CN114619041B - Cerium-modified gold nanocluster and preparation method and application thereof - Google Patents
Cerium-modified gold nanocluster and preparation method and application thereof Download PDFInfo
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- CN114619041B CN114619041B CN202210283232.7A CN202210283232A CN114619041B CN 114619041 B CN114619041 B CN 114619041B CN 202210283232 A CN202210283232 A CN 202210283232A CN 114619041 B CN114619041 B CN 114619041B
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- Prior art keywords
- cerium
- modified gold
- gold nanocluster
- lipoic acid
- preparation
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229910052684 Cerium Inorganic materials 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 235000019136 lipoic acid Nutrition 0.000 claims abstract description 16
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- HSJPMRKMPBAUAU-UHFFFAOYSA-N cerium(3+);trinitrate Chemical group [Ce+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O HSJPMRKMPBAUAU-UHFFFAOYSA-N 0.000 claims description 8
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- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 claims description 5
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- VGBWDOLBWVJTRZ-UHFFFAOYSA-K cerium(3+);triacetate Chemical compound [Ce+3].CC([O-])=O.CC([O-])=O.CC([O-])=O VGBWDOLBWVJTRZ-UHFFFAOYSA-K 0.000 claims description 3
- OZECDDHOAMNMQI-UHFFFAOYSA-H cerium(3+);trisulfate Chemical compound [Ce+3].[Ce+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O OZECDDHOAMNMQI-UHFFFAOYSA-H 0.000 claims description 3
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- ZMZNLKYXLARXFY-UHFFFAOYSA-H cerium(3+);oxalate Chemical compound [Ce+3].[Ce+3].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O ZMZNLKYXLARXFY-UHFFFAOYSA-H 0.000 claims description 2
- GHLITDDQOMIBFS-UHFFFAOYSA-H cerium(3+);tricarbonate Chemical compound [Ce+3].[Ce+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O GHLITDDQOMIBFS-UHFFFAOYSA-H 0.000 claims description 2
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Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B22—CASTING; POWDER METALLURGY
- B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
- B22F9/00—Making metallic powder or suspensions thereof
- B22F9/16—Making metallic powder or suspensions thereof using chemical processes
- B22F9/18—Making metallic powder or suspensions thereof using chemical processes with reduction of metal compounds
- B22F9/24—Making metallic powder or suspensions thereof using chemical processes with reduction of metal compounds starting from liquid metal compounds, e.g. solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/242—Gold; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/244—Lanthanides; Compounds thereof
-
- 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
-
- 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]
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nanotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- General Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Physics & Mathematics (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- General Physics & Mathematics (AREA)
- Manufacturing & Machinery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to a cerium-modified gold nanocluster, and a preparation method and application thereof. The cerium modified gold nanocluster is prepared by the following method: dissolving lipoic acid and chloroauric acid, mixing, sequentially adding cerium salt and sodium borohydride at pH of 10-12, stirring to react, and purifying the obtained reaction solution. The cerium modified gold nanocluster can effectively treat RA and has very good biological safety.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a cerium-modified gold nanocluster, and a preparation method and application thereof.
Background
Rheumatoid arthritis (Rheumatoid arthritis, RA) is a chronic, systemic immune disease with autoantibody formation and aggressiveness as the main clinical manifestation, and basic pathology changes into persistent inflammation, pain and joint swelling caused by macrophage activation and secretion of a large amount of cytokines, accompanied by chronic inflammation of joint synovium, pannus formation, and gradual destruction of joint cartilage and bone, eventually leading to joint deformity and loss of function. The pathological mechanism of RA is very complex. The first-line drug therapy (non-steroidal anti-inflammatory drugs, antirheumatic drugs, biological agents and glucocorticoid drugs) still has some problems in clinic, such as obvious gastrointestinal reactions of the anti-inflammatory antirheumatic drugs, high blood pressure, secondary diabetes, osteoporosis, liver and kidney damage, gastrointestinal reactions, electrolyte disturbance, disease resistance reduction and the like, excessive cost of the biological agents and the like.
