CN113476424A - Composite nano-medicine and preparation method and application thereof - Google Patents
Composite nano-medicine and preparation method and application thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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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
- A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
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- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
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Abstract
The invention discloses a composite nano-drug and a preparation method and application thereof, wherein the composite nano-drug adopts a metal organic framework material MIL-101(Fe) is used as a carrier, a biological reduction tumor sensitizing drug is loaded, and phospholipid-polyethylene glycol-folic acid is coated on the surface of MIL-101 (Fe). The phospholipid-polyethylene glycol-folic acid ligand modified on the surface of the composite nano-drug can specifically target the surface of tumor cells rich in folic acid receptors, so that the tumor cells have tumor targeting property. Moreover, the phospholipid-polyethylene glycol-folic acid ligand modified on the surface of the composite nano-drug can also increase the biocompatibility of the composite nano-drug. The composite nano-drug can be decomposed in a slightly acidic environment inside a tumor to respectively release Fe3+And biological reduction tumor sensitizing drugs, which play the drug effect in tumor hypoxia environment and relieve tumor hypoxia condition. Moreover, the composite nano-drug is safe, nontoxic, friendly to biology and has high potential application value in tumor treatment.
Description
Technical Field
The invention relates to the field of nano biomedicine, in particular to a composite nano medicament and a preparation method and application thereof.
Background
Metal Organic Framework (MOF) has advantages of large specific surface area, adjustable porous structure, etc., and thus is widely used in the fields of industrial and scientific research, such as gas storage and separation, photocatalysis, seawater cleaning and treatment, nano medicine, etc. MOF materials are generally highly porous materials composed of metal ions and their organic ligands, thus providing many opportunities for biological applications. In particular as metallic iron ions (Fe)3+) Copper ion (Cu)2+) MOF materials, which are active centers, have coordination environments that mimic the catalytic centers of natural enzymes, and these MOF materials have characteristics of biological enzymes, and are therefore called nanoenzymes. More importantly, in the field of tumor treatment, the nano-enzymes can be degraded in the slightly acidic environment of tumors, and the nano-enzymes are very beneficial to nano-drug delivery in the field of tumor treatment. And, degraded Fe3+、Cu2+Ionic, tumor-high hydrogen peroxide (H)2O2) And Glutathione (GSH) to generate free radicals such as active oxygen, thereby further killing tumor cells.
Research shows that the tumor cells have the characteristics of high pressure, reducibility and lack of oxygen inside the tumor due to massive proliferation, excessive nutrient metabolism, malformation of vascular development and the like. Moreover, hypoxic conditions of tumors further lead to tumor tolerance to chemotherapy, radiotherapy and immunotherapy, affecting the tumor treatment effect.
Therefore, designing a drug which can overcome tumor hypoxia microenvironment and exert drug effect in tumor hypoxia environment is a potential problem to be solved.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a composite nano-drug, which adopts a metal organic framework material MIL-101(Fe) as a carrier, loads a bioreductive tumor sensitizing drug, and coats phospholipid-polyethylene glycol-folic acid (DSPE-mPEG-FA) on the surface of the MIL-101(Fe), and aims to solve the problem that the tumor microenvironment is anoxic so as to be resistant to other treatment means such as chemotherapy, radiotherapy, immunotherapy and the like in the prior art.
The technical scheme of the invention is as follows:
a preparation method of a composite nano-drug comprises the following steps:
preparing an MIL-101(Fe) nano material;
loading a tumor sensitizing drug on the MIL-101(Fe) nano material to prepare the MIL-101(Fe) nano drug;
and coating phospholipid-polyethylene glycol-folic acid on the surface of the MIL-101(Fe) nano-medicament to obtain the composite nano-medicament.
The preparation method of the composite nano-drug is characterized in that the tumor sensitizing drug is AQ 4N.
