CN114652841B - pH, redox and near infrared triple-response type dual-drug-carrying system and preparation method and application thereof - Google Patents
pH, redox and near infrared triple-response type dual-drug-carrying system and preparation method and application thereof Download PDFInfo
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- CN114652841B CN114652841B CN202210243181.5A CN202210243181A CN114652841B CN 114652841 B CN114652841 B CN 114652841B CN 202210243181 A CN202210243181 A CN 202210243181A CN 114652841 B CN114652841 B CN 114652841B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 172
- 239000003814 drug Substances 0.000 claims abstract description 89
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 44
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 9
- 238000001354 calcination Methods 0.000 claims description 9
- OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 claims description 8
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 claims description 5
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 5
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 5
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- 229960001149 dopamine hydrochloride Drugs 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000012286 potassium permanganate Substances 0.000 claims description 5
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- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 abstract description 76
- 229960000485 methotrexate Drugs 0.000 abstract description 76
- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 abstract description 51
- 229940052490 naringin Drugs 0.000 abstract description 51
- 229930019673 naringin Natural products 0.000 abstract description 51
- DFPMSGMNTNDNHN-ZPHOTFPESA-N naringin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC=2C=C3O[C@@H](CC(=O)C3=C(O)C=2)C=2C=CC(O)=CC=2)O[C@H](CO)[C@@H](O)[C@@H]1O DFPMSGMNTNDNHN-ZPHOTFPESA-N 0.000 abstract description 51
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- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
A pH, redox and near infrared triple-response type dual-drug-carrying system and a preparation method and application thereof belong to the technical field of biological medicine. The preparation method comprises the following steps: (1) preparing medicine A/mesoporous silica; (2) preparing medicine A/mesoporous silica@polydopamine; (3) Preparing a drug A/mesoporous silica@polydopamine@graphene oxide; (4) Preparing a drug A/mesoporous silica@polydopamine@graphene oxide/drug B/sodium carboxymethyl cellulose triple response type double drug carrying system. The triple-response type double-drug-carrying system can simultaneously carry two anticancer drugs, such as methotrexate and naringin, realize the rapid release of the drugs at tumor sites by irradiation of near infrared light, and realize the triple-response drug release under the slightly acidic and high-concentration glutathione environments of tumors. The double drug carrying system is simple to prepare, has high biocompatibility and can be widely applied to the field of biological medicine.
Description
Technical Field
The invention belongs to the technical field of biological medicine, and particularly relates to a pH, redox and near infrared triple-response type double-drug-carrying system, and a preparation method and application thereof.
Technical Field
Current treatments for cancer include surgical resection, radiation therapy and chemotherapy. Among them, chemotherapy remains the main strategy for treating cancer clinically. However, previous studies focused on chemotherapy with a single drug delivery system, which often failed to meet the clinical needs of treatment. Therefore, the development of controlled release systems capable of encapsulating and delivering a variety of drugs is an important research direction for intelligent drug delivery.
Mesoporous silica has the characteristics of large specific surface area, large pore volume, adjustable pore size, easiness in surface functionalization and the like, and is often used for constructing a stimulus response type drug controlled release system. Although mesoporous silica has been used in the field of drug delivery, there are also disadvantages such as premature or burst release of the drug. We therefore selected polydopamine and graphene oxide to overcome the above disadvantages. The unique physicochemical properties of polydopamine make it widely used for surface modification in various fields. Graphene oxide is a photosensitive material with high near infrared light absorption and has potential photo-thermal treatment capability. Most importantly, polydopamine and graphene oxide have good biocompatibility, so that the polydopamine and graphene oxide have wide application in the field of medicine.
Carboxymethyl cellulose is prepared by derivatization of cellulose, and the long chain structure of the carboxymethyl cellulose is rich in carboxymethyl. The polymer has the characteristics of biodegradability, nontoxicity, high biocompatibility, high viscosity, good film forming property and the like, so that the polymer is widely paid attention to.
Methotrexate is widely used in cancer chemotherapy, and is mainly used for treating various acute leukemia, breast cancer, lung cancer, head and neck cancer, digestive tract cancer, cervical cancer, osteosarcoma and the like. Naringin is a traditional Chinese medicinal material and is the main active ingredient of total flavonoids of rhizoma drynariae.
