues is reduced; the adriamycin and the phenylboronic acid are combined through reversible boron ester bonds, so that the adriamycin is released in an acidic environment, and the damage to normal cells is reduced.
The different pH conditions are respectively that the pH value is equal to 5.0 and 7.0; under the condition of different pH values, the release rate of the capsaicin is 44.86-68.27%, and the release rate of the adriamycin is 40.95-67.24%.
Compared with the prior art, the invention has the following beneficial technical effects:
the preparation method of the capsaicin and adriamycin combined dual-pH-response intelligent nano drug delivery system is simple to operate, and the mesoporous silica nanospheres are used as carriers, so that the good dispersibility and biological safety of the carriers can be ensured, and drug loading can be realized; the silica nanospheres loaded with capsaicin are coated with chitosan, so that capsaicin is prevented from being leaked in advance, capsaicin irritation is reduced, and functional groups on the surfaces of the mesoporous silica nanospheres are enriched. In addition, the chitosan and phenylboronic acid can realize drug release under an acidic condition, and the combination of capsaicin and adriamycin can reduce the drug resistance of cells and enhance the cytotoxicity of adriamycin, so that the aims of dual pH response and drug combination are fulfilled.
The capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system prepared by the invention has uniform particle size, good water solubility and dual-pH responsiveness, and can regulate and control the release of drugs through the change of pH; in addition, the nano drug delivery system prepared by the invention can realize the loading of two drugs and can achieve better treatment effect by combined drug administration.
Drawings
FIG. 1 is a transmission electron microscope image of the amino mesoporous silica nanospheres synthesized in example 1 of the present invention;
FIG. 2 is a transmission electron microscope image of chitosan-coated mesoporous silica nanospheres prepared in example 1 of the present invention;
Detailed Description
The present invention will now be described in further detail with reference to specific examples, which are intended to be illustrative, but not limiting, of the invention.
Example 1
Firstly, the preparation of the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system comprises the following steps:
the method comprises the following steps: 0.1g of polypropylenepoyrrolidone, 0.3g of cetyltrimethylammonium bromide, 60mL of methanol and 90mL of water were placed in a beaker and the pH was adjusted to 10.0. Adding 0.12mL of 3-aminopropyltriethoxysilane and 0.6mL of ethyl orthosilicate into the mixed system, magnetically stirring at room temperature for 2h, placing the product into 150mL of ethanol solution of hydrochloric acid, stirring and refluxing at 70 ℃ for 12h, centrifugally separating, washing and vacuum drying the obtained reaction product to obtain mesoporous silica nanospheres with amino on the surface; as shown in FIG. 1, the particle size of the prepared amino mesoporous silica nanosphere is about 140 nm.
Step two: adding 10mg of amino mesoporous silica nanospheres into 20mL of capsaicin ethanol solution with the concentration of 120 mug/mL, shaking at room temperature for 60min, and separating out supernate by centrifugation; measuring and calculating the concentration of Cap in the obtained supernatant to be 108.2 mug/mL by using an ultraviolet spectrophotometer, wherein the calculation formula of the adsorption quantity of the amino mesoporous silica nanospheres to the capsaicin is as follows:
in the formula C0、CeInitial concentration of Cap and concentration in supernatant (μ g/mL), respectively; calculating the adsorption capacity of the amino mesoporous silica nanospheres to Cap to be 23.60 mg/g; and washing the centrifugal product, and drying in vacuum to prepare the Cap-loaded mesoporous silica nanospheres.
Step three: and (3) putting 90mg of chitosan and 30mL of glacial acetic acid aqueous solution into a beaker, adding 100mg of drug-loaded mesoporous silica nanospheres, stirring at room temperature for 6 hours, and centrifugally separating, washing and vacuum drying a reaction product to obtain the drug-loaded mesoporous silica nanospheres coated by chitosan. As shown in fig. 2, the prepared chitosan-coated mesoporous silica nanosphere has a particle size of about 145 nm.
