CN110302397B - PH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loading composite nanoparticle and preparation method thereof - Google Patents
PH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loading composite nanoparticle and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a pH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loading composite nanoparticle and a preparation method thereof. The preparation method comprises the steps of loading cinnamaldehyde and adriamycin on the aminated mesoporous silica nanoparticles and the graphene oxide nanosheets respectively through physical loading and pi-pi conjugation, and then obtaining the aminated mesoporous silica nanoparticles and the graphene oxide nanosheets through electrostatic adsorption. The composite nano particle prepared by the invention has good biocompatibility and high drug loading, releases less drug in a neutral pH range, and quickly removes a surface covering layer through the surface charge change of the graphene oxide nano sheet in a low pH environment in a tumor cell, so that the drug response release is realized, the drug accumulation in the cell is finally improved, the drug treatment effect is enhanced, and the toxic and side effects are reduced.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and relates to a pH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loaded composite nanoparticle and a preparation method thereof.
Background
The tumor is one of major diseases threatening human health, and the existing treatment method aiming at malignant tumor mainly comprises operation and is assisted with the means of chemotherapy, radiotherapy and the like for comprehensive treatment. Chemotherapy (chemotherapy) primarily uses chemical drugs to inhibit tumor proliferation, metastasis and ultimately kill the tumor. However, most chemotherapy drugs often have many defects in clinical use, such as poor water solubility and stability, short circulation time in vivo, lack of targeting property, and the like, which not only affect the curative effect, but also cause serious toxic and side effects, thereby bringing additional pain to patients.
Nanotechnology is an emerging technology for studying material properties and applications with structure sizes in the nanoscale range. The unique physical and chemical properties of the nano material enable the nano material to be widely applied to the field of biological medicine. The nano-particle can be used for constructing a drug carrier by loading drug molecules in the nano-particle, and can be combined with a receptor specifically expressed on the surface of a tumor by connecting targeting molecules on the surface, so that the targeted drug delivery to the tumor is realized. The ideal nano-drug carrier should have the properties of specific targeting, drug release controllability, good biodegradability and biocompatibility and the like.
Mesoporous Silica Nanoparticles (MSNs) refer to a class of porous materials with a pore diameter of 2-50nm, and have the characteristics of ordered mesoporous structure, high specific surface area, easy surface modification, good biocompatibility and the like, so that the mesoporous silica nanoparticles are widely applied to the field of biomedicine. The mesoporous structure of the MSN enables the MSN to absorb more drug molecules in the pore channel, and various types of drugs from small molecules to macromolecular proteins and the like can be loaded by changing the pore size. The medicament is encapsulated in the MSN mesoporous pore canal, so that the loss of the medicament in the transportation process can be reduced, the toxic and side effects on normal tissues are reduced, and the pore canal structure of the MSN plays a certain slow release role on the medicament. By adjusting the pore size of the MSN mesopore, the invasion of biological enzyme can be blocked, thereby reducing the possibility of degrading the drug. The MSN surface is rich in silanol groups, so that the MSN surface can be subjected to functional modification through corresponding chemical reaction, and different drug delivery requirements are met.
Graphene Oxide (GO) is a two-dimensional carbon nanosheet, has a large specific surface area and good biocompatibility, and can be used as a biomedical material. The unique hexagonal carbon ring structure of GO enables pi-pi conjugation effect with aromatic ring structures in many drug molecules, thus being capable of loading drugs efficiently. The GO structure contains a large number of carboxyl, hydroxyl and epoxy groups, so that the water solubility of GO can be improved, and the GO can circularly flow in a body fluid environment and keep stable. At present, research shows that the functionalized GO can efficiently load various anti-tumor drugs, and control the drug release under different pH conditions, so as to obtain better treatment effect [ Journal of Materials Chemistry,2011,21 (10): 3448-3454].
