CN113616588A - Preparation method and application of rosiglitazone Pd @ ZIF-8-containing nanoparticle sustained and controlled release membrane - Google Patents
Preparation method and application of rosiglitazone Pd @ ZIF-8-containing nanoparticle sustained and controlled release membrane Download PDFInfo
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- CN113616588A CN113616588A CN202110943534.8A CN202110943534A CN113616588A CN 113616588 A CN113616588 A CN 113616588A CN 202110943534 A CN202110943534 A CN 202110943534A CN 113616588 A CN113616588 A CN 113616588A
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- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 title claims abstract description 162
- 239000012528 membrane Substances 0.000 title claims abstract description 82
- 229960004586 rosiglitazone Drugs 0.000 title claims abstract description 81
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 67
- 238000013268 sustained release Methods 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 238000013270 controlled release Methods 0.000 title claims abstract description 25
- 230000002459 sustained effect Effects 0.000 title claims abstract description 19
- 229920000520 poly(3-hydroxybutyrate-co-3-hydroxyvalerate) Polymers 0.000 claims abstract description 54
- 239000003814 drug Substances 0.000 claims abstract description 47
- 229940079593 drug Drugs 0.000 claims abstract description 45
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- 239000012730 sustained-release form Substances 0.000 claims abstract description 20
- 238000009987 spinning Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 6
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims abstract description 5
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 20
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- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 8
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- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 3
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- 239000013154 zeolitic imidazolate framework-8 Substances 0.000 description 3
- MFLKDEMTKSVIBK-UHFFFAOYSA-N zinc;2-methylimidazol-3-ide Chemical compound [Zn+2].CC1=NC=C[N-]1.CC1=NC=C[N-]1 MFLKDEMTKSVIBK-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
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- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 description 2
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- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
The invention provides a preparation method and application of a rosiglitazone Pd @ ZI F-8 nanoparticle sustained and controlled release membrane, and relates to the technical field of medicines. The preparation method of the slow controlled release film based on the nano-particles containing rosiglitazone Pd @ Z IF-8 comprises the following steps: s1, preparing rosiglitazone/Pd @ ZIF-8 nano particles to obtain composite medicine-carrying nano particles RSG/Pd @ ZIF-8 doped with nano Pd tablets; s2, preparing a composite nano particle/PHBV slow-control membrane to obtain a blue-black final spinning solution, transferring the final spinning solution into a glass syringe, and performing electrostatic spinning; s3, after spinning is finished, the composite drug-loaded nanoparticle/PHBV sustained-release membrane on the aluminum foil paper is placed in a fume hood at room temperature for drying for 3 days to remove residual organic solvent. Zn and rosiglitazone in the composite medicine-carrying nano-particles prepared by the method can synergistically inhibit scarring, reduce the dosage of the medicine rosiglitazone, meet the principles of individualized and precise medical treatment, have the characteristics of higher precision, higher efficiency and higher safety, and are suitable for popularization and application.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method and application of a rosiglitazone Pd @ ZIF-8 nanoparticle sustained and controlled release membrane.
Background
Glaucoma is the first irreversible blinding eye disease worldwide, the ultimate goal of treatment is to protect the optic nerve, and studies have shown that the most effective therapeutic means for protecting the optic nerve is to control intraocular pressure. Currently, the methods commonly used to control intraocular pressure are drug, laser and surgical treatments. The current surgical treatment mainly focuses on Glaucoma Filtration Surgery (GFS), however, scarring of the filtration channel affects the near-term and far-term effects of the surgery. The previous research of the project group discovers that the rosiglitazone can control the scarring of the filtering channel and develops a rosiglitazone/PHBV sustained-release membrane for the long-term anti-scarring of the filtering channel. However, the probability and level of scarring of different individual patients are different due to differences in genetic background, living habits and the like, and the originally developed sustained-release membrane cannot be readjusted according to actual conditions of the patients after being implanted. Therefore, the development of the implant which can be implanted in the operation and can regulate the sustained-release rate of the anti-scarring drug in a non-destructive way after the operation according to the conditions of the post-operation filtration bleb form, the intraocular pressure and the like of a patient has more important clinical significance and better conforms to the principles of individualized treatment and accurate treatment.