Auranofin (aurofin) is an oral antirheumatic drug containing gold, which can reduce the formation of rheumatoid factors and antibodies thereof, inhibit prostaglandin synthesis and lysozyme release, and block the development of arthritis through the action of complement binding with immunoglobulins. It can be used in combination with non-steroidal drugs to improve cure rate for treating adult rheumatoid arthritis. However, auranofin also has many side effects, such as diarrhea, loose stool, abdominal pain, nausea or other gastrointestinal discomfort, other more common side effects such as rash, itching, stomatitis, conjunctivitis, severe leucocyte and platelet count drop, purpura, simple red blood cell hypoplasia, transient proteinuria or hematuria, glomerulonephritis and nephrotic syndrome, interstitial pneumonia and cornea, lens gold salt deposition, and slight and transient abnormalities in liver function. Therefore, the search for safe and effective therapeutic drugs is a major problem to be solved urgently in RA research.
In recent years, nanomaterials have become a hotspot in biomedical research. The nano gold can play a certain role in treating RA and reduce the side effect of the medicament. However, the pure nano gold has a general curative effect, and additional drugs are required to be loaded, and the introduction of complex factors still has difficulty in avoiding the problems of long-term toxicity and side effects.
Disclosure of Invention
In view of the technical problems, the invention provides a preparation method of cerium-modified gold nanoclusters, and the obtained cerium-modified gold nanoclusters can be used for effectively treating RA and have very good biological safety.
The preparation method of the cerium-modified gold nanocluster provided by the invention comprises the following steps: dissolving lipoic acid and chloroauric acid, mixing, sequentially adding cerium salt and sodium borohydride at pH of 10-12, stirring to react, and dialyzing the obtained reaction solution to obtain the cerium modified gold nanocluster;
the mass ratio of the lipoic acid to the chloroauric acid is 1-3:1;
the molar ratio of the sodium borohydride to the chloroauric acid is 1-3:1, a step of;
the molar ratio of the cerium salt to the chloroauric acid is 0.5-3:100.
Preferably, the lipoic acid is R-lipoic acid, S-lipoic acid or alpha-lipoic acid.
Preferably, the cerium salt is cerium nitrate, cerium sulfate, cerium carbonate, cerium oxalate or cerium acetate.
Preferably, the reaction is continued for 20-36 hours.
Preferably, the purification is dialysis using dialysis bags for 20-30 hours or centrifugation at 2000-10000rpm for 5-30min.
The invention also provides the cerium modified gold nanocluster prepared by the method.
The cerium modified gold nanocluster provided by the invention can be used for preparing anti-inflammatory, antirheumatic and damaged joint repairing medicines.
Preferably, the cerium-modified gold nanoclusters are used for preparing inhibitors of TNF- α and/or PGE 2.
In another aspect, the invention provides a pharmaceutical formulation for treating rheumatoid arthritis comprising the cerium modified gold nanocluster, and a pharmaceutically acceptable adjuvant or carrier.
Compared with the prior art, the invention has the beneficial effects that:
1. because of its small size, metallic nanomaterials are easily oxidized in aqueous solutions, releasing metallic ions, which tend to have greater biotoxicity than nanomaterials. In the cerium modified gold nanocluster provided by the invention, the direct contact between the metal core and the oxide is shielded by the protection of lipoic acid, so that the material exists stably, and meanwhile, the biotoxicity caused by the release of gold ions is avoided.
2. The cerium material itself was found to have a role in mimicking the action of reductase in humans, i.e. anti-inflammatory activity. However, cerium materials alone are often difficult to dissolve in body fluids and are not advantageous for use as an injectable drug. According to the invention, cerium is modified into a metal cluster, and researches show that the modified material has better anti-inflammatory activity compared with methotrexate, and the modified material can be completely mutually dissolved with body fluid. This allows the material to combine the efficacy of gold and cerium metal nanomaterials while facilitating drug delivery in disease.
3. The invention makes the raw materials fully react under the condition of pH10-12, the disulfide bond of lipoic acid is opened, and lipoic acid is degraded into reduced lipoic acid to form two independent sulfhydryl groups; then, the sulfhydryl groups and gold ions form a complex, and the complex forms nanoclusters with small size under the condition of a reducing agent, and the nanocluster materials with small size do not interfere with biological functions and can be cleared in vivo.
4. The material has the effect of treating RA without loading additional therapeutic drugs; and the system is simple, and side effects are not easy to generate.
5. Experiments prove that the cerium modified gold nanocluster provided by the invention can improve joint symptoms, reduce arthritis scores, and inhibit high expression of inflammatory factors such as tumor necrosis factor alpha (TNF-alpha) and prostaglandin 2 (PGE 2).
6. The cerium modified gold nanoclusters have very good biosafety through toxicological analysis, and no side effects were found during the study.