Step four: adding 200mg of chitosan-coated drug-loaded mesoporous silica nanospheres, 600mg of 4-formylphenylboronic acid and 700mg of sodium borohydride into 30mL of methanol solution, reacting at room temperature for 24h to generate phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres, and centrifuging to separate solid polymers in reaction liquid to obtain phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres;
step five: adding 10mg of phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres into 20mL of doxorubicin PBS buffer solution (pH is 8.0) with the concentration of 240 mu g/mL, shaking at room temperature for 2h, and centrifuging to separate out supernate; and (3) measuring and calculating the concentration of DOX in the obtained supernatant by using an ultraviolet spectrophotometer as follows: 204.55 mu g/mL, and the adsorption quantity of the phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres to DOX is calculated as follows: 70.90mg/g, the calculation method is the same as the calculation of the Cap adsorption amount in the step two; and (4) washing the centrifugal product, and drying in vacuum to prepare the capsaicin and adriamycin combined dual-pH-response intelligent nano drug delivery system.
Second, the drug is released in vitro
The preparation of the capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system for drug release performance detection specifically comprises the following steps:
the 10mg capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system and 10mL PBS buffer solution are filled into a dialysis bag, and the dialysis bag is immersed into 10mL PBS buffer solution for drug release experiment. Drug release experiments were performed in PBS buffer solutions at pH 5.0 and 7.0, respectively. 5mL of PBS buffer solution was removed at intervals, 5mL of fresh PBS buffer solution was immediately added thereto, and the resulting supernatant was assayed for the concentration of Cap and DOX by UV spectrophotometer.
In the formula WrIs the total cumulative release rate of Cap or DOX; ciAnd CnThe concentrations of Cap or DOX (μ g/mL) in the i-th and n-th replacement solutions, respectively; veIs the volume of PBS removed (5 mL); v0Is the total volume of PBS (20 mL); m isdrugIs the total amount of Cap or DOX loading (. mu.g).
By calculation, the cumulative release rate of Cap at pH 5.0 and 7.0 is: 64.90 percent and 44.86 percent. The cumulative release rates of DOX were: 66.53% and 40.95%.
Wherein the structural formula of the capsaicin and the adriamycin is as follows:
example 2
Firstly, the preparation of the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system comprises the following steps:
the method comprises the following steps: 0.15g of polypropylenepoyrrolidone, 0.45g of cetyltrimethylammonium bromide, 80mL of methanol and 120mL of water were placed in a beaker and the pH was adjusted to 10.5. Adding 0.2mL of 3-aminopropyltriethoxysilane and 1.0mL of ethyl orthosilicate into the mixed system, magnetically stirring at room temperature for 3h, placing the product into 160mL of ethanol solution of hydrochloric acid, stirring and refluxing at 75 ℃ for 14h, centrifugally separating, washing and vacuum drying the obtained reaction product to obtain mesoporous silica nanospheres with amino on the surface;
step two: adding 10mg of amino mesoporous silica nanospheres into 20mL of capsaicin ethanol solution with the concentration of 150 mug/mL, shaking for 80min at room temperature, and separating out supernate by centrifugation; measuring and calculating the concentration of Cap in the obtained supernatant fluid to be 137.53 mug/mL by using an ultraviolet spectrophotometer, wherein the calculation formula of the adsorption quantity of the amino mesoporous silica nanospheres to the capsaicin is as follows:
in the formula C0、CeInitial concentration of Cap and concentration in supernatant (μ g/mL), respectively; calculating the adsorption capacity of the amino mesoporous silica nanospheres to Cap to be 24.94 mg/g; and washing the centrifugal product, and drying in vacuum to prepare the Cap-loaded mesoporous silica nanospheres.