The preparation method of the composite nano-drug comprises the following steps of:
providing ferric trichloride and terephthalic acid;
dissolving the ferric trichloride and the terephthalic acid in dimethylformamide;
and (3) reacting in a high-pressure reaction kettle to obtain the MIL-101(Fe) nano material.
The preparation method of the composite nano-drug comprises the step of mixing ferric trichloride and terephthalic acid in a molar ratio of 2: 1.
The preparation method of the composite nano-drug comprises the following steps of loading the tumor sensitizing drug on the MIL-101(Fe) nano-material to prepare the MIL-101(Fe) nano-drug:
adding the tumor sensitizing drug into a 2- (N-morpholine) ethanesulfonic acid buffer solution for full dissolution to prepare a tumor sensitizing drug solution;
and adding the MIL-101(Fe) nano material into the tumor sensitizing drug solution, and stirring for 10 hours in a dark place to prepare the MIL-101(Fe) nano drug.
The preparation method of the composite nano-drug comprises the following steps of coating phospholipid-polyethylene glycol-folic acid on the surface of the MIL-101(Fe) nano-drug to prepare the composite nano-drug:
and (3) providing phospholipid-polyethylene glycol-folic acid, dissolving in water, adding the MIL-101(Fe) nano-drug, stirring in the dark for 24 hours for reaction, and dispersing the product in a phosphate buffer solution to obtain the composite nano-drug.
A composite nano-drug comprises a tumor sensitizing drug, an MIL-101(Fe) nano-material and phospholipid-polyethylene glycol-folic acid, wherein the tumor sensitizing drug is loaded on an MIL-101(Fe) nano-material carrier, and the surface of the MIL-101(Fe) nano-material carrier is coated with the phospholipid-polyethylene glycol-folic acid.
A composite nano-drug, wherein the composite nano-drug is degradable in a tumor microenvironment.
The application of the composite nano-medicament, wherein the composite nano-medicament is used for preparing a tumor treatment medicament.
The application of the composite nano-drug is characterized in that the tumor is a tumor in a hypoxic microenvironment.
Has the advantages that: the composite nano-drug provided by the invention adopts a metal organic framework material MIL-101(Fe) as a carrier, loads a biological reduction tumor sensitizing drug, and coats phospholipid-polyethylene glycol-folic acid (DSPE-mPEG-FA) on the surface of the MIL-101 (Fe). The phospholipid-polyethylene glycol-folic acid ligand modified on the surface of the composite nano-medicament can specifically target folic acid, so that the composite nano-medicament can target the surface of tumor cells rich in folic acid receptors and has tumor targeting property. Moreover, the phospholipid-polyethylene glycol-folic acid ligand modified on the surface of the composite nano-drug can also increase the content of the phospholipid-polyethylene glycol-folic acid ligandBiocompatibility. The composite nano-drug can play a drug effect in a tumor hypoxia environment, and is decomposed to respectively release Fe in a slightly acidic environment inside a tumor3+And a bioreductive tumor sensitizing drug such as AQ4N, wherein said tumor sensitizing drug exerts a drug toxic effect in a hypoxic, reductive tumor microenvironment, killing tumor cells; and Fe3+Then it will react with H in tumor cells2O2The reaction generates active oxygen free radicals, relieves the tumor hypoxia condition and further accelerates the apoptosis of tumor cells. Moreover, the composite nano-drug is safe, nontoxic, friendly to biology and has high potential application value in tumor treatment.
Drawings
FIG. 1 is a schematic flow chart of a method for preparing a composite nano-drug in an embodiment of the present invention;
FIG. 2 is a schematic diagram of the construction of a composite nano-drug in an embodiment of the present invention;
FIG. 3 is a TEM image of the MIL-101(Fe) nano-material prepared in the example of the present invention;
FIG. 4 is an absorption spectrum of AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug prepared in the examples of the present invention;
FIG. 5 is a drug release profile of AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug prepared in an example of the present invention;
FIG. 6 is a cytotoxicity assessment of AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug prepared in the examples of the present invention;
FIG. 7 is the confocal imaging of cells in hypoxic environment of AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug prepared in the examples of the present invention;
FIG. 8 is a graph showing the improvement of tumor hypoxia status in mice by AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug prepared in the examples of the present invention;
FIG. 9 shows the killing effect of AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug on tumor cells under hypoxic condition, which is prepared in the example of the present invention.
