CN117919205A - Bionic medicine carrying nano particle for expressing CXCR4 and preparation method and application thereof - Google Patents
Bionic medicine carrying nano particle for expressing CXCR4 and preparation method and application thereof Download PDFInfo
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- CN117919205A CN117919205A CN202410101360.4A CN202410101360A CN117919205A CN 117919205 A CN117919205 A CN 117919205A CN 202410101360 A CN202410101360 A CN 202410101360A CN 117919205 A CN117919205 A CN 117919205A
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- A61K9/51—Nanocapsules; Nanoparticles
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- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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Abstract
The invention discloses a bionic drug-loaded nanoparticle for expressing CXCR4, and a preparation method and application thereof, comprising the following steps: mixing lactic acid-glycolic acid copolymer and immunosuppressant in a certain proportion, and preparing into drug-carrying nano particles by adopting a microfluidic technology; preparing MSC cells stably expressing CXCR4 membrane proteins, and cracking the MSC cells to extract cell membranes to obtain engineering stem cell membranes; the engineering stem cell membrane is fused with the drug-loaded nanoparticle to obtain the bionic drug-loaded nanoparticle expressing CXCR4, wherein the bionic drug-loaded nanoparticle expressing CXCR4 is the bionic cell membrane drug-loaded nanoparticle with chemotactic performance. The invention reforms the engineering stem cell membrane and wraps the clinical therapeutic drug by genetic engineering means, and the engineering stem cell membrane directionally migrates to the damaged part in the body and targets to specific cells, thereby improving the in-vivo distribution of the drug and reducing the toxic and side effects of the immunosuppression drug.
Description
Technical Field
The invention relates to the field of bionic cells, in particular to a bionic drug-loaded nanoparticle for expressing CXCR4, and a preparation method and application thereof.
Background
Mesenchymal Stem Cells (MSCs) have been widely used in clinical treatment of various diseases due to their low immunogenicity and broad-spectrum immunomodulatory function. MSCs benefit from the lack of expression or low expression of major histocompatibility complex class I, class II and costimulatory molecules on the cell membrane, making them naturally hypoimmunogenic, which allows them to avoid clearance of immune cells of the body after entering the body, prolonging blood circulation time. In recent years, research into "carrier stem cells" based on stem cells has come into the field of view. MSCs express a number of receptors and cell adhesion molecules that can help them migrate and home to the target tissue. The CXCR4/SDF-1 signal axis formed by the membrane chemokine receptor CXCR4 and high concentration of matrix-derived factor-1 (SDF-1) at the inflammation injury part is one of the most main mechanisms of the chemotactic homing of MSCs. This is the basis of targeting therapy of tumors and inflammatory diseases by stem cell transport nanoparticles. Deregulation of the SDF-1/CXCR4 axis plays a critical role in the differentiation, migration, recruitment and transplantation, survival and proliferation of bone marrow mesenchymal stem cells.
Although stem cell drug delivery systems can improve the environmental adaptability of nano-drugs, the micro-size of MSCs themselves also limits their precise homing to target tissues and organs, and many studies show that surface intravenous MSCs are distributed in lung, liver and spleen. In addition, MSCs migration and homing to damaged tissues is affected by a number of factors, including age and passage number of cells, culture conditions, and delivery pattern, among others. These all limit the use of MSCs transport vectors in the biomedical field.
Currently, immunosuppressants are mainly used for organ transplantation rejection, autoimmune diseases and malignant tumors. However, patients have larger toxic and side effects on high-dose immunosuppressants, and the curative effect is severely restricted by low-dose treatment. The design of the nano drug delivery system can solubilize the drug, improve the half life of the drug, improve the in vivo distribution of the drug, enhance the targeting property and reduce the toxic and side effects, and has great application potential in the field of disease diagnosis and treatment. The capillary cells at the damaged part of the patient proliferate, while the lymphatic system is blocked, so that the nano-drug is easily accumulated at the part. Most studies consider that one of the main reasons for poor nanodrug efficacy is that nanoparticles have insufficient arthritis targeting, but have relatively low safety.
