CN117338722A - Graphene quantum dot liposome for treating liver fibrosis and preparation method thereof - Google Patents
Graphene quantum dot liposome for treating liver fibrosis and preparation method thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims abstract description 46
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1277—Preparation processes; Proliposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/44—Elemental carbon, e.g. charcoal, carbon black
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Abstract
The invention discloses a graphene quantum dot liposome for treating hepatic fibrosis and a preparation method thereof, wherein the graphene quantum dot liposome comprises a graphene quantum dot solution, distearoyl phosphatidylcholine and polyethylene glycol phospholipid, wherein the graphene quantum dot solution is used as an anti-hepatic fibrosis drug effect component, and distearoyl phosphatidylcholine is used as a carrier material; polyethylene glycol phospholipid is used as a membrane modifier, a lipid membrane is formed by the polyethylene glycol phospholipid and distearoyl phosphatidylcholine, and the graphene quantum dots are loaded in the lipid membrane to form graphene quantum dot liposome. According to the graphene quantum dot liposome disclosed by the invention, according to the characteristic that nanoparticles are enriched in the liver in vivo, graphene quantum dots are wrapped in lipid nanoparticles, so that the problem of poor liver targeting is solved, the biological safety is ensured, and the aim of enhancing the effect of treating liver fibrosis is fulfilled.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a graphene quantum dot liposome for treating hepatic fibrosis and a preparation method thereof.
Background
Chronic liver diseases such as viral hepatitis, alcoholic liver, fatty liver, etc. can cause liver fibrosis, for example, about 3-6% of patients per year can develop cirrhosis without receiving correct anti-fibrosis treatment. These patients have repeated disease conditions and very poor prognosis. Recent researches show that the graphene quantum dots can relieve liver injury. However, the graphene quantum dots have smaller particle size, are easy to discharge through kidneys, have poor liver targeting, and limit the effect of treating liver fibrosis.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the related art to some extent. Therefore, the invention aims to provide a graphene quantum dot liposome for treating liver fibrosis and a preparation method thereof.
To achieve the above object, according to a first aspect of the present invention, there is provided a graphene quantum dot liposome for treating liver fibrosis, comprising:
the graphene quantum dot solution is used as an anti-hepatic fibrosis drug effect component;
distearoyl phosphatidylcholine as a carrier material;
polyethylene glycol phospholipid is used as a membrane modifier, a lipid membrane is formed by the polyethylene glycol phospholipid and distearoyl phosphatidylcholine, and the graphene quantum dots are loaded in the lipid membrane to form graphene quantum dot liposome.
According to one embodiment of the invention, the volume ratio of the graphene quantum dot solution to the distearoyl phosphatidyl choline to the polyethylene glycol phospholipid is 1:80-120: 20 to 50.
According to one embodiment of the invention, the graphene quantum dot solution comprises a PBS buffer solution and graphene quantum dots added into the PBS buffer solution, wherein the graphene quantum dots added into the PBS buffer solution are 0.8-1.5 mg per 1. 1m l.
According to one embodiment of the invention, the solubility of the distearoyl phosphatidylcholine is 15-25 mg/ml, and the concentration of the polyethylene glycol phospholipid is 20-30 mg/ml.
According to one embodiment of the invention, the lipid membrane is a bilayer lipid membrane.
According to a second aspect of the present invention, the preparation method of the graphene quantum dot liposome provided by the present invention includes:
preparing a graphene quantum solution, wherein 0.8-1.5 mg of graphene quantum dots are added into 1ml of PBS buffer solution;
preparing distearoyl phosphatidylcholine solution with the concentration of 5-25 mg/ml and polyethylene glycol phosphatidylcholine solution with the concentration of 20-30 mg/ml for standby;
according to the volume ratio of distearoyl phosphatidylcholine to polyethylene glycol phospholipid of 80-120: 20-50, adding distearoyl phosphatidylcholine solution and polyethylene glycol phosphatidylcholine solution into a test tube;
drying the organic solvent in the test tube, and vacuumizing the test tube after drying;
after the vacuumizing is finished, adding a graphene quantum solution into the test tube, wherein the volume ratio of the graphene quantum dot solution to distearoyl phosphatidylcholine is 1:80-120, sealing the tube orifice of the test tube by using a sealing film, and performing ultrasonic hydration by using ultrasonic equipment until the material in the test tube is completely suspended in PBS buffer.