The mesoporous silica, polydopamine, graphene oxide and sodium carboxymethyl cellulose are combined together through mild chemical reaction, and a pH, redox and near infrared triple-response type dual-drug-carrying system is prepared. The dual drug-carrying system can simultaneously carry two anticancer drugs, such as methotrexate and naringin, and can realize the accelerated release of the drugs at tumor sites by near infrared light irradiation, and can realize triple response drug release under the slightly acidic and high-concentration glutathione environments of tumors.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to design and provide a pH, redox and near infrared triple response type dual drug delivery system, and a preparation method and application thereof. The triple-response type double-drug-carrying system is simple to prepare, has high biocompatibility and can be widely applied to the field of biological medicine.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a method for preparing a pH, redox and near infrared triple-response type dual drug delivery system, which is characterized by comprising the following steps:
(1) Weighing the medicine A, dissolving in deionized water, adding mesoporous silica, magnetically stirring, and centrifugally separating to obtain medicine A/mesoporous silica;
(2) Dispersing the medicine A/mesoporous silica obtained in the step (1) in phosphate buffer solution, adding dopamine hydrochloride, magnetically stirring at room temperature in a dark place, washing precipitate after solid-liquid separation, and drying at constant temperature to obtain medicine A/mesoporous silica@polydopamine;
(3) Weighing graphene oxide, dispersing the graphene oxide in deionized water, performing ultrasonic dispersion until the graphene oxide is completely yellow and no solid matter exists, adding the medicine A/mesoporous silica@polydopamine obtained in the step (2), performing magnetic stirring, performing solid-liquid separation, washing and precipitating, and performing constant-temperature drying to obtain the medicine A/mesoporous silica@polydopamine@graphene oxide;
(4) And (3) weighing the medicine B, dissolving the medicine B in a phosphate buffer solution, adding sodium carboxymethyl cellulose, stirring and mixing uniformly, adding 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride and N-hydroxysuccinimide, magnetically stirring at room temperature, adding the medicine A/mesoporous silica@polydopamine@graphene oxide obtained in the step (3), adding cystamine, continuously stirring, and freeze-drying to obtain the medicine A/mesoporous silica@polydopamine@graphene oxide/medicine B/sodium carboxymethyl cellulose triple-response type double-drug-carrying system.
The preparation method is characterized in that the magnetic stirring time in the step (1) is 2-4 hours, and the mass volume ratio of the medicine A to the mesoporous silica to the deionized water is 3-8:500-1100:40-60 mg/mg/mL;
the specific preparation method of the mesoporous silica in the step (1) comprises the following steps: and (3) weighing cetyl trimethyl ammonium bromide, adding the cetyl trimethyl ammonium bromide into a mixed solution containing ammonia water, deionized water and ethanol, mechanically stirring, dropwise adding tetraethoxysilane in a stirring state for reaction, centrifuging, alternately and repeatedly washing with the deionized water and the absolute ethanol, drying, placing into a crucible, and calcining in a muffle furnace to obtain the mesoporous silica.
The preparation method is characterized in that the volume ratio of ammonia water, deionized water and ethanol in the mixed solution is 1.3-1.5:70-110:50-90, the mass volume ratio of hexadecyl trimethyl ammonium bromide to the mixed solution is 0.5-1.0:121.3-201.5 g/mL, the mass volume ratio of hexadecyl trimethyl ammonium bromide to tetraethoxysilane is 0.5-1.0:0.5-1.1 g/mL, the mechanical stirring time is 20-40 min, the reaction time is 4-8 h, and the calcining condition is that: the calcination temperature is 500-560 ℃ and the calcination time is 5-8 h.
The preparation method is characterized in that the pH value of the phosphate buffer solution in the step (2) is 7.5-8.5, the magnetic stirring time is 3-5h, and the constant-temperature drying condition is as follows: the temperature is 50-70 ℃ and the time is 3-5 hours, and the mass volume ratio of the medicine A/mesoporous silica to the dopamine hydrochloride to the phosphate buffer solution is 400-800:120-180:40-60 mg/mg/mL.
The preparation method is characterized in that the mass volume ratio of graphene oxide to the drug A/mesoporous silica@polydopamine to deionized water in the step (3) is 0.5-1.1:0.2-0.4:20-40 g/g/mL, the ultrasonic time is 1-3h, the magnetic stirring is 2-6h, and the constant temperature drying condition is as follows: the temperature is 40-80 ℃ and the time is 3-5 h;
the specific preparation method of the graphene oxide in the step (3) comprises the following steps: and (3) slowly adding the potassium permanganate and the graphite powder into a mixed solution containing concentrated sulfuric acid and phosphoric acid, heating and stirring in a water bath, cooling to room temperature, adding hydrogen peroxide, standing in an ice water bath, taking precipitate, centrifugally washing to remove residual acid, naturally airing, and grinding to obtain the graphene oxide.