Cinnamaldehyde (CA) is a natural aldehyde compound extracted from the volatile oil of the traditional Chinese medicine cinnamon, contains an active michael acceptor pharmacophore, has good safety, and is approved by the FDA to be used as a food additive. Current studies indicate that CA can inhibit tumor proliferation by elevating levels of Reactive Oxygen Species (ROS) in the mitochondria of cells and is less toxic to normal cells [ Cancer letters, 2003,196 (2), 143-152]. However, the aldehyde group in the CA structure is easily oxidized, so that its bioavailability is low. Doxorubicin (DOX) is an anti-tumor drug widely used clinically at present, has a wide anti-cancer spectrum, and can interfere the transcription process of DNA (deoxyribonucleic acid) nuclear base pairs by being directly embedded between the DNA nuclear base pairs to prevent the formation of mRNA (messenger ribonucleic acid) to play an anti-tumor role. However, DOX also has toxic and side effects such as bone marrow suppression, cardiotoxicity and the like in the clinical use process. Therefore, the pores of the MSN are used for loading CA, mutual adsorption generated by the pi-pi conjugation of the GO and the anthracycline in the DOX structure can be used for respectively loading two medicines in the two carriers, and the composite nano particles simultaneously loading the two medicines are prepared by electrostatic adsorption, so that the oxidation degree of the CA structure can be reduced, the toxic and side effects of the DOX can be reduced by improving the targeting property, and the treatment effect is finally improved. Therefore, the composite nano particle has better research value and application prospect.
Disclosure of Invention
Technical problem to be solved
In order to avoid the defects of the prior art, the invention provides a pH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loaded composite nanoparticle and a preparation method thereof, so as to achieve the purposes of improving the chemotherapy effect and reducing the toxic and side effects.
Technical scheme
A pH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loading composite nanoparticle is characterized by comprising mesoporous silica nanoparticles, cinnamaldehyde, graphene oxide nanosheets and doxorubicin hydrochloride; the cinnamaldehyde is loaded inside the mesoporous silica nanoparticle, the graphene oxide nanosheet is coated on the surface of the mesoporous silica nanoparticle, and the doxorubicin hydrochloride is loaded in the graphene oxide nanosheet structure.
The diameter of the sheet layer of the graphene oxide nanosheet is 100-200 nm.
A preparation method of pH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loaded composite nanoparticles is characterized by comprising the following steps:
preparing mesoporous silica nanoparticles with aminated surfaces:
(1) Adding hexadecyl trimethyl ammonium bromide, absolute ethyl alcohol and triethanolamine into water, heating, mixing and stirring, adding tetraethyl orthosilicate, and carrying out heating reaction at the temperature of 20-80 ℃; repeatedly washing, centrifuging and vacuum drying to obtain mesoporous silica nanoparticles containing a template agent; the molar ratio of the hexadecyl trimethyl ammonium bromide to the absolute ethyl alcohol to the triethanolamine to the tetraethyl orthosilicate is as follows: 0.14;
(2) Dispersing mesoporous silica nanoparticles containing a template agent in an acidic ethanol solution containing hydrochloric acid, carrying out heating reflux reaction at the temperature of 60-80 ℃ for 24-48 h, and repeatedly washing, centrifuging and vacuum drying to obtain the mesoporous silica nanoparticles without the template agent; the acidic ethanol solution containing hydrochloric acid accounts for 10-15% of the total volume of the solution, and the unit is v/v; the concentration of the concentrated hydrochloric acid in the acidic ethanol solution is 36-38%, and the unit is w/w;
