CN109865141B

CN109865141B - Method for synthesizing anticancer drug/MOFs composite functional material through pressure

Info

Publication number: CN109865141B
Application number: CN201910242156.3A
Authority: CN
Inventors: 霍峰蔚; 任臻; 沈宇; 张伟娜; 张江维
Original assignee: Nanjing Tech University
Current assignee: Nanjing Tech University
Priority date: 2019-03-27
Filing date: 2019-03-27
Publication date: 2022-02-18
Anticipated expiration: 2039-03-27
Also published as: CN109865141A

Abstract

The invention discloses a method for synthesizing an anticancer drug/MOFs composite functional material by pressure, which comprises the following steps: mixing MOFs and anticancer drug molecules, and then obtaining a self-assembled composite material of the MOFs particles and the anticancer drug molecules through the action of axial pressure; placing the self-assembly composite material in a solvent or steam containing the solvent; and (3) heating the solvent or steam containing the solvent to 25-50 ℃, keeping the temperature for 5-120h, and performing post-treatment to obtain the anticancer drug/MOFs composite functional material. The anti-cancer drug has high loading rate in MOFs materials, and the method is simple and easy to implement, and realizes the selective release in PBS buffer solution.

Description

Method for synthesizing anticancer drug/MOFs composite functional material through pressure

Technical Field

The invention relates to the field of multifunctional coordination polymer composite materials, in particular to a method for synthesizing an anticancer drug/MOFs composite functional material by pressure.

Background

Cancer has been one of the major diseases threatening the health of human beings, and scientists and medical researchers from all over the world are struggling to fight it. The treatment method of cancer mainly comprises operation treatment, radiotherapy, chemotherapy and the like in clinic at present. The chemotherapy drugs generally have great cytotoxicity, and the drugs are brought to the whole body through blood vessels, have great damage effect on cancer cells and normal cells in the body, and have obvious toxic and side effects. Therefore, the direction of efforts to bring chemotherapeutic drugs to malignant tumor tissues in a targeted manner so as to kill cancer cells without affecting normal cells and improve the survival rate and the quality of life of patients is the direction of people. It is expected that the pH responsive effect can be achieved by finding a suitable drug carrier which provides less release of the anti-cancer drug at pH7.4, i.e., the in vivo environment of the human body, and which provides rapid release of the anti-cancer drug at pH5.0, i.e., the tumor microenvironment. MOF materials, which are porous coordination compounds, are different from porous materials such as zeolites and activated carbon in their construction mode, are networks formed by self-assembly of metal ions and organic ligands.

However, the size of anticancer drug molecules is generally in the nanometer level, but the pore channels of MOFs materials, such as ZIF-8, are

Anticancer drug molecules cannot be directly encapsulated in ZIF-8.

Disclosure of Invention

The present invention is directed to a method for synthesizing an anticancer drug/MOFs composite functional material by pressure, which solves one or more of the above-mentioned problems of the prior art.

The invention provides a method for synthesizing an anticancer drug/MOFs composite functional material by pressure, which comprises the following steps:

alpha 1, mixing MOFs and anticancer drug molecules, and obtaining a self-assembled composite material of the MOFs particles and the anticancer drug molecules through the action of axial pressure;

α 2, placing the self-assembly composite material in a solvent or steam containing the solvent;

and alpha 3, raising the temperature of the solvent or steam containing the solvent to 25-50 ℃, keeping the temperature for 5-120h, and performing post-treatment to obtain the anticancer drug/MOFs composite functional material.

In some embodiments, the MOFs are ZIF-8 or ZIF-67

In some embodiments, the anti-cancer drug molecule is Doxorubicine (DOX).

In some embodiments, the solvent is at least one of methanol, ethanol, propanol, butanol, N-dimethylformamide, N-dimethylhexanamide, or dimethylsulfoxide.

In some embodiments, the method for achieving self-assembly of MOFs particles with anticancer drug molecules by axial pressure effect in step α 1 comprises the following steps:

placing the mixed MOFs and anticancer drug molecules in a cavity of an infrared tablet press, knocking the cavity wall to enable the MOFs and the anticancer drug molecules to be uniformly attached to the bottom of a wafer of the infrared tablet press, and then applying pressure to the wafer, wherein the pressure is not lower than 1364 MPa.

In some embodiments, in step α 1, the MOFs are mixed with the anticancer drug molecules in a mass ratio of 1: 1.

In some embodiments, step α 1 further comprises: the MOFs are mixed with anticancer drug molecules and then ground.

In some embodiments, the post-treatment in step α 3 comprises: the solution is centrifuged, washed and finally dried.

In some embodiments, the MOFs were activated by vacuum drying at 100-140 ℃ for 10-14 h.

Has the advantages that:

the embodiment of the invention constructs the anticancer drug/MOFs composite functional material by using a simpler and milder method. The method is beneficial to improving the loading rate of anticancer drug molecules on one hand, and enables the anticancer drug molecules larger than MOFs pore channels to be coated in the pore channels of the MOFs material on the other hand, so that the influence of pore channel limitation during synthesis of the MOFs composite material is eliminated, and the synergistic effect of the MOFs and the anticancer drug molecules is finally realized. The anticancer drug molecules coated by the method have higher loading rate.

In addition, the invention can load drug molecules on the MOF surface by means of pressure induction and recovery, and simultaneously realizes the selective release of the anticancer drugs/MOFs material under different pH conditions by utilizing the instability of MOFs under acidic conditions.

Drawings

FIG. 1 is a standard curve for DOX of example 1 in a 1 wt% aqueous hydrochloric acid solution;

FIG. 2 is a TEM picture of DOX/ZIF-8 after recovery of example 1;

FIG. 3 is a graph of data comparing the molecular encapsulation amount of the DOX/ZIF-8 material of example 1 with that of other methods;

FIG. 4 is a drug release profile of the DOX/ZIF-8 material of example 1.