According to one embodiment of the present invention, further comprising: after ultrasonic hydration, graphene quantum dots not encapsulated within lipid nanoparticles were filtered out using an ultrafiltration tube.
According to one embodiment of the present invention, configuring a distearoyl phosphatidylcholine solution and a polyethylene glycol phospholipid solution includes:
weighing a certain amount of distearoyl phosphatidylcholine and polyethylene glycol phospholipid powder;
distearoyl phosphatidylcholine and polyethylene glycol phospholipid powder were dissolved by chloroform, respectively.
According to one embodiment of the present invention, the drying the organic solvent in the test tube, and vacuumizing the test tube after drying includes:
firstly transferring the test tube to a ventilation kitchen, blowing the organic solvent in the test tube by using nitrogen gas flow until the test tube is dried, transferring the dried test tube to a vacuum bottle, and vacuumizing the vacuum bottle for 1.5 to 3 hours by using vacuum equipment.
According to the technical scheme, according to the graphene quantum dot liposome disclosed by the invention, according to the characteristic that nanoparticles are enriched in the liver in vivo, graphene quantum dots are wrapped in lipid nanoparticles, so that the problem of poor liver targeting is solved, the biological safety is ensured, and the aim of enhancing the effect of treating liver fibrosis is fulfilled.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Drawings
FIG. 1 is a schematic diagram of a graphene quantum dot liposome of the present invention;
FIG. 2 is a diagram showing structural characterization of graphene quantum dot liposomes under Transmission Electron Microscopy (TEM) and dynamic light scattering;
FIG. 3 is a graph showing the comparative effect of the graphene quantum dot liposome of the present invention in experimental treatment of liver fibrosis;
FIG. 4 is a graph showing the results of the serum collection test related index according to the present invention.
Detailed Description
The following describes specific embodiments of the present invention in detail. It should be understood that the detailed description and specific examples, while indicating and illustrating the invention, are not intended to limit the invention.
The invention provides a lipid nanoparticle drug delivery system for better playing the anti-hepatic fibrosis role of graphene quantum dots. According to the characteristic that the nanoparticles are enriched in the liver in vivo, the graphene quantum dots are wrapped in the lipid nanoparticles, so that the problem of poor liver targeting is solved, the biosafety is ensured, and the aim of enhancing the effect of treating liver fibrosis is fulfilled.
The invention provides a graphene quantum dot liposome for treating liver fibrosis, which comprises a graphene quantum dot solution, distearoyl phosphatidylcholine and polyethylene glycol phospholipid.
Specifically, the graphene quantum dot solution is used as an anti-hepatic fibrosis drug effect component. Graphene Quantum Dots (GQDs) are carbon-based nanoparticles with excellent chemical, physical and biological properties, and have also been used in nanomedicine. The unique electronic structure of GQD imparts powerful and tunable Photoluminescence (PL) functions to these nanomaterials for fluorescent bioimaging and biosensing, small molecule drug delivery of high loading capacity aromatic compounds, the ability to absorb incident radiation, and for photothermal and photodynamic therapy cancer killing therapies.
Distearoyl phosphatidylcholine (DSPC) as a carrier material. Distearoyl phosphatidylcholine is a synthetic phospholipid which is widely used in the field. The tail group of DSPC is saturated alkane chain with melting point of-54 deg.C, and forms a layer structure in the lipid nanoparticle, so that the lipid nanoparticle has more stable structure.
Polyethylene glycol phospholipid (DSPE-PEG 2000) is used as a membrane modifier, a lipid membrane is formed by the polyethylene glycol phospholipid and the distearoyl phosphatidylcholine, and the graphene quantum dots are loaded in the lipid membrane to form graphene quantum dot liposome. Preferably, the lipid membrane is a bilayer lipid membrane.