(3) Adding the mesoporous silica nanoparticles without the template agent into isopropanol, adding 3-aminopropyltriethoxysilane, carrying out heating reflux reaction at the temperature of 60-80 ℃ for 24-48 h, and repeatedly washing, centrifuging and vacuum drying to obtain mesoporous silica nanoparticles with aminated surfaces; the mesoporous silica nanoparticle for removing the template agent comprises 3-aminopropyltriethoxysilane and isopropanol, wherein the ratio of the 3-aminopropyltriethoxysilane to the isopropanol is 1;
preparing mesoporous silica nanoparticles loaded with cinnamaldehyde: preparing a mixed ethanol solution from the mesoporous silica nanoparticles with aminated surfaces and cinnamaldehyde according to the mass ratio of (5);
step 3, preparing the mesoporous silica drug double-loading composite nanoparticles coated by the pH responsive graphene oxide nanosheets: mixing a mesoporous silica nanoparticle aqueous solution loaded with cinnamaldehyde at a concentration of 0.05-0.1 g/mL and an graphene oxide nanosheet aqueous solution loaded with doxorubicin at a concentration of 0.05-0.1 g/mL, stirring at room temperature, washing, centrifuging, and drying in vacuum to obtain pH-responsive graphene oxide nanosheet-coated mesoporous silica drug dual-loading composite nanoparticles; the volume ratio of the mesoporous silica nanoparticle aqueous solution loaded with the cinnamaldehyde to the graphene oxide nanosheet aqueous solution loaded with the adriamycin is 1-1; the concentration of the cinnamaldehyde-loaded mesoporous silica nanoparticle aqueous solution is calculated by the mass of the mesoporous silica nanoparticles; the concentration of the adriamycin-loaded graphene oxide nanosheet aqueous solution is calculated by the mass of the graphene oxide nanosheets.
The graphene oxide nanosheet: preparing a graphene oxide aqueous solution from the single-layer graphene oxide according to a mass volume ratio (m/v is 1-1).
The thickness of the single-layer graphene oxide is 0.335-1 nm, and the diameter of the sheet layer is 0.5-5 mu m.
The particle size of the mesoporous silica nano-particle is 60-100nm, and the Zeta potential is between 20-30 mV.
A use method of the pH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loaded composite nanoparticle is characterized by comprising the following steps: is used in the field of controlled release of drugs.
Advantageous effects
The invention provides a pH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loading composite nanoparticle and a preparation method thereof. The preparation method comprises the steps of loading cinnamaldehyde and adriamycin on the aminated mesoporous silica nanoparticles and the graphene oxide nanosheets respectively through physical loading and pi-pi conjugation, and then obtaining the aminated mesoporous silica nanoparticles and the graphene oxide nanosheets through electrostatic adsorption. The composite nano particles prepared by the invention have good biocompatibility and high drug loading, release less drug in a neutral pH range, and quickly remove a surface covering layer through the surface charge change of the graphene oxide nano sheets in a low pH environment in tumor cells, so that the drug response release is realized, the drug accumulation in the cells is finally improved, the drug treatment effect is enhanced, and the toxic and side effects are reduced.
Compared with the prior art, the invention has the beneficial effects that:
1. the MSN and GO-ns with good biocompatibility are adopted to prepare the composite nano particles, and the composite nano particles have good biocompatibility and low toxicity.
2. GO-ns is coated on the surface of the MSN, so that the effect of blocking the MSN surface gap can be achieved, and the release of the loaded drug can be controlled.
3. The loading of the MSN and GO-ns to the medicine and the preparation of the final composite nano particles can be realized only by a simple stirring process, and the operation is simple and convenient.
4. The prepared composite nano particles can be responsively stripped through the change of GO-ns surface charge in an acidic environment, so that the pH responsive release of the loaded medicine is realized.