Disclosure of Invention
The invention provides a bionic drug-carrying nanoparticle for expressing CXCR4, a preparation method and application thereof, aiming at solving the problems of low homing rate, large toxic and side effects, unstable treatment effect and the like of the traditional nano drug for treating autoimmune diseases, wherein the nano drug is prepared by using a degradable nano material with excellent biocompatibility to carry an immunosuppressant, a mesenchymal stem cell membrane for over-expressing the CXCR4 is coated on the surface of the nano drug, and the immune escape and inflammatory chemotactic functions of the stem cell are further cooperated to prepare the bionic nano drug coated by the cell membrane, so that the in-vivo distribution of the drug is improved, the toxic and side effects of the immunosuppressive drug are reduced, and an effective strategy for delivering the drug to a lesion site is realized.
A method for preparing bionic drug-loaded nano-particles expressing CXCR4, comprising:
mixing lactic acid-glycolic acid copolymer and immunosuppressant in a certain proportion, and preparing into drug-carrying nano particles by adopting a microfluidic technology;
preparing MSC cells stably expressing CXCR4 membrane proteins, and cracking the MSC cells to extract cell membranes to obtain engineering stem cell membranes;
Fusing the engineering stem cell membrane with the drug-loaded nano-particles to obtain the CXCR 4-expressing bionic drug-loaded nano-particles, wherein the CXCR 4-expressing bionic drug-loaded nano-particles are bionic cell membrane drug-loaded nano-particles with chemotactic performance;
the method for fusing the engineering stem cell membrane and the drug-loaded nano-particles comprises the following steps: the engineering stem cell membrane and the drug-loaded nano particles are blended according to the mass ratio of 0.8-1:0.8-1, and ultrasonic fusion is carried out, wherein the ultrasonic treatment frequency is 10-30 kHz, the time is 30-60 s, and the temperature is 5-10 ℃.
In order to optimize the technical scheme, the specific measures/limitations adopted further comprise:
The immunosuppressant is at least one selected from cyclosporine, methotrexate and cyclophosphamide.
The lactic acid-glycolic acid copolymer and the immunosuppressant are mixed according to the mass ratio of 5-10:1.
The specific method for preparing the drug-loaded nano-particles by adopting the microfluidic technology comprises the following steps: mixing the lactic acid-glycolic acid copolymer and the immunosuppressant and dissolving in dimethyl sulfoxide to obtain an aqueous phase mixture, wherein the mass/volume ratio of the lactic acid-glycolic acid copolymer to the immunosuppressant to the dimethyl sulfoxide is 5-15:1mg/mL, dropwise adding the aqueous phase mixture into ultrapure water, the volume ratio of the ultrapure water to the aqueous phase mixture is 6-10:1, and stirring for 0.5-3 h at room temperature.
Purifying drug-loaded nano-particles: transferring the prepared drug-loaded nano-particles into a dialysis bag to remove redundant organic phases and reagents, removing water by distillation and dialyzing with water for 30 hours, and freeze-drying the suspension to obtain the purified nano-particles. The molecular weight cut-off of the filter membrane is 3-7 kDa.
The MSC cell is selected from at least one of human umbilical cord MSC cells, human fat MSC cells or human bone marrow MSC cells.
The preparation method of MSC cells stably expressing CXCR4 membrane protein comprises the following steps: culturing the MSC cells of the P3 generation until the fusion reaches 80-90%, transfecting the MSC cells by using a culture medium containing the Lv-CXCR4 over-expression slow virus, culturing for 12-24 hours at 37 ℃, replacing the culture medium containing the Lv-CXCR4 over-expression slow virus by using a DMEM culture medium, continuously culturing for 36-48 hours, and then carrying out resistance screening to obtain the MSC cells stably expressing the CXCR4 membrane protein.
The method for preparing the engineering stem cell membrane by cracking the cell membrane comprises the following steps: washing cells with a precooled phosphate buffer solution for two to three times, re-suspending the cells with a hypotonic lysate, repeatedly freezing and thawing the cells in liquid nitrogen for 4 to 5 times to fully lyse the cells, centrifuging to extract cell membrane sediment, re-suspending the cells with the phosphate buffer solution, and repeatedly extruding the cells in a polycarbonate membrane for 8 to 13 times to obtain the engineering dry cell membrane. The polycarbonate membrane has a pore size of 400nm, 200nm or 100nm, preferably 200nm.
Hypotonic lysates include Tris-HCl buffer, protease inhibitors and phosphatase inhibitors.
The invention also protects the bionic drug-loaded nanoparticle expressing CXCR4 prepared by the method.
The invention also protects the application of the bionic drug-loaded nano-particles in preparing immunosuppressant drugs.