DSPE-PEG2000 is a PEGylated phospholipid, the PEGylated phospholipid has multiple effects on the characteristics of lipid nanoparticles, the dosage of the PEGylated phospholipid affects the particle size and the potential of the lipid nanoparticles, particle aggregation is reduced, the stability of the lipid nanoparticles is improved, the circulation time of the particles is prolonged, the functional groups on the surface can be modified by ligands, and the targeted delivery capacity is improved. DSG-PEG2000 is neutral phospholipid, has long saturated alkyl chain length, is separated from lipid nanoparticles more quickly, is favorable for the uptake and endosome escape of the nanoparticles by cells, and has high delivery efficiency.
Preferably, the volume ratio of the graphene quantum dot solution, distearoyl phosphatidylcholine and polyethylene glycol phospholipid is 1:80-120: 20 to 50. The solubility of distearoyl phosphatidylcholine is 15-25 mg/ml, and the concentration of polyethylene glycol phosphatide is 20-30 mg/ml. The use amount of distearoyl phosphatidylcholine and polyethylene glycol phosphatide affects the characteristics of lipid nanoparticles, and the adoption of the volume ratio and the solubility can ensure that the graphene quantum dot liposome has good targeted delivery capacity and efficiency.
In one embodiment of the invention, the graphene quantum dot solution comprises PBS buffer solution and graphene quantum dots added into the PBS buffer solution, wherein the graphene quantum dots added into each 1ml of PBS buffer solution are 0.8-1.5 mg.
In the embodiment, the graphene quantum dots are added into the PBS buffer solution to prepare graphene quantum dot solution, the PBS buffer solution has proper pH buffering effect with balanced and adjustable salt, the structure and biological characteristics of biological protein are not damaged, the pH value is balanced, the complete characteristics of the graphene quantum dots, distearoyl phosphatidylcholine and polyethylene glycol phosphatide can be ensured, and high-quality liposome nano particles are prepared by an ultrasonic film dispersion method.
The invention also provides a preparation method of the graphene quantum dot liposome, which comprises the following steps:
1) Preparing graphene quantum solution, wherein 0.8-1.5 mg of graphene quantum dots are added into each 1ml of PBS buffer solution.
2) Preparing distearoyl phosphatidylcholine solution with the concentration of 5-25 mg/ml and polyethylene glycol phosphatidylcholine solution with the concentration of 20-30 mg/ml for standby. Specifically, a certain amount of distearoyl phosphatidylcholine and polyethylene glycol phospholipid powder are weighed first; and dissolving distearoyl phosphatidylcholine and polyethylene glycol phospholipid powder respectively by chloroform.
3) According to the volume ratio of distearoyl phosphatidylcholine to polyethylene glycol phospholipid of 80-120: 20-50, adding distearoyl phosphatidylcholine solution and polyethylene glycol phosphatidylcholine solution into a test tube.
4) Drying the organic solvent in the test tube, and vacuumizing the test tube after drying. Specifically, the test tube is firstly transferred to a ventilation kitchen, the organic solvent in the test tube is blown by nitrogen flow until the test tube is dried, the dried test tube is transferred to a vacuum bottle, and the vacuum bottle is vacuumized for 1.5 to 3 hours by utilizing vacuum equipment.
5) After the vacuumizing is finished, adding a graphene quantum solution into the test tube, wherein the volume ratio of the graphene quantum dot solution to distearoyl phosphatidylcholine is 1:80-120, sealing the tube orifice of the test tube by using a sealing film, and performing ultrasonic hydration by using ultrasonic equipment until the material in the test tube is completely suspended in PBS buffer.
6) After ultrasonic hydration, graphene quantum dots not encapsulated within lipid nanoparticles were filtered out using an ultrafiltration tube.
According to the technical scheme, according to the graphene quantum dot liposome disclosed by the invention, according to the characteristic that nanoparticles are enriched in the liver in vivo, graphene quantum dots are wrapped in lipid nanoparticles, so that the problem of poor liver targeting is solved, the biological safety is ensured, and the aim of enhancing the effect of treating liver fibrosis is fulfilled.