Drawings
FIG. 1 is the MSN particle size, potential detection results and transmission electron microscope image
FIG. 2 shows MSN-NH 2 Particle diameter, potential detection result and transmission electron micrograph
FIG. 3 is a MSN CA Transmission electron micrograph of
FIG. 4 is transmission electron micrograph of GO (a) and GO-ns (b)
FIG. 5 shows the particle size and potential detection results of GO (a) and GO-ns (b)
FIG. 6 is GO DOX Transmission electron micrograph
FIG. 7 shows MSN CA @GO DOX Transmission electron microscope and X-ray energy spectrum analysis result of composite nano particles
FIG. 8 is a MSN CA @GO DOX The in vitro release result of the composite nano particle is shown in (a) graph of CA release trend and (b) graph of DOX release trend
Detailed Description
The invention will now be further described with reference to the following examples, and the accompanying drawings:
example (b):
1. preparation of Mesoporous Silica Nanoparticles (MSN):
hexadecyltrimethylammonium bromide (CTAB) 2.1g was precisely weighed into a 100mL round-bottomed flask, 52mL of distilled water was added to the flask, and magnetic stirring (600 rpm) was carried out in a water bath at 60 ℃ to obtain a clear solution. Keeping stirring state, continuously dropwise adding 12mL of anhydrous ethanol and 2.8g of triethanolamine into the mixed solution, continuously stirring for 15min, dropwise and slowly adding 4.7mL of tetraethyl orthosilicate, and continuously stirring for 2h at 60 ℃ in a water bath. After the reaction was completed, the solution was cooled to room temperature, centrifuged (10,000rpm, 5 min) to discard the supernatant, and a white solid was collected and washed with distilled water and anhydrous ethanol repeatedly. The washed sample was added to 200mL of anhydrous ethanol solution containing 10% concentrated hydrochloric acid (36%) and refluxed in a water bath at 80 ℃ for 24 hours. And after the solution is cooled to room temperature, centrifuging (10,000rpm, 5 min) to collect the MSN from which the template is removed, repeatedly washing with distilled water and absolute ethyl alcohol, and performing vacuum drying at 60 ℃ for 24 hours to obtain the MSN.
In another example, the amount of cetyltrimethylammonium bromide added was varied under the present process, with the molar ratio of the four species: 0.14;
as another example, the amount of cetyltrimethylammonium bromide added was varied under the present process, with the molar ratio of the four materials: 1.14;
2. aminated mesoporous silica nanoparticle (MSN-NH) 2 ) The preparation of (1):
200mg of the prepared MSN is weighed and evenly dispersed into 200mL of isopropanol, then 2mL of 3-Aminopropyltriethoxysilane (APTES) solution is added, and the mixture is refluxed for 24h in a water bath at 80 ℃. After the solution is cooled to room temperature, the solution is centrifuged (10,000rpm, 5 min) to collect MSN-NH 2 Repeatedly washing with distilled water and anhydrous ethanol, and vacuum drying at 60 deg.C for 24 hr to obtain MSN-NH 2 。
In another embodiment, under the process, the molar ratio of the three-substance mesoporous silica nanoparticles to 3-aminopropyltriethoxysilane to isopropanol is changed as follows: 1;
in another embodiment, under the process, the molar ratio of the three-substance mesoporous silica nanoparticles to the 3-aminopropyltriethoxysilane to the isopropanol is changed as follows: 1;
3、MSN-NH 2 loading of Cinnamaldehyde (CA)
50mg of CA is precisely weighed, and is added with a proper amount of absolute ethyl alcohol to be dissolved, and then the volume is determined to be 1mg/mL by a 50mL volumetric flask. Accurately weigh 0.2g MSN-NH 2 Adding 20mL of a 1mg/mL ethanol solution of CA, stirring at room temperature for 12h (400 rpm), centrifuging (10,000rpm, 5 min), collecting light yellow solid, repeatedly washing with distilled water and ethanol, and vacuum drying at 60 deg.C for 24h to obtain MSN-NH loaded with CA 2 (MSN CA )。
In another embodiment, the mass ratio of the mesoporous silica nanoparticles with aminated surfaces to the cinnamaldehyde is changed to be 10;
3. preparing graphene oxide nanosheets (GO-ns):
accurately weighing 0.2g of unprocessed GO, uniformly dispersing the unprocessed GO into 20mL of distilled water, and continuously performing ultrasonic treatment for 2h under the ice bath condition by using a cell disruptor to obtain GO-ns.
