CN117138055A - Double-carrier doxorubicin drug-loaded nano material and preparation method thereof - Google Patents
Double-carrier doxorubicin drug-loaded nano material and preparation method thereof Download PDFInfo
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Classifications
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- 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
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- A—HUMAN NECESSITIES
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- 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
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61P35/00—Antineoplastic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The invention discloses a double-carrier doxorubicin drug-loaded nano material and a preparation method thereof, wherein the preparation method comprises the following steps: s1: weighing distearoyl phosphatidyl ethanolamine-polyethylene glycol and folic acid, completely dissolving in tetrahydrofuran, stirring at room temperature for 5min, then dripping high-purity water at the speed of 5s/d, and continuously stirring until the tetrahydrofuran is completely volatilized after the dripping is finished; s2: dissolving ZIF-8 in ethanol, uniformly mixing with the mixed solution obtained in the step S1, adding pure water, stirring for 6 hours, and collecting the obtained particles; s3: and (3) centrifugally purifying the particles collected in the step (S2) for 15min, adding the doxorubicin, placing the particles in a small light-resistant flask, stirring for 24 hours at room temperature, dialyzing, and freeze-drying to obtain the double-carrier doxorubicin drug-loaded nano material. The preparation method is simple in process, and the prepared doxorubicin drug-loaded nano material of the double carrier is small in particle size, strong in stability, good in dispersity, good in drug combination effect, and remarkable in cell inhibition effect in a cell experiment.
Description
Technical Field
The invention relates to the technical field of nano composite materials, in particular to a double-carrier doxorubicin drug-loaded nano material and a preparation method thereof.
Background
Doxorubicin (Doxorubicin) or Doxorubicin hydrochloride (Doxorubicin hydrochloride, DOX) is an antitumor antibiotic with the chemical formula C 27 H 29 NO 11 . Doxorubicin can inhibit synthesis of RNA and DNA, has the strongest inhibition effect on RNA, has a broad antitumor spectrum, has an effect on various tumors, belongs to a period nonspecific drug, has a killing effect on tumor cells in various growth periods, and is considered as the best drug in the current anthracycline anticancer drugs. DOX has serious side effects besides strong antitumor effect, and can generate bone marrow depression and myocardial toxicity reaction besides gastrointestinal tract reaction and alopecia, and can generate congestive heart failure in serious cases.
Polyethylene glycol (PEG) is widely used in biomedical fields because of its non-toxic, non-immunogenic and protein-resistant properties. PEG can make polymer micelle have invisible property, and avoid recognition and elimination by reticuloendothelial system (RES), thereby prolonging biological circulation time.
The zeolite imidazole skeleton 8 (ZIF-8) is composed of Zn 2+ And 2-methylimidazole (2-MIM) coordination. Because of the advantages of high porosity, degradation under low pH, good biocompatibility and the like, the modified polypropylene is widely used as a drug carrier. Polyethylene glycol (PEG) can be used as a mineralizer to synthesize ZIF-8NPs, which have higher stability and dispersibility in aqueous solutions.
Folic Acid (FA) -modified polymer nanoparticles are expected to deliver genes and drugs to FR-overexpressed cancer cells, enter tumor cells by endocytosis, and release therapeutic agents to achieve therapeutic effects.
