CN113081976B - MMP-2 enzyme sensitivity-based nano preparation and preparation method and application thereof - Google Patents
MMP-2 enzyme sensitivity-based nano preparation and preparation method and application thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
Abstract
The invention provides an MMP-2 enzyme-sensitive based nano preparation, and a preparation method and application thereof. The preparation method comprises the steps of firstly preparing an amphiphilic carrier material with a dextran sulfate-PVGLIG-tripterine structure, and then preparing an MMP-2 enzyme-sensitive nano preparation. The carrier material uses dextran sulfate as a target head, targets scavenger receptors on the surface of macrophages at an inflammation part, and has MMP-2 enzyme-sensitive PVGLIG hexapeptide of micro-environmental response at the inflammation part. The MMP-2 enzyme-sensitive based nano preparation prepared from the carrier material has the effect of specifically releasing medicines at inflammation sites; can improve the bioavailability of the medicine, avoid adverse reaction of the whole body and treat rheumatoid arthritis more efficiently.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an MMP-2 enzyme-sensitive based nano preparation and a preparation method and application thereof.
Background
Rheumatoid arthritis (rheumatic arthritis, RA) is an autoimmune inflammatory disease that has not yet been specifically diagnosed, is aggressive, has a high disability rate, and can lead to loss of function and joint deformity. At present, no specific medicine for treating RA exists, and some natural plant medicinal materials such as tripterine have the effects of regulating immune imbalance, reducing the release of inflammatory mediators and relieving bone destruction for treating RA.
In recent years, nano-targeting agents have played a significant role in the treatment of diseases such as tumors and inflammation. Macrophages are involved in the progression and maintenance of disease by producing pro-inflammatory factors, and have a critical role in the maintenance of inflammation, joint destruction, and the like, so activated macrophages are ideal targets for the treatment of RA. Therefore, there is a need to design a nano-preparation that effectively targets the joint inflammation site, thereby solving the above-mentioned rheumatoid arthritis problem.
Disclosure of Invention
Aiming at the technical problems, the invention provides a nano preparation based on MMP-2 enzyme sensitivity, a preparation method and application thereof, wherein the nano preparation based on MMP-2 enzyme sensitivity is a nano carrier material with specificity targeting inflammation sites and micro-environment response.
In order to achieve the above object, the present invention has the following technical scheme:
the invention provides a preparation method of an MMP-2 enzyme-sensitive nano preparation, which comprises the following steps:
(1) Dissolving tripterine to obtain a tripterine solution, adding EDC and NHS into the tripterine solution, and activating carboxyl; preparing PVGLIG solution, and adding the PVGLIG solution into the activated tripterine solution for reaction to obtain PVGLIG-Cel;
(2) Adding EDC and DMAP into PVGLIG-Cel obtained in the step (1), activating carboxyl, preparing dextran sulfate solution, mixing the dextran sulfate solution with the activated PVGLIG-Cel, reacting, dialyzing by using a dialysis bag, centrifuging after the dialysis is completed, taking out supernatant, and freeze-drying and preserving to obtain DS-PVGLIG-Cel, namely an amphiphilic carrier material;
(3) Dissolving the amphiphilic carrier material obtained in the step (2) to obtain a blank carrier solution; preparing a tripterine solution, mixing the blank carrier solution with the tripterine solution, performing dialysis reaction by using a dialysis bag, centrifuging to obtain supernatant after dialysis is completed, filtering, freeze-drying and preserving to obtain the MMP-2 enzyme-sensitive nano preparation.
Further, in the step (1), the mole ratio of the tripterine to the PVGLIG is 1:1.5-1:1.
Further, the molar ratio of EDC to NHS in the step (1) is 1:1.2-1.2:1; the mole ratio of the tripterine to the EDC is 1:2-2:1.
Further, the solvents of the tripterine solution and the PVGLIG solution in the step (1) are DMSO.
Further, the specific steps of activating the hydroxyl groups in the steps (1) - (2) are that the carboxyl groups are activated in an oil bath at the temperature of 30-40 ℃ for 2-3 h.