Drawings
FIG. 1 is a reaction mechanism diagram;
FIG. 2 is a state diagram of cerium-modified gold nanoclusters being miscible with PBS solution and water;
FIG. 3 is a state diagram showing the miscibility of cerium-modified gold nanoclusters with physiological saline (left) and glucose (right);
FIG. 4 is a microscopic morphology of cerium modified gold nanoclusters; a-b, morphology and size distribution diagram of gold nanoclusters; c-d, morphology and size distribution diagram of cerium modified gold nanoclusters;
FIG. 5 shows the results of HE staining in animal experiments;
FIG. 6 is a comparison of eosin staining areas of ankle synovial tissue of rats of each group;
FIG. 7 is a comparison of eosin staining areas of ankle bone tissue of each group of rats;
FIG. 8 is the expression of inflammatory factor TNF- α in rats;
FIG. 9 is inflammatory factor PGE2 expression in rats;
FIG. 10 is an improvement of ankle arthritis in animal experiments;
FIG. 11 is an in vivo toxicity profile for different groups of rats (Heart, liver, spleen, spleen, lung, lung, kidney, kidney).
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the following examples of the invention, M is the molar concentration, i.e. mol/L; mu M is micromole per liter and mM is millimole per liter.
Example 1
The preparation method of the cerium-modified gold nanocluster specifically comprises the following steps:
5.2mg of R-lipoic acid was added to a 50mL beaker at room temperature, 16mL of distilled water was added, and then 100. Mu.L (1 mol/L) of sodium hydroxide was injected. Next, chloroauric acid solution (chloroauric acid solution was prepared by preparing 5.0mg chloroauric acid into a solution with a mass fraction of 0.2%) was injected, and 5. Mu.L (10 mM) of cerium nitrate was added under the condition that 100. Mu.L of 100mM sodium borohydride was added so that the material was not aggregated. The mixture was stirred for five minutes and the reaction continued for an additional 24 hours (the reaction mechanism is shown in figure 1). The samples were transferred to dialysis bags (MWCO.3500) of about 3-5cm in length and 1cm in width. Then, the dialysis bag was placed in a 2L beaker containing 1L of ultrapure water. The mixture was stirred with a magnetic stirrer at room temperature at about 500 rpm. Thus, the sample was dialyzed for 24 hours to obtain a purified sample.
The reaction mechanism of the cerium modified gold nanocluster preparation process is shown in fig. 1.
The cerium modified gold nanocluster can be used by intravenous injection; the injection can be any physiological saline, glucose, sterile water for injection, etc.
FIG. 2 is a state diagram of cerium-modified gold nanoclusters dissolved in PBS solution and water, respectively, and a state diagram after 30 days of standing. As can be seen from fig. 2, the PBS solution and the aqueous solution of the cerium-modified gold nanoclusters have better stability.
FIG. 3 is a state diagram of a cerium-modified gold nanocluster dissolved in physiological saline and glucose, illustrating that the cerium-modified gold nanocluster is miscible with body fluids.
The micro-morphology of the prepared cerium-modified gold nanocluster is shown in fig. 4. The transmission electron microscope result shows that the gold cluster is smaller than 2nm, and the size of the material is slightly increased but still smaller than 2nm after Ce modification. According to the high-definition transmission electron microscope, the gold clusters and the cerium-modified gold clusters are uniformly distributed to form single twin crystal structures and polyhedral crystal structures respectively. The results of the transmission electron microscope verify the successful formation of gold nanoclusters and cerium-modified gold nanoclusters.
Example 2
The preparation method of the cerium-modified gold nanocluster specifically comprises the following steps:
15.6mg of R-lipoic acid was added to a 50mL beaker at room temperature. Next, 16mL of distilled water was added, then 200 μl (1 mol/L) of sodium hydroxide was injected, next, chloroauric acid solution (chloroauric acid solution was prepared by taking 5.0mg of chloroauric acid to prepare a solution with a mass fraction of 0.2%) was injected, then 300 μl of 100mM sodium borohydride was added, the mixture was stirred for five minutes, and the reaction continued for 36 hours; mu.L (10 mM) of cerium sulfate was added to the solution to prepare a suspension. Centrifugation at 4000rpm, the supernatant was discarded, leaving a bottom precipitate. The precipitate was redispersed by dropping an appropriate volume of 0.1mol/L sodium hydroxide. The samples were transferred to dialysis bags (MWCO.3500) of about 3-5cm in length and 1cm in width. Then, the dialysis bag was placed in a 2L beaker containing 1L of ultrapure water. The mixture was stirred at room temperature using a magnetic stirrer at a speed of about 500 rpm. Thus, the sample was dialyzed for 30 hours to obtain a purified sample.
