CN107970454B - Preparation method and application of graphene oxide-lipid nanocomposite - Google Patents
Preparation method and application of graphene oxide-lipid nanocomposite Download PDFInfo
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Abstract
The invention discloses a preparation method of a graphene oxide-lipid nano composite material, belonging to the technical field of material synthesis and biological medicine; the specific method comprises the following steps: the composite material is obtained by using nano-sized graphene oxide as a matrix, synthesizing a liposome by using a rotary evaporation method, and then carrying out lipid modification on the graphene oxide through electrostatic adsorption. The lipid modified nano-carrier synthesized by the invention has better stability and dispersibility under physiological conditions; the graphene oxide nano-particles are used as an inner core, a layer of liposome is wrapped outside the inner core, and the two materials have good biocompatibility; the antitumor drug adriamycin is loaded on the graphene oxide, so that the drug loading rate is high, the stability is good, the drug has the targeted slow release effect, the drug effect is effectively improved, and the toxic and side effects of the drug are reduced.
Description
Technical Field
The invention belongs to the technical field of material synthesis and biomedicine, and particularly relates to a preparation method of a graphene oxide-lipid nanocomposite and application of the graphene oxide-lipid nanocomposite in an anti-tumor drug carrier.
Background
Tumors are one of the intractable diseases seriously harming human health, and the treatment results of chemical drugs are poor due to serious side effects. The drug carrier is used for carrying out targeted therapy on the cancer to improve the curative effect and reduce the toxic and side effects, and a new idea is developed for the treatment of the tumor. The anticancer drug carriers discovered at present are various, including organic materials (such as protein and lipid), inorganic materials, and polymeric materials. In order to overcome the defects that organic materials and high polymer materials are easy to degrade and leak and have high cost and the like as drug carriers, the invention adopts an inorganic material graphene oxide as a carrier of the anticancer drug, and has the advantages of stable structure, stable drug loading, large drug loading amount, easy preparation, low cost and the like.
In recent years, with the rapid development of nanotechnology, the application of nanomaterials in many fields shows an increasingly important position. The nano drug-carrying system has the advantages of improving the stability of the drug, reducing the toxic and side effects of the drug, realizing targeting, sustained and controlled release of the drug, improving the bioavailability and the like, and draws attention to the field of biological medicine.
The graphene oxide has a stable two-dimensional monoatomic layer structure, a large specific surface area, a large drug loading capacity and good biocompatibility. Meanwhile, the functional modification can be carried out on the graphene oxide through the reaction of the oxygen-containing activated group and a specific substance, so as to achieve different application purposes. These properties make graphene oxide an ideal material for loading and delivering a variety of drugs, such as doxorubicin, ellagic acid, camptothecin, and the like. In recent years, graphene oxide has shown great application potential in many aspects of the biomedical field, and thus has received attention from a large number of researchers.
However, unmodified graphene oxide is sensitive to solute, ph value, ionic strength and other solution environments, and has extremely poor solubility in physiological environments (such as cell culture solution and phosphate buffer solution), and agglomeration is easy to occur, which limits the application of graphene oxide to a certain extent. The graphene oxide does not have functions of targeting, sustained and controlled release and the like in vivo, and can be functionalized to increase the stability and endow new functions of targeting, sustained and controlled release and the like. The functionalized modification of the graphene oxide can be divided into covalent functionalization and non-covalent functionalization, and the covalent modification has the defects that the acting force between a modified molecule and the graphene oxide is strong, and an organic solvent is used in the preparation process, so that the graphene oxide is possibly harmful to a human body; therefore, the graphene oxide is subjected to lipid modification by utilizing a non-covalent effect, the preparation is simple, and an organic solvent is not used. The non-covalent bond functionalization is to utilize pi interaction, ionic bond, hydrogen bond, electrostatic interaction and other non-covalent bond actions to functionalize the graphene oxide to improve the dispersibility and stability of the graphene oxide.
Liposomes (liposomes) are closed vesicles formed by lipid molecules dispersed in an aqueous phase, and their main components are phospholipids and cholesterol, similar to the structure of cell membranes. As a drug carrier, the liposome has the advantages of targeting property, slow release and long-acting effect, reduction of drug toxicity, increase of drug stability, good histocompatibility and cell affinity, and the like.
According to the invention, the graphene oxide with a nano size is prepared by an ultrasonic crushing method, a liposome is synthesized by a rotary evaporation method, and then the graphene oxide is subjected to surface modification by utilizing an electrostatic effect, so that the graphene oxide-lipid nano composite material with good stability and dispersibility under physiological conditions is obtained. Meanwhile, the lipid coating enables the drug carrier to have the targeted sustained-release effect, so that the toxic and side effects of the drug are effectively reduced.
Disclosure of Invention
The invention aims to solve the defects that graphene oxide lamella is sensitive to the environment and easy to agglomerate in the physiological environment, and provides a preparation method of a graphene oxide-lipid composite material.
The invention firstly provides a graphene oxide-lipid composite material;
the invention also provides a preparation method of the graphene oxide-lipid nanocomposite, which comprises the following steps:
(1) dissolving graphene oxide in water to obtain a suspension, and performing water bath ultrasound to obtain a graphene oxide aqueous dispersion;
(2) dissolving yolk phospholipid in chloroform, placing on a rotary evaporator, rotating to form a film to obtain liposome, dissolving in water-soluble phosphate buffer solution, rotating to make the film fall off, and performing ultrasonic treatment to obtain liposome dispersion;
(3) and (3) mixing the magnetic graphene oxide obtained in the step (1) and the liposome dispersion liquid obtained in the step (2), placing the mixture in a constant-temperature oscillator for stirring, centrifuging to obtain a precipitate, dissolving the precipitate with a water-soluble phosphate buffer solution, and performing ultrasonic treatment to obtain the graphene oxide-lipid nanocomposite.
And (2) performing ultrasonic treatment on the mixture in the step (1) for 0.5-2 h at an ultrasonic power of 250-400W in an ice-water bath.
The concentration of the graphene oxide aqueous dispersion in the step (1) is 0.2mg/mL-1 mg/mL.
The mass ratio of the yolk phospholipids to the chloroform in the step (2) is 1: 75.
The concentration of the liposome dispersion liquid in the step (2) was 35 mg/mL.
The mass ratio of the liposome to the graphene oxide in the step (3) is 1: 10-30.
The graphene oxide-lipid nanocomposite is applied to the aspect of antitumor drug carriers.
The invention has the beneficial effects that:
(1) the particle size of the graphene oxide-lipid nanocomposite material prepared by the invention is in the range of 200400 nm, the drug loading rate is up to 120%, and the defects of dispersibility of the carrier material in water and easy agglomeration under physiological conditions are obviously improved after lipid modification. After 48 hours, the GO generates an obvious coagulation phenomenon in a cell culture solution, and the GO-lipo keeps good dispersibility and stability in three dispersion media.
(2) Compared with the common nano drug-carrying particles, the modification of the lipid enables the drug carrier to have the function of targeting positioning, namely, the drug can be quickly released in a targeted manner under lower pH, so that the toxic and side effects of the drug are reduced, and the drug carrier has a wide application prospect.
(3) According to the preparation method of the graphene oxide-lipid composite material, the defect that graphene oxide is easy to agglomerate under physiological conditions is overcome through non-covalent modification.
(4) The invention has simple operation, low cost and easy large-scale production, can be widely applied to the fields of sensors, biological medicines and the like, and particularly applied to the fields of medicine carrying and medicine controlled release.