Further, the reaction conditions of the PVGLIG solution and the activated tripterine solution in the step (1) are as follows: in an oil bath at 35 ℃ for 30-40 h.
Further, the molar ratio of PVGLIG-Cel to dextran sulfate in the step (2) is 1:1.5-1:1; the molar ratio of PVGLIG-Cel to EDC is 1:2-1.5:1; the molar ratio of EDC to DMAP is 1:1.5-1.5:1.
Further, the molecular weight cut-off of the dialysis bag in the steps (2) - (3) is 3000 Da-4000 Da.
Further, the solvent of the dextran sulfate solution in the step (2) is water.
Further, the reaction conditions in the step (2) are as follows: reacting for 40-50 h at 30-40 ℃.
Furthermore, the solvent of the hollow white carrier solution in the step (3) is a mixed solution of DMSO and formamide, and the volume ratio of the DMSO to the formamide is 1:1.5-1.5:1.
Further, the dialysis reaction time in the step (3) is 10-20 hours.
Further, the solvent of the tripterine solution in the step (3) is DMSO.
Further, in the step (3), the mass ratio of the amphiphilic carrier material to the tripterine is 8:1-12:1.
Further, the filtering method in the step (3) is filtering by using a microporous membrane with the diameter of 0.8 μm.
The invention also provides the MMP-2 enzyme-sensitive nano preparation prepared by the preparation method. The MMP-2 enzyme-based sensitive nanoformulation includes a carrier material having PVGLIG hexapeptide and dextran sulfate structures.
The invention also provides application of the MMP-2 enzyme-sensitive nano preparation in preparing medicaments for treating rheumatoid arthritis.
Compared with the prior art, the invention has the advantages that:
1. by targeting the scavenger receptor on the surface of activated macrophages, the medicine is specifically gathered at the focus part, the low medicine availability and systemic adverse reaction are avoided, and the rheumatoid arthritis is treated more efficiently.
2. By combining with the micro-environmental characteristics of the inflammation site, PVGLIG hexapeptide is cited as polypeptide sensitive to high MMP-2/9, dextran Sulfate (DS) is taken as a hydrophilic end, meanwhile, the effect of well targeting a macrophage surface Scavenger Receptor (SR) is also achieved, PVGLIG hexapeptide is taken as an MMP-2 sensitive response bond, and the PVGLIG hexapeptide can be broken at the inflammation site, so that the effect of specific drug release at the inflammation site is achieved.
3. Preparing DS-PVGLIG-Cel (DPC) blank carrier, wrapping tripterine, solving the key problems of poor solubility, low bioavailability and the like of natural traditional Chinese medicinal materials.
4. The prepared nano medicine carrying preparation can be phagocytized in cytoplasm by inflammatory macrophages to realize cure of rheumatoid arthritis, and solves the key problems of strong side effect of western medicines, low availability of traditional Chinese medicines and the like.
Drawings
FIG. 1 is a synthetic route pattern for amphiphilic carrier materials.
FIG. 2 is an amphiphilic support material 1 H-NMR chart.
FIG. 3 is a diagram of a nanofabricated formulation of the present invention.
FIG. 4 is a graph of particle size of a nanofabricated formulation of the present invention.
Fig. 5 is a potential diagram of a nanofabricated formulation of the present invention.
FIG. 6 is a transmission electron microscope image of a nano-formulation of the present invention.
Fig. 7 is a graph of particle size of DPC carriers over time.
FIG. 8 is a graph of RAW264.7 cell concentration dependent and time dependent uptake.
Fig. 9 is a RAW264.7 cell localization map.
Fig. 10 is a fluorescence imaging of drug-loaded formulations incubated in RAW264.7 cells for 2h and 4h, respectively.
FIG. 11 is a cytotoxicity experiment; cytotoxicity of blank vector (a) cytotoxicity of different formulations after 24h of RAW264.7 cells were cultured (C) cytotoxicity of different formulations after 48h of RAW264.7 cells were cultured.
Detailed Description
The following embodiments better illustrate the present invention. The present invention is not limited to the following examples.
