CN109111575B - Preparation method and application of metal-organic framework nano-particles - Google Patents
Preparation method and application of metal-organic framework nano-particles Download PDFInfo
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Abstract
The invention discloses a preparation method and application of metal-organic framework nanoparticles, wherein iron salt is dissolved by absolute ethyl alcohol, muconic acid is dissolved by DMF and then diluted by absolute ethyl alcohol, the two solutions are stirred and uniformly mixed, the mixture is heated by microwaves at 50-150 ℃ for 1-60 min, and after natural cooling, centrifugation, washing and freeze drying are carried out to obtain the MOF nanoparticles. Compared with cationic compounds and cationic liposomes, the compound of the invention has simple preparation, greatly simplifies the preparation process, improves the yield, avoids using expensive phospholipid and reduces the cost. The prepared MOF nano-particles have good biocompatibility, are easy to degrade in vivo, cannot cause toxic or side effect in vivo, and even can promote cell proliferation due to low-concentration MOF. By injecting the micro-ring DNA-MOF solution into the abdominal cavity, the target gene can be expressed in the abdominal cavity, so that the abdominal organ pathological changes or tumors can be hopefully treated, and the application prospect is wide.
Description
Technical Field
The invention belongs to the technical field of biomedical engineering. More particularly, it relates to a preparation method and application of metal-organic framework nano-particles.
Background
Gene therapy is the introduction of a foreign gene into a target cell to treat a disease caused by a gene defect or gene abnormality. However, the gene itself cannot be successfully introduced into the target cell, and therefore, it is necessary to rely on a gene vector. Viruses are a common group of gene vectors, including Adenovirus Vectors (AV), adeno-associated virus vectors (AAV), retroviruses, etc., which utilize infection of host cells by viruses to introduce foreign genes into cells and express them with high efficiency. Although the viral vector has higher transfection efficiency, the viral vector has limited gene loading capacity and immunogenicity, and has potential biological safety hazards. In recent years, the appearance of Minicircle DNA (mcDNA) has become a large highlight in gene vectors, and Minicircle DNA is a circular expression cassette, which is a product obtained by removing the backbone DNA of a standard plasmid by a DNA recombination technique, and contains only one gene expression cassette without an external bacterial backbone sequence. However, since naked DNA is rapidly cleared in a physiological environment and cannot efficiently enter target cells, a suitable delivery system is still required to deliver the minicircle DNA to the target tissue or organ.
Common gene delivery systems include calcium phosphate, cationic liposomes, cationic polymers (polyethyleneimine PEI, dendrimer PAMAM), and the like. Such delivery systems have low immunogenicity, large gene loading capacity, but low transfection efficiency, greatly limiting their clinical application. The in vivo virus-free transfection techniques of the prior art generally deliver the gene of interest to an organ or tissue in vivo mediated by cationic liposomes or cationic polymers. Cationic liposome materials, however, are expensive and highly toxic. Cationic polymers, typically including Polyethyleneimine (PEI), dendrimers, polyaminoesters, and the like, coat DNA by positive and negative charge attraction, and are commercially available as in vivo-jetPEI series from Polyplus. The transfection efficiency of the cationic liposome and the cationic polymer on an in vitro cell line is high, but the in vivo transfection efficiency is not high and the biotoxicity is high,
therefore, the gene delivery system which is efficient in research and development, good in biocompatibility and targeted can solve the key problem of clinical application of gene medicines.
Metal Organic Frameworks (MOFs), also known as Metal Organic coordination polymers, are a new class of functionalized crystalline materials. The material is a crystal material which is formed by connecting inorganic metal centers by organic bridging ligands in a coordination bond mode to form an infinitely-extended network structure. The structure of the organic and inorganic components is diversified and adjustable due to different structures, and the organic and inorganic components have potential applications in many aspects. For example, the storage and separation of gases, and the applications of chemical sensing, optics, and catalysis have been studied. The MOF material with a certain structure has biocompatibility and degradability, so that the MOF material has potential application prospects in the biological direction, and the application of the MOF in the aspects of drug delivery and biological imaging is reported.
However, at present, there is no report on the use of metal organic nanoparticles for in vivo transfection of micro-circle DNA.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects and shortcomings existing in the effective delivery of the micro-ring DNA in vitro and in vivo, and the metal-organic framework nano-particles are prepared by microwave solvothermal, have good biocompatibility and easy degradation in vivo, cannot cause toxic or side effect in vivo, and even can promote cell proliferation at low concentration. The metal-organic framework nano-particles can mediate the efficient transfection of the micro-ring DNA in the abdominal cavity, and express target gene protein in the abdominal cavity, thereby treating abdominal organ pathological changes or tumors.
The invention aims to provide a preparation method of metal-organic framework nano particles.