Drawings
Fig. 1 is an atomic force microscope spectrum of the graphene oxide (a) and graphene oxide-lipid (b) materials prepared in example 1 (the right-side graph shows specific values of the thickness of particles on a straight line drawn in the AFM spectrum);
FIG. 2 (a) is a graph showing the stability of graphene oxide prepared in example 1 in purified water (left), phosphate buffered saline (PBS, pH 7.4) and a culture solution RPMI-1640 containing 10% fetal bovine serum (right), respectively;
FIG. 2 (b) is a graph showing the stability of graphene oxide-lipid prepared in example 1 in purified water (left), phosphate buffered saline (PBS, pH 7.4) and a culture solution containing 10% fetal bovine serum RPMI-1640 (right), respectively;
fig. 3 is a dispersion diagram of free doxorubicin (a), graphene oxide-doxorubicin (b) and graphene oxide-lipid-doxorubicin (c) in a PBS solution in example 4;
fig. 4 is a graph of in vitro drug release of the graphene oxide-lipid-doxorubicin composite material in example 5.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
example 1:
(1) crushing the graphene oxide aqueous dispersion into a nano-sized graphene oxide aqueous dispersion by using a cell crusher, wherein the power is 400w, the ultrasonic time is 0.5 h, and the operation is carried out in an ice-water bath; (2) weighing yolk phospholipids, dissolving the yolk phospholipids in a proper amount of chloroform, measuring the solution, placing the solution in an eggplant-shaped bottle, and rotating the bottle by using a rotary evaporator to form a film (rotating for half a minute and then vacuumizing). Then adding a proper amount of PBS solution into the container and rotating to enable the membrane to fall off; (3) pouring the content in the eggplant-shaped bottle into a 10mL centrifuge tube, and performing ultrasonic dispersion to clarify the content; (4) preparing a certain amount of graphene oxide aqueous solution with the concentration of 1 mg/mL. Taking a plurality of 5mL centrifuge tubes, respectively adding a graphene oxide solution, a liposome solution and a proper amount of pure water, wherein the mass ratio of the graphene oxide to the liposome is 15: 1, stirring overnight (37 ℃) on a constant temperature shaker; (5) and (3) centrifuging the solution (13000 r for 30 min), discarding the supernatant, dispersing the precipitate in a proper amount of PBS solution, and performing ultrasonic dispersion to clarify the precipitate to obtain the lipid-modified graphene oxide (with the concentration of 0.2 mg/mL).
As shown by the atomic force microscope (FIG. 1 a), the average size of the graphene oxide is 200 +/-2 nm, and the thickness of the graphene oxide is about 1 nm, which indicates that the cell disruption method is used for successfully preparing the nano-sized graphene oxide. After encapsulation of the liposomes onto graphene oxide, the thickness was increased to 8nm, indicating that the lipids had been successfully coated onto the surface of graphene oxide. Particle size measurement results also show that the particle size of graphene oxide is 237 +/-2 nm, while the particle size of lipid-modified graphene oxide is increased to 250 +/-2 nm, the particle size is slightly increased but still in a nanometer level, which indicates that the liposome is successfully coated on the surface of the graphene oxide, and the lipid-modified graphene oxide has good dispersibility. The Zeta potential of the graphene oxide is-33.82 mV, and the potential of the liposome is-40.36 mV; the potential of the lipid-modified graphene oxide is changed to-42.79 mV, and the change of the Zeta potential shows that the liposome is successfully wrapped on the surface of the graphene oxide. The stability results (as shown in fig. 2) indicate that the graphene oxide-lipid maintains good dispersibility and stability in all three dispersion media. Further, the defect that graphene oxide is easy to agglomerate in a physiological environment can be obviously improved after the surface of the graphene oxide is modified by using the liposome, and the stability and the dispersity of the graphene oxide are enhanced.