Detailed Description
The invention provides a composite nano-drug, a preparation method and an application thereof, and the invention is further described in detail below in order to make the purpose, technical scheme and effect of the invention clearer and more clear and definite. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In a first aspect, an embodiment of the present invention provides a method for preparing a composite nano-drug, as shown in fig. 1, including the following steps:
s10, preparing an MIL-101(Fe) nano material;
s20, loading a tumor sensitizing drug on the MIL-101(Fe) nano material to prepare the MIL-101(Fe) nano drug;
s30, coating phospholipid-polyethylene glycol-folic acid on the surface of the MIL-101(Fe) nano-drug to obtain the composite nano-drug.
In some embodiments, the tumor sensitizing drug is AQ4N, but is not limited thereto, and can also be a bioreductive tumor sensitizing drug with other structures. In recent years, researchers find that the biological reduction type tumor sensitizing drug AQ4N has the function of playing drug toxicity under the condition of tumor hypoxia without harming normal cells or tissues, thereby having the potential of being applied to the treatment of the hypoxia tumor.
Fig. 2 is a schematic diagram of AQ4N as an example for constructing a composite nano-drug. As can be seen from the figure, the composite nano-drug adopts a metal organic framework material MIL-101(Fe) as a carrier, a biological reduction tumor sensitizing drug such as AQ4N is loaded, and phospholipid-polyethylene glycol-folic acid is coated on the surface of the MIL-101 (Fe).
In some embodiments, the specific steps for preparing MIL-101(Fe) nanomaterial in step S10 described above include:
s101, providing ferric trichloride and terephthalic acid;
s102, dissolving the ferric trichloride and the terephthalic acid in dimethylformamide;
s103, reacting in a high-pressure reaction kettle to obtain the MIL-101(Fe) nano material.
Specifically, a proper amount of ferric chloride (FeCl) is weighed3·6H2O) and terephthalic acid (H)2BDC) Putting into a beaker, adding a certain amount of Dimethylformamide (DMF), and stirring to fully dissolve the powder; then pouring the solution into a high-pressure reaction kettle, tightly covering a cover, and putting the reaction kettle into a reaction kettle for reaction at 120 ℃; then cooling to room temperature, washing the product with absolute ethyl alcohol, centrifuging for 3 times, and drying in vacuum for later use.
Preferably, the molar ratio of ferric trichloride to terephthalic acid is 2: 1. When the ratio of ferric trichloride to terephthalic acid is too high, the finally prepared MIL-101(Fe) nano material is unstable, and when the ratio is too low, the prepared nano material is too large in size.
Preferably, the solvothermal reaction time is 10 hours.
The MIL-101(Fe) carrier of the metal organic framework material is prepared by a solvothermal method and synthesized in a high-pressure reaction kettle, and the preparation process is relatively simple, has strong universality and is easy to control. The transmission electron micrograph of the MIL-101(Fe) nano-material prepared is shown in FIG. 3.
In some embodiments, the specific step of loading the tumor sensitizing drug on the MIL-101(Fe) nanomaterial in the above step S20 comprises:
s201, adding the tumor sensitizing drug into a 2- (N-morpholine) ethanesulfonic acid buffer solution for full dissolution to prepare a tumor sensitizing drug solution;
s202, adding the MIL-101(Fe) nano material into the tumor sensitization medicine solution, and stirring for 10 hours in a dark place to prepare the MIL-101(Fe) nano medicine.
Further, the method also comprises the following steps after stirring for 10 hours in a dark place: washing the product with anhydrous ethanol, centrifuging for 3 times, and vacuum drying for use.