Example 3
The preparation method of the cerium-modified gold nanocluster specifically comprises the following steps:
5.2mg of S-lipoic acid was added to a 50mL beaker at room temperature. Next, 16mL of distilled water was added, followed by injection of 100. Mu.L (1 mol/L) of sodium hydroxide. Next, chloroauric acid solution (chloroauric acid solution was prepared by preparing 5.0mg chloroauric acid into a solution with a mass fraction of 0.2%) was injected, and 16. Mu.L (10 mM) of cerium nitrate was added under the condition that 200. Mu.L of 100mM sodium borohydride was added so that aggregation of the material did not occur. The mixture was stirred for five minutes and the reaction continued for an additional 24 hours (the reaction mechanism is shown in figure 1). The sample was centrifuged at 2000rpm for 30min and the supernatant was collected to obtain a purified sample.
Example 4
The preparation method of the cerium-modified gold nanocluster specifically comprises the following steps:
10.4mg (. + -.) -alpha lipoic acid was added to a 50mL beaker at room temperature, then 16mL of distilled water was added, then 200. Mu.L (1 mol/L) of sodium hydroxide was injected, then a chloroauric acid solution (chloroauric acid solution was prepared as a solution with a mass fraction of 0.2% by taking 5.0mg chloroauric acid), then 100. Mu.L of 100mM sodium borohydride was added, the mixture was stirred for five minutes, the reaction was continued for 20 hours, 32. Mu.L (10 mM) of cerium acetate was added to make the solution a suspension, centrifuged at 4000rpm, the supernatant was discarded, leaving a bottom precipitate, an appropriate volume of 0.1mol/L of sodium hydroxide was dropped, and the precipitate was redispersed, the sample was transferred to a dialysis bag (MWCO.3500) of about 3-5cm in length and 1cm width, then the dialysis bag was put into a 2L large beaker containing 1L of ultrapure water, stirred with a magnetic stirrer at room temperature for 20 hours.
Experimental example
1. Method of
About 40 cleaning grade 200 grams SD rats were randomly divided into a Sham (Sham) group, a positive control (PBS) group, a Methotrexate Treatment (MTX) group, and a cerium modified gold nanocluster group (expressed as R-DHLA-AuNCs-Ce) by body weight (as also referred to as treatment group of the present invention).
Taking 0.3g of glacial acetic acid, adding purified water for dissolution, fixing 100mL of volume, and storing at normal temperature for standby. 5mg of type II collagen was taken and 2.5mL of 0.05M Freund's adjuvant was added to prepare a collagen-Freund's adjuvant solution having a concentration of 2 mg/mL. A Hamilton syringe was used to subcutaneously inject a collagen-freund's adjuvant solution into the tail of the animals, 200 μl per rat. 7 days after the first immunization, the boost immunization was performed. The collagen-IFA emulsion was subcutaneously injected into the ankle joint of animals using a syringe, and 100 μl of each rat of the positive control group, methotrexate-treated group, and R-DHLA-AuNCs-Ce group was injected with a booster injection 1 time after 21 days. The effect of the R-DHLA-AuNCs-Ce group was demonstrated by intravenous injection of 100. Mu.l/cerium-modified gold nanocluster prepared in example 1 only (the properties of the cerium-modified gold nanoclusters prepared in examples 1 to 4 were substantially the same, so the cerium-modified gold nanocluster prepared in example 1 was used only as an example to prepare a 300. Mu.M solution with physiological saline), and the Sham group and the positive control group were intravenous injected with an equivalent amount of physiological saline 2 times per week, and the methotrexate treatment group was injected with methotrexate (0.5 mg/kg) per week. Ankle joints were obtained after 4 weeks of continuous treatment, 10 μm frozen specimens were prepared, and hematoxylin-eosin (HE) staining was performed to observe inflammatory infiltration, synovial hyperplasia, and joint bone destruction.