The preparation method is characterized in that the mass ratio of potassium permanganate to graphite powder is 5-7:0.8-1.2, the volume ratio of concentrated sulfuric acid to phosphoric acid in the mixed solution is 110-130:12.2-14.4, the volume ratio of hydrogen peroxide to the mixed solution is 122.2-144.4:0.8-1.2, the temperature of the water bath is 40-60 ℃, the stirring time is 10-14 h, and the standing time is 8-12 h.
The preparation method is characterized in that the mass volume ratio of the drug B to sodium carboxymethyl cellulose to phosphate buffer solution in the step (4) is 3-8:200-800:40-60 mg/mg/mL, the mass ratio of sodium carboxymethyl cellulose to 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride to N-hydroxysuccinimide is 0.2-0.8:1.5-2.0:0.8-1.1, the mass ratio of sodium carboxymethyl cellulose to drug A/mesoporous silica@polydopamine@graphene oxide to cystamine is 0.2-0.8:0.1-0.5:0.1-0.5, the pH of the phosphate buffer solution is 5.0-6.0, the magnetic stirring time is 0.5-2 h, and the continuous stirring time is 5-7 h.
A dual drug delivery system having three pH, redox and near infrared light responses, characterized by being obtained by any of the preparation methods.
The application of the triple-response type double-drug-carrying system with pH, redox and near infrared light in the encapsulation and drug delivery is provided.
The application is characterized by comprising the steps of delivering drugs under different pH values, delivering drugs under glutathione stimulation conditions and delivering drugs under near infrared light stimulation conditions.
Compared with the prior art, the invention has the following beneficial effects:
the pH, redox and near infrared triple-response type double-drug-carrying system can simultaneously carry two anticancer drugs, such as methotrexate and naringin, realize the rapid release of the drugs at tumor sites by near infrared light irradiation, and realize the triple-response drug release under the slightly acidic and high-concentration glutathione environments of tumors. The double drug carrying system is simple to prepare, has high biocompatibility and can be widely applied to the field of biological medicine.
Drawings
Fig. 1 is a scanning electron microscope image of methotrexate/mesoporous silica according to example one;
fig. 2 is a scanning electron microscope image of methotrexate/mesoporous silica @ polydopamine in example one;
fig. 3 is a scanning electron microscope image of methotrexate/mesoporous silica @ polydopamine @ graphene oxide in example one;
fig. 4 is a scanning electron microscope image of methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose in example one;
fig. 5 is an infrared spectrum of methotrexate, mesoporous silica, graphene oxide, methotrexate/mesoporous silica @ polydopamine @ graphene oxide in example one;
fig. 6 is an infrared spectrum of a sodium carboxymethyl cellulose, naringin, methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethyl cellulose triple-response type dual drug delivery system in example one;
FIG. 7 is a graph showing the release profile of naringin from a methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose triple-response dual drug delivery system at different pH values at a concentration of 10mM glutathione under near infrared light irradiation;
fig. 8 is a graph of the release profile of methotrexate from methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose triple-response dual drug delivery system at different pH, concentrations of 10mM glutathione, and near infrared light irradiation.
Detailed Description
The invention will now be further described with reference to specific examples and figures, the following examples being intended to illustrate the invention and not to limit it further.
Embodiment one:
a preparation method of a pH, redox and near infrared triple-response type dual-drug-carrying system selects a drug A of methotrexate and a drug B of naringin, and comprises the following steps:
(1) Weighing 0.9g of cetyltrimethylammonium bromide, adding into a mixed solution of 1.4mL of ammonia water, 90mL of deionized water and 70mL of ethanol, mechanically stirring the mixed solution for 30min, then dropwise adding 0.8mL of tetraethoxysilane into the continuously stirred solution, reacting for 6h, centrifuging a sample, repeatedly washing with deionized water and absolute ethyl alcohol, drying, placing the dried sample into a crucible, and calcining for 6h at 540 ℃ in a muffle furnace to obtain mesoporous silica.
(2) 6g of potassium permanganate and 1.0g of graphite powder are weighed and slowly added into a mixed solution of 120mL of concentrated sulfuric acid and 13.3mL of phosphoric acid, the mixture is heated and stirred in a water bath at 50 ℃ for 12 hours, then the mixture is cooled to room temperature, 1mL of hydrogen peroxide is added, the mixture is placed in an ice water bath for one night, the product is centrifugally washed to remove residual acid, and graphene oxide is obtained after natural airing and grinding.