Rosiglitazone (RSG) is a PPAR γ agonist and has effects of inhibiting inflammation and resisting fibrosis in different organ systems. For ten years, the project group verifies the anti-fibrosis effect of the sustained release membrane on eye Tenon's capsular fibroblasts under the funding of national science foundation (project numbers: 81170843, 81670859 and 81970801), further discusses the possible mechanism of the anti-fibrosis, and successfully develops a rosiglitazone/PHBV sustained release membrane reported in Drug Delivery.
ZIF-8 is a classic organic Metal framework (Metal organic framework), is synthesized by zinc nitrate and 2-methylimidazole, has the characteristics of easy synthesis, high stability and the like, and is developed to be used for carrying medicine nanoparticles in large quantity; pd is a transition element, the Pd nanosheet is a two-dimensional nanomaterial, and the Pd nanosheet has the characteristics of high near-infrared absorption rate, high photo-thermal conversion efficiency, low toxicity and the like, and is easy to synthesize.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a preparation method and application of a rosiglitazone Pd @ ZIF-8 nanoparticle sustained and controlled release membrane, and solves the problems of poor anti-scarring effect, low accuracy and low safety.
(II) technical scheme
In order to achieve the purpose, the invention is realized by the following technical scheme: a preparation method of a rosiglitazone Pd @ ZIF-8 nanoparticle sustained and controlled release membrane comprises the following steps:
s1, preparing rosiglitazone/Pd @ ZIF-8 nanoparticles, mixing a DMSO solution containing nano palladium sheets (Pd) and rosiglitazone with a Zn (NO3)2 aqueous solution, carrying out water bath magnetic stirring for 5 minutes at 20 ℃, adding a 2-methylimidazole aqueous solution, carrying out magnetic stirring for 30-60 minutes, centrifuging, removing a supernatant, washing for 3 times by using ethanol to obtain the nano Pd sheets doped composite drug-loaded nanoparticles RSG/Pd @ ZIF-8;
s2, preparing the composite nano-particle/PHBV slow-control membrane, weighing PHBV powder, dissolving the PHBV powder into chloroform TCM solution, and magnetically stirring the solution at the temperature of 60 ℃ for 20 to 30 minutes until the solution is colorless and transparent, so as to prepare PHBV-TCM 55.6mg/ml solution for later use; weighing the composite drug-loaded nano-particles RSG/Pd @ ZIF-8 prepared in S1, dissolving in dimethyl formamide DMF, adding a DMF solution containing nano-particles into the PHBV-TCM solution, and magnetically stirring for 10 minutes at 60 ℃ to obtain a blue-black final spinning solution; transferring the final spinning solution into a glass syringe, fixing the glass syringe into a clamping groove of an injection pump, connecting the positive electrode of a high-voltage power supply with a dull-ground metal needle at the front section of the syringe, connecting the negative electrode of the high-voltage power supply with an aluminum plate coated with aluminum foil paper, keeping the distance between the needle and a receiver at 10-15cm, adjusting the voltage of the high-voltage power supply to 15KV, controlling the propelling speed of the injection pump to be 5-8ml/h, controlling the ambient temperature to be 20-30 ℃ and the humidity to be 20-40%, and performing electrostatic spinning;
and S3, after spinning is finished, the composite nano drug-loaded particles/PHBV sustained-release membrane on the aluminum-foil paper is placed in a fume hood at room temperature for drying for 3 days to remove residual organic solvent.
Preferably, the diameter of the Pd sheet in the S1 is 13-17nm, and the concentration of the Pd sheet in the DMSO solution is 0.1-1.0 mg/ml.
Preferably, the mass-to-volume ratio of the aqueous solution of Zn (NO3) 2.6H 2O in S1 is 92 mg/ml.
Preferably, the mass-to-volume ratio of the 2-methylimidazole water solution in the S1 is 257.5 mg/ml.