Examples
1. Preparation of graphene quantum dot solution (GQD solution) and graphene quantum dot liposome solution (gqd@l I PO):
1) Graphene quantum dot solution (GQD solution)
Graphene quantum solution is prepared by adding 1.0mg of graphene quantum dots into 1ml of PBS buffer solution.
2) Graphene quantum dot liposome solution (GQD@LiPO)
A quantity of distearoyl phosphatidylcholine (DSPC) and polyethylene glycol phospholipid (DSPE-PEG 2000) powders were precisely weighed, and DSPC and DSPE-PEG2000 powders were dissolved in chloroform in a 1.5 ml EP tube, respectively, and sonicated with an ultrasonic cleaner for 3 min.
DSPC concentration is 20.63mg/m l and DSPE-PEG2000 concentration is 26.33mg/ml for standby. Several sterilized glass test tubes were placed in a test tube rack, and 104.3ml of the prepared DSPC chloroform solution and 32.2ml of the prepared DSPE-PEG2000 chloroform solution were added to each test tube.
The test tube was rapidly transferred to a fume hood and nitrogen was adjusted to a small air flow to blow the organic solvent in the test tube until blow-dried for about 1 hour. And transferring the blow-dried test tube into a vacuum bottle, and connecting a vacuum pump to vacuum for about 2 hours. After the evacuation, the test tube was taken out and subjected to a hydration step, and 1ml of Graphene Quantum Dot (GQD) solution (1 mg GQD/ml PBS) was added for hydration. The mouth of the tube is sealed by a sealing film, the test tube is not shaken, the test tube added with PBS is placed in a 60 DEG ultrasonic cleaner which is heated in advance for ultrasonic hydration until the material is completely suspended in PBS buffer solution, and the tube bottom of the test tube has no obvious residue, about 5 min. Graphene Quantum Dots (GQDs) not encapsulated within lipid nanoparticles are filtered out using ultrafiltration tubing.
2. Graphene quantum dot liposome characterization
As shown in FIG. 2, the transmission electron microscope observation shows a spherical structure (shown as A), and the particle size of GQD@LIPO detected by a dynamic light scattering instrument is about 150nm (shown as B).
3. Liver fibrosis mouse model treatment experiment
In the liver fibrosis mouse model treatment experiments, a control group (liver is normal), a model group (liver fibrosis), and a GQD@LIPO group. Wherein, GQD@LIPO group adopts graphene quantum dot liposome solution (GQD@LIPO solution) to administer, specifically, 2 g GQD@LIPO/kg body weight is administered for 2 times per week for 2 weeks.
After 2 weeks of treatment, liver tissue sections were stained with masson. HE staining of liver tissue sections showed that the liver fibrosis model group had a large number of inflammatory factor invasion (arrow position in FIG. 3), and that the GQD@LiPO group inflammatory factor was not apparent. Masson staining analysis showed a significant decrease in gqd@li PO group fibrotic tissue, indicating that gqd@l I PO has a therapeutic effect on liver fibrosis, as shown in fig. 3.
The serum collection assay-related index showed that gqd@lipo restored liver function to some extent while reducing inflammatory response accompanying liver fibrosis, as shown in fig. 4.
The invention shows that using a lipid nanoparticle drug delivery system to deliver graphene quantum dots, with a 2-week co-treatment regimen for 2 weeks, would reduce the extent of liver fibrosis.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Moreover, any combination of the various embodiments of the invention can be made without departing from the spirit of the invention, which should also be considered as disclosed herein.
Claims (9)
1. A graphene quantum dot liposome for treating liver fibrosis, comprising:
the graphene quantum dot solution is used as an anti-hepatic fibrosis drug effect component;
distearoyl phosphatidylcholine as a carrier material;
polyethylene glycol phospholipid is used as a membrane modifier, a lipid membrane is formed by the polyethylene glycol phospholipid and distearoyl phosphatidylcholine, and the graphene quantum dots are loaded in the lipid membrane to form graphene quantum dot liposome.
2. The graphene quantum dot liposome for treating hepatic fibrosis according to claim 1, wherein the volume ratio of the graphene quantum dot solution, distearoyl phosphatidylcholine, polyethylene glycol phospholipid is 1:80-120: 20 to 50.