4. Loading of GO-ns for doxorubicin hydrochloride (DOX. HCl):
10mg of DOX & HCl was precisely weighed, dissolved in an appropriate amount of distilled water, and the solution was brought to a constant volume of 1mg/mL in a 10mL brown flask. Mixing GO-ns solution and DOX & HCl according to the mass ratio of GO-ns to DOX & HCl of 1Washing with distilled water, and freeze-drying to obtain graphene oxide nanosheet (GO) loaded with adriamycin DOX )。
5. Mesoporous silica drug double-loading composite nanoparticle coated with graphene oxide nanosheets (MSN) CA @GO DOX ) Preparation:
GO with the concentration of 0.1mg/mL is prepared respectively DOX And MSN CA The two solutions were mixed at a ratio of 1 CA @GO DOX 。
In another embodiment, GO is modified under the present process DOX And MSN CA The volume ratio of the aqueous solution is 1; or change GO DOX And MSN CA The volume ratio of the aqueous solution is 1;
MSN CA @GO DOX in vitro release of
In this example, MSN was investigated by dialysis CA @GO DOX The in vitro drug release behavior. The endosome/lysosome pH environment was simulated with pH5.0PBS, and the pH environment in blood circulation was simulated with pH7.4PBS. Precision weighing 10mg MSN CA @GO DOX A dialysis bag having a molecular weight cut-off of 3.5kDa was added, and 2mL of pH5.0PBS and pH7.4PBS were added to the bag, respectively. The dialysis bag was sealed and immersed in 8mL of PBS solution at the corresponding pH. Placing in a shaking table, performing release test at 100rpm and 37 deg.C, collecting all solutions outside the dialysis bag at selected time, simultaneously supplementing release solution with equal volume, measuring with ultraviolet spectrophotometer and high performance liquid chromatograph, calculating cumulative release rate, and drawing cumulative release curve.
The experimental result shows that within 48h, the MSN CA @GO DOX In pH5.0PBS, both CA and DOX can be quickly released, and its cumulative release rate is higher (89% and 81%), and in pH7.4PBS, MSN CA @GO DOX Only 66% CA and 24% DOX were released. The results show that MSN CA @GO DOX Electrostatic attraction is weakened by GO surface charge changes in low pH environments in lysosomes/endosomes within tumor cells, thereby enabling GO to be rapidly detached and accelerating release of CAAnd (4) placing. Meanwhile, the protonation of DOX in an acid environment enables DOX to be separated from the pi-pi conjugation effect of GO, so that the release of DOX is accelerated. This release profile is effective in enhancing drug accumulation in tumor cells, reducing toxicity due to premature release in the blood circulation, and ultimately enhancing therapeutic efficacy.
Claims (6)
1. A pH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loading composite nanoparticle is characterized by comprising mesoporous silica nanoparticles, cinnamaldehyde, graphene oxide nanosheets and doxorubicin hydrochloride; the method comprises the steps of loading cinnamaldehyde in mesoporous silica nanoparticles, coating graphene oxide nanosheets on the surfaces of the mesoporous silica nanoparticles, loading doxorubicin hydrochloride in a graphene oxide nanosheet structure, wherein the diameter of sheet layers of the graphene oxide nanosheets is 100-200nm.