Preferably, the volume ratio of the Zn (NO3)2 aqueous solution, the DMSO solution and the 2-methylimidazole aqueous solution in the S1 is 1:2: 1.
Preferably, the mass of the PHBV powder in S2 is 500-1000 mg.
Preferably, the mass-to-volume ratio of the DMF solution containing the composite drug-loaded nanoparticles in S2 is 0-50 mg/ml.
Preferably, in the final spinning solution in S2, TCM: the volume ratio of DMF is 9: 1.
preferably, the PHBV powder in S2 can be replaced by PLGA powder.
(III) advantageous effects
The invention provides a preparation method and application of a rosiglitazone Pd @ ZIF-8 nanoparticle sustained and controlled release membrane. The method has the following beneficial effects:
1. earlier researches of the invention find that rosiglitazone has a good effect on inhibiting the scar formation after glaucoma operation, and Zn2+ has an obvious inhibiting effect on the scar formation, Zn and rosiglitazone in the composite drug-loading nano-particles prepared by the invention can synergistically inhibit the scar formation, and the dosage of the drug rosiglitazone is reduced.
2. The rosiglitazone/Pd @ ZIF-8/PHBV sustained-release membrane has good effect of continuously resisting scar formation after glaucoma filtration, and can adjust the decomposition rate of the composite drug-loaded nanoparticles thereof through 808nm near-infrared laser irradiation to adapt to the anti-fibrosis requirements of different individual patients, so that the characteristic better conforms to the principles of individualized and precise medical treatment, and the success rate of the operation is further improved.
3. The rosiglitazone/Pd @ ZIF-8/PHBV sustained-release membrane can monitor the content of composite drug-loaded nanoparticles in the membrane in real time by a Photoacoustic Imaging (PAI) technology.
4. The invention discusses the drug release behavior of the rosiglitazone/Pd @ ZIF-8/PHBV sustained and controlled release membrane from multiple aspects through in vitro release experiments, in vitro degradation experiments, cell experiments and in vivo animal experiments, and confirms the effectiveness and the safety of the sustained and controlled release membrane. Lays a solid theoretical foundation for clinical popularization and application.
5. The invention has the characteristics of more accuracy, more effectiveness and more safety, and is suitable for popularization and application.
Drawings
FIG. 1 is a transmission electron microscope image of a nano palladium sheet (Pd) with a diameter of 13-17nm according to the present invention;
FIG. 2 is a scanning electron microscope and transmission electron microscope image of ZIF-8, Pd @ ZIF-8, and rosiglitazone/Pd @ ZIF-8 composite drug-loaded nanoparticles provided by an embodiment of the present invention;
FIG. 3 is a scanning electron microscope image of rosiglitazone/Pd @ ZIF-8/PHBV composite drug-loaded nanoparticle/PHBV sustained-release membrane at different concentrations provided by the example of the present invention;
FIG. 4 is a Fourier transform infrared spectra of ZIF-8, Pd @ ZIF-8, and rosiglitazone/Pd @ ZIF-8 composite drug loaded nanoparticles provided in accordance with an embodiment of the present invention;
FIG. 5 is an ultraviolet spectrophotometer image of Pd @ ZIF-8 and rosiglitazone/Pd @ ZIF-8 composite drug loaded nanoparticles provided in an example of the present invention;
FIG. 6 is a scanning electron microscope image of hFTFs (human Total tens's fibrosis cells) cells seeded on 2.5% rosiglitazone/Pd @ ZIF-8/PHBV membrane in accordance with an embodiment of the present invention;
FIG. 7 is a graphical representation of CCK-8 toxicity test data for hFTFs for rosiglitazone/Pd @ ZIF-8 composite drug-loaded nanoparticles provided in accordance with an embodiment of the present invention;
FIG. 8 is a graphical representation of CCK-8 toxicity test data for hFTFs for rosiglitazone/Pd @ ZIF-8/PHBV composite drug-loaded nanoparticle/PHBV sustained-release membrane provided in accordance with an embodiment of the present invention;