Example 2:
(1) crushing the graphene oxide aqueous dispersion into a nano-sized graphene oxide aqueous dispersion by using a cell crusher, wherein the power is 300w, the ultrasonic time is 1 h, and the operation is carried out in an ice-water bath; (2) weighing yolk phospholipids, dissolving the yolk phospholipids in a proper amount of chloroform, then weighing the solution, placing the solution in an eggplant-shaped bottle, rotating the bottle by using a rotary evaporator to form a film (firstly rotating for half a minute and then vacuumizing), then adding a proper amount of PBS solution into a container, and rotating the container to enable the film to fall off; (3) pouring the content in the eggplant-shaped bottle into a 10mL centrifuge tube, and performing ultrasonic dispersion to clarify the content; (4) preparing a certain amount of graphene oxide aqueous solution with the concentration of 1 mg/mL, taking a plurality of 5mL centrifuge tubes, respectively adding the graphene oxide solution, the liposome solution and a proper amount of pure water, wherein the mass ratio of the graphene oxide to the liposome is 10: 1, stirring overnight (37 ℃) on a constant temperature shaker; (5) and (3) centrifuging the solution (13000 r for 30 min), discarding the supernatant, dispersing the precipitate in a proper amount of PBS solution, and performing ultrasonic dispersion to clarify the precipitate to obtain the lipid-modified graphene oxide (with the concentration of 0.2 mg/mL).
The particle size measurement result shows that the particle size of the graphene oxide is 229 +/-2 nm, and the particle size of the graphene oxide is 246 +/-2 nm after lipid modification. The Zeta potential of the graphene oxide is-33.78 mV, and the Zeta potential is-41.58 mV after lipid coating.
Example 3:
(1) crushing the graphene oxide aqueous dispersion into a nano-sized graphene oxide aqueous dispersion by using a cell crusher, wherein the power is 250w, and the ultrasonic time is 1.5 h, and the operation is carried out in an ice-water bath; (2) weighing yolk phospholipids, dissolving the yolk phospholipids in a proper amount of chloroform, then weighing the solution, placing the solution in an eggplant-shaped bottle, rotating the bottle by using a rotary evaporator to form a film (firstly rotating for half a minute and then vacuumizing), then adding a proper amount of PBS solution into a container, and rotating the container to enable the film to fall off; (3) pouring the content in the eggplant-shaped bottle into a 10mL centrifuge tube, and performing ultrasonic dispersion to clarify the content; (4) preparing a certain amount of graphene oxide aqueous solution with the concentration of 1 mg/mL, taking a plurality of 5mL centrifuge tubes, and respectively adding the graphene oxide solution, the phospholipid solution and a proper amount of pure water, wherein the mass ratio of the graphene oxide to the liposome is 20: 1 placed in a constant temperature shaker and stirred overnight (37 ℃); (5) and (3) centrifuging the solution (13000 r for 30 min), discarding the supernatant, dispersing the precipitate in a proper amount of PBS solution, and performing ultrasonic dispersion to clarify the precipitate to obtain the lipid-modified graphene oxide (with the concentration of 0.2 mg/mL).
The particle size measurement result shows that the particle size of the graphene oxide is 231 +/-2 nm, and the particle size of the graphene oxide is 258 +/-2 nm after lipid modification. The Zeta potential of the graphene oxide is-34.08 mV, and the Zeta potential is-42.36 mV after lipid coating.
Example 4:
(1) crushing the graphene oxide aqueous dispersion into a nano-sized graphene oxide aqueous dispersion by using a cell crusher, wherein the power is 250w, and the ultrasonic time is 1.5 h, and the operation is carried out in an ice-water bath; (2) weighing yolk phospholipids, dissolving the yolk phospholipids in a proper amount of chloroform, then weighing the solution, placing the solution in an eggplant-shaped bottle, rotating the bottle by using a rotary evaporator to form a film (firstly rotating for half a minute and then vacuumizing), then adding a proper amount of PBS solution into a container, and rotating the container to enable the film to fall off; (3) pouring the content in the eggplant-shaped bottle into a 10mL centrifuge tube, and performing ultrasonic dispersion to clarify the content; (4) preparing a certain amount of graphene oxide aqueous solution with the concentration of 1 mg/mL, taking a plurality of 5mL centrifuge tubes, and respectively adding the graphene oxide solution, the phospholipid solution and a proper amount of pure water, wherein the mass ratio of the graphene oxide to the liposome is 30: 1 placed in a constant temperature shaker and stirred overnight (37 ℃); (5) and (3) centrifuging the solution (13000 r for 30 min), discarding the supernatant, dispersing the precipitate in a proper amount of PBS solution, and performing ultrasonic dispersion to clarify the precipitate to obtain the lipid-modified graphene oxide (with the concentration of 0.2 mg/mL).