(3) 5mg of methotrexate is weighed and dissolved in 50mL of deionized water, 0.8g of mesoporous silica prepared in the step (1) is added, and centrifugal separation is carried out after magnetic stirring is carried out for 3 hours, thus obtaining the methotrexate/mesoporous silica, wherein a scanning electron microscope diagram of the methotrexate/mesoporous silica is shown as figure 1, and the methotrexate/mesoporous silica can be clearly seen from figure 1 to be in a spherical structure with uniform particle size.
(4) Weighing 0.6g of the methotrexate/mesoporous silica prepared in the step (3), dispersing in 50ml of phosphate buffer solution with pH of 8.0, adding 150mg of dopamine hydrochloride, magnetically stirring for 4 hours at room temperature in a dark place, carrying out solid-liquid separation, washing a solid product, and drying at a constant temperature of 60 ℃ for 4 hours to obtain the methotrexate/mesoporous silica@polydopamine. The scanning electron microscope image of methotrexate/mesoporous silica@polydopamine is shown in fig. 2, and it can be seen from fig. 2 that the particle size is significantly increased after spherical methotrexate/mesoporous silica is coated with polydopamine.
(5) And (3) weighing 0.8g of graphene oxide, dispersing in 30mL of deionized water, performing ultrasonic dispersion for 2 hours, adding 0.3g of methotrexate/mesoporous silica@polydopamine prepared in the step (4) when the graphene oxide solution is completely yellow and no obvious solid matter is seen, performing magnetic stirring for 4 hours, performing solid-liquid separation, washing a solid product, and performing constant-temperature drying at 60 ℃ for 4 hours to obtain the methotrexate/mesoporous silica@polydopamine@graphene oxide. The scanning electron microscope image of the methotrexate/mesoporous silica@polydopamine@graphene oxide is shown in fig. 3, and the stacked graphene oxide nano sheets can be seen in fig. 3 to sandwich the methotrexate/mesoporous silica@polydopamine.
(6) 5mg naringin is weighed and dissolved in 50ml phosphate buffer solution with pH value of 5.5, 0.5g sodium carboxymethyl cellulose is added, stirring is carried out to uniformly mix, 1.85g 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride and 0.92g N-hydroxysuccinimide are added, magnetic stirring is carried out for 1h at room temperature, then 0.3g methotrexate/mesoporous silica@polydopamine@graphene oxide prepared in step (5) is added, finally 0.3g cystamine is added, stirring is continued for 6h, and the obtained sample is frozen and dried at-45 ℃ for 24h, thus obtaining the methotrexate/mesoporous silica@polydopamine@graphene oxide/naringin sodium carboxymethyl cellulose triple response type dual drug carrier system. The scanning electron microscope image of the methotrexate/mesoporous silica@polydopamine@graphene oxide/naringin/sodium carboxymethyl cellulose is shown in fig. 4, and it can be clearly seen from fig. 4 that the methotrexate/mesoporous silica@polydopamine@graphene oxide still presents a relatively uniform and regular spherical shape, and the gel formed by sodium carboxymethyl cellulose and cystamine can be perfectly coated.
Fig. 5 shows an infrared spectrum of methotrexate, mesoporous silica, graphene oxide, methotrexate/mesoporous silica @ polydopamine @ graphene oxide. As can be seen from fig. 5, in the spectrum of methotrexate, 1645cm -1 The absorption peak at the position is attributed to the stretching vibration of the amide I band, 1207cm -1 The absorption peak at this point is attributed to the stretching vibration of the amide III band. 1095cm in spectrum of mesoporous silica -1 The absorption peak at this point is attributed to the stretching vibration of Si-O-Si. Methotrexate/mesoporous silica at 1643 and 1207cm -1 The characteristic peaks at the positions are respectively attributed to the stretching vibration of an amide I band and an amide III band in the original methotrexate molecule, and the stretching vibration is 1095cm -1 The characteristic peak at the position is attributed to the characteristic peak of Si-O-Si in the original mesoporous silica. From the above results, methotrexate was successfully supported in the pores of mesoporous silica. When methotrexate/mesoporous silica was coated with polydopamine, it was used at 2858cm -1 There appears a new characteristic peak, which is attributed to CH in polydopamine 2 Asymmetric vibration of the unit. 1735cm in the spectrum of graphene oxide -1 The absorption peak at is due to the stretching vibration of c=o. In the spectrum of methotrexate/mesoporous silica @ polydopamine @ graphene oxide, methotrexate (1642 and 1207cm -1 ) Mesoporous silica (1095 cm) -1 ) Polydopamine (2858 cm) -1 ) And graphene oxide (1735 cm) -1 ) Can be found, indicating successful preparation of methotrexate/mesoporous silica @ polydopamine @ graphene oxide.