FIG. 9 is a fluorescence quantitative PCR assay data diagram of fibrosis related genes of rosiglitazone/Pd @ ZIF-8/PHBV composite drug-loaded nanoparticle/PHBV sustained-release membrane for inhibiting the fibrosis effect of hFTFs.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The first embodiment is as follows:
as shown in fig. 1 to 9, an embodiment of the present invention provides a preparation method of a Pd @ ZIF-8 nanoparticle sustained/controlled release membrane containing rosiglitazone, including the following steps:
for the preparation of rosiglitazone/Pd @ ZIF-8 nanoparticles, 0.23g of Zn (NO3) 2.6H 2O was weighed and dissolved in 2.5ml of ddH2O to obtain a solution A; weighing 0.515g of 2-methylimidazole, and dissolving in 2ml of water to obtain a solution B; adding 46.67ml of acetone solution into 3.33ml of PVP (polyvinylpyrrolidone) solution containing 0.6mg/ml of palladium tablet, mixing, centrifuging at 5000rpm for 5-10min, removing supernatant to obtain 2mg of palladium tablet, adding 5ml of DMSO solution, dissolving completely, and adding 60mg of rosiglitazone to obtain solution C;
fully mixing 2.5ml of the solution A and 5ml of the solution C in a constant-temperature water bath at the temperature of 20 ℃, magnetically stirring for 5min, adding 2.5ml of the solution B into the mixed solution, and magnetically stirring for 30-60 min. Centrifuging the obtained mixed solution at 7000rpm for 10min, discarding the supernatant, adding an appropriate amount of ethanol solution, washing for 3 times, and finally drying to obtain about 109.0mg of rosiglitazone/Pd @ ZIF-8 composite drug-loaded nanoparticles;
sending the rosiglitazone/Pd @ ZIF-8 composite drug-loaded nanoparticles to a scanning electron microscope, a transmission electron microscope and a Fourier infrared spectrum respectively to obtain physicochemical parameters shown in figures 2 and 4, and analyzing to obtain RSG/Pd @ ZIF-8: fig. 2 shows that after rosiglitazone is added in the synthesis process, the morphology of the nanoparticles changes, and although the octahedral configuration is lost, the surface becomes rough, the rosiglitazone is laterally proved to be in the nanoparticles; the particle diameter has good uniformity, and the diameter is about 200 nm. FIG. 4 shows that the infrared has distinct absorption peaks from Pd @ ZIF-8 at wave numbers of 1606 and 1240cm-1, demonstrating the presence of drug in the composite drug-loaded nanoparticles;
preparing 1ug/ml, 2.5ug/ml, 5ug/ml, 10ug/ml and 20ug/ml of rosiglitazone aqueous solution, measuring the absorbance value at 315nm, weighing 1mg of the rosiglitazone/Pd @ ZIF-8 composite drug-loaded nanoparticles, dissolving the 1mg in 10ml of water to obtain 100ug/ml of aqueous solution, adding 1ml of hydrochloric acid with PH ═ 1 into the 1ml of aqueous solution, fully cracking the nanoparticles, measuring the absorbance at 315nm, and measuring the concentration of rosiglitazone in the cracked solution to be 27.8ug/ml according to the absorbance;
drug loading rate (Wd/Wd) 100% ═ 27.8% (Wd: mass of drug, Wn: mass of composite drug-loaded nanoparticles), 100% ═ Wd/Wn ═ 100% (27.8ug/ml 1050ml)/(100ug/ml 1050ml) × 27.8% (Wd: mass of drug, Wn: mass of composite drug-loaded nanoparticles), encapsulation rate (Wd/Wd) 100% ═ 29.19mg/60mg ═ 100% > -48.7% (Wd: mass of rosiglitazone added in total);
example two:
for the preparation of the composite nano-particle/PHBV slow-control membrane, PHBV powder is weighed and dissolved into chloroform TCM solution, and the solution is prepared into PHBV-TCM 55.6mg/ml solution for standby after being magnetically stirred for 20-30min at 60 ℃; weighing composite drug-loaded nanoparticles RSG/Pd @ ZIF-8, dissolving in dimethylformamide DMF, adding the DMF solution containing the nanoparticles into the PHBV-TCM solution, and magnetically stirring for 10 minutes at 60 ℃ to obtain a blue-black final spinning solution, wherein the PHBV powder can be replaced by PLGA powder;