Step three: putting 120mg of chitosan and 40mL of glacial acetic acid aqueous solution into a beaker, adding 150mg of drug-loaded mesoporous silica nanospheres, stirring at room temperature for 8 hours, centrifugally separating, washing and vacuum drying a reaction product to obtain the drug-loaded mesoporous silica nanospheres coated by chitosan;
step four: adding 250mg of chitosan-coated drug-loaded mesoporous silica nanospheres, 750mg of 4-formylphenylboronic acid and 900mg of sodium borohydride into 35mL of methanol solution, reacting at room temperature for 26h to generate phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres, and centrifuging to separate solid polymers in reaction liquid to obtain phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres;
step five: adding 10mg of phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres into 20mL of adriamycin PBS buffer solution (pH is 8.0) with the concentration of 280 mu g/mL, shaking at room temperature for 2.5h, and separating out supernate by centrifugation; and (3) measuring and calculating the concentration of DOX in the obtained supernatant by using an ultraviolet spectrophotometer as follows: 242.55 mu g/mL, and the adsorption quantity of the phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres to DOX is calculated as follows: 74.90mg/g, the calculation method is the same as the calculation of the Cap adsorption amount in the step two; and (4) washing the centrifugal product, and drying in vacuum to prepare the capsaicin and adriamycin combined dual-pH-response intelligent nano drug delivery system.
Second, the drug is released in vitro
The capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system is used for detecting the drug release performance, and specifically comprises the following steps:
the 10mg capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system and 10mL PBS buffer solution are filled into a dialysis bag, and the dialysis bag is immersed into 10mL PBS buffer solution for drug release experiment. Drug release experiments were performed in PBS buffer solutions at pH 5.0 and 7.0, respectively. 5mL of PBS buffer solution was removed at intervals, 5mL of fresh PBS buffer solution was immediately added thereto, and the resulting supernatant was assayed for the concentration of Cap and DOX by UV spectrophotometer.
In the formula WrIs the total cumulative release rate of Cap or DOX; ciAnd CnThe concentrations of Cap or DOX (μ g/mL) in the i-th and n-th replacement solutions, respectively; veIs the volume of PBS removed (5 mL); v0Is the total volume of PBS (20 mL); m isdrugIs the total amount of Cap or DOX loading (. mu.g).
By calculation, the cumulative release rate of Cap at pH 5.0 and 7.0 is: 65.97% and 42.82%. The cumulative release rates of DOX were: 63.42% and 38.09%.
Example 3
Firstly, the preparation of the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system comprises the following steps:
the method comprises the following steps: 0.2g of polypropylenepoyrrolidone, 0.6g of cetyltrimethylammonium bromide, 90mL of methanol and 140mL of water were placed in a beaker and the pH was adjusted to 11.0. Then adding 0.3mL of 3-aminopropyltriethoxysilane and 1.5mL of ethyl orthosilicate into the mixed system, magnetically stirring at room temperature for 3.5h, placing the product into 170mL of ethanol solution of hydrochloric acid, stirring and refluxing at 78 ℃ for 16h, centrifugally separating, washing and vacuum drying the obtained reaction product to obtain mesoporous silica nanospheres with amino on the surface;
step two: adding 10mg of amino mesoporous silica nanospheres into 20mL of capsaicin ethanol solution with the concentration of 180 mug/mL, shaking for 100min at room temperature, and separating out supernate by centrifugation; measuring and calculating the concentration of Cap in the obtained supernatant fluid to be 167.36 mug/mL by using an ultraviolet spectrophotometer, wherein the calculation formula of the adsorption quantity of the amino mesoporous silica nanospheres to the capsaicin is as follows:
in the formula C0、CeInitial concentration of Cap and concentration in supernatant (μ g/mL), respectively; calculating the adsorption capacity of the amino mesoporous silica nanospheres to Cap to be 25.28 mg/g; and washing the centrifugal product, and drying in vacuum to prepare the Cap-loaded mesoporous silica nanospheres.