2. HE staining detection of experimental animals
SD rat ankle joint was harvested, fixed with 10% Paraformaldehyde (PFA) for 48h, washed with Phosphate Buffer (PBS) for 30 days, decalcified with EDTA decalcified solution, changed every 5 days, embedded in a frozen microtome, sagittal sections (10 μm) were routinely HE stained in a fume hood (distilled water wash 5 min. Times. Zhong Shui hematoxylin stain 45 sec. Water wash 25 min. Minute. Hydrochloric acid ethanol differentiation 10 sec. Distilled water wash 5 min. 3 Zhong Yigong stain 1 min. Distilled water wash 5 min. Times. Zhong Shuixi alcohol% ethanol 5 min. Zhong Chun% ethanol 5 min. Zhong Chun% ethanol 5 min. Zhong Chun% ethanol 5 min. Absolute ethanol 5 min. Xylene 10 min. Times. Zhong Ben neutral resin sealing sheet were placed in a fume hood and observed under a microscope overnight.
As shown in FIGS. 5 to 7, in the ankle joint of the Sham rat, the composition of eosin-stained bone tissue and synovial tissue was seen, and the presence of hematoxylin cell nucleus-stained inflammatory tissue was not seen. In the ankle joints of the positive control rats, extensive hematoxylin cell nucleus-stained inflammatory tissue infiltration occurred, while eosin-stained bone tissue was significantly reduced. Compared with the positive control group, the R-DHLA-AuNCs-Ce group has obviously reduced inflammatory area and synovial hyperplasia area, and the synovial area is lower than that of the positive control group. In addition, the R-DHLA-AuNCs-Ce group showed significantly less bone destruction than the methotrexate treated group. The results indicate that R-DHLA-AuNCs-Ce reduces joint inflammation of RA rats and reduces the damage of the inflammation to joint bone tissue and cartilage tissue, and the R-DHLA-AuNCs-Ce is an effective drug for preventing and treating RA.
3. ELISA detection of experimental animals
After the SD rat fundus was bled, whole blood was left at room temperature for 45 minutes. Does not need to shake vigorously to avoid hemolysis, and after the whole blood is naturally coagulated and the serum is separated out, the whole blood is centrifugated at the temperature of between 1000 and 2000g for 10 minutes at the temperature of 4 ℃ to obtain the serum by taking yellow supernatant, and the white or light yellow sediment is not required to be sucked. The prepared serum is placed on ice for standby. Preparing a proper amount of standard substance diluent: the standard dilutions (5 min) were diluted to 1 with deionized water, the washes (20 washes) were diluted to 1 with deionized water and incubated for 15 min at room temperature. The standard was then thoroughly dissolved by gentle mixing and blowing with a pipette several times. The final standard concentration was then brought to 2000pg/ml and used after mixing. 250 μl of standard dilution is added in advance to each tube, and the dilution is performed to obtain six standard concentrations of 2000, 1000, 500, 250, 125 and 62.5 pg/ml. Finally, the diluted standard substances are sequentially added into the pre-coated plate holes, and the standard substance diluent is directly added as the concentration of 0pg/ml, and the total concentration of seven standard substances is seven. Samples or standards of different concentrations were added to the corresponding wells at 100 μl/well, and the reaction wells were sealed with a sealing plate membrane (transparent) and incubated at room temperature for 120 minutes. The plate is washed 5 times, and finally the plate is placed on thick water absorbing paper for beating. 100 μl/well of biotinylated antibody was added. The reaction wells were sealed with a sealing plate membrane (transparent) and incubated for 1 hour at room temperature. The plate is washed 5 times, and finally the plate is placed on thick water absorbing paper for beating. Horseradish peroxidase-labeled strepitavidin was added at 100 μl/well. The reaction wells were sealed with a sealing plate membrane (white), and incubated at room temperature for 20 minutes in the dark. The plate is washed 5 times, and finally the plate is placed on thick water absorbing paper for beating. The stop solution was added at 50. Mu.l/well, and the A450 value was measured immediately after mixing.
As shown in fig. 8-9, TNF-serum and PGE2 expression was significantly increased in serum samples from rats in the positive control group compared to Sham group. The R-DHLA-AuNCs-Ce group TNF-s and PGE2 expression were significantly reduced compared to the positive control group. In addition, R-DHLA-AuNCs-Ce group TNF-s and PGE2 expression were also reduced compared to the methotrexate-treated group. The above results suggest that R-DHLA-AuNCs-Ce alleviates the systemic inflammatory response in RA rats.