for a scanning electron microscope for preparing rosiglitazone/Pd @ ZIF-8/PHBV sustained-release membranes with different concentrations, an electrostatic spinning method is used, the spinning voltage is 15KV, the distance between a syringe needle and a receiving plate is 15cm, the propelling speed of an injection pump is 5ml/h, 3ml of final spinning solution containing 50mg/ml of PHBV is consumed by each membrane, wherein the ratio of TCM to DMF is 9:1, and the composite drug-loaded nanoparticles are prepared by the following steps: the PHBV mass ratios are 0%, 2.5%, 5% and 10%, respectively. After spinning is finished, the membrane is placed under a fume hood for 3 days to fully volatilize the organic solvent, then the membrane is sent to a scanning electron microscope for detection, and the graph shown in figure 3 is obtained, the diameter of the PHBV membrane fiber prepared by the composite drug-loaded nano-particles is between 0.5 and 2um, the nano-particles uniformly distributed in the fiber can be seen, and the nano-particles in the SEM are more obvious along with the increase of the concentration of the nano-particles.
The first test example:
in vitro sustained-release and controlled-release experiments of rosiglitazone/Pd @ ZIF-8/PHBV sustained-release membrane:
s1, rosiglitazone/Pd @ ZIF-8/PHBV membrane slow release curve determination: films of 0%, 2.5%, 5%, and 10% groups obtained in example 2 were cut to obtain uniform (2X2CM) size and similar quality sheets. The 4 groups of slices are placed in an equal amount of physiological saline and placed in an incubator at 37 ℃, after the slow release membrane is placed, an equal amount of slow release medium is taken at each time point, and an absorbance value at 315nm of the medium is measured by an ultraviolet spectrophotometer and the concentration of the medium is calculated. Drawing a sustained-release curve of the sustained-release film rosiglitazone with different concentrations;
s2, rosiglitazone/Pd @ ZIF-8/PHBV membrane controlled release curve determination: films of 0%, 2.5%, 5%, and 10% groups obtained in example 2 were cut to obtain uniform (2X2CM) size and similar quality sheets. Placing the 4 groups of slices in an appropriate amount of physiological saline, placing each group under the irradiation of 250mW 808nm laser for 10 minutes, placing the slices in an incubator at 37 ℃, taking an equivalent sustained-release medium at each time point after placing a sustained-release membrane, measuring the absorbance value of the 315nm position of the medium by using an ultraviolet spectrophotometer, and calculating the concentration of the medium. And drawing a slow release curve of the membrane after 808nm laser controlled release.
Test example two:
in vitro experiments (cell experiments):
s1, rosiglitazone/Pd @ ZIF-8 nanoparticle cytotoxicity assay: inoculating 1ml of hFTF cells with the concentration of 10000/ml into a 24-pore plate, sequentially adding 0ul, 10ul, 20ul, 30ul, 40ul, 50ul and 60ul of 1mg/ml rosiglitazone/Pd @ ZIF-8 nanoparticle aqueous solution after culturing for 24h, adding 10ul of CCK-8 reagent into each pore after culturing for 24h, incubating for 2h at 37 ℃, sucking 100ul of culture medium/CCK-8 mixed liquid in each pore, setting 3 auxiliary pores in each pore, measuring the absorbance at 450 position under an enzyme labeling instrument, and obtaining a graph 7, wherein the graph 7 shows that the rosiglitazone/Pd @ F-8 nanoparticles start to generate toxicity to the hFTF cells after the concentration of ZIug/ml;
s2, rosiglitazone/Pd @ ZIF-8/PHBV membrane biocompatibility: placing a rosiglitazone/Pd @ ZIF-8/PHBV membrane with proper size in a 24-hole plate, adding 1ml of DMEM high-sugar culture medium for pretreatment overnight, then inoculating 0.5ml of hFTF cells with the concentration of 10000/ml, absorbing and removing the culture medium after 48 hours, after PBS (phosphate buffer solution) is slightly rinsed, adding an electron microscope fixing solution, fixing for 2 hours at room temperature, then sequentially dehydrating by 50% of 60% of 70% of 80% of 90% of 95% of 100% of alcohol, and sending to a scanning electron microscope for detection to obtain a graph 6, wherein the fibroblasts under the scanning electron microscope are stretched to be uniformly attached to the surface of the rosiglitazone/Pd @ ZIF-8/PHBV membrane, and the biocompatibility of the membrane is proved to be enough;