Step three: placing 150mg of chitosan and 50mL of glacial acetic acid aqueous solution in a beaker, adding 200mg of drug-loaded mesoporous silica nanospheres, stirring at room temperature for 9 hours, centrifugally separating, washing and vacuum drying a reaction product to obtain the drug-loaded mesoporous silica nanospheres coated by chitosan;
step four: adding 300mg of chitosan-coated drug-loaded mesoporous silica nanospheres, 900mg of 4-formylphenylboronic acid and 1100mg of sodium borohydride into 40mL of methanol solution, reacting at room temperature for 30h to generate phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres, and centrifuging to separate solid polymers in reaction liquid to obtain phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres;
step five: adding 10mg of phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres into 20mL of adriamycin PBS buffer solution (pH is 8.0) with the concentration of 300 mu g/mL, shaking at room temperature for 3h, and separating out supernate by centrifugation; and (3) measuring and calculating the concentration of DOX in the obtained supernatant by using an ultraviolet spectrophotometer as follows: 264.68 mu g/mL, and the adsorption quantity of the phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres to DOX is calculated as follows: 70.64mg/g, and the calculation method is the same as that of the Cap adsorption amount in the step two; and (4) washing the centrifugal product, and drying in vacuum to prepare the capsaicin and adriamycin combined dual-pH-response intelligent nano drug delivery system.
Second, the drug is released in vitro
The capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system is used for detecting the drug release performance, and specifically comprises the following steps:
the 10mg capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system and 10mL PBS buffer solution are filled into a dialysis bag, and the dialysis bag is immersed into 10mL PBS buffer solution for drug release experiment. Drug release experiments were performed in PBS buffer solutions at pH 5.0 and 7.0, respectively. 5mL of PBS buffer solution was removed at intervals, 5mL of fresh PBS buffer solution was immediately added thereto, and the resulting supernatant was assayed for the concentration of Cap and DOX by UV spectrophotometer.
In the formula WrIs the total cumulative release rate of Cap or DOX; ciAnd CnThe concentrations of Cap or DOX (μ g/mL) in the i-th and n-th replacement solutions, respectively; veIs the volume of PBS removed (5 mL); v0Is the total volume of PBS (20 mL); m isdrugIs the total amount of Cap or DOX loading (. mu.g).
By calculation, the cumulative release rate of Cap at pH 5.0 and 7.0 is: 66.17%, 43.88%, cumulative release rate of DOX: 64.25 percent and 39.17 percent.
Example 4
Firstly, the preparation of the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system comprises the following steps:
the method comprises the following steps: 0.3g of polypropylenepoyrrolidone, 0.9g of cetyltrimethylammonium bromide, 100mL of methanol and 150mL of water were placed in a beaker and the pH was adjusted to 11.5. Adding 0.4mL of 3-aminopropyltriethoxysilane and 2.0mL of ethyl orthosilicate into the mixed system, magnetically stirring at room temperature for 4 hours, placing the product into 180mL of ethanol solution of hydrochloric acid, stirring and refluxing at 80 ℃ for 20 hours, and centrifugally separating, washing and vacuum drying the obtained reaction product to obtain mesoporous silica nanospheres with amino on the surface;
step two: adding 10mg of amino mesoporous silica nanospheres into 20mL of capsaicin ethanol solution with the concentration of 200 mug/mL, shaking at room temperature for 120min, and separating out supernate by centrifugation; measuring and calculating the concentration of Cap in the obtained supernatant fluid to be 186.98 mug/mL by using an ultraviolet spectrophotometer, wherein the calculation formula of the adsorption quantity of the amino mesoporous silica nanospheres to the capsaicin is as follows:
in the formula C0、CeInitial concentration of Cap and concentration in supernatant (μ g/mL), respectively; calculating the adsorption capacity of the amino mesoporous silica nanospheres to Cap to be 26.04 mg/g; and washing the centrifugal product, and drying in vacuum to prepare the Cap-loaded mesoporous silica nanospheres.