The second purpose of the invention is to provide the application of the metal-organic framework nano-particles in mediating gene transfection in vivo.
The above object of the present invention is achieved by the following technical solutions:
a preparation method of metal-organic framework nanoparticles comprises the steps of dissolving ferric salt with absolute ethyl alcohol, dissolving muconic acid with DMF, diluting with absolute ethyl alcohol, stirring and uniformly mixing the two solutions, heating for 1-60 min at 50-150 ℃ by using microwaves, naturally cooling, centrifuging, washing, and freeze-drying to obtain the MOF nanoparticles.
Preferably, the iron salt may be ferric chloride hexahydrate, anhydrous ferric chloride, ferric chloride tetrahydrate, or ferric nitrate, but the present invention is not limited thereto.
Preferably, the muconic acid is trans-trans muconic acid.
Preferably, the molar ratio of the iron salt to muconic acid is 1: 0.1 to 10.
Preferably, the hydrothermal reaction is performed under conditions of microwave heating at 100 ℃ for 60 min.
Preferably, the centrifugation is 14000g for 10 min.
Specifically, the preparation method of the metal-organic framework nano-particles comprises the following steps:
s1, dissolving ferric chloride hexahydrate into sewage ethanol to obtain a yellow transparent solution A;
s2, adding trans, trans-muconic acid into dimethyl formamide (DMF), stirring until the trans, trans-muconic acid is completely dissolved to obtain a clear and transparent solution, and adding absolute ethyl alcohol to dilute the solution to obtain a solution B;
s3, transferring the solution A into the solution B, and fully stirring for 3 minutes to obtain a solution C;
s4, pouring the solution C into a microwave hydrothermal reaction kettle, heating for 60min at 100 ℃, and taking out the solution when the solution is naturally cooled to below 60 ℃;
s5, centrifuging the solution at 14000g for 10min, washing with absolute ethyl alcohol for three times, and finally freeze-drying to obtain the MOF nano-particles.
Meanwhile, the invention also claims that the metal-organic framework nano-particles prepared by the preparation method are formed by coordination of metal ions (Fe) and trans, trans-muconic acid to form a Secondary Building Unit (SBU) with an octahedral stable structure, and the secondary building unit reconstructs a solid structure. Fe ions and organic matters are linked by chemical coordination bonds, and the forces can be dissociated under the condition of aqueous solution. Therefore, the iron-based MOFs mentioned in this invention are all degradable in vivo. In terms of the degradation rule of a common nano/micron material, the degradation rate is related to the conditions of particle size, porosity and the like, and the larger the particle is, the slower the degradation speed is, and the higher the porosity is, the faster the degradation speed is.
The research of the invention finds that the prepared MOF nano-particles have good biocompatibility, are easy to degrade in vivo, can not cause toxic or side effect in vivo, can even promote cell proliferation at low concentration, and are MOF materials capable of mediating gene transfection; the prepared metal-organic framework nano-particles are mixed with DNA, and enter the body through intraperitoneal injection, so that the high-efficiency transfection can be realized, and the DNA product can be expressed in the abdominal cavity.
Therefore, the invention also protects the application of the metal-organic framework nano-particles in mediating gene transfection in vivo.
Meanwhile, the invention also claims the application of the metal-organic framework nano-particles in the preparation of a micro-ring DNA transfection preparation.
Specifically, the application is that metal-organic framework nanoparticles are dispersed in PBS and then mixed with micro-ring DNA.
More specifically, dispersing an MOF particle sample in water, and performing ultrasonic treatment for 10-20 minutes to form a solution A; dispersing the micro-ring DNA with the target expression gene in water to form a solution B; and adding the solution B into the solution A to form a solution C, thus obtaining the micro-ring DNA transfection preparation.
Preferably, the mass ratio of the metal-organic framework nanoparticles to the micro-ring DNA is 0.5-1 mg: 20 μ g.
The research of the invention finds that different from MOF medicine carrying, when MOF medicine carrying is used, the specific surface area of MOF is required to be larger, and the medicine carrying purpose is achieved through the combination of physical adsorption or chemical bond and medicine molecules. However, when MOF mediated DNA transfection in the abdominal cavity, rod-shaped, needle-shaped and other two-dimensional materials are needed, which can slightly stimulate mesothelial cells in the abdominal cavity and enhance phagocytosis of DNA by cells so as to promote transfection.