The particle size measurement result shows that the particle size of the graphene oxide is 230 +/-2 nm, and the particle size of the graphene oxide is 254 +/-2 nm after lipid modification. The Zeta potential of graphene oxide is-34.08 mV (figure 2), and after lipid coating, the Zeta potential becomes-42.36 mV.
Example 5: preparation of adriamycin-loaded graphene oxide-lipid composite material
Taking 200 mg of the graphene oxide-lipid composite material, placing the graphene oxide-lipid composite material in a centrifuge tube, adding 200 mu l of adriamycin solution (1 mg/mL), shaking at a constant temperature for 24 h (37 ℃), centrifuging, taking the supernatant, diluting, measuring the absorbance of the supernatant and the adriamycin reference solution at 480 nm by using an ultraviolet spectrophotometry, and further calculating the drug loading rate. The experimental result shows that the doxorubicin loading capacity of the graphene oxide-lipid is 121.2%, which is lower than that of graphene oxide, but the stability of the graphene oxide-lipid-doxorubicin under physiological conditions (PBS buffer solution, cell culture solution and the like) is obviously improved (fig. 3).
Example 6: doxorubicin-loaded graphene oxide-lipid composite material drug release investigation
1mL of drug-loaded graphene oxide-lipid is respectively added into a dialysis bag, tightened, then immersed in 20 mL of PBS buffer solution with pH of 5.0 and 7.4, placed in a 37 ℃ constant temperature oscillation box for oscillation and timing, and all dissolution media are sequentially taken out at different time points and supplemented into new 20 mL of PBS buffer solution for continuous oscillation. The fluorescence intensity of the thus-taken dissolution medium was measured by fluorescence spectrophotometry (excitation wavelength: 488 nm, measurement wavelength: 591 nm, slit 10 nm), and the released amount of doxorubicin was determined from the calibration curve. The obtained result is shown in figure 4, the release of the drug from the carrier material has obvious pH dependence, the release is quicker when the pH is lower, the release amount is large, and the toxic and side effects of the drug can be effectively reduced.
Claims (2)
1. A preparation method of a graphene oxide-lipid nanocomposite material is characterized by comprising the following steps:
(1) dissolving graphene oxide in water to obtain a suspension, and performing water bath ultrasound to obtain a graphene oxide aqueous dispersion; the ultrasonic power is 250W-400W, the ultrasonic time is 0.5 h-2 h, and the ice water bath is carried out; the concentration of the graphene oxide aqueous dispersion is 0.2mg/mL-1 mg/mL;
(2) dissolving yolk phospholipid in chloroform, placing on a rotary evaporator, rotating to form a film to obtain liposome, dissolving in water-soluble phosphate buffer solution, rotating to make the film fall off, and performing ultrasonic treatment to obtain liposome dispersion; the mass ratio of the yolk phospholipids to the chloroform is 1: 75; the concentration of the liposome dispersion liquid is 35 mg/mL;
(3) mixing the graphene oxide aqueous dispersion liquid obtained in the step (1) and the liposome dispersion liquid obtained in the step (2), placing the mixture in a constant-temperature oscillator for stirring, centrifuging to obtain a precipitate, dissolving the precipitate with a water-soluble phosphate buffer solution, and performing ultrasonic treatment to obtain a graphene oxide-lipid nanocomposite; the mass ratio of the liposome to the graphene oxide is 1: 10-30.
2. The graphene oxide-lipid nanocomposite prepared by the method according to claim 1, wherein the nanocomposite takes nano-sized graphene oxide as an inner core, yolk phospholipids are synthesized into liposomes by a rotary evaporation method, and the liposomes are coated on the surface of a carrier by electrostatic adsorption; the composite material is applied to the control of drug release and the preparation of an anti-tumor drug carrier.
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