placing a rosiglitazone/Pd @ ZIF-8/PHBV membrane with proper size in a 24-pore plate, adding 1ml of DMEM high-glucose medium for pretreatment overnight, then inoculating 0.5ml of hFTF cells with the concentration of 10000/ml, adding 10ul of CCK-8 reagent into each pore after 24h, then incubating for 2h at 37 ℃, absorbing 100ul of culture medium/CCK-8 mixed liquid in each pore, arranging 3 auxiliary pores in each pore, measuring the absorbance at 450 positions under an enzyme-labeling instrument, and obtaining a graph 8, wherein the rosiglitazone/Pd @ ZIF-8/PHBV membrane with the concentrations of 0% and 2.5% has better biocompatibility;
s3, 2.5% rosiglitazone/Pd @ ZIF-8/PHBV membrane anti-fibrotic effect on hFTF cell fibrosis model: hFTF cells were seeded in 6cm dishes containing approximately 1X106 cells per dish, for a total of 8 groups a: control, no substance added after inoculation of cells; group B: adding 10uM rosiglitazone for pretreatment for 2h, and then adding TGF beta 1; group C: a PHBV (-) group, wherein each dish is added with a 0% rosiglitazone/Pd @ ZIF-8/PHBV membrane with the size of 2X2cm in advance, the membrane is not subjected to 808nm laser irradiation, and TGF beta 1 is added after 2 h; group D: in the PHBV (+) group, 0% rosiglitazone/Pd @ ZIF-8/PHBV film with the size of 2X2cm is added in advance into each dish, the film is subjected to 808nm laser irradiation group, and TGF beta 1 is added after 2 h; group E: adding 2.5% Pd @ ZIF-8/PHBV membrane in advance, carrying out laser irradiation group of 808nm on the membrane, and adding TGF beta 1 after 2 h; and F group: adding 2.5% Pd @ ZIF-8/PHBV membrane in advance, carrying out 808nm laser irradiation on the membrane, and adding TGF beta 1 after 2 hours; group G: adding 2.5% of rosiglitazone/Pd @ ZIF-8/PHBV membrane in advance, carrying out a laser irradiation group with the wavelength of 808nm on the membrane, and adding TGF beta 1 after 2 hours; group H: adding 2.5% rosiglitazone/Pd @ ZIF-8/PHBV membrane in advance, irradiating the membrane with 808nm laser for 2h, adding TGF beta 1, culturing for 24h under constant temperature, and performing subsequent tests;
extracting RNA of each group of cells, performing reverse transcription, and measuring the mRNA expression condition of each fibrosis related gene by using RT-PCR (reverse transcription-polymerase chain reaction) to obtain a figure 9, wherein figure 9 shows that 1. rosiglitazone has an anti-fibrosis effect; 2. no anti-fibrosis effect is seen after the irradiation of near infrared 808 nm; 3. the unloaded membrane has anti-fibrosis effect and is not weaker than the rosiglitazone group; 4. after near-infrared irradiation, the anti-fibrosis capability of the no-load membrane is enhanced, and the near-infrared laser is verified to promote the no-load particle decomposition, so that the no-load membrane has a controlled release effect; 5. the drug-loaded membrane has the function of anti-fibrosis, but has no obvious enhancement effect compared with the idle-load membrane; 6. the anti-fibrosis effect of the drug-loaded membrane after the infrared light irradiation is enhanced, the near-infrared laser is verified to promote the decomposition of the drug-loaded particles, and the drug-loaded membrane has the effect of controlled release; 7. the effect of the drug-loaded membrane after infrared irradiation is stronger than that of the unloaded membrane after infrared irradiation, and the drug-loaded membrane is the group with the optimal anti-fibrosis effect in all groups;
the protein of each group of cells is extracted and Western-blot test is carried out, and the anti-fibrosis effect of the membrane on the hFTF cell fibrosis model can be verified at the protein level.