The tumor sensitizing drug is doped and combined into the organic framework, so that the drug can be decomposed after reaching a target, and the drug effect is exerted.
In some embodiments, the step S30 of coating phospholipid-polyethylene glycol-folic acid on the surface of the MIL-101(Fe) nano-drug comprises:
and (3) providing phospholipid-polyethylene glycol-folic acid, dissolving in water, adding the MIL-101(Fe) nano-drug, stirring in the dark for 24 hours for reaction, and dispersing the product in a phosphate buffer solution to obtain the composite nano-drug.
Further, the method for dispersing the product in the phosphate buffer solution further comprises the following steps: the product was centrifuged 3 times with deionized water.
In a second aspect, the embodiment of the invention also provides a composite nano-drug, wherein the composite nano-drug adopts a metal organic framework material MIL-101(Fe) as a carrier, a biological reduction tumor sensitizing drug is loaded, and phospholipid-polyethylene glycol-folic acid (DSPE-mPEG-FA) is coated on the surface of the MIL-101 (Fe).
According to the composite nano-drug provided by the embodiment, the phospholipid-polyethylene glycol-folic acid ligand is modified on the surface of the MIL-101(Fe) nano-drug, so that folic acid can be specifically targeted, and the composite nano-drug can be targeted to the surface of tumor cells rich in folic acid receptors, so that the composite nano-drug has tumor targeting property; especially breast cancer cells, the folate receptor on the surface of the breast cancer cells is highly expressed, so that the breast cancer cells can be specifically and targeted combined with the composite nano-drug modified by the folate ligand. Moreover, the phospholipid-polyethylene glycol-folic acid ligand modified on the surface of the composite nano-drug can also increase the biocompatibility of the composite nano-drug. The reason is that the phospholipid-polyethylene glycol part in the phospholipid-polyethylene glycol-folic acid ligand forms a long-chain hydrophilic passivation layer structure on the surface of the composite nano-drug, and the passivation structure greatly reduces adverse reactions caused by the combination of protein and platelets in blood on the passivation layer and increases biocompatibility.
In some embodiments, the composite nano-drug is degradable in the tumor microenvironment. This is because the tumor microenvironment is weakly acidic, and under acidic conditions, the metal-organic framework in the composite nano-drug interacts with hydrogen ions (H) under acidic conditions+) The chemical reaction takes place and gradually degrades.
In some embodiments, the tumor sensitizing drug comprises AQ 4N. Under the slightly acidic environment inside the tumor, the composite nano-drug prepared by the embodiment can be decomposed to release AQ4N and Fe respectively3+Wherein AQ4N is reduced in oxygenCan exert the toxic action of the medicine under the tumor microenvironment to kill tumor cells; and Fe3+Then it will react with H in tumor cells2O2The reaction generates active oxygen free radicals, relieves the tumor hypoxia condition and further accelerates the apoptosis of tumor cells.
In a third aspect, the present embodiment further provides an application of a composite nano-drug, which can be applied to the preparation of a tumor therapeutic drug.
In some embodiments, the tumor is a tumor in a hypoxic microenvironment. The composite nano-drug comprises a biological reductive hypoxic drug AQ4N, can play a toxic role of the drug in a hypoxic and reductive tumor microenvironment when being applied to the hypoxic tumor microenvironment, and is harmless to normal cells or tissues, so that the composite nano-drug can be applied to hypoxic tumor treatment.
The composite nano-drug of the present invention, the preparation method and the application thereof are further explained by the following specific examples:
example 1
Preparing the composite nano-medicament:
(1) preparing MIL-101(Fe) nano material: 1.35g of ferric chloride (FeCl) was weighed3·6H2O),0.412g terephthalic acid (H)2BDC) is placed into a beaker, 30mL of Dimethylformamide (DMF) is measured and added into the beaker, and the mixture is stirred to fully dissolve the powder; then pouring the mixture into a high-pressure reaction kettle, tightly covering a cover, putting the reaction kettle into a condition of 120 ℃, and reacting for 10 hours; then, the mixture is cooled to room temperature, washed and centrifuged for 3 times by using absolute ethyl alcohol, and a product is dried in vacuum for later use.