Example 1 preparation method of MMP-2 enzyme-sensitive nanoformulations
The MMP-2 enzyme-sensitive nano preparation provided by the invention comprises a Scavenger Receptor (SR) which takes dextran sulfate as a target head and targets the surface of macrophages at an inflammation part, and a MMP-2 enzyme-sensitive carrier material with micro-environmental response at the inflammation part is constructed, wherein the synthetic route of the carrier material is shown in figure 1, and meanwhile, the design of a tripterine prodrug greatly improves the treatment effect at a focus part. The preparation method comprises the following steps:
1. synthesis of amphiphilic carrier material-dextran sulfate-PVGLIG-tripterine (DS-PVGLIG-Cel) material
(1) PVGLIG hexapeptide is selected as polypeptide with high MMP-2/9 sensitivity. Dissolving tripterine with DMSO as solvent to obtain tripterine solution, adding EDC and NHS into the tripterine solution, wherein the mol ratio of the tripterine to the EDC is 1:1.5, and the mol ratio of the EDC to the NHS is 1:1; activating carboxyl in an oil bath at 35 ℃ for 2-3 hours; preparing PVGLIG solution, wherein the solvent is DMSO, and adding the PVGLIG solution into the activated tripterine solution, wherein the mol ratio of the tripterine to the PVGLIG is 1:1.5-1:1; the mixture was reacted in an oil bath at 35℃for 36 hours to obtain PVGLIG-Cel.
(2) Dextran sulfate with macrophage surface Scavenger Receptor (SR) was chosen as the hydrophilic end of the nano-formulation. Adding EDC and DMAP into the PVGLIG-Cel obtained in the step (1), wherein the molar ratio of the PVGLIG-Cel to the EDC is 1:1.5, and the molar ratio of the EDC to the DMAP is 1:1; activating carboxyl groups for 2-3 h in an oil bath at 35 ℃, preparing a dextran sulfate solution, mixing the dextran sulfate solution with activated PVGLIG-Cel, wherein the molar ratio of PVGLIG-Cel to dextran sulfate is 1:1.5-1:1; reacting at 35 ℃ for 48 hours, dialyzing with a dialysis bag with molecular weight cutoff of 3500Da, centrifuging to take out supernatant after dialyzing, and freeze-drying and preserving to obtain DS-PVGLIG-Cel (DPC), namely an amphiphilic carrier material; the structural formula is shown in formula 1.
By using 1 The structure was characterized by H-NMR as shown in FIG. 2.
2. Preparation of MMP-2 enzyme-sensitive based nano-formulations (DPC@Cel)
(3) Dissolving the amphiphilic carrier material obtained in the step (2) in a mixed solution of DMSO and formamide, wherein the volume ratio of DMSO to formamide is 1:1; obtaining a blank carrier solution with a concentration of 5 mg/mL; preparing a tripterine solution with the concentration of 1mg/mL, mixing the blank carrier solution with the tripterine solution with a solvent of DMSO, wherein the mass ratio of the carrier material to the tripterine is 10:1; and (3) performing dialysis reaction for 10-20 hours by using a dialysis bag with the molecular weight cutoff of 3500Da, centrifuging to obtain supernatant after dialysis is completed, filtering by using a microporous filter membrane with the size of 0.8 mu m, and freeze-drying and preserving to obtain the MMP-2 enzyme-sensitive nano-preparation.
Example 2: characterization and performance experiments of MMP-2 enzyme-sensitive nano-formulations
1. Determination of drug-loading and encapsulation efficiency of nano-preparation
The nano-formulation prepared in example 1 was shown in fig. 3, and the encapsulation efficiency and drug loading rate of dpc@cel were measured by ultraviolet spectrophotometry. And demulsifying 1mL of the prepared nano preparation with methanol, diluting to the required concentration, passing through a microporous filter membrane with the thickness of 0.45 mu m, measuring absorbance at the wavelength of 425 by an ultraviolet spectrophotometry, and calculating the drug loading rate and encapsulation rate of the nano preparation according to a formula.
Drug loading (%) = (content of drug entrapped in formulation/total mass of formulation) ×100%;
encapsulation efficiency (%) = (content of drug entrapped in formulation/initial addition of drug) ×100%.