3. The graphene quantum dot liposome for treating liver fibrosis according to claim 1, wherein the graphene quantum dot solution comprises a PBS buffer and graphene quantum dots added to the PBS buffer, wherein the graphene quantum dots added to each 1ml of the PBS buffer are 0.8-1.5 mg.
4. The graphene quantum dot liposome for treating hepatic fibrosis according to claim 1, wherein the solubility of distearoyl phosphatidylcholine is 15-25 mg/ml and the concentration of polyethylene glycol phospholipid is 20-30 mg/ml.
5. The graphene quantum dot liposome for treating liver fibrosis according to claim 1, wherein the lipid membrane is a bilayer lipid membrane.
6. The preparation method of the graphene quantum dot liposome is characterized by comprising the following steps of:
preparing a graphene quantum solution, wherein 0.8-1.5 mg of graphene quantum dots are added into each 1ml of PBS buffer solution;
preparing distearoyl phosphatidylcholine solution with the concentration of 5-25 mg/ml and polyethylene glycol phosphatidylcholine solution with the concentration of 20-30 mg/ml for standby;
according to the volume ratio of distearoyl phosphatidylcholine to polyethylene glycol phospholipid of 80-120: 20-50, adding distearoyl phosphatidylcholine solution and polyethylene glycol phosphatidylcholine solution into a test tube;
drying the organic solvent in the test tube, and vacuumizing the test tube after drying;
after the vacuumizing is finished, adding a graphene quantum solution into the test tube, wherein the volume ratio of the graphene quantum dot solution to distearoyl phosphatidylcholine is 1:80-120, sealing the tube orifice of the test tube by using a sealing film, and performing ultrasonic hydration by using ultrasonic equipment until the material in the test tube is completely suspended in PBS buffer.
7. The method for preparing graphene quantum dot liposome according to claim 6, further comprising: after ultrasonic hydration, graphene quantum dots not encapsulated within lipid nanoparticles were filtered out using an ultrafiltration tube.
8. The method of preparing graphene quantum dot liposomes according to claim 6, wherein preparing distearoyl phosphatidylcholine solution and polyethylene glycol phospholipid solution comprises:
weighing a certain amount of distearoyl phosphatidylcholine and polyethylene glycol phospholipid powder;
distearoyl phosphatidylcholine and polyethylene glycol phospholipid powder were dissolved by chloroform, respectively.
9. The method for preparing graphene quantum dot liposome according to claim 6, wherein drying the organic solvent in the test tube, and vacuumizing the test tube after drying comprises:
firstly transferring the test tube to a ventilation kitchen, blowing the organic solvent in the test tube by using nitrogen gas flow until the test tube is dried, transferring the dried test tube to a vacuum bottle, and vacuumizing the vacuum bottle for 1.5 to 3 hours by using vacuum equipment.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5013556A (en) * | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
| CN111500284A (en) * | 2020-05-13 | 2020-08-07 | 暨南大学 | A kind of nanoliposome encapsulating graphene quantum dots and its preparation and its application in the detection of biological enzyme activity |
| CN112618570A (en) * | 2020-01-07 | 2021-04-09 | 武汉大学 | Preparation method of graphene quantum dots and application of graphene quantum dots in preparation of medicine for treating non-alcoholic fatty liver disease |
-
2023
- 2023-02-27 CN CN202310170504.7A patent/CN117338722A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5013556A (en) * | 1989-10-20 | 1991-05-07 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
| CN112618570A (en) * | 2020-01-07 | 2021-04-09 | 武汉大学 | Preparation method of graphene quantum dots and application of graphene quantum dots in preparation of medicine for treating non-alcoholic fatty liver disease |
| CN111500284A (en) * | 2020-05-13 | 2020-08-07 | 暨南大学 | A kind of nanoliposome encapsulating graphene quantum dots and its preparation and its application in the detection of biological enzyme activity |
Non-Patent Citations (1)
| Title |
|---|
| GABRIELE BLUME AND GREGOR CEVC: "Liposomes for the sustained drug release in vivo", BIOCHIMICA ET BIOPHYSICA ACTA, 31 December 1990 (1990-12-31), pages 91 - 97 * |
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