(2) Preparing MIL-101(Fe) nano-drug: adding 5mg of AQ4N into 2- (N-morpholine) ethanesulfonic acid buffer solution for full dissolution, then adding 10mg of MIL-101(Fe) nano material, stirring under the condition of keeping out of the sun, reacting for 10 hours, washing with absolute ethyl alcohol and centrifuging for 3 times to obtain the MIL-101(Fe) nano drug, which is marked as AQ4N @ MIL-101(Fe), and then drying in vacuum for later use.
(3) Preparing the composite nano-medicament: dissolving 20mg of phospholipid-polyethylene glycol-folic acid (DSPE-mPEG-FA) in 10mL of water, adding 5mg of AQ4N @ MIL-101(Fe), sufficiently stirring for reaction for 24 hours in the absence of light, washing and centrifuging a product for 3 times by using deionized water, dispersing the product in 5mL of Phosphate Buffer Solution (PBS), and thus obtaining the composite nano-drug which is marked as AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA, and then placing the composite nano-drug in a refrigerator at 4 ℃ in the absence of light for later use.
Example 2
Performance testing of AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA NanoTaceutical prepared in example 1 above:
(1) AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug absorption spectrum test
2mL of AQ4N solution, 2mL of AQ4N @ MIL-101(Fe) solution and 2mL of AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA solution were respectively used to test the absorption wavelength from 400nm to 800nm, and the results are shown in FIG. 4.
As can be seen from the figure, the composite nano-drug doped with AQ4N has an absorption peak around 650nm similar to that of a free AQ4N solution, which indicates that AQ4N is successfully loaded in a metal organic framework.
(2) AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug release curve
1mg/mL of AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug solutions are respectively taken and dispersed in PBS buffer solutions with different pH values (pH 5.0, pH6.5 and pH 7.4), the absorption wavelength of the initial solution is tested, and then the initial solution is stored in a dark place, the absorption wavelength is tested every 10min for the first 1 hour, and then the absorption wavelength is tested every 30min for 24 hours, and the result is shown in FIG. 5.
As can be seen from the figure, when AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug is incubated with buffer solutions with different pH values, the release is slowest under the condition of neutral pH value; the pH value is 6.5, and the release time is close to 70% after 20 hours; whereas at pH5.5, after incubation for 10h, the release was approximately 83%. This indicates that AQ4N drug is gradually released with time, and the more the drug is released with the increase of acidity, which also indicates that AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug is an acidity sensitive composite nano-drug.
(3) Cytotoxicity assessment of AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug
First, 4T1 cells were cultured in a 96-well plate under normoxic conditions, and the cells were cultured in the 96-well plateMedium adherence was good. Thereafter, 4T1 cells were placed in an oxygen deficient environment (5% CO)2/1％O2/94％N2) Culturing for 6h, and then incubating the cells with fresh culture medium containing AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug with the drug concentration of 0, 12.5, 25, 50 and 100 mug/mL respectively. After an additional 48h incubation, the cells were removed and the medium was replaced with fresh medium. Cytotoxicity was then determined using a enhanced cell count kit (CCK 8). The results are shown in fig. 6, in which cell viability (%) ═ OD450 (sample)/OD 450 (control) × 100%.
As can be seen from the figure, when the concentration of the drug reaches 200 mug/mL, the cell survival rate is still above 90%, which indicates that the biological toxicity of the AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano drug is very low.