Compared with the prior art, the invention has the following beneficial effects:
compared with cationic compounds and cationic liposomes, the metal-organic framework nano-particles have the advantages that the compound preparation is simple, the preparation process is greatly simplified, the yield is improved, expensive phospholipid is avoided, the cost is reduced, and the particle size and the morphology of the metal-organic framework compound can be regulated and controlled by controlling the temperature and/or the time of hydrothermal reaction. The prepared MOF nano-particles have good biocompatibility, are easy to degrade in vivo, cannot cause toxic or side effect in vivo, and even can promote cell proliferation due to low-concentration MOF. By injecting the micro-ring DNA-MOF solution into the abdominal cavity, the target gene can be expressed in the abdominal cavity, so that the abdominal organ pathological changes or tumors can be hopefully treated, and the application prospect is wide.
Drawings
Fig. 1 is a scanning electron microscope picture of a sample. Where A is sample 10, B is sample 8, and C is sample 1.
Fig. 2 is a picture of the particle size distribution of sample 1.
Fig. 3 shows cell viability after 24 hours of co-culture of sample 1 of the organic metal framework compound with HEPG2 cells.
FIG. 4 shows that sample 1 was mixed with mcDNA-Luc and injected intraperitoneally into mice. After a period of time, the transfection of mcDNA-Luc in mice was observed using an IVIS small animal imager.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1
A preparation method of metal-organic framework nano-particles comprises the following steps:
s1, dissolving 0.277g of ferric chloride hexahydrate in 10ml of ethanol to obtain a yellow transparent solution A;
s2, adding 3mL of Dimethylformamide (DMF) into 0.277g of trans-trans muconic acid, stirring until the mixture is completely dissolved to obtain a clear and transparent solution, and adding 10mL of ethanol to obtain a solution B;
s3, transferring the solution A into the solution B, and fully stirring for 3 minutes to obtain a solution C;
s4, pouring the solution C into a microwave-assisted hydrothermal reaction kettle, heating for 60min at 100 ℃ by using microwave, and taking out the solution C when the solution C is naturally cooled to below 60 ℃;
s5, centrifuging the solution at 14000g for 10min, washing with absolute ethyl alcohol for three times, and finally freeze-drying to obtain the MOF nano-particles; this sample was designated sample 1.
Example 2
A method for preparing metal-organic framework nanoparticles, which is substantially the same as in example 1 except that the microwave hydrothermal reaction conditions of step S4 are 80 ℃ and the microwave heating is performed for 1 min; MOF nanoparticles were prepared and this sample was named sample 2.
Example 3
A method for preparing metal-organic framework nanoparticles, which is substantially the same as in example 1 except that the microwave hydrothermal reaction conditions of step S4 are 90 ℃ and the microwave heating is performed for 1 min; MOF nanoparticles were prepared and this sample was named sample 3.
Example 4
A method for preparing metal-organic framework nanoparticles, which is substantially the same as in example 1 except that the microwave hydrothermal reaction conditions of step S4 are 100 ℃ and the microwave heating is carried out for 5 min; MOF nanoparticles were prepared and this sample was named sample 4.
Example 5
A method for preparing metal-organic framework nanoparticles, which is substantially the same as in example 1 except that the microwave hydrothermal reaction conditions of step S4 are 70 ℃ and the microwave heating is performed for 1 min; MOF nanoparticles were prepared and this sample was named sample 5.
Example 6
A method for preparing metal-organic framework nanoparticles, which is substantially the same as in example 1 except that the microwave hydrothermal reaction conditions of step S4 are 100 ℃ and the microwave heating is carried out for 30 min; MOF nanoparticles were prepared and this sample was named sample 6.
Example 7
A method for preparing metal-organic framework nanoparticles, which is substantially the same as in example 1 except that the microwave hydrothermal reaction conditions of step S4 are 100 ℃ and the microwave heating is carried out for 10 min; MOF nanoparticles were prepared and this sample was named sample 7.
Example 8
A method for preparing metal-organic framework nanoparticles, which is substantially the same as in example 1 except that the microwave hydrothermal reaction conditions of step S4 are 150 ℃ and the microwave heating is performed for 1 min; MOF nanoparticles were prepared and this sample was named sample 8.
Example 9
A method for preparing metal-organic framework nanoparticles, which is substantially the same as in example 1 except that the microwave hydrothermal reaction conditions of step S4 are 100 ℃ and the microwave heating is carried out for 10 min; MOF nanoparticles were prepared and this sample was named sample 9.
Example 10
A method for preparing metal-organic framework nanoparticles, which is substantially the same as in example 1 except that the microwave hydrothermal reaction conditions of step S4 are 50 ℃ and the microwave heating is performed for 1 min; MOF nanoparticles were prepared and this sample was named sample 10.
Example 11
A method for preparing metal-organic framework nanoparticles, which is substantially the same as in example 1 except that the microwave hydrothermal reaction conditions of step S4 are 100 ℃ and the microwave heating is performed for 1 min; MOF nanoparticles were prepared and this sample was named sample 11.