Fig. 6 is an infrared spectrum of a sodium carboxymethyl cellulose, naringin, methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethyl cellulose triple-response type dual drug delivery system in example one. As can be seen from FIG. 6, the sodium carboxymethylcellulose is present at 1600 and 1413cm -1 The characteristic peaks at the positions are respectively attributed to COO – Asymmetric stretching vibration and symmetric stretching vibration of the device. Naringin at 2931 and 1582cm -1 The characteristic peaks at these are respectively assigned to the C-H aliphatic stretch band and the c=c bond. The prepared methotrexate/mesoporous silica@polydopamine@graphene oxide/naringin/sodium carboxymethylcellulose triple response type double drug delivery system is 2931 cm and 1589cm -1 The absorption peaks at the positions are respectively attributed to a C-H aliphatic stretching band and a C=C bond in Nar, 2858cm -1 The absorption peak at the site is attributed to CH in polydopamine 2 Asymmetric vibration of the unit, 1735cm -1 The absorption peak at which is attributed to the stretching vibration of c=o in original GO, 1645 and 1207cm -1 The absorption peaks of (a) are respectively assigned to the stretching vibration of an amide I band and an amide III band in the original methotrexate molecule, and 1095cm -1 The characteristic peak at the position is attributed to the absorption peak of Si-O-Si in the original mesoporous silica, and the absorption peak is 1560 cm and 572cm -1 Two new types appear at the siteThis is attributed to the stretching vibration of the amide II band and the S-S bond, respectively, which indicates that the carboxyl group on sodium carboxymethylcellulose and the amino group on cystamine have undergone amidation reaction and a disulfide bond has been successfully introduced. The results of the infrared spectrum show that the methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose triple response type double drug delivery system is successfully prepared.
Embodiment two:
the preparation method of the dual drug delivery system with pH, redox and near infrared light triple response prepared in the first embodiment can release drugs at different pH values, and the specific method is as follows:
phosphate buffer solutions with pH values of 5.0, 6.5 and 7.4 are respectively prepared, 200mg of methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethyl cellulose triple response type double drug delivery system is taken, the double drug delivery system is placed in dialysis bags with molecular retention of 3500, the dialysis bags are respectively placed in 50ml of phosphate buffer solutions with different pH values, and magnetic stirring is carried out at 37 ℃ to release the two drugs. 5mL of the solution was withdrawn every 1 hour, and the amount of both drugs released was determined while replenishing 5mL of fresh phosphate buffer solution. The naringin concentration was measured for its characteristic absorption peak intensity at 282nm using an ultraviolet spectrophotometer, and the methotrexate concentration was measured for its characteristic absorption peak intensity at 302nm using an ultraviolet spectrophotometer and calculated according to lambert-beer's law. The cumulative percent release of the two drugs at different times was calculated from the measured amounts of naringin and methotrexate, as shown in figures 7 and 8.
Embodiment III:
the preparation method of the dual drug delivery system with pH, redox and near infrared light triple response prepared in the first embodiment can release drugs under the condition of glutathione stimulation, and the specific method is as follows:
200mg of methotrexate/mesoporous silica@polydopamine@graphene oxide/naringin/sodium carboxymethylcellulose triple response type double drug delivery system is taken, placed in a dialysis bag with molecular cutoff of 3500, placed in a phosphate buffer solution with 50ml of pH of 5.0 and containing 10mM glutathione, magnetically stirred at 37 ℃ to release the two drugs. 5mL of the solution was withdrawn every 1 hour, and the amount of both drugs released was determined while replenishing 5mL of fresh phosphate buffer solution. The naringin concentration was measured for its characteristic absorption peak intensity at 282nm using an ultraviolet spectrophotometer, and the methotrexate concentration was measured for its characteristic absorption peak intensity at 302nm using an ultraviolet spectrophotometer and calculated according to lambert-beer's law. The cumulative percent release of the two drugs at different times was calculated from the measured amounts of naringin and methotrexate, as shown in figures 7 and 8.