The biggest problem in general cancer therapy is the inability to enrich drugs targeted to cancer cells, and thus the inability to minimize side effects. The nanometer biological material is the leading edge and hot spot research subject in the international biological engineering technical field, and the research in the application aspect of the medical field is still in the primary stage, but has wide application prospect. Since the preparation of the first Nanoparticle (NP) in the 70 s, nanotechnology has made tremendous progress in targeted therapy of malignant tumors. The nanoparticle is a drug-carrying particle with a diameter of 10-500nm, which is prepared by using natural polymer or synthetic chemical substances as carriers. Depending on the structure, nanospheres (nanospheres) and nanocapsules (nanocapsules) can be classified. Recently, with the continuous development of nano technology, nanoparticles are expected to be used for research of targeted drug release and synchronous tumor imaging. Nanoparticles between 10-100nm have longer in vivo circulation times compared to other small molecules due to their unique pharmacokinetic properties, i.e. the nanoparticles are not excreted by the kidneys in a short time nor are they significantly absorbed by the reticuloendothelial system in the liver and spleen. Furthermore, studies indicate that the tumor system is underdeveloped and that there are leaks, which allow nanoparticles smaller than 100nm in size to pass through the endothelial cell layer into the tumor lesion. The use of nanoparticles for drug delivery can improve the water solubility and bioavailability of hydrophobic drugs. Because the nano particles have larger surface area and various surface chemical characteristics, compared with other systems, the nano particles have more advantages in the aspect of simultaneously performing multifunctional application on tumor focus positions. In addition, the receptor targeting ligand highly expressed in tumor cells can be connected to the nano particles to directly deliver the drug to target organs, target cells or intracellular target structures, and meanwhile, the preparation method has the advantages of slow release, drug protection, improvement of curative effect, reduction of toxic and side effects and the like.
At present, the targeting drugs aiming at tumor cells are still in continuous research and development, and how to prepare the targeting drugs with better treatment effect, smaller volume and fewer toxic and side effects is still a research direction of continuous attention of related researchers.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a preparation method of a double-carrier doxorubicin drug-loaded nano material, which has the advantages of simple process, small particle size, strong stability and good dispersity, and can inhibit the cell effect in a cell experiment.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the invention provides a preparation method of a double-carrier doxorubicin drug-loaded nano material, which comprises the following steps:
s1: weighing distearoyl phosphatidyl ethanolamine-polyethylene glycol and folic acid, completely dissolving in tetrahydrofuran, stirring at room temperature for 5min, then dripping high-purity water at the speed of 5s/d, and continuously stirring until the tetrahydrofuran is completely volatilized after the dripping is finished;
s2: dissolving ZIF-8 in ethanol, uniformly mixing with the mixed solution obtained in the step S1, adding pure water, stirring for 6 hours, and collecting the obtained particles;
s3: and (3) centrifugally purifying the particles collected in the step (S2) for 15min, adding the doxorubicin, placing the particles in a small light-resistant flask, stirring for 24 hours at room temperature, dialyzing, and freeze-drying to obtain the double-carrier doxorubicin drug-loaded nano material.
Compared with the prior art, the preparation method disclosed by the invention has the advantages that the steps are simple, the operation is convenient, two carriers of distearoyl phosphatidylethanolamine-polyethylene glycol and ZIF-8 (zeolite imidazole skeleton 8) are adopted, folic acid is used for modification, and the ZIF-8+methyl-PEG2000-DSPE+FA+DOX nano medicine carrying material is creatively prepared, so that the stability of the material is greatly improved, and meanwhile, the possible toxic and side effects caused by a single carrier are avoided. The prepared double-carrier doxorubicin drug-loaded nano material has high stability, small particle size and good dispersibility, has obvious effect of inhibiting breast cancer cells in cell experiments, and has small toxic and side effects on normal cells.
Further, in step S1, the mass ratio of distearoyl phosphatidylethanolamine-polyethylene glycol to folic acid is 2:1.
Further, in steps S1 to S3, the stirring speed was 300r/min.
Further, in the step S2, the mass-volume ratio of ZIF-8 to ethanol is 1 mg/2 mL.
Further, in step S3, the centrifugal rotational speed is 7000rpm.
Further, the mass ratio of distearoyl phosphatidylethanolamine-polyethylene glycol, folic acid, ZIF-8 and doxorubicin is 10:5:75:2; the volume ratio of tetrahydrofuran to high-purity water to ethanol to pure water is 1:10:225:215.
The invention also provides the double-carrier doxorubicin drug-loaded nano material prepared by the preparation method.