Performance testing
First, MOF sample characterization experiment
1. Transmission Electron Microscope (TEM) observation: and dispersing the prepared samples 1-11 in an alcohol solution, and carrying out ultrasonic treatment for more than 10min until the samples are completely dispersed. Dropping calcium phosphate sample on copper net, obtaining transmission picture of sample by FEI Tecnai G2F 20S-Twin electron microscope under 110V voltage, and measuring the size of organic metal frame nano particle by Malvern laser particle size scattering instrument.
2. As shown in FIG. 1, samples with different shapes and sizes can be prepared by different reaction times or reaction temperatures, and the longer the reaction time is, the larger the particle size of the obtained MOF sample is, and the maximum particle size can be about 1 micron. However, the reaction temperature has little influence on the particle size of the sample, but has influence on the appearance of the sample, and the influence has no regularity. At 100oAnd C, reacting for 1h to obtain the tapered compound with two sharp ends. As a result of the particle size distribution of sample 1, as shown in FIG. 2, the average particle size (DLS) measured by a dynamic light scattering apparatus was 187.8nm, and the particle size distribution was relatively uniform.
Second, experiment of biocompatibility and degradability of MOF sample
1. Sample 1 was formulated with different concentrations of MOF particles dispersed in PBS and co-cultured with 5000 HEPG2 cells for 24 hours, during which time the fluid treatment was not changed. Cell viability was tested after 24 hours by CCK8 kit with different concentrations of MOF cells added.
2. The results are shown in fig. 3A, where low to high concentrations of MOF particles were incubated with 293T cells for 48 hours, without showing significant toxicity. The cell survival rate is about 100%. More interestingly, even low concentrations of MOF can promote cell proliferation. As can be seen from the 3B graph, in the PBS solution, the MOF (sample 1) can be degraded within 160 hours, and neither Fe particles nor organic acids generated by degradation cause toxicity to the body, which indicates that the prepared MOF particles have good biocompatibility and degradability. Meanwhile, samples 2-11 are good in biocompatibility and degradation performance.
Third, MOF sample mediated micro-loop DNA abdominal cavity transfection (luciferase) experiment
1. 1mg of MOF particle sample 1 was dispersed in 200. mu.l of water and sonicated for 10 minutes to form a solution A. Mu.g of the micro-loop DNA carrying the luciferase (luciferase) expressing gene was dispersed in 200. mu.l of water to form a solution B. Adding the solution B into the solution A to form a solution C. The solution C is injected into a mouse body through intraperitoneal injection, and the expression condition of luciferase in the body is observed by an IVIS small animal imager after 24 hours.
2. As shown in FIG. 4, the injection of the MOF/DNA mixture solution into the abdominal cavity resulted in significant gene transfection in the abdominal cavity of mice, with the transfection efficiency decreasing with time, and the transfection time lasting over 96 hours. In experiments, we found that the MOF samples in examples 1-12 can mediate DNA transfection in vivo, which is mainly determined by the special shapes of two tips of the MOF samples.
Claims (6)
1. A preparation method of metal-organic framework nanoparticles is characterized in that ferric salt is dissolved by absolute ethyl alcohol, muconic acid is dissolved by DMF and then diluted by absolute ethyl alcohol, then the two solutions are stirred and mixed uniformly, the mixture is heated by microwave at 50-150 ℃ for 1-60 min, naturally cooled and then centrifuged, washed and freeze-dried to obtain MOF nanoparticles;
the ferric salt is ferric chloride hexahydrate, anhydrous ferric chloride, ferric chloride tetrahydrate or ferric nitrate;
the muconic acid is trans-trans muconic acid;
the mass ratio of the ferric salt to the muconic acid is 1: 1.
2. the method of claim 1, wherein the centrifugation is 14000g for 10 min.
3. Metal-organic framework nanoparticles prepared by the process according to any one of claims 1 to 2.
4. Use of the metal-organic framework nanoparticle of claim 3 for the preparation of a minicircle DNA transfection formulation.
5. The use of claim 4, wherein the metal-organic framework nanoparticles of claim 3 are dispersed in PBS and mixed with the micro-circular DNA.
6. The use according to claim 5, wherein the mass ratio of the metal-organic framework nanoparticles to the micro-ring DNA is 0.5-1 mg: 20 μ g.
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| CN111948391A (en) * | 2019-05-16 | 2020-11-17 | 南京大学 | Array sensor based on nano metal organic framework for histological diagnosis of colon cancer |
| CN110384685A (en) * | 2019-09-04 | 2019-10-29 | 临沂大学 | A kind of metal organic frame pharmaceutical carrier and preparation method thereof of nucleic acid modification |
| KR20220109152A (en) | 2021-01-28 | 2022-08-04 | 서울대학교병원 | Silicone patch comprising metal-organic framework and silicone composition |
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