Embodiment four:
the preparation method of the dual drug delivery system with pH, redox and near infrared triple response prepared in the first embodiment can release drugs under the near infrared light stimulation condition, and the specific method is as follows:
200mg of methotrexate/mesoporous silica@polydopamine@graphene oxide/naringin/sodium carboxymethylcellulose triple response type double drug delivery system is taken, placed in a dialysis bag with molecular cutoff of 3500, placed in a phosphate buffer solution with 50ml of pH of 5.0 and containing 10mM of glutathione, magnetically stirred at 37 ℃, and irradiated with near infrared light with power of 1.0W and wavelength of 808nm while stirring, so as to release the two drugs. 5mL of the solution was withdrawn every 1 hour, and the amount of both drugs released was determined while replenishing 5mL of fresh phosphate buffer solution. The naringin concentration was measured for its characteristic absorption peak intensity at 282nm using an ultraviolet spectrophotometer, and the methotrexate concentration was measured for its characteristic absorption peak intensity at 302nm using an ultraviolet spectrophotometer and calculated according to lambert-beer's law. The cumulative percent release of the two drugs at different times was calculated from the measured amounts of naringin and methotrexate, as shown in figures 7 and 8.
The release profiles of naringin and methotrexate from methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose triple-response dual drug delivery system at different pH values, pH 5.0 and concentration of 10mM glutathione, near infrared light irradiation are shown in FIGS. 7 and 8. Fig. 7 is a graph showing the release profile of naringin from methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose triple-responsive dual drug delivery system. As can be seen from fig. 7, the cumulative drug release percentage of naringin has a remarkable pH sensitivity, and the more acidic the cumulative drug release percentage is in the same time. The acid condition is favorable for hydrolyzing an amide bond, so that the three-dimensional cavity structure of the methotrexate/mesoporous silica@polydopamine@graphene oxide/naringin/sodium carboxymethylcellulose triple-response type double-drug-carrying system is damaged, and the release of the drug naringin is further caused. The drug release was substantially balanced at 12 hours, at which time the cumulative drug release percentages of naringin were 49.28%, 34.88% and 16.53% at pH 5.0, 6.5 and 7.4, respectively. The method is more favorable for releasing naringin from a methotrexate/mesoporous silica@polydopamine@graphene oxide/naringin/sodium carboxymethyl cellulose triple-response type double drug-carrying system under an acidic condition. To verify whether the methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose triple-response dual-carrier had redox response properties, 200mg of the methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose triple-response dual-carrier was placed in 50mL of phosphate buffer solution having a pH of 5.0 and containing 10mM glutathione. The cumulative release of naringin at 12h was significantly increased (65.66%) in the presence of 10mM glutathione compared to the cumulative release without 10mM glutathione (49.28%). The result shows that the methotrexate/mesoporous silica@polydopamine@graphene oxide/naringin/sodium carboxymethylcellulose triple-response type double-drug-carrying system has good redox response performance. This phenomenon is mainly due to the fact that the presence of glutathione reduces disulfide bonds in cystamine to mercapto groups, thereby causing the degradation of a methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose triple-response type dual drug delivery system, and further leading to increased naringin release. The cumulative drug release percentage at the equilibrium of naringin drug release under the conditions of pH value of 5.0 and 10mM glutathione and accompanied by near infrared light irradiation is 75.37 percent, and the cumulative drug release percentage under the conditions of near infrared light irradiation is larger than that under the conditions of no near infrared light irradiation, so that the result shows that the methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose triple-response type dual-drug delivery system has obvious near infrared light responsiveness mainly due to the fact that graphene oxide and polydopamine coated on the surface of the mesoporous silica have near infrared light responsiveness, so that near infrared light can be well converted into heat to enable the local environment temperature to be high, and the release of naringin is promoted.
As can be seen in fig. 8, the release of methotrexate was substantially balanced at 12h, when the cumulative drug release percentages of methotrexate were 45.35%, 30.44% and 11.02% at pH 5.0, 6.5 and 7.4, respectively. The drug release results mainly comprise the following two reasons: (1) At pH of 5.0, the hydrolysis of the amide bond is easier to hydrolyze, so that the three-dimensional cavity structure of the methotrexate/mesoporous silica@polydopamine@graphene oxide/naringin/sodium carboxymethyl cellulose triple-response type dual-drug-carrying system is destroyed, and further the release of the methotrexate/mesoporous silica@polydopamine@graphene oxide from the gel is caused; (2) Under the acidic condition, polydopamine is easier to fall off from the surface of mesoporous silica, so that the pore canal of the mesoporous silica cannot be plugged, and further the methotrexate is released. To verify whether the methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose triple-response dual-carrier had redox response properties, 200mg of the methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethylcellulose triple-response dual-carrier was placed in 50mL of phosphate buffer solution having a pH of 5.0 and containing 10mM glutathione. The cumulative release of methotrexate at 12h was significantly enhanced (59.04%) in the presence of 10mM glutathione compared to the cumulative release in the absence of 10mM glutathione (45.35%). The result shows that the methotrexate/mesoporous silica@polydopamine@graphene oxide/naringin/sodium carboxymethylcellulose triple-response type double-drug-carrying system has good redox response performance. The cumulative drug release percentage at the equilibrium of methotrexate drug release under the conditions of pH value of 5.0 and 10mM glutathione and accompanied by near infrared light irradiation is 67.14 percent, and the cumulative drug release percentage under the conditions of near infrared light irradiation is larger than that under the conditions of no near infrared light irradiation, so that the result shows that the methotrexate/mesoporous silica @ polydopamine @ graphene oxide/naringin/sodium carboxymethyl cellulose triple-response type dual drug delivery system has obvious near infrared light responsiveness mainly due to the fact that the graphene oxide and polydopamine coated on the surface of the mesoporous silica have near infrared light responsiveness, so that near infrared light can be well converted into heat to enable the local environment temperature to be high, and the release of the methotrexate is promoted.