Further, the application is the application of the bionic drug-loaded nano-particles in the preparation of rheumatoid arthritis delivery drugs.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, chemotaxis-weakened in-vitro 2D cultured stem cells are modified, so that the stem cells can be "homing" to inflammatory injury or tumor microenvironment, the separated CXCR4 stem cell membranes are used for wrapping clinical therapeutic drugs, and the obtained bionic cell membrane drug-loaded nano-particles can directionally migrate to an in-vivo injured part and target specific cells.
According to the invention, MSC cell membrane characteristics are analyzed, biological material properties are combined, stem cells over-expressing CXCR4 are constructed through a genetic engineering technology, PLGA drug-loaded nano particles are prepared by adopting a nano precipitation method, the CXCR4 stem cell membrane is wrapped to form a bionic nano drug, the bionic membrane is wrapped to systematically deliver the nano drug to a damaged part, the course of the disease is relieved, and the method is simple and convenient to operate.
The method for preparing the drug-loaded nano-particles by fusing the engineering stem cell membrane and the drug-loaded nano-particles and adopting the microfluidic technology is critical to the successful acquisition of the product CMPNs and the influence of the product performance, and the process method can achieve ideal experimental effects.
Further research shows that the MSC with the engineering structure of the invention highly expresses CXCR4 to ensure that cells obtain stronger migration capacity, and the proportion of co-cultured inflammatory cells is reduced; therefore, the nano-drug wrapped by the engineered MSCs film is injected in the disease progression period, the directional migration and the immunoregulation capability of the bionic nano-particle to the damaged viscera are enhanced, and the disease treatment effect of the MSC bionic film is further improved.
The invention also provides related medical pharmaceutical application, such as organ transplantation rejection, autoimmune diseases and malignant tumor treatment, so as to relieve the problem of systemic toxicity of nano-drugs, and ensure that the carried therapeutic drugs survive for a long time at the damaged part and stably exert biological functions, thereby enabling the immunosuppressive drugs to reach the therapeutic minimum dose in vivo.
The invention has better application prospect for the treatment research of bionic nano-drugs, such as development of bionic vein preparations, and has safety, feasibility and effectiveness.
Drawings
Fig. 1 is a transmission electron microscope image of a bionic drug-loaded nanoparticle expressing CXCR4 according to the present invention.
FIG. 2 is a schematic representation of the preparation and identification of the bionic drug-loaded nanoparticle of the present invention expressing CXCR 4.
Fig. 3 is a hemolytic assay of bionic drug-loaded nanoparticles expressing CXCR4 according to the present invention.
Fig. 4 is a graph showing chemotaxis validation of bionic drug-loaded nanoparticles expressing CXCR4 according to the present invention.
Fig. 5 is a photograph of a joint of a RA treatment with a biomimetic drug-loaded nanoparticle of the present invention expressing CXCR 4.
FIG. 6 is a photograph of H & E pathology for RA treatment with the bionic drug-loaded nanoparticle of the present invention expressing CXCR 4.
Detailed Description
The above-described matters of the present invention will be further described in detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
The experimental methods used in the examples below are conventional methods, and the reagents, methods and apparatus used are conventional in the art, unless otherwise indicated.
Example 1
The preparation method of the bionic drug-loaded nanoparticle for expressing CXCR4 comprises the following steps:
1. The drug-loaded nano-particles are prepared by adopting a microfluidic technology: 10mg of PLGA (lactic acid-glycolic acid copolymer) was dissolved in 1mL of DMSO (dimethyl sulfoxide), and 1mg of MTX (methotrexate) was added to obtain an aqueous phase mixture; the resulting aqueous phase mixture was dropped into 8ml of ultrapure water and stirred at 25℃for 1 hour; the resulting product was transferred to a dialysis tube (MW: 3500 Da) to remove excess organic phase and reagents; after 24h dialysis with distilled deionized water, the suspension was freeze-dried to obtain purified drug-loaded nanoparticles.