The nano-formulation of example 1 had a drug loading of 4.17% and an encapsulation efficiency of 44.04%.
2. Determination of critical concentration of nano-formulations
First, 5×10 pyrene was prepared -5 The standard solution of mg/mL, 50 mu L of the standard solution is taken in each volumetric flask by a liquid-transfering gun, and acetone is volatilized; preparing nano-preparation solution of DPC@Cel with concentration of 3.125X10 respectively -5 mg/mL、1.0×10 -4 mg/mL、3.125×10 -4 mg/mL、1.0×10 -5 mg/mL、3.125×10 -5 mg/mL、1.0×10 -2 mg/mL、3.125×10 -2 mg/mL、6.25×10 -2 mg/mL、1.25×10 -1 mg/mL、2.5×10 -1 mg/mL、5.0×10 -1 mg/mL, 1.0mg/mL. Transferring the nano preparation solution into a volumetric flask containing pyrene, carrying out ultrasonic treatment for 30 minutes, standing in a dark place for 24 hours, measuring fluorescence spectrograms of solutions with different concentrations in each volumetric flask, measuring fluorescence intensities at two wavelengths of 373nm and 384nm, and drawing the charts.
The critical micelle concentration of the nano preparation of DPC@Cel is 0.1762mg/mL through calculation. Therefore, in the micelle preparation process, the concentration of the carrier material is larger than 0.1762mg/mL.
3. Particle size and potential of DPC@Cel
The prepared DPC@Cel is passed through a microporous filter membrane with the thickness of 0.80 μm, 0.45 μm and 0.22 μm, then the particle size and the electric potential of the DPC@Cel are detected by a particle size analyzer, and the experimental results are shown in figures 4 and 5, and the particle size is 204.6nm and the particle size distribution is uniform after passing through the microporous filter membrane with the thickness of 0.8 μm.
4. Electron microscope detection of DPC@Cel
The prepared DPC@Cel was fixed and stained with a copper mesh, and the appearance morphology of the DPC@Cel was photographed by a transmission electron microscope as shown in FIG. 6.
5. Stability study of DPC@Cel
The prepared DPC@Cel was subjected to a 0.80 μm microporous filter membrane and stored in a refrigerator at 4℃and the particle sizes were taken out and measured at 12 hours, 24 hours, 48 hours and 72 hours, and the change of the particle size with time was plotted (FIG. 7). After the nano preparation prepared by the invention is placed for 72 hours, the micelle particle size is not changed greatly, and the stability of the prepared nano preparation is proved to be better.
6. Study on cellular uptake and distribution of nano-preparation
The cell nucleus is subjected to specific staining by a cell nucleus staining method, the distribution condition of the nano preparation in cells after the nano preparation is endocytosed by macrophage cells is observed by a laser confocal microscope, the phagocytosis condition of the macrophages with the increase of concentration and the extension of time is observed, and compared with free tripterine (free Cel), and the experimental results are shown in figures 8, 9 and 10.
With increasing concentrations of different preparations, the fluorescence intensity of cells increases, which indicates that RAW264.7 cells have concentration dependence on the cell uptake behavior of free Cel and DPC@Cel, and cells have higher uptake of DPC@Cel at the same concentration, which proves that nano-carrier micelles have better cell uptake efficiency.
Along with the increase of the uptake time of different preparations, the fluorescence intensity of cells can be increased, which shows that RAW264.7 cells have time dependence on the uptake behavior of free Cel and DPC@Cel, and cells have higher uptake amount on DPC@Cel, which proves that the nano-carrier micelle has better bioavailability and can achieve better therapeutic purpose.
The scavenger receptor on the surface of RAW264.7 cells treated with free DS is basically saturated, and the picture proves that the more DS is more favorable for the probability of binding with the scavenger receptor on the surface of macrophages, so DPC@Cel can specifically target the scavenger receptor on the surface of macrophages, and the targeting of the carrier material is well explained.
7. Cytotoxicity evaluation of empty vector and nanofabric
The cytotoxicity of the nano-preparation was evaluated by measuring the culture medium solution of the drug substance and the blank carrier by MTT method, and the experimental results are shown in FIG. 11.