Test example three:
in vivo experiments (animal experiments):
s1, establishing a rabbit eye filtration type surgical model: new Zealand white rabbits are anesthetized with 3% sodium pentobarbital (30mg/kg) and are fixed on a rabbit table, and then are subjected to simple trabeculectomy under a body microscope. Performing eye puffiness control on rabbit eyes within one week after operation, measuring the intraocular pressure of the rabbit eyes by a Tono-vet rebound tonometer within the same time period every day after operation, recording the condition of filtering bleb, grading, and recording side reaction;
s2, randomly dividing 60 New Zealand white rabbits with the weight of 2.5-3Kg into 6 groups with 120 eyes in total, and uniformly taking the right eye as an operation eye; the experimental groups were as follows:
1) and blank control group: left eyes of each group of experimental rabbits without any surgery and related treatment
2) And blank operation control group: performing GFS operation on 10 eyes of the group, and infiltrating the scleral flap part with physiological saline for 5min in the operation;
3) and positive operation control group: the group of 10 eyes underwent GFS surgery, and the sclera flap was infiltrated with a 0.4mg/ml cotton swab of mitomycin C for 5min during the surgery, and the cotton swab was removed and washed with normal saline.
4) And an air-borne film (-) group: the group of 10 eyes underwent GFS surgery in which 2.5% Pd @ ZIF-8/PHBV membrane was implanted under the scleral flap without post-operative 808nm laser irradiation.
5) And air-supported film (+) group: the group of 10 eyes underwent GFS surgery, in which 2.5% Pd @ ZIF-8/PHBV membrane was implanted under the scleral flap and the implant was post-operatively irradiated with 808nm laser for 5 min.
6) And a drug-loaded film (-) group: the group of 10 eyes underwent GFS surgery in which 2.5% rosiglitazone/Pd @ ZIF-8/PHBV membrane was implanted under the scleral flap without post-operative laser irradiation at 808 nm.
7) And a drug-loaded film (+): the group of 10 eyes underwent GFS surgery with 2.5% rosiglitazone/Pd @ ZIF-8/PHBV membrane implanted under the scleral flap and post-surgery with 808nm laser irradiation of the implant for 5 min.
S3, monitoring intraocular pressure daily after surgery and grading blebs using IBAGS system, and monitoring bleb morphology, filter channel patency and presence of individual membranes weekly after surgery using UBM per group. And performing on-site optical acoustic imaging on the filtering bubble part every month after the operation, and monitoring the content of the nanoparticles of each drug-loaded membrane. At time points of 1W, 2W, 4W, 6W, 8W, and 12W after each operation, tissues of the filtered area were taken for the following experiments:
1) HE staining compares the opening of the filtration channels in each group.
2) The degree of fibrosis was monitored for each group by Masson staining.
3) And immunohistochemical technology, which monitors the expression condition of each fibrosis index by using SP1 Coll gene 1 alpha-SMA CTGF antibody marker.
4) And monitoring the mRNA expression of each fibrosis index in the tissue by using a q-PCR technology.