(4) Cell confocal imaging of AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug in anoxic environment
In a normoxic environment (5% CO)2/21％O2/74％N2) The 4T1 cells with good growth state are digested by pancreatin and inoculated in a small culture dish with a glass bottom plate with the diameter of 20mm, after culturing for 24h, the culture plate is placed in an oxygen-deficient environment (5% CO)2/1％O2/94％N2) Continuing to culture for 6h, then continuing to incubate with fresh culture media respectively containing 100 mug/mL AQ4N, AQ4N @ MIL-101(Fe) and AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drugs for 6h under an anoxic condition, then respectively adding a nuclear probe Hoechst 33342, incubating for 30min again, and finally performing cell imaging by using a laser confocal microscope.
The results are shown in fig. 7, which shows that the composite nano-drug has the strongest fluorescence at 650nm red under hypoxic conditions, indicating that the composite nano-drug is a nano-drug responding under hypoxic conditions and can be used for imaging guiding treatment in the treatment of 650nm red fluorescence hypoxic tumors.
(5) AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug for killing mouse tumor and improving hypoxic condition
4T1 tumor-bearing mice were injected with PBS or AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA (50. mu.L, 1mg/mL), respectively. Mice were injected intraperitoneally with pimonidazole (60mg/kg) (hypoxic probe kit). After 90 minutes of administration, the mice were suddenly killed and mouse tumor tissues were obtained. At this time, the hypoxic probe pimonidazole in hypoxic cells is reduced and activated, and the activated intermediate forms a stable complex with thiol groups of proteins, polypeptides and amino acids. And FITC-Mab1 antibody bound to these complexes and detected by immunochemistry. Anti-pimozole, anti-cd 31 and DAPI staining were performed on hypoxic regions, vessels and nuclei, respectively.
The results are shown in fig. 8, where the green fluorescence of the tumor tissue is strongest in the control mice injected with PBS buffer, indicating severe tumor hypoxia; the green fluorescence of the tumor tissue of the mice injected with the drug group of the composite nano-drug is weak, which indicates that the hypoxic condition of the tumor tissue is improved, and also indicates that the iron ions in the composite nano-drug generate Fenton reaction to generate O2And the hypoxic condition is improved.
(6) Killing condition of AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug on hypoxic condition tumor cells
In a normal oxygen environment (5% CO)2/21％O2/74％N2) After 4T1 cells in good growth state were trypsinized and seeded in a 96-well plate, and cultured for 24 hours, the plate was placed in an oxygen-deficient environment (5% CO)2/1％O2/94％N2) Continuously culturing for 6h, then incubating with fresh culture medium respectively containing 100 μ g/mL AQ4N, AQ4N @ MIL-101(Fe), AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug for 6h, and replacing the fresh culture medium to continuously culture for 48 h. Cells were then counted using the enhanced cell count kit (CCK 8). In this case, cell viability (%) was OD450 (sample)/OD 450 (control) × 100%.
The results are shown in fig. 9, and it can be seen from the figure that the cell survival rate after the cells are incubated with the composite nano-drug is reduced by 75% under the hypoxic condition compared with the normal oxygen condition, which indicates that the released AQ4N plays a killing role on the cells under the hypoxic condition.
From the results, the AQ4N @ MIL-101(Fe) @ DSPE-mPEG-FA nano-drug is an acid-sensitive composite nano-drug, and the biological toxicity is low. Under hypoxic conditions, the composite nano-drug can respond and can improve the hypoxic condition of tumor tissues. Moreover, the AQ4N released by the composite nano-drug plays an effective role in killing tumor cells under hypoxic conditions.