2. Preparation of MSC cells stably expressing CXCR4 membrane protein: culturing the MSC cells of the P3 generation until the fusion reaches 80%, then transfecting the MSC cells by using a culture medium containing the Lv-CXCR4 over-expression slow virus, culturing for 12-24 hours at 37 ℃, replacing the culture medium containing the Lv-CXCR4 over-expression slow virus by using a DMEM culture medium, continuing culturing for 36-48 hours, and then performing resistance screening by using a puromycin culture medium containing 1-3 mg/ml to obtain cells which can stably express CXCR4 membrane proteins by stable transfection;
3. Identification of CXCR4 engineered stem cell membranes: cell growth cycle and stem cell surface markers were detected using Flow Cytometry (FCM); the human CXCR4 gene is compared by BLAST software to obtain a gene sequence, a pDsRed-CXCR4 plasmid is constructed and packaged into lentivirus, the MSCs are subjected to gene transfection, and the expression condition of CXCR4 receptors is detected by using a laser confocal microscope (LASER SCANNING confocal microscope, LSCM), reverse transcription PCR (Reverse transcription PCR, RT-PCR), western Blot (WB), immunofluorescence, FCM and other technologies, and the change of the in vitro migration capacity of the MSCs after transfection is evaluated by a Transwell experiment.
4. Preparation of CXCR4 engineered stem cell membranes: washing MSC cells which are prepared in the step 2 and stably express CXCR4 membrane protein for two to three times by using a precooled phosphate buffer solution, re-suspending by using a hypotonic lysate, repeatedly freezing and thawing for 5 times in liquid nitrogen, fully lysing the cells, centrifuging for 10 minutes at the temperature of 4 ℃ and 1850g, and extracting cell membrane precipitation; finally, re-suspending the proposed cell membrane sediment by using phosphate buffer salt solution, and extruding the cell membrane suspension back and forth in a 200nm polycarbonate membrane for 11 times by a micro extruder to obtain CXCR4 engineering stem cell membrane;
5. Preparing chemotactic performance bionic cell membrane drug-loaded nano particles CMPNs: and (3) carrying out ultrasonic treatment on the engineering cell membrane prepared in the step (3), then blending the engineering cell membrane with the drug-loaded nano particles prepared in the step (1) according to the mass ratio of 1:1, and carrying out ultrasonic fusion on the engineering cell membrane with the ultrasonic treatment frequency of 20kHz, the ultrasonic treatment time of 30s and the temperature of 8 ℃ to obtain the bionic cell membrane drug-loaded nano particles with chemotactic performance. The result shows that the obtained bionic cell membrane drug-loaded nano-particles have obvious core-shell structure, are round and uniform, have the particle diameter of about 121.4nm, have the charge of about-20 mV, have the drug loading rate of about MCPNs of 4.3 percent and the encapsulation rate of 93.2 percent, and realize the effective loading of the methotrexate.
Example 2
In vitro characterization of bionic drug-loaded nanoparticles expressing CXCR 4.
In order to examine the long-term stability of the prepared bionic drug-loaded nanoparticle expressing CXCR4, the nanoparticle was dispersed in PBS buffer solution to a final concentration of 1mg/mL, and the particle size of the nanoparticle was observed by a dynamic light scattering instrument. The particle size of the particles within one week is not greatly changed, which indicates that the bionic drug-loaded nano-particles expressing CXCR4 have better solution stability.
In-vitro drug release experiments are carried out to research the drug release capacity of the bionic drug-loaded nano-particles expressing CXCR 4; the blood compatibility of the bionic drug-loaded nanoparticle expressing CXCR4 is evaluated by adopting a erythrocyte hemolysis experiment, and the result shows that the bionic drug-loaded nanoparticle expressing CXCR4 has good blood compatibility, as shown in figure 3.
Example 3
Application of bionic drug-loaded nanoparticles expressing CXCR4 in RA joint targeted therapy. In order to evaluate the in vivo therapeutic effect of the bionic drug-loaded nanoparticle expressing CXCR4, a collagen adjuvant-induced rheumatoid arthritis mouse model was used in the experiment, and model groups, MTX group, MPNs group, CMPNs group were set, wherein the model groups were not treated with any treatment, MTX group was directly injected with MTX solution (methotrexate injection), MPNs group was injected with MPNs (PLGA & MTX encapsulated by stem cell membrane), CMPNs group was injected with CMPNs (PLGA & MTX encapsulated by stem cell membrane modified by CXCR 4), and each group concentration was 100ul,2.5mg MTX/kg; mice are sacrificed at day28 and day35 respectively through tail intravenous injection for observing curative effect, and peripheral blood, synovium and joint tissues are collected at the same time; as shown in fig. 5, which is a joint tissue diagram, it can be found that joint redness and swelling of CIA mice are obviously inhibited after being treated by stem cell membrane nano particles, and the swelling degree of soles of the mice is obviously relieved; pathological analysis of the knee joint (HE staining) showed significant relief of inflammation and bone destruction at the joint after nanoparticle treatment, see fig. 6.