Furthermore, the double-carrier doxorubicin drug-carrying nano material takes distearoyl phosphatidylethanolamine-polyethylene glycol and ZIF-8 as double carriers, and doxorubicin particles are uniformly distributed in the double-carrier doxorubicin drug-carrying nano material through folic acid modification.
Further, the particle size of the doxorubicin drug-loaded nano material of the double carrier is smaller than 50nm.
Compared with the prior art, the invention has the following beneficial effects:
(1) The prepared double-carrier doxorubicin drug-loaded nano material has the particle size reaching the drug-loaded standard, the particle diameter being smaller than 50nm, good particle dispersity and strong stability, has obvious cell inhibition effect on breast cancer cells in cell experiments, and has weak toxic and side effects on common cells. In addition, the innovative structure of the double carrier makes the double carrier hopefully carry a plurality of anticancer drugs at the same time, and has more advantages in the aspect of simultaneously performing multifunctional application on tumor focus positions.
(2) The preparation method disclosed by the invention is simple and convenient in steps, simple in related process, low in operation difficulty and beneficial to large-scale batch production.
Drawings
FIG. 1 is a schematic diagram of the synthesis principle of a double-carrier doxorubicin drug-loaded nanomaterial of the present invention;
FIG. 2 is a TEM image of ZIF-8+methyl-PEG2000-DSPE+FA+DOX nanomaterial prepared in example 1;
FIG. 3 is an SEM image of ZIF-8+methyl-PEG2000-DSPE+FA+DOX nanomaterial prepared in example 1;
FIG. 4 is a potential diagram of ZIF-8+methyl-PEG2000-DSPE+FA+DOX nanomaterial obtained in test example 1;
FIG. 5 is a bar graph (24 h) showing the cytotoxicity test results obtained in test example 2;
FIG. 6 is a bar graph (48 h) of the cytotoxicity test results obtained in test example 2;
FIG. 7 is a bar graph (24 h) showing the cytotoxicity test results obtained in test example 3;
FIG. 8 is a bar graph (48 h) of the cytotoxicity test results of test example 3;
FIG. 9 is a photograph showing a cell fluorescence test of test example 4;
fig. 10 is a migration test microscope image obtained in test example 5.
The invention will now be further described with reference to the drawings and specific examples.
Detailed Description
The purity and manufacturer of the raw materials and reagents used in the following examples are shown in table 1:
TABLE 1 purity of raw materials and reagents and manufacturer
The present invention is further illustrated by the following specific embodiments and the accompanying drawings, but the technical solution of the present invention is not limited to the specific embodiments.
EXAMPLE 1 preparation of double-Carrier Adriamycin drug-loaded nanomaterial
30mg of methyl-PEG2000-DSPE and 15mg of folic acid were weighed into a 50mL beaker, added with 2mL of THF to be completely dissolved and stirred at a speed of 300r/min at room temperature for 5min, then added with 20mL of high-purity water at a speed of 5s/d, and stirring was continued until THF was completely volatilized (24 h) after completion of the dropwise addition. 225mgZIF-8 was dissolved in 450mL of ethanol, mixed with the above solution, added with 430mL of pure water, stirred for 6 hours, collected particles, centrifuged at 7000rpm for purification for 15 minutes, added with 6mgDOX, stirred, placed in a small light-shielding flask, stirred at room temperature for 24 hours, dialyzed (molecular retention amount 7000, dialyzed against pure water for 3 days), and lyophilized (-80 ℃).
Referring to FIG. 1, the invention adopts Methyl-PEG2000-DSPE and ZIF-8 dual-carrier, folic Acid (FA) is used as a modifier, and is combined with Doxorubicin (DOX) drug through chemical reaction, so that the doxorubicin drug-loaded nano material ZIF-8+methyl-PEG2000-DSPE+FA+DOX of the dual-carrier is synthesized, and doxorubicin particles are uniformly distributed in the nano material.