Claims (10)
1. A method for preparing a pH, redox and near infrared triple-response type dual drug delivery system, which is characterized by comprising the following steps:
(1) Weighing the medicine A, dissolving in deionized water, adding mesoporous silica, magnetically stirring, and centrifugally separating to obtain medicine A/mesoporous silica;
(2) Dispersing the medicine A/mesoporous silica obtained in the step (1) in phosphate buffer solution, adding dopamine hydrochloride, magnetically stirring at room temperature in a dark place, washing precipitate after solid-liquid separation, and drying at constant temperature to obtain medicine A/mesoporous silica@polydopamine;
(3) Weighing graphene oxide, dispersing the graphene oxide in deionized water, performing ultrasonic dispersion until the graphene oxide is completely yellow and no solid matter exists, adding the medicine A/mesoporous silica@polydopamine obtained in the step (2), performing magnetic stirring, performing solid-liquid separation, washing and precipitating, and performing constant-temperature drying to obtain the medicine A/mesoporous silica@polydopamine@graphene oxide;
(4) And (3) weighing the medicine B, dissolving the medicine B in a phosphate buffer solution, adding sodium carboxymethyl cellulose, stirring and mixing uniformly, adding 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride and N-hydroxysuccinimide, magnetically stirring at room temperature, adding the medicine A/mesoporous silica@polydopamine@graphene oxide obtained in the step (3), adding cystamine, continuously stirring, and freeze-drying to obtain the medicine A/mesoporous silica@polydopamine@graphene oxide/medicine B/sodium carboxymethyl cellulose triple-response type double-drug-carrying system.
2. The preparation method of claim 1, wherein the magnetic stirring time in the step (1) is 2-4 hours, and the mass volume ratio of the medicine A to the mesoporous silica to the deionized water is 3-8:500-1100:40-60 mg/mg/mL;
the specific preparation method of the mesoporous silica in the step (1) comprises the following steps: and (3) weighing cetyl trimethyl ammonium bromide, adding the cetyl trimethyl ammonium bromide into a mixed solution containing ammonia water, deionized water and ethanol, mechanically stirring, dropwise adding tetraethoxysilane in a stirring state for reaction, centrifuging, alternately and repeatedly washing with the deionized water and the absolute ethanol, drying, placing into a crucible, and calcining in a muffle furnace to obtain the mesoporous silica.
3. The preparation method of claim 2, wherein the volume ratio of ammonia water, deionized water and ethanol in the mixed solution is 1.3-1.5:70-110:50-90, the mass volume ratio of cetyltrimethylammonium bromide to the mixed solution is 0.5-1.0:121.3-201.5 g/mL, the mass volume ratio of cetyltrimethylammonium bromide to tetraethoxysilane is 0.5-1.0:0.5-1.1 g/mL, the mechanical stirring time is 20-40 min, the reaction time is 4-8 h, and the calcining condition is that: the calcination temperature is 500-560 ℃ and the calcination time is 5-8 h.
4. The method according to claim 1, wherein the pH of the phosphate buffer solution in the step (2) is 7.5 to 8.5, the magnetic stirring time is 3 to 5 hours, and the constant temperature drying conditions are as follows: the temperature is 50-70 ℃ and the time is 3-5 hours, and the mass volume ratio of the medicine A/mesoporous silica to the dopamine hydrochloride to the phosphate buffer solution is 400-800:120-180:40-60 mg/mg/mL.