Step three: putting 200mg of chitosan and 60mL of glacial acetic acid aqueous solution into a beaker, adding 250mg of drug-loaded mesoporous silica nanospheres, stirring at room temperature for 10 hours, centrifugally separating, washing and vacuum drying a reaction product to obtain the drug-loaded mesoporous silica nanospheres coated by chitosan;
step four: adding 400mg of chitosan-coated drug-loaded mesoporous silica nanospheres, 1200mg of 4-formylphenylboronic acid and 1400mg of sodium borohydride into 50mL of methanol solution, reacting at room temperature for 32h to generate phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres, and centrifuging to separate solid polymers in reaction liquid to obtain phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres;
step five: adding 10mg of phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres into 20mL of doxorubicin PBS buffer solution (pH is 8.0) with the concentration of 320 mu g/mL, shaking at room temperature for 3.5h, and separating out supernate by centrifugation; and (3) measuring and calculating the concentration of DOX in the obtained supernatant by using an ultraviolet spectrophotometer as follows: 284.18 mu g/mL, and the adsorption quantity of the phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres to DOX is calculated as follows: 71.64mg/g, the calculation method is the same as the calculation of the Cap adsorption amount in the step two; and (4) washing the centrifugal product, and drying in vacuum to prepare the capsaicin and adriamycin combined dual-pH-response intelligent nano drug delivery system.
Second, the drug is released in vitro
The capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system is used for detecting the drug release performance, and specifically comprises the following steps:
the 10mg capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system and 10mL PBS buffer solution are filled into a dialysis bag, and the dialysis bag is immersed into 10mL PBS buffer solution for drug release experiment. Drug release experiments were performed in PBS buffer solutions at pH 5.0 and 7.0, respectively. 5mL of PBS buffer solution was removed at intervals, 5mL of fresh PBS buffer solution was immediately added thereto, and the resulting supernatant was assayed for the concentration of Cap and DOX by UV spectrophotometer.
In the formula WrIs the total cumulative release rate of Cap or DOX; ciAnd CnThe concentrations of Cap or DOX (μ g/mL) in the i-th and n-th replacement solutions, respectively; veIs the volume of PBS removed (5 mL); v0Is the total volume of PBS (20 mL); m isdrugIs the total amount of Cap or DOX loading (. mu.g).
By calculation, the cumulative release rate of Cap at pH 5.0 and 7.0 is: 67.55%, 44.61%, the cumulative release rate of DOX is: 65.38% and 40.47%.
Example 5
Firstly, the preparation of the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system comprises the following steps:
the method comprises the following steps: 0.4g of polypropylenepoyrrolidone, 1.2g of cetyltrimethylammonium bromide, 120mL of methanol and 180mL of water were placed in a beaker and the pH was adjusted to 12.0. Adding 0.5mL of 3-aminopropyltriethoxysilane and 2.5mL of ethyl orthosilicate into the mixed system, magnetically stirring at room temperature for 4.5 hours, placing the product into 190mL of ethanol solution of hydrochloric acid, stirring and refluxing at 83 ℃ for 22 hours, and centrifugally separating, washing and vacuum drying the obtained reaction product to obtain mesoporous silica nanospheres with amino on the surface;
step two: adding 10mg of amino mesoporous silica nanospheres into 20mL of capsaicin ethanol solution with the concentration of 220 mug/mL, shaking for 150min at room temperature, and separating out supernate by centrifugation; measuring and calculating the concentration of Cap in the obtained supernatant fluid to be 206.59 mug/mL by using an ultraviolet spectrophotometer, wherein the calculation formula of the adsorption quantity of the amino mesoporous silica nanospheres to the capsaicin is as follows:
in the formula C0、CeInitial concentration of Cap and concentration in supernatant (μ g/mL), respectively; calculating the adsorption capacity of the amino mesoporous silica nanospheres to Cap to be 26.82 mg/g; and washing the centrifugal product, and drying in vacuum to prepare the Cap-loaded mesoporous silica nanospheres.