The present invention is not limited to the preferred embodiments, and any simple modification, equivalent replacement, and improvement made to the above embodiments by those skilled in the art without departing from the technical scope of the present invention, will fall within the scope of the present invention.
Claims (10)
1. A method for preparing bionic drug-loaded nano-particles expressing CXCR4, which is characterized by comprising the following steps:
mixing lactic acid-glycolic acid copolymer and immunosuppressant in a certain proportion, and preparing into drug-carrying nano particles by adopting a microfluidic technology;
preparing MSC cells stably expressing CXCR4 membrane proteins, and cracking the MSC cells to extract cell membranes to obtain engineering stem cell membranes;
Fusing the engineering stem cell membrane with the drug-loaded nano-particles to obtain the CXCR 4-expressing bionic drug-loaded nano-particles, wherein the CXCR 4-expressing bionic drug-loaded nano-particles are bionic cell membrane drug-loaded nano-particles with chemotactic performance;
the method for fusing the engineering stem cell membrane and the drug-loaded nano-particles comprises the following steps: the engineering stem cell membrane and the drug-loaded nano particles are blended according to the mass ratio of 0.8-1:0.8-1, and ultrasonic fusion is carried out, wherein the ultrasonic treatment frequency is 10-30 kHz, the time is 30-60 s, and the temperature is 5-10 ℃.
2. The method for preparing the bionic drug-loaded nanoparticle expressing CXCR4 according to claim 1, wherein the method comprises the following steps: the immunosuppressant is at least one selected from cyclosporine, methotrexate and cyclophosphamide.
3. The method for preparing the bionic drug-loaded nanoparticle expressing CXCR4 according to claim 1, wherein the method comprises the following steps: the lactic acid-glycolic acid copolymer and the immunosuppressant are mixed according to the mass ratio of 5-10:1.
4. The method for preparing the bionic drug-loaded nanoparticle expressing CXCR4 according to claim 1, wherein the method comprises the following steps: the specific method for preparing the drug-loaded nano-particles by adopting the microfluidic technology comprises the following steps: mixing the lactic acid-glycolic acid copolymer and the immunosuppressant and dissolving in dimethyl sulfoxide to obtain an aqueous phase mixture, wherein the mass/volume ratio of the lactic acid-glycolic acid copolymer to the immunosuppressant to the dimethyl sulfoxide is 5-15:1mg/mL, dropwise adding the aqueous phase mixture into ultrapure water, the volume ratio of the ultrapure water to the aqueous phase mixture is 6-10:1, and stirring for 0.5-3 h at room temperature.
5. The method for preparing the bionic drug-loaded nanoparticle expressing CXCR4 according to claim 1, wherein the method comprises the following steps: the MSC cell is selected from at least one of human umbilical cord MSC cells, human fat MSC cells or human bone marrow MSC cells.
6. The method for preparing the bionic drug-loaded nanoparticle expressing CXCR4 according to claim 1, wherein the method comprises the following steps: the preparation method of MSC cells stably expressing CXCR4 membrane protein comprises the following steps: culturing the MSC cells of the P3 generation until the fusion reaches 80-90%, transfecting the MSC cells by using a culture medium containing the Lv-CXCR4 over-expression slow virus, replacing the culture medium containing the Lv-CXCR4 over-expression slow virus by using a DMEM culture medium, continuously culturing, and then carrying out resistance screening to obtain the MSC cells stably expressing the CXCR4 membrane protein.
7. The method for preparing the bionic drug-loaded nanoparticle expressing CXCR4 according to claim 1, wherein the method comprises the following steps: the method for preparing the engineering stem cell membrane by cracking the cell membrane comprises the following steps: washing cells with precooled phosphate buffer solution, re-suspending with hypotonic lysate, repeatedly freezing and thawing in liquid nitrogen to make cells fully lyse, centrifuging to extract cell membrane precipitate, re-suspending with phosphate buffer solution, and repeatedly extruding to obtain engineering stem cell membrane.
8. A biomimetic drug-loaded nanoparticle expressing CXCR4 prepared by the method of any one of claims 1-7.
9. The use of the biomimetic drug-loaded nanoparticle of claim 8 in the preparation of immunosuppressant drugs.
10. The use according to claim 9, characterized in that: the bionic drug-loaded nano-particles are applied to the preparation of rheumatoid arthritis delivery drugs.
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