In conclusion, the composite nano-drug provided by the invention adopts the metal organic framework material MIL-101(Fe) as a carrier, loads the biological reduction tumor sensitizing drug, and coats phospholipid-polyethylene glycol-folic acid (DSPE-mPEG-FA) on the surface of the MIL-101 (Fe). The phospholipid-polyethylene glycol-folic acid ligand modified on the surface of the composite nano-medicament can specifically target folic acid, so that the composite nano-medicament can target the surface of tumor cells rich in folic acid and has tumor targeting property; especially breast cancer cells, the folate receptor on the surface of the breast cancer cells is highly expressed, so that the breast cancer cells can be specifically and targeted combined with the composite nano-drug modified by the folate ligand. Moreover, the surface modification phospholipid-polyethylene glycol-folic acid ligand of the composite nano-drug can also increase the biocompatibility of the composite nano-drug. The reason is that the phospholipid-polyethylene glycol part in the phospholipid-polyethylene glycol-folic acid ligand forms a long-chain hydrophilic passivation layer structure on the surface of the composite nano-drug, and the passivation structure greatly reduces adverse reactions caused by the combination of protein and platelets in blood on the passivation layer and increases biocompatibility. The composite nano-drug is an acid-sensitive composite nano-drug, and is decomposed under the slightly acidic environment in the tumor to release Fe respectively3+And bioreductive tumor sensitizing drugs such as AQ4N, wherein AQ4N plays a toxic role of the drug in hypoxic and reductive tumor microenvironment to kill tumor cells; and Fe3+Then it will react with H in tumor cells2O2The reaction generates active oxygen free radicals, relieves the tumor hypoxia condition and further accelerates the apoptosis of tumor cells. Moreover, the composite nano-drug is safe, nontoxic, friendly to biology and has high potential application value in tumor treatment.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (10)
1. A preparation method of a composite nano-drug is characterized by comprising the following steps:
preparing an MIL-101(Fe) nano material;
loading a tumor sensitizing drug on the MIL-101(Fe) nano material to prepare the MIL-101(Fe) nano drug;
and coating phospholipid-polyethylene glycol-folic acid on the surface of the MIL-101(Fe) nano-medicament to obtain the composite nano-medicament.
2. The method for preparing a composite nano-drug according to claim 1, wherein the tumor sensitizing drug is AQ 4N.
3. The method for preparing a composite nano-drug according to claim 1, wherein the step of preparing the MIL-101(Fe) nano-material comprises:
providing ferric trichloride and terephthalic acid;
dissolving the ferric trichloride and the terephthalic acid in dimethylformamide;
and (3) reacting in a high-pressure reaction kettle to obtain the MIL-101(Fe) nano material.
4. The method for preparing a composite nano-drug according to claim 3, wherein the molar ratio of the ferric trichloride to the terephthalic acid is 2: 1.
5. The method for preparing the compound nano-drug according to claim 1, wherein the step of loading the tumor sensitizing drug on the MIL-101(Fe) nanomaterial to prepare the MIL-101(Fe) nano-drug comprises:
adding the tumor sensitizing drug into a 2- (N-morpholine) ethanesulfonic acid buffer solution for full dissolution to prepare a tumor sensitizing drug solution;
and adding the MIL-101(Fe) nano material into the tumor sensitizing drug solution, and stirring for 10 hours in a dark place to prepare the MIL-101(Fe) nano drug.
6. The method for preparing the composite nano-drug according to claim 1, wherein the step of coating phospholipid-polyethylene glycol-folic acid on the surface of the MIL-101(Fe) nano-drug to prepare the composite nano-drug comprises:
and (3) providing phospholipid-polyethylene glycol-folic acid, dissolving in water, adding the MIL-101(Fe) nano-drug, stirring in the dark for 24 hours for reaction, and dispersing the product in a phosphate buffer solution to obtain the composite nano-drug.
7. The composite nano-drug is characterized by comprising a tumor sensitizing drug, an MIL-101(Fe) nano-material and phospholipid-polyethylene glycol-folic acid, wherein the tumor sensitizing drug is loaded on an MIL-101(Fe) nano-material carrier, and the surface of the MIL-101(Fe) nano-material carrier is coated with the phospholipid-polyethylene glycol-folic acid.
8. The composite nano-drug of claim 7, wherein the composite nano-drug is degradable in a tumor microenvironment.
9. Use of a composite nano-drug according to any one of claims 7 to 8 in the preparation of a medicament for the treatment of tumors.
10. The use of the composite nano-drug according to claim 9, wherein the tumor is a tumor in a hypoxic microenvironment.
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