Step three: placing 250mg of chitosan and 80mL of glacial acetic acid aqueous solution into a beaker, adding 300mg of drug-loaded mesoporous silica nanospheres, stirring at room temperature for 11h, centrifugally separating, washing and vacuum drying a reaction product to obtain the drug-loaded mesoporous silica nanospheres coated by chitosan;
step four: adding 500mg of chitosan-coated drug-loaded mesoporous silica nanospheres, 1500mg of 4-formylphenylboronic acid and 1800mg of sodium borohydride into 60mL of methanol solution, reacting at room temperature for 34h to generate phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres, and centrifuging to separate solid polymers in reaction liquid to obtain phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres;
step five: adding 10mg of phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres into 20mL of adriamycin PBS buffer solution (pH is 8.0) with the concentration of 350 mu g/mL, shaking at room temperature for 4h, and separating out supernate by centrifugation; and (3) measuring and calculating the concentration of DOX in the obtained supernatant by using an ultraviolet spectrophotometer as follows: 310.29 mu g/mL, and the adsorption quantity of the phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres to DOX is calculated as follows: 79.42mg/g, the calculation method is the same as the calculation of the Cap adsorption amount in the step two; and (4) washing the centrifugal product, and drying in vacuum to prepare the capsaicin and adriamycin combined dual-pH-response intelligent nano drug delivery system.
Second, the drug is released in vitro
The capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system is used for detecting the drug release performance, and specifically comprises the following steps:
the 10mg capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system and 10mL PBS buffer solution are filled into a dialysis bag, and the dialysis bag is immersed into 10mL PBS buffer solution for drug release experiment. Drug release experiments were performed in PBS buffer solutions at pH 5.0 and 7.0, respectively. 5mL of PBS buffer solution was removed at intervals, 5mL of fresh PBS buffer solution was immediately added thereto, and the resulting supernatant was assayed for the concentration of Cap and DOX by UV spectrophotometer.
In the formula WrIs the total cumulative release rate of Cap or DOX; ciAnd CnThe concentrations of Cap or DOX (μ g/mL) in the i-th and n-th replacement solutions, respectively; veIs the volume of PBS removed (5 mL); v0Is the total volume of PBS (20 mL); m isdrugIs the total amount of Cap or DOX loading (. mu.g).
By calculation, the cumulative release rates of capsaicin at pH 5.0 and 7.0 are: 67.22%, 45.19%, the cumulative release rates of DOX were 66.45%, 42.47%, respectively.
Example 6
Firstly, the preparation of the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system comprises the following steps:
the method comprises the following steps: 0.5g of polypropylenepoyrrolidone, 1.5g of cetyltrimethylammonium bromide, 140mL of methanol and 210mL of water were placed in a beaker and the pH was adjusted to 13.0. Then adding 0.6mL of 3-aminopropyltriethoxysilane and 3.0mL of ethyl orthosilicate into the mixed system, magnetically stirring at room temperature for 5h, placing the product into 200mL of ethanol solution of hydrochloric acid, stirring and refluxing at 85 ℃ for 24h, centrifugally separating, washing and vacuum drying the obtained reaction product to obtain mesoporous silica nanospheres with amino on the surface;
step two: adding 10mg of amino mesoporous silica nanospheres into 20mL of 250 microgram/mL capsaicin ethanol solution, shaking at room temperature for 180min, and separating out supernate by centrifugation; measuring and calculating the concentration of Cap in the obtained supernatant fluid to be 236.28 mug/mL by using an ultraviolet spectrophotometer, wherein the calculation formula of the adsorption quantity of the amino mesoporous silica nanospheres to the capsaicin is as follows:
in the formula C0、CeInitial concentration of Cap and concentration in supernatant (μ g/mL), respectively; calculating the adsorption capacity of the amino mesoporous silica nanospheres to Cap to be 27.44 mg/g; and washing the centrifugal product, and drying in vacuum to prepare the Cap-loaded mesoporous silica nanospheres.