5) And detecting the expression condition of each fibrosis protein in each group of filtering areas by using Western-blot.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (9)
1. A preparation method and application of a rosiglitazone Pd @ ZIF-8 nanoparticle sustained and controlled release membrane are characterized in that: the method comprises the following steps:
s1, preparing rosiglitazone/Pd @ ZIF-8 nanoparticles, namely mixing a DMSO solution containing nano palladium sheets (Pd) and rosiglitazone with a Zn (NO3)2 aqueous solution, carrying out water bath magnetic stirring for 5 minutes at 20 ℃, adding an aqueous solution of 2-methylimidazole, carrying out magnetic stirring for 30-60 minutes, centrifuging, removing a supernatant, washing for 3 times by using ethanol, and thus obtaining the composite medicament-carrying nanoparticles RSG/Pd @ ZIF-8 doped with the nano Pd sheets;
s2, preparing a composite nano particle/PHBV slow-control membrane, weighing PHBV powder, dissolving the PHBV powder into chloroform TCM solution, and magnetically stirring the solution at the temperature of 60 ℃ for 20 to 30 minutes until the solution is colorless and transparent to prepare PHBV-TCM 55.6mg/ml solution for later use; weighing the composite drug-loaded nano-particles RSG/Pd @ ZIF-8 prepared in S1, dissolving in dimethyl formamide DMF, adding a DMF solution containing nano-particles into the PHBV-TCM solution, and magnetically stirring for 10 minutes at 60 ℃ to obtain a blue-black final spinning solution; transferring the final spinning solution into a glass syringe, fixing the glass syringe into a clamping groove of an injection pump, connecting the positive electrode of a high-voltage power supply with a dull-ground metal needle at the front section of the syringe, connecting the negative electrode of the high-voltage power supply with an aluminum plate coated with aluminum foil paper, keeping the distance between the needle and a receiver at 10-15cm, adjusting the voltage of the high-voltage power supply to 15KV, controlling the propelling speed of the injection pump to be 5-8ml/h, controlling the ambient temperature to be 20-30 ℃ and the humidity to be 20-40%, and performing electrostatic spinning;
and S3, after spinning is finished, the composite nano drug-loaded particles/PHBV sustained-release membrane on the aluminum-foil paper is placed in a fume hood at room temperature for drying for 3 days to remove residual organic solvent.
2. The preparation method of the rosiglitazone-containing Pd @ ZIF-8 nanoparticle sustained and controlled release membrane as claimed in claim 1, wherein the preparation method comprises the following steps: the diameter of the Pd sheet in the S1 is 13-17nm, and the concentration in the DMSO solution is 0.1-1.0 mg/ml.
3. The preparation method of the rosiglitazone-containing Pd @ ZIF-8 nanoparticle sustained and controlled release membrane as claimed in claim 1, wherein the preparation method comprises the following steps: the mass-to-volume ratio of the aqueous solution of Zn (NO3) 2.6H 2O in the S1 is 92 mg/ml.
4. The preparation method of the rosiglitazone-containing Pd @ ZIF-8 nanoparticle sustained and controlled release membrane as claimed in claim 1, wherein the preparation method comprises the following steps: the mass-to-volume ratio of the 2-methylimidazole aqueous solution in the S1 is 257.5 mg/ml.
5. The preparation method of the rosiglitazone-containing Pd @ ZIF-8 nanoparticle sustained and controlled release membrane as claimed in claim 1, wherein the preparation method comprises the following steps: the volume ratio of the Zn (NO3)2 aqueous solution, the DMSO solution and the 2-methylimidazole aqueous solution in the S1 is 1:2: 1.
6. The preparation method of the rosiglitazone-containing Pd @ ZIF-8 nanoparticle sustained and controlled release membrane as claimed in claim 1, wherein the preparation method comprises the following steps: the mass of the PHBV powder in the S2 is 500-1000 mg.
7. The preparation method of the rosiglitazone-containing Pd @ ZIF-8 nanoparticle sustained and controlled release membrane as claimed in claim 1, wherein the preparation method comprises the following steps: the mass-to-volume ratio of the DMF solution containing the composite nano drug-loaded particles in the S2 is 0-50 mg/ml.
8. The preparation method of the rosiglitazone-containing Pd @ ZIF-8 nanoparticle sustained and controlled release membrane as claimed in claim 1, wherein the preparation method comprises the following steps: TCM in the final spinning solution in S2: the volume ratio of DMF is 9: 1.
9. the preparation method of the rosiglitazone-containing Pd @ ZIF-8 nanoparticle sustained and controlled release membrane as claimed in claim 1, wherein the preparation method comprises the following steps: the PHBV powder in S2 can be replaced by PLGA powder.
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