The DPC blank micelle has small damage to RAW264.7 cells, and the cell survival rate is still more than 70% when the DPC blank micelle concentration is 5 mug/mL after 48 hours of culture, so that the DPC blank nano micelle has low cytotoxicity.
After 24h and 48h of treatment of different preparations, the RAW264.7 cells obviously reduce the cell survival rate along with the increase of the concentration of the preparations. At the same time and at the same concentration, the DPC@Cel drug-loaded preparation has better inhibition effect compared with the free drug. When the concentration of tripterine in the DPC@Cel nano preparation is 500ng/mL, the IC50 of three cells is almost achieved when the acting time is 24 hours or 48 hours.
Aiming at the problem of low solubility of tripterine, the carrier material is made into a nano preparation material, so that the defects of poor solubility and poor biocompatibility of natural plant medicaments are overcome, and the stability of the medicaments is improved. The MMP-2 enzyme-sensitive nano preparation provided by the invention has a scavenger receptor on the surface of a targeted activated macrophage, and PVGLIG hexapeptide is cited as a polypeptide with high MMP-2/9 sensitivity, so that the effect of specific drug release at an inflammation site is achieved; improves the bioavailability of the medicine, avoids adverse reaction of the whole body, and treats the rheumatoid arthritis more efficiently.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be apparent to one skilled in the art that modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some of the technical features thereof; such modifications and substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (3)
1. A method of preparing an MMP-2 enzyme-sensitive nanoformulation, the method comprising the steps of:
(1) Dissolving tripterine with DMSO as solvent to obtain tripterine solution, adding EDC and NHS into the tripterine solution, wherein the mol ratio of the tripterine to the EDC is 1:1.5, and the mol ratio of the EDC to the NHS is 1:1; activating carboxyl in an oil bath at 35 ℃ for 2-3 hours; preparing PVGLIG solution, wherein the solvent is DMSO, and adding the PVGLIG solution into the activated tripterine solution for reaction, wherein the mol ratio of the tripterine to the PVGLIG is 1:1.5-1:1; reacting for 36h in an oil bath pot at 35 ℃ to obtain PVGLIG-Cel;
(2) Adding EDC and DMAP into the PVGLIG-Cel obtained in the step (1), wherein the molar ratio of the PVGLIG-Cel to the EDC is 1:1.5, and the molar ratio of the EDC to the DMAP is 1:1; activating carboxyl groups for 2-3 hours in an oil bath at 35 ℃; preparing a dextran sulfate solution, wherein a solvent is water, and mixing the dextran sulfate solution with activated PVGLIG-Cel, wherein the molar ratio of the PVGLIG-Cel to the dextran sulfate is 1:1.5-1:1; reacting at 35 ℃ for 48 hours, dialyzing with a dialysis bag with the molecular weight cut-off of 3500Da, centrifuging to take out supernatant after the dialysis is completed, and freeze-drying and preserving to obtain DS-PVGLIG-Cel, namely an amphiphilic carrier material;
(3) Dissolving the amphiphilic carrier material obtained in the step (2) in a mixed solution of DMSO and formamide, wherein the volume ratio of DMSO to formamide is 1:1, and obtaining a blank carrier solution with the concentration of 5 mg/mL; preparing a tripterine solution with the concentration of 1mg/mL, mixing the blank carrier solution with the tripterine solution with a solvent of DMSO, wherein the mass ratio of the carrier material to the tripterine is 10:1; and (3) carrying out dialysis reaction for 10-20 h by using a dialysis bag with the molecular weight cutoff of 3500Da, centrifuging to obtain supernatant after dialysis is completed, filtering by using a microporous filter membrane with the size of 0.8 mu m, and freeze-drying and preserving to obtain the MMP-2 enzyme-sensitive nano-preparation.
2. The MMP-2 enzyme-sensitive based nano-formulation prepared by the method of claim 1.
3. Use of a MMP-2 enzyme-sensitive nano-formulation according to claim 2 in the manufacture of a medicament for the treatment of rheumatoid arthritis.
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