Test example 1 characterization of double-carrier Adriamycin drug-loaded nanomaterial
Please refer to fig. 2, which is a TEM image of the ZIF-8+methyl-PEG2000-dspe+fa+dox prepared in example 1. As can be seen from the figure, the prepared ZIF-8+methyl-PEG2000-DSPE+FA+DOX particles are relatively uniform in dispersion degree, small in particle size and smaller than 50nm. FIG. 3 is a SEM image of ZIF-8+methyl-PEG2000-DSPE+FA+DOX obtained in example 1, and it can be seen from the image that the prepared ZIF-8+methyl-PEG2000-DSPE+FA+DOX has good dispersibility.
In order to obtain more accurate particle size distribution and potential data, a Nano-particle size potentiometer (Nano-ZS) is used for detecting the particle size and potential of the drug-loaded Nano-material of the double carrier.
TABLE 2ZIF-8+methyl-PEG2000-DSPE+FA+DOX particle size distribution Table
As shown in Table 2, the particle sizes of ZIF-8+methyl-PEG2000-DSPE+FA+DOX are all smaller than 50nm, and the average particle size is 29.14nm, so that the drug loading standard of the nano material is achieved.
The potential test results of ZIF-8+methyl-PEG2000-DSPE+FA+DOX materials are shown in FIG. 4, and it can be seen that the materials are negatively charged, while the cell surfaces are positively charged, thus facilitating the binding of the nanomaterials to the cells. Meanwhile, the stability of the nano material is better as can be seen from the potential value.
Test example 2 determination of toxicity of double-carrier Adriamycin drug-loaded nanomaterial to MAD-MB-231 cells
Determination of DSPE-PEG2000 (CCK-8; model Co.: melam) Using a cell counting kit 100. Mu.LMAD-MB-231 cell suspension (8X 10) 4 cells/mL) were inoculated in 96-well plates, cultured with ZIF-8+methyl-PEG2000-DSPE+FA+DOX at various concentrations at 37℃for 24h, 48h, respectively, and CCK-8 reagent (10. Mu.L) was added to each well, and the resulting mixtures were cultured at 37℃for 1h, respectively. The absorbance of the mixture at 450nm was recorded and cell viability was counted. The same concentration (based on doxorubicin content) of the doxorubicin pure drug group was set at the same time for control.
As shown in fig. 5 and 6, it can be seen that the inhibition effect of the ZIF-8+methyl-PEG2000-dspe+fa+dox material with different concentrations on cells is stronger than that of the doxorubicin pure drug with the same concentration at 24h, and the inhibition effect is larger than that of the doxorubicin pure drug with the same concentration. And at 48h, besides the strong inhibition effect of the pure doxorubicin drug to cells at low concentration (7.8125 mug/mL), the inhibition effect of the ZIF-8+methyl-PEG2000-DSPE+FA+DOX material to MAD-MB-231 cells is obviously enhanced along with the increase of the concentration, and the inhibition effect is far more than that of the pure doxorubicin drug at high concentration.
Test example 3 determination of toxicity of double-carrier doxorubicin-loaded nanomaterial to Hacat cells (keratinocytes)
Determination of DSPE-PEG2000 (CCK-8; model Co.: melam) Using a cell counting kit, 100. Mu.L of Hacat cell suspension (8X 10) 4 cells/mL) were inoculated in 96-well plates, cultured with ZIF-8+methyl-PEG2000-DSPE+FA+DOX at various concentrations at 37℃for 24h, 48h, respectively, and CCK-8 reagent (10. Mu.L) was added to each well, and the resulting mixtures were cultured at 37℃for 1h, respectively. The absorbance of the mixture at 450nm was recorded and cell viability was counted. The same concentration (based on doxorubicin content) of the doxorubicin pure drug group was set at the same time for control.
As shown in fig. 7 and 8, it can be seen that the inhibition effect of the ZIF-8+methyl-PEG2000-dspe+fa+dox material with different concentrations on Hacat cells is weaker than that of the pure doxorubicin with the same concentration, and thus the ZIF-8+methyl-PEG2000-dspe+fa+dox material has weaker toxicity on normal cells and better safety compared with the pure doxorubicin.