4. Arthritis index detection in experimental animals
The condition and joint swelling of the rats were observed daily and the arthritis of the rats was scored at 12, 16, 20, 24 and 28 days after the second immunization, as follows: 0 = normal; 1 = mild, but with a pronounced ankle or wrist joint redness, or a pronounced single toe redness, irrespective of the number of affected toes; 2 = moderate ankle or wrist redness; 3 = severe red swelling of the entire paw including the toe; 4 = maximum inflammation of the affected limb of the multi-joint.
As shown in FIG. 10, the arthritis index of the R-DHLA-AuNCs-Ce group was significantly decreased as compared to the positive control group. Furthermore, the arthritis index was significantly decreased in the R-DHLA-AuNCs-Ce group compared to the methotrexate treated group.
5. In vivo toxicity detection in laboratory animals
SD rat heart, liver, lung, spleen and kidney were harvested, fixed with 10% Paraformaldehyde (PFA) for 3 days, dehydrated with 10% Paraformaldehyde (PFA) containing 30% sucrose for 3 days, embedded in a frozen microtome, sagittal sections (10 μm) were routinely HE stained in a fume hood (distilled water wash 5 min. Times. Zhong Shui hematoxylin stain 45 seconds → water wash 25 minutes → clock ethanol differentiation 10 seconds → distilled water wash 5 min 3 Zhong Yigong stain 1 minute → distilled water wash 5 min. Times. Zhong Shui wash 5 min → Zhong Chun% ethanol 5 min → Zhong Chun% ethanol 5 min, zhong Chun% ethanol 5 min → 8625% ethanol 5 min, 10 min xylene x Zhong Ben neutral resin seal after standing overnight in a fume hood.
As shown in FIG. 11, the important organs of the R-DHLA-AuNCs-Ce group were not abnormal as compared with the normal group.
The above results suggest that R-DHLA-AuNCs-Ce treats RA rats and is non-toxic.
The foregoing has shown and described the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made therein without departing from the spirit and scope of the invention, which is defined by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. The preparation method of the cerium-modified gold nanocluster for treating rheumatoid arthritis is characterized by comprising the following steps of: dissolving lipoic acid and chloroauric acid, mixing, sequentially adding cerium salt and sodium borohydride under the condition of pH of 10-12, stirring to react, and purifying the obtained reaction solution to obtain the cerium modified gold nanocluster;
wherein the mass ratio of the lipoic acid to the chloroauric acid is 1-3:1;
the molar ratio of the sodium borohydride to the chloroauric acid is 1-3:1, a step of;
the molar ratio of the cerium salt to the chloroauric acid is 0.5-3:100;
the reaction is continuous reaction 20-36 h;
the purification is to dialyze 20-30h with a dialysis bag or centrifuge at 2000-10000rpm for 5-30min;
the prepared cerium-modified gold nanocluster can improve joint symptoms, reduce arthritis scores, and inhibit high expression of tumor necrosis factor alpha and prostaglandin 2.
2. The method for preparing a cerium-modified gold nanocluster according to claim 1, wherein the lipoic acid is R-lipoic acid, S-lipoic acid or α -lipoic acid.
3. The method for preparing the cerium-modified gold nanoclusters according to claim 2, wherein the cerium salt is cerium nitrate, cerium sulfate, cerium carbonate, cerium oxalate or cerium acetate.
4. A cerium-modified gold nanocluster prepared according to the method of any one of claims 1 to 3.
5. Use of the cerium modified gold nanocluster according to claim 4 for the preparation of a medicament for anti-inflammatory, antirheumatic and repair of damaged joints.
6. The use according to claim 5, characterized in that the cerium modified gold nanoclusters are used for the preparation of inhibitors of TNF-a and/or PGE 2.
7. A pharmaceutical formulation for the treatment of rheumatoid arthritis, comprising the cerium modified gold nanoclusters of claim 4 and a pharmaceutically acceptable adjuvant or carrier.
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| CN113953522A (en) * | 2020-07-20 | 2022-01-21 | 华南师范大学 | Electropositive gold nanocluster and preparation method and application thereof |
| CN111849467A (en) * | 2020-08-11 | 2020-10-30 | 苏州大学 | Infrared II-region fluorescence gold nanocluster and preparation and application thereof |
| CN113318272A (en) * | 2021-04-22 | 2021-08-31 | 南京大学 | Bone implantation material based on nano enzyme drug modification and preparation method and application thereof |
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