Step three: placing 300mg of chitosan and 100mL of glacial acetic acid aqueous solution in a beaker, adding 400mg of drug-loaded mesoporous silica nanospheres, stirring at room temperature for 12h, centrifugally separating, washing and vacuum drying a reaction product to obtain the drug-loaded mesoporous silica nanospheres coated by chitosan;
step four: adding 600mg of chitosan-coated drug-loaded mesoporous silica nanospheres, 1800mg of 4-formylphenylboronic acid and 2100mg of sodium borohydride into 70mL of methanol solution, reacting at room temperature for 36h to generate phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres, and centrifuging to separate solid polymers in reaction liquid to obtain phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres;
step five: adding 10mg of phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres into 20mL of adriamycin PBS buffer solution (pH is 8.0) with the concentration of 400 mu g/mL, shaking at room temperature for 5h, and separating out supernate by centrifugation; and (3) measuring and calculating the concentration of DOX in the obtained supernatant by using an ultraviolet spectrophotometer as follows: 363.13 mu g/mL, and the adsorption quantity of the phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres to DOX is calculated as follows: 73.74mg/g, and the calculation method is the same as that of the Cap adsorption amount in the step two; and (4) washing the centrifugal product, and drying in vacuum to prepare the capsaicin and adriamycin combined dual-pH-response intelligent nano drug delivery system.
Second, the drug is released in vitro
The capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system is used for detecting the drug release performance, and specifically comprises the following steps:
the 10mg capsaicin and adriamycin combined dual-pH response intelligent nano drug delivery system and 10mL PBS buffer solution are filled into a dialysis bag, and the dialysis bag is immersed into 10mL PBS buffer solution for drug release experiment. Drug release experiments were performed in PBS buffer solutions at pH 5.0 and 7.0, respectively. 5mL of PBS buffer solution was removed at intervals, 5mL of fresh PBS buffer solution was immediately added thereto, and the resulting supernatant was assayed for the concentration of Cap and DOX by UV spectrophotometer.
In the formula WrIs the total cumulative release of Cap or DOXRate; ciAnd CnThe concentrations of Cap or DOX (μ g/mL) in the i-th and n-th replacement solutions, respectively; veIs the volume of PBS removed (5 mL); v0Is the total volume of PBS (20 mL); m isdrugIs the total amount of Cap or DOX loading (. mu.g).
By calculation, the cumulative release rate of Cap at pH 5.0 and 7.0 is: 68.27%, 46.04%, the cumulative release rates of DOX are: 67.24% and 42.47%.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, changes and equivalent structural changes made to the above embodiment according to the technical spirit of the present invention still fall within the protection scope of the technical solution of the present invention.
Claims (10)
1. A preparation method of a capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system is characterized by comprising the following steps:
(1) synthesizing mesoporous silica nanospheres with amino groups on the surfaces by a sol-gel method; secondly, loading capsaicin in the pore canal of the mesoporous silicon dioxide;
(2) coating chitosan on the surface of the drug-loaded mesoporous silica nanospheres treated in the step (1);
(3) modifying the surface of the mesoporous silica nanospheres coated with the chitosan processed in the step (3) by using 4-formylphenylboronic acid through Schiff base reaction, and combining adriamycin with phenylboronic acid through reversible boron ester bonds to realize drug loading;
(4) and (4) performing centrifugal treatment on the product prepared in the step (3) to realize separation of nano particles, and then washing and vacuum drying to prepare the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system.
2. The preparation method of the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system according to claim 1, wherein in the step (1), the preparation method of the mesoporous silica nanospheres with amino groups on the surface comprises the following steps:
mixing polypropylene pyrrolidone, cetyl trimethyl ammonium bromide, methanol and water according to the weight ratio of (0.1-0.5): (0.3-1.5) g: (60-140) mL: (90-210) mL, and adjusting the pH value to 10.0-13.0;
adding 3-aminopropyltriethoxysilane and ethyl orthosilicate into the mixed system, magnetically stirring at room temperature for 2-5 hours, then placing the product into an ethanol solution of hydrochloric acid, stirring and refluxing at 70-85 ℃ for 12-24 hours, centrifugally separating, washing and vacuum drying the obtained reaction product to obtain mesoporous silica nanospheres with amino groups on the surface;
wherein the dosage ratio of ethanol solution of cetyl trimethyl ammonium bromide, 3-aminopropyl triethoxysilane, ethyl orthosilicate and hydrochloric acid is (0.3-1.5) g: (0.12-0.6) mL: (0.6-3) mL: (150-200) mL; the volume concentration of the hydrochloric acid in the ethanol solution of the hydrochloric acid is 2-4%.
3. The preparation method of the capsaicin and adriamycin combined dual-pH-response intelligent nano drug delivery system according to claim 1, wherein in the step (1), the mesoporous silica nanospheres with amino groups on the surface and the capsaicin ethanol solution with the concentration of 120-250 μ g/mL are mixed according to the weight ratio of 10 mg: and after mixing the components in the dosage ratio of 20mL, shaking at room temperature for 60-180 min, separating out the supernatant through centrifugation, washing the centrifuged product, and drying in vacuum to obtain the capsaicin-loaded mesoporous silica nanospheres.
4. The preparation method of the capsaicin and doxorubicin combined dual-pH-response intelligent nano drug delivery system according to claim 1, wherein in the step (2), the chitosan, the glacial acetic acid and the drug-loaded mesoporous silica nanospheres are mixed according to a ratio of (90-300) mg: (30-100) mL: (100-400) mg, stirring at room temperature for 6-12 hours, and centrifugally separating, washing and vacuum drying a reaction product to obtain the chitosan-coated drug-loaded mesoporous silica nanosphere; wherein the volume concentration of the glacial acetic acid is 2-5%.
5. The preparation method of the capsaicin and adriamycin combined dual-pH-response intelligent nano drug delivery system according to claim 1, wherein in the step (3), the chitosan-coated drug-loaded mesoporous silica nanospheres, 4-formylphenylboronic acid, sodium borohydride and methanol are mixed according to the weight ratio of (200-600) mg: (600-1800) mg: (700-2100) mg: (30-70) mL, reacting at room temperature for 24-36 h, and centrifuging to separate out solid polymers in the reaction solution to obtain the phenylboronic acid modified chitosan coated drug-loaded mesoporous silica nanospheres.
6. The preparation method of the capsaicin and adriamycin combined dual-pH-response intelligent nano drug delivery system according to claim 1, wherein in the step (4), the phenylboronic acid-modified chitosan-coated drug-loaded mesoporous silica nanospheres and the adriamycin PBS buffer solution with the concentration of 240-400 μ g/mL are mixed according to the weight ratio of 10 mg: and after mixing the components in the dosage ratio of 20mL, shaking for 2-5 h at room temperature, separating out the supernatant through centrifugation, washing the centrifuged product, and drying in vacuum to obtain the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system.
7. The preparation method of the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system as claimed in claims 1 to 6, wherein the washing in the steps (1) to (4) is to wash the reaction product to be neutral by using ultrapure water, and the vacuum drying is to carry out vacuum drying treatment for 4 to 10 hours at 30 to 60 ℃ and 0.04 to 0.06 MPa.
8. The capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system prepared by the preparation method of any one of claims 1 to 7 is characterized in that the capsaicin and adriamycin combined dual pH response intelligent nano drug delivery system takes mesoporous silica nanospheres with the particle size of 100 to 150nm as cores.
9. The use of the capsaicin and doxorubicin combination dual pH-responsive intelligent nano-drug delivery system as a drug delivery system for the treatment of tumors as claimed in claim 8, wherein the capsaicin and doxorubicin combination dual pH-responsive intelligent nano-drug delivery system is capable of achieving dual pH-responsive drug release and combination, and the capsaicin and doxorubicin combination is capable of reducing drug resistance in tumor cells.
10. The use as claimed in claim 9, wherein the chitosan coated on the surface of the carrier is dissolved in an acidic environment, so that capsaicin is released in a tumor slightly acidic environment, and the irritation of capsaicin to normal tissues is reduced; doxorubicin and phenylboronic acid are combined through a reversible boron ester bond, and the boron ester bond is broken in an acidic environment, so that doxorubicin is released, and damage to normal cells is reduced;
the dual pH conditions are pH values equal to 5.0 and 7.0, respectively; under the condition of different pH values, the release rate of the capsaicin is 44.86-68.27%, and the release rate of the adriamycin is 40.95-67.24%.
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