Test example 4 fluorescence test of double-carrier doxorubicin drug-loaded nanomaterial on MAD-MB-231 cells
Fluorescence testing was performed using the following steps:
on the first day, 30 ten thousand/well (6-well plate) MDA-MB-231 was plated
The next day, ZIF-8+methyl-PEG2000-DSPE+FA+DOX (50 μg/mL) (material group) was dosed; blank groups (no drug addition) were set at the same time; 24h;
on the third day, the medium was aspirated (original medium was retained), the pbs was washed 2-3 times, fixed for 30min with 4% paraformaldehyde (meilunbio), washed 2-3 times, diluted with pbs 0.25% Triton-x 10min (aladin), washed 2-3 times, and mixed 1: DAPI (10 mg/mL) was diluted 1000, added to the cell culture medium, cells were cultured at 37℃for 10-20min, and the resulting mixture was washed 2 times with pbs, and observed under a fluorescence microscope (Olympus, international trade company for Gene Biotechnology) at an excitation wavelength of 360-400nm.
As shown in fig. 9, where fig. (a) is a blank set bright-field fluorescent chart, fig. (b) is a blank set DAPI fluorescent chart, fig. (c) is a material set bright-field fluorescent chart, and fig. (d) is a material set DAPI fluorescent chart. From the figure, the material group is rounded and has larger cell nucleus than the blank group, because ZIF-8+methyl-PEG2000-DSPE+FA+DOX nano material enters the cell nucleus of MAD-MB-231 cells, so that apoptosis is promoted, and the cell nucleus is broken, so that the cell is rounded.
Test example 5 migration experiment of double-carrier doxorubicin drug-loaded nanomaterial on MAD-MB-231 cells
The migration experiment was further performed using the following method: the method comprises the following specific steps:
6 well plates 35 ten thousand/well MAD-MB-231 cells were plated on the first day;
the following day: scratching with a white gun head, washing with PBS buffer solution for 2-3 times, adding 1% serum, and then adding ZIF-8+methyl-PEG2000-DSPE+FA+DOX at concentrations of 15 μg/mL and 30 μg/mL respectively; in a grown monolayer of cells (HaCaT), the blank areas are created artificially, and the cells will automatically migrate to the blank areas. The scratch width was measured at different time points (0, 24, 48, 72 h) after the scratch and the cell migration efficiencies were compared. Photographs were taken with a microscope at different time points (0, 24, 48, 72 h), respectively, the area of the blank area was measured, and the mobility was calculated. A blank group (ZIF-8+methyl-PEG 2000-DSPE+FA+DOX was not added the next day) was set at the same time, and the migration experiment was performed by the same method, and the three groups of data were compared. The results are shown in Table 3 and FIG. 10.
TABLE 3 cell migration test data sheet
As can be seen from table 3 and fig. 10, the blank group was completely filled after 72h of scratch, whereas the material group was remarkable in the cell migration inhibition efficiency, and the inhibition effect was remarkable at higher concentrations.
Test example 6 double-carrier doxorubicin drug-loading nanomaterial drug-loading rate test
The ZIF-8+methyl-PEG2000-DSPE+FA+DOX prepared in example 1 was subjected to drug loading rate test by high performance liquid chromatography, and experimental conditions were:
instrument: shimadzu LC-20AD
Chromatographic column: ultimate XB-C18.6 x 100mm 5um
Flow rate: 1.0ml/min
Column temperature: 35
Detection wavelength: 222nm
Sample injection amount: 5ul
Mobile phase: 10mM sodium acetate pH 3.40-methanol=40-60
Sample configuration:
control solution: precisely weighing reference substance, adding methanol, dissolving, diluting to various concentrations, and looking up in EXCEL table
Sample solution: accurately weighing 2.00mg of the sample, adding 1.0ml of water, performing ultrasonic treatment for 15min, shaking, and passing through a membrane.