2. A preparation method of the pH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-supported composite nanoparticle as defined in claim 1, the preparation method being characterized by comprising the steps of:
step 1, preparing an doxorubicin-loaded graphene oxide nanosheet: preparing a mixed aqueous solution from the graphene oxide nanosheet and doxorubicin hydrochloride according to the mass ratio of 1 to 8, stirring at room temperature for 12 to 48h, washing, centrifuging and freeze-drying to obtain an doxorubicin-loaded graphene oxide nanosheet; the diameter of the graphene oxide nanosheet is 100 to 200nm;
step 2, preparing the mesoporous silica nanoparticles loaded with cinnamaldehyde:
preparing mesoporous silica nanoparticles with aminated surfaces:
(1) Adding hexadecyl trimethyl ammonium bromide, absolute ethyl alcohol and triethanolamine into water, heating, mixing and stirring, adding tetraethyl orthosilicate, and carrying out heating reaction at the temperature of 20-80 ℃; repeatedly washing, centrifuging and vacuum drying to obtain mesoporous silica nanoparticles containing a template agent; the molar ratio of the hexadecyl trimethyl ammonium bromide to the absolute ethyl alcohol to the triethanolamine to the tetraethyl orthosilicate is as follows: 0.14;
(2) Dispersing mesoporous silica nanoparticles containing a template agent in an acidic ethanol solution containing hydrochloric acid, carrying out heating reflux reaction at the temperature of 60-80 ℃ for 24-48h, and repeatedly washing, centrifuging and vacuum drying to obtain the mesoporous silica nanoparticles without the template agent; the acidic ethanol solution containing hydrochloric acid accounts for 10-15% of the total solution volume, and the unit is v/v; the concentration of concentrated hydrochloric acid in the acidic ethanol solution is 36 to 38 percent, and the unit is w/w;
(3) Adding the mesoporous silica nanoparticles without the template agent into isopropanol, adding 3-aminopropyltriethoxysilane, carrying out heating reflux reaction at the temperature of 60-80 ℃ for 24-48h, repeatedly washing, centrifuging and vacuum drying to obtain mesoporous silica nanoparticles with aminated surfaces; the mesoporous silica nanoparticle for removing the template agent comprises 3-aminopropyltriethoxysilane and isopropanol, wherein the ratio of the 3-aminopropyltriethoxysilane to the isopropanol is 1;
preparing mesoporous silica nanoparticles loaded with cinnamaldehyde: preparing a mixed ethanol solution from the mesoporous silica nanoparticles with aminated surfaces and cinnamaldehyde according to the mass ratio of 5 to 1 to 10, stirring at room temperature for 12 to 24h, washing, centrifuging, and drying in vacuum to obtain mesoporous silica nanoparticles loaded with cinnamaldehyde;
step 3, preparing the mesoporous silica drug double-loading composite nanoparticles coated by the pH responsive graphene oxide nanosheets: mixing mesoporous silica nanoparticle aqueous solution loaded with cinnamaldehyde and graphene oxide nanosheet aqueous solution loaded with adriamycin, wherein the concentrations of the mesoporous silica nanoparticle aqueous solution and the graphene oxide nanosheet aqueous solution are 0.05-0.1g/mL, stirring at room temperature, washing, centrifuging and drying in vacuum to obtain pH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loading composite nanoparticles; the volume ratio of the mesoporous silica nanoparticle aqueous solution loaded with the cinnamaldehyde to the graphene oxide nanosheet aqueous solution loaded with the adriamycin is 1 to 1; the concentration of the cinnamaldehyde-loaded mesoporous silica nanoparticle aqueous solution is calculated by the mass of the mesoporous silica nanoparticles; the concentration of the adriamycin-loaded graphene oxide nanosheet aqueous solution is calculated by the mass of the graphene oxide nanosheets.
3. The method of claim 2, wherein: the preparation method of the graphene oxide nanosheet comprises the following steps:
preparing a graphene oxide aqueous solution from the single-layer graphene oxide according to a mass volume ratio (m/v is 1 to 1000 to 1).
4. The method of claim 3, wherein: the thickness of the single-layer graphene oxide is 0.335 to 1nm, and the diameter of the sheet layer is 0.5 to 5 mu m.
5. The method of claim 3, wherein: the particle size of the mesoporous silica nano-particle is 60 to 100nm, and the Zeta potential is 20-30 mV.
6. Application of the pH-responsive graphene oxide nanosheet-coated mesoporous silica drug double-loaded composite nanoparticle of claim 1 in preparation of materials for controlled release of drugs.
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