5. The preparation method of claim 1, wherein in the step (3), the mass volume ratio of graphene oxide to drug A/mesoporous silica @ polydopamine to deionized water is 0.5-1.1:0.2-0.4:20-40 g/g/mL, the time of the ultrasonic treatment is 1-3h, the magnetic stirring is 2-6h, and the constant temperature drying condition is: the temperature is 40-80 ℃ and the time is 3-5 h;
the specific preparation method of the graphene oxide in the step (3) comprises the following steps: and (3) slowly adding the potassium permanganate and the graphite powder into a mixed solution containing concentrated sulfuric acid and phosphoric acid, heating and stirring in a water bath, cooling to room temperature, adding hydrogen peroxide, standing in an ice water bath, taking precipitate, centrifugally washing to remove residual acid, naturally airing, and grinding to obtain the graphene oxide.
6. The preparation method of claim 5, wherein the mass ratio of potassium permanganate to graphite powder is 5-7:0.8-1.2, the volume ratio of concentrated sulfuric acid to phosphoric acid in the mixed solution is 110-130:12.2-14.4, the volume ratio of hydrogen peroxide to the mixed solution is 122.2-144.4:0.8-1.2, the temperature of the water bath is 40-60 ℃, the stirring time is 10-14 h, and the standing time is 8-12 h.
7. The preparation method of claim 1, wherein the mass volume ratio of the drug B to the sodium carboxymethyl cellulose to the phosphate buffer solution in the step (4) is 3-8:200-800:40-60 mg/mg/mL, the mass ratio of the sodium carboxymethyl cellulose to the 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride to the N-hydroxysuccinimide is 0.2-0.8:1.5-2.0:0.8-1.1, the mass ratio of the sodium carboxymethyl cellulose to the drug A/mesoporous silica@polydopamine@graphene oxide to the cystamine is 0.2-0.8:0.1-0.5:0.1-0.5, the pH of the phosphate buffer solution is 5.0-6.0, the magnetic stirring time is 0.5-2 h, and the continuous stirring time is 5-7 h.
8. A dual drug delivery system having a pH, redox and near infrared triple response, characterized by being obtainable by the preparation method according to any one of claims 1-7.
9. Use of a dual drug delivery system having pH, redox and near infrared triple response according to claim 8 for the preparation of a composition for encapsulation and delivery of a drug.
10. The use according to claim 9, comprising delivering the drug at different pH, delivering the drug under glutathione stimulation conditions, delivering the drug under near infrared light stimulation conditions.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111214655A (en) * | 2020-02-19 | 2020-06-02 | 常州大学 | Preparation method of drug sustained-release system with pH and near-infrared dual responses |
| CN111354939A (en) * | 2020-02-24 | 2020-06-30 | 广东东岛新能源股份有限公司 | Porous silicon composite material and preparation method and application thereof |
| CN112220760A (en) * | 2020-10-16 | 2021-01-15 | 常州大学 | PH-responsive double-drug-loading system and preparation method and application thereof |
| CN113018251A (en) * | 2021-03-03 | 2021-06-25 | 常州大学 | Dual-drug controlled release system with pH and glutathione dual responses and preparation method thereof |
| CN113289030A (en) * | 2021-03-04 | 2021-08-24 | 石河子大学 | Preparation method of targeted long-circulating nano-drug carrier for photothermal synergistic chemotherapy |
| CN113519510A (en) * | 2021-07-20 | 2021-10-22 | 南京大学 | Preparation and application of polydopamine-encapsulated mesoporous silica nano drug delivery system |
-
2022
- 2022-03-11 CN CN202210243181.5A patent/CN114652841B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111214655A (en) * | 2020-02-19 | 2020-06-02 | 常州大学 | Preparation method of drug sustained-release system with pH and near-infrared dual responses |
| CN111354939A (en) * | 2020-02-24 | 2020-06-30 | 广东东岛新能源股份有限公司 | Porous silicon composite material and preparation method and application thereof |
| CN112220760A (en) * | 2020-10-16 | 2021-01-15 | 常州大学 | PH-responsive double-drug-loading system and preparation method and application thereof |
| CN113018251A (en) * | 2021-03-03 | 2021-06-25 | 常州大学 | Dual-drug controlled release system with pH and glutathione dual responses and preparation method thereof |
| CN113289030A (en) * | 2021-03-04 | 2021-08-24 | 石河子大学 | Preparation method of targeted long-circulating nano-drug carrier for photothermal synergistic chemotherapy |
| CN113519510A (en) * | 2021-07-20 | 2021-10-22 | 南京大学 | Preparation and application of polydopamine-encapsulated mesoporous silica nano drug delivery system |
Non-Patent Citations (1)
| Title |
|---|
| 刘卫等.《经皮给药纳米技术》.中国医药科学技术出版社,2020,第268页. * |
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