TABLE 4ZIF-8+methyl-PEG2000-DSPE+FA+DOX drug loading rate data table
Through testing, the drug loading rate of ZIF-8+methyl-PEG2000-DSPE+FA+DOX is 0.05891%. Although the drug loading rate is lower, as can be seen from the previous test examples, the drug loading nano material has a remarkable inhibition effect on tumor cells, has obviously weaker toxic and side effects on normal cells than that of pure doxorubicin, has stronger safety, and is favorable for being applied to targeted treatment of tumors.
Compared with the prior art, the preparation method disclosed by the invention has the advantages of simple steps and convenience in operation, adopts two carriers of METHYL-PEG2000-DSPE and ZIF-8 (zeolite imidazole skeleton 8) and is modified by folic acid, and the prepared double-carrier doxorubicin drug-loaded nano material has the advantages of high stability, small particle size and good dispersibility, has an obvious effect of inhibiting breast cancer cells in cell experiments, and has low toxic and side effects on normal cells.
The present invention is not limited to the above-described embodiments, but it is intended that the present invention also includes modifications and variations if they fall within the scope of the claims and the equivalents thereof, if they do not depart from the spirit and scope of the present invention.
Claims (9)
1. The preparation method of the double-carrier doxorubicin drug-loaded nano material is characterized by comprising the following steps of:
s1: weighing distearoyl phosphatidyl ethanolamine-polyethylene glycol and folic acid, completely dissolving in tetrahydrofuran, stirring at room temperature for 5min, then dripping high-purity water at the speed of 5s/d, and continuously stirring until the tetrahydrofuran is completely volatilized after the dripping is finished;
s2: dissolving ZIF-8 in ethanol, uniformly mixing with the mixed solution obtained in the step S1, adding pure water, stirring for 6 hours, and collecting the obtained particles;
s3: and (3) centrifugally purifying the particles collected in the step (S2) for 15min, adding the doxorubicin, placing the particles in a small light-resistant flask, stirring for 24 hours at room temperature, dialyzing, and freeze-drying to obtain the double-carrier doxorubicin drug-loaded nano material.
2. The method for preparing the double-carrier doxorubicin drug-loaded nanomaterial according to claim 1, characterized by comprising the following steps: in the step S1, the mass ratio of the distearoyl phosphatidyl ethanolamine-polyethylene glycol to folic acid is 2:1.
3. The method for preparing the double-carrier doxorubicin drug-loaded nanomaterial according to claim 1, characterized by comprising the following steps: in the steps S1 to S3, the stirring speed was 300r/min.
4. The method for preparing the double-carrier doxorubicin drug-loaded nanomaterial according to claim 2, characterized in that: in the step S2, the mass-volume ratio of ZIF-8 to ethanol is 1 mg/2 mL.
5. The method for preparing the double-carrier doxorubicin drug-loaded nanomaterial according to claim 1, characterized by comprising the following steps: in step S3, the centrifugal rotational speed was 7000rpm.
6. The method for preparing the double-carrier doxorubicin drug-loaded nanomaterial according to claim 4, characterized in that: the mass ratio of distearoyl phosphatidylethanolamine-polyethylene glycol, folic acid, ZIF-8 and doxorubicin is 10:5:75:2; the volume ratio of tetrahydrofuran to high-purity water to ethanol to pure water is 1:10:225:215.
7. A dual-carrier doxorubicin-loaded nanomaterial made according to the method of any one of claims 1-6.
8. The dual-carrier doxorubicin-loaded nanomaterial of claim 7, wherein: distearoyl phosphatidylethanolamine-polyethylene glycol and ZIF-8 are used as double carriers, and through folic acid modification, doxorubicin particles are uniformly distributed in the doxorubicin drug-carrying nano-materials of the double carriers.
9. The dual-carrier doxorubicin-loaded nanomaterial of claim 7, wherein: the particle size of the doxorubicin drug-loaded nano material of the double carrier is smaller than 50nm.
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