Detailed Description

The present invention will be further described with reference to the following examples. The following examples are only for illustrating the performance of the present invention more clearly and are not limited to the following examples.

Example 1

Preparing MOFs materials (taking ZIF-8 as an example):

2-methylimidazole (22.7g, 0.28mol) was weighed out and dissolved in 8mL of water (0.03mol mL-1). Weighing Zn (NO)₃)₂·6H₂O (1.17g, 3.9mmol) was dissolved in 80mL of water (0.049mmol mL-1). The solution is sonicated from turbid to clear and transparent respectively, and Zn (NO) is added₃)₂·6H₂The O aqueous solution was poured into the 2-methylimidazole aqueous solution, and the solution instantly turned into a white emulsion, stirred for 5 minutes at 600 rpm. And then centrifuging the white emulsion by using a centrifuge tube, performing ultrasonic treatment for a few minutes, washing the white emulsion for 3 times by using water, and then activating the white emulsion in a vacuum drying oven at 120 ℃ to obtain the 100 nm-sized dodecahedron ZIF-8. Preparing an anticancer drug/ZIF-8 composite material:

weighing 50mg of activated ZIF-8 material and 50mg of anticancer drug hydrochloric acid carbendazim, fully mixing, respectively putting 20mg of mixture into a cavity of an infrared tablet press, knocking the cavity wall to enable the mixture to be uniformly attached to the bottom of a wafer, applying pressure of 30MPa (gauge pressure, actual pressure is 1364MPa) to the wafer, removing the pressure after 5 minutes, obviously seeing that the material is changed into a deep red wafer after demolding, and recording as DOX/ZIF-8 after tabletting.

And (3) taking part of the tabletted composite material, putting the composite material in methanol steam, raising the temperature of the methanol steam to 25 ℃, keeping the temperature for 48 hours for later use, and recording as recovered DOX/ZIF-8. The resulting product is visualized by Transmission Electron Microscopy (TEM) of fig. 2.

Usually, the dialysis bag can be used for dialysis for one week, and the bag is dried, wherein the dialysis process is to remove the drug molecules on the surface.

And (3) performance testing:

preparing 1 wt% of HCl (H)₂O) solution. We first prepared DOX HCl (H) at 0.013mg/mL, 0.01625mg/mL, 0.0195mg/mL, 0.02275mg/mL, 0.026mg/mL, and 0.02925mg/mL₂O) solution. A standard curve of DOX was drawn by testing the UV spectrum with the maximum absorbance at 480nm as the ordinate. As shown in FIG. 1, DOX/HCl (H)₂O) standard solution has higher linear correlation.

2mg of DOX/ZIF-8 composite was dissolved in HCl (H)₂O) solution, ultrasonic treatment to completely dissolve DOX/ZIF-8 into homogeneous solution, continuously diluting, and measuring the content of drug molecules by ultraviolet and standard curve method, wherein the result is that the content of DOX is 40%.

Referring to FIG. 3, the amount of encapsulation of DOX/ZIF-8 after recovery in embodiments of the present invention is much higher than other strategies for encapsulating DOX, which is the highest amount of encapsulation reported in the literature.

The slow release experiment of the anticancer drug/ZIF-8 composite material comprises the following steps:

two 1.5mgDOX/ZIF-8 portions of the composite material were weighed, ultrasonically dissolved in 3mL of PBS 7.4 buffer solution, and then transferred to a dialysis bag through a pipette, and 30mL of PBS (pH7.4) and PBS (pH5.0) buffer solutions were respectively added outside the dialysis bag. Thereafter, the fluorescence of the solution outside the dialysis bag was monitored every hour, and the released amount of polyDOX/was determined by a standard curve.

As can be seen from FIG. 4, the drug molecules DOX are slowly released in the PBS buffer solution with pH7.4, while most of the drug molecules are almost completely released within 30h in the PBS buffer solution with pH5.0, thereby showing the pH responsiveness of the material in the drug slow-release process.

The anti-cancer drug in the embodiment provided by the invention has high loading rate in MOFs materials, and the method is simple and easy to implement, and realizes the selective release in PBS buffer solution.

The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these should also be construed as being within the scope of the present invention.

Claims

1. A method for synthesizing an anticancer drug/MOFs composite functional material by pressure is characterized by comprising the following steps:

alpha 1, mixing ZIF-8 and hydrochloric acid multi-ratio soft star according to a mass ratio of 1:1, placing the mixed ZIF-8 and hydrochloric acid multi-ratio soft star in a cavity of an infrared tablet press, knocking the cavity wall to enable the mixed ZIF-8 and hydrochloric acid multi-ratio soft star to be uniformly attached to the bottom of a wafer of the infrared tablet press, and then applying pressure to the wafer, wherein the pressure is not lower than 1364MPa, so that a self-assembly composite material is obtained;

α 2, placing the self-assembled composite material in steam containing a methanol solvent;

and alpha 3, raising the temperature of steam containing a methanol solvent to 25 ℃, keeping the temperature for 48 hours, and performing post-treatment to obtain the anticancer drug/MOFs composite functional material.

2. The method for synthesizing anticancer drugs/MOFs composite functional material according to claim 1, wherein said step α 1 further comprises: mixing ZIF-8 with doxorubicin hydrochloride, and grinding.

3. The method for synthesizing anticancer drugs/MOFs composite functional material by pressure according to claim 1, wherein said post-processing in step α 3 comprises: the solution is centrifuged, washed and finally dried.

4. The method as claimed in claim 1, wherein the ZIF-8 is activated by vacuum drying at 140 ℃ for 10-14h in step α 1.