CN114619041A - Cerium-modified gold nanocluster and preparation method and application thereof - Google Patents
Cerium-modified gold nanocluster and preparation method and application thereof Download PDFInfo
- Publication number
- CN114619041A CN114619041A CN202210283232.7A CN202210283232A CN114619041A CN 114619041 A CN114619041 A CN 114619041A CN 202210283232 A CN202210283232 A CN 202210283232A CN 114619041 A CN114619041 A CN 114619041A
- Authority
- CN
- China
- Prior art keywords
- cerium
- modified gold
- gold nanocluster
- lipoic acid
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
The invention relates to the technical field of medicines, and particularly relates 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 the pH of 10-12, stirring for reaction, and purifying the obtained reaction solution to obtain the alpha-lipoic acid. 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, and particularly relates to a cerium-modified gold nanocluster and a preparation method and application thereof.
Background
Rheumatoid Arthritis (RA) is a chronic, systemic immune disease with autoantibody formation and aggressive, major clinical manifestations, with a fundamental pathological shift to persistent inflammation, pain and joint swelling caused by macrophage activation and secretion of large amounts of cytokines, accompanied by chronic inflammation of the joint synovium, pannus formation, and progressive cartilage and bone destruction, ultimately leading to joint deformity and loss of function. The pathological mechanisms of RA are very complex. The existing first-line clinical drug therapy (non-steroidal anti-inflammatory drugs, antirheumatic drugs, biological agents and glucocorticoid drugs) still has some problems, for example, the anti-inflammatory and antirheumatic drugs have obvious gastrointestinal reactions, the glucocorticoid therapy is easy to cause blood pressure rise, secondary diabetes, osteoporosis, liver and kidney damage, gastrointestinal reactions, electrolyte disorder, disease resistance reduction and the like, and the cost of the biological agent is too high.
Auranofin (Auranofin) is a gold-containing oral antirheumatic drug, which can reduce the formation of rheumatoid factor and its antibody, inhibit the synthesis of prostaglandin and the release of lysozyme, and block the development of arthritis by the action of combining with immunoglobulin complement. It can be used in combination with non-steroidal drugs to improve the cure rate and treat adult rheumatoid arthritis. However, auranofin also has many side effects, such as diarrhea, loose stools, occasional abdominal pain, nausea or other gastrointestinal discomfort, and other more common side effects of rash, itching, stomatitis, conjunctivitis, severe leukopenia and thrombocytopenia, purpura, hypoplasia of pure red blood cells, transient proteinuria or hematuria, glomerulonephritis and nephrotic syndrome, interstitial pneumonia and corneal, lens gold salt deposition, and occasional 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 the research of RA.
In recent years, nanomaterials are becoming hot spots for biomedical research. The nano-gold can play a certain role in treating RA and reduce the side effect of the medicament. However, the pure nanogold has a common curative effect, needs to be loaded with additional drugs, and the introduction of complex factors still cannot avoid the problems of long-term toxicity and side effects.
Disclosure of Invention
In view of the above technical problems, the present invention provides a method for preparing a cerium-modified gold nanocluster, which can effectively treat RA and has excellent biosafety.
The preparation method of the cerium modified gold nanocluster provided by the invention is carried out according to the following steps: dissolving lipoic acid and chloroauric acid, mixing, sequentially adding cerium salt and sodium borohydride at the pH value of 10-12, stirring for reaction, 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;
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 to 36 h.
Preferably, the purification is dialysis for 20-30h using dialysis bags or centrifugation at 2000-10000rpm for 5-30 min.
The invention also provides a cerium modified gold nanocluster prepared according to the method.
The cerium modified gold nanocluster provided by the invention can be used for preparing medicines for resisting inflammation and rheumatism and repairing damaged joints.
Preferably, the cerium-modified gold nanoclusters are used for preparing inhibitors of TNF-a and/or PGE 2.
In another aspect, the present invention provides a pharmaceutical preparation for treating rheumatoid arthritis, which comprises 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. the metal nano material is easy to be oxidized in aqueous solution due to small size, so that metal ions are released, and the metal ions are often more toxic than the nano material. In the cerium modified gold nanocluster provided by the invention, the direct contact between a metal core and an oxide is shielded under the protection of lipoic acid, so that the material stably exists, and the biotoxicity caused by the release of gold ions is avoided.
2. The cerium material itself was found to have a role in mimicking reductase in the human body, i.e. anti-inflammatory activity. However, cerium materials alone are often difficult to dissolve in body fluids, and are not conducive to use as injectable drugs. According to the invention, cerium is modified into a metal cluster, and researches show that the modified material generates better anti-inflammatory activity compared with methotrexate, and the material can be completely dissolved with body fluid. This allows the material to combine the effects of both gold and cerium 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 the lipoic acid is opened, the lipoic acid is degraded into reduced lipoic acid, and two independent sulfydryl groups are formed; then, the sulfydryl and gold ions form a complex, the complex forms nanoclusters with small sizes under the condition of a reducing agent, and the small-size nanocluster materials do not interfere with biological functions and can be removed in vivo.
4. The material has the effect of treating RA, and no additional treatment medicine is required to be loaded; and the system is simple and is not easy to generate side effects.
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 effect is found in the research period.
Drawings
FIG. 1 is a reaction scheme;
FIG. 2 is a state diagram of cerium-modified gold nanoclusters being miscible with PBS solution and water;
fig. 3 is a diagram showing the state in which cerium-modified gold nanoclusters are soluble in physiological saline (left) and glucose (right);
fig. 4 is a microstructure of cerium modified gold nanoclusters; a-b, the morphology and size distribution map of gold nanoclusters; c-d, modifying the morphology and size distribution map of the gold nanoclusters by cerium;
FIG. 5 is the results of HE staining assays in animal experiments;
FIG. 6 is a comparison of eosin stained areas of synovial tissue of ankle joints of rats in each group;
FIG. 7 is a comparison of eosin staining areas of ankle bone tissue of rats in each group;
FIG. 8 is inflammatory factor TNF- α expression in rats;
FIG. 9 is the inflammatory factor PGE2 expression in rats;
FIG. 10 shows experimental ankle arthritis improvement in animals;
FIG. 11 is the toxicity profile in different groups of rats (Heart; Liver; Spleen, Spleen; Lung, Lung; Kidney, Kidney).
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.
In the following examples of the invention, M is the molar concentration, i.e., mol/L; μ M is micromoles per liter and mM is millimoles per liter.
Example 1
A preparation method of a 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 (1mol/L) of sodium hydroxide was injected. Next, a chloroauric acid solution (5.0 mg of chloroauric acid was prepared as a 0.2% solution) was injected, and 5. mu.L (10mM) of cerium nitrate was added thereto, while 100. mu.L of 100mM sodium borohydride was added to prevent aggregation of the material. 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) approximately 3-5cm long and 1cm wide. Then, the dialysis bag was placed in a 2L beaker containing 1L of ultrapure water. Stirring was carried out at room temperature with a magnetic stirrer at about 500 rpm. Dialyzed thus for 24h to obtain a purified sample.
The reaction mechanism of the preparation process of the cerium modified gold nanocluster is shown in figure 1.
The cerium modified gold nanocluster can be subjected to intravenous injection when in use; the injection can be selected from normal saline, glucose, and sterile water for injection.
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 cerium-modified gold nanoclusters dissolved in physiological saline and glucose, illustrating that the cerium-modified gold nanoclusters are miscible with body fluids.
The micro-morphology of the prepared cerium-modified gold nanoclusters is shown in fig. 4. The result of a transmission electron microscope shows that the gold cluster is less than 2nm, and the material size is slightly increased but still less than 2nm by modification of Ce. According to a high-definition transmission electron microscope, the gold clusters and the cerium-modified gold clusters are uniformly distributed and respectively form a single twin crystal structure and a polyhedral crystal structure. The results of the transmission electron microscope verify the successful formation of the gold nanoclusters and the cerium-modified gold nanoclusters.
Example 2
A preparation method of a 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 μ L (1mol/L) of sodium hydroxide was injected, next, chloroauric acid solution (5.0 mg of chloroauric acid was prepared as a 0.2% mass solution) was injected, then 300 μ L of 100mM sodium borohydride was added, the mixture was stirred for five minutes, and the reaction was continued for another 36 hours; 30 μ L (10mM) of cerium sulfate was added to make the solution into a suspension. Centrifugation was carried out at 4000rpm and the supernatant was discarded, leaving a bottom precipitate. The appropriate volume of 0.1mol/L NaOH was added dropwise to redisperse the precipitate. The samples were transferred to dialysis bags (MWCO.3500) approximately 3-5cm long and 1cm wide. Then, the dialysis bag was placed in a 2L beaker containing 1L of ultrapure water. Stirring was carried out at room temperature using a magnetic stirrer at about 500 rpm. The purified sample was thus obtained by dialysis for 30 h.
Example 3
A preparation method of a 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 (1mol/L) of sodium hydroxide. Next, a chloroauric acid solution (5.0 mg of chloroauric acid was prepared as a 0.2% solution) was injected, and then, under the condition that 200. mu.L of 100mM sodium borohydride was added to prevent aggregation of the material, 16. mu.L (10mM) of cerium nitrate was added. 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
A preparation method of a cerium modified gold nanocluster specifically comprises the following steps:
adding 10.4mg (±) - α lipoic acid to a 50mL beaker at room temperature, then adding 16mL distilled water, then adding 200 μ L (1mol/L) sodium hydroxide, then adding chloroauric acid solution (5.0 mg chloroauric acid is prepared as a 0.2% by mass solution), then adding 100 μ L100mM sodium borohydride, stirring the mixture for five minutes, reacting for another 20 hours, adding 32 μ L (10mM) cerium acetate, allowing the solution to become a suspension, centrifuging at 4000rpm, discarding the supernatant, leaving a bottom precipitate, dropping an appropriate volume of 0.1mol/L sodium hydroxide, redispersing the precipitate, transferring the sample to a dialysis bag (mwco.3500) having a length of about 3 to 5cm and a width of 1cm, placing the dialysis bag in a 2L beaker containing 1L of ultrapure water, magnetically stirring at room temperature with a stirrer, dialyzing at about 500rpm for 20 hours, obtaining a purified sample.
Examples of the experiments
1. Method of producing a composite material
About 200 g of SD rats of 40 cleaning grades were randomly divided by body weight into a Sham (Sham) group, a positive control (PBS) group, a Methotrexate Treatment (MTX) group, and a cerium-modified gold nanocluster group (denoted by R-DHLA-aucns-Ce) (referred to as a treatment group, as the present invention).
0.3g of glacial acetic acid is taken, is added with purified water to dissolve and have a constant volume of 100mL, and is stored at normal temperature for standby. 5mg of type II collagen is taken and added with 2.5mL of 0.05M Freund's adjuvant to prepare a collagen-Freund's adjuvant solution with the content of 2 mg/mL. The tail roots of the animals were injected subcutaneously with collagen-Freund's adjuvant solution using a Hamilton syringe, 200. mu.l per rat. 7 days after the first immunization, the booster immunization was performed. The collagen-IFA emulsion was injected subcutaneously into the ankle of animals using a syringe, and 100. mu.l of each rat was injected into the positive control group, the methotrexate-treated group and the R-DHLA-AuNCs-Ce group, and the injections were given 1 time after 21 days as a booster. R-DHLA-AuNCs-Ce group was intravenously injected 2 times a week with 100 μ l/one of the cerium-modified gold nanoclusters prepared in example 1 (since the performance of the cerium-modified gold nanoclusters prepared in examples 1 to 4 was substantially the same, the effect was described here only with the cerium-modified gold nanoclusters prepared in example 1 as an example, which were prepared in a 300 μ M solution with physiological saline), Sham group and positive control group were intravenously injected 2 times a week with an equivalent amount of physiological saline, and methotrexate-treated group was intravenously injected weekly with methotrexate (0.5 mg/kg). Continuously treating ankle joint after 4 weeks, collecting material, preparing 10 μm frozen specimen, and staining with hematoxylin-eosin (HE) to observe inflammatory infiltration, synovial hyperplasia and joint bone destruction.
2. HE staining assay for laboratory animals
SD rats were collected on ankle joints, fixed with 10% Paraformaldehyde (PFA) for 48 hours, soaked and washed with Phosphate Buffered Saline (PBS), decalcified with EDTA decalcifying solution for 30 days, changed every 5 days, soaked and washed with PBS, embedded in a microtome, sectioned in sagittal position (10 μm), and subjected to conventional HE staining in a fume hood (distilled water washing 5 minutes × Stachys stachyose lignin staining solution 45 seconds → water washing 25 minutes → Stachys% hydrochloric acid ethanol differentiation 10 seconds → distilled water washing 5 minutes 3 minutes eosin staining solution 1 minute → distilled water washing 5 minutes × Stachys% ethanol washing 5 minutes → Stachys% ethanol 5 minutes → anhydrous ethanol 5 minutes → xylene 10 minutes × Stachys benzene neutral gum sealing sheet, placed in the fume hood overnight and observed under a microscope.
As shown in FIGS. 5 to 7, in the ankle joints of Sham rats, the composition of bone tissue and synovial tissue stained with eosin was observed, and no inflammatory tissue stained with hematoxylin nuclei was observed. In the ankle joints of rats in the positive control group, large-area hematoxylin nucleus-stained inflammatory tissue infiltration occurs, while eosin-stained bone tissue is obviously reduced. Compared with the positive control group, the inflammatory area and the synovial hyperplasia area of the R-DHLA-AuNCs-Ce group are obviously reduced, and the synovial area is lower than that of the positive control group. In addition, bone destruction was significantly reduced in the R-DHLA-AuNCs-Ce group compared to the methotrexate-treated group. The results indicate that the R-DHLA-AuNCs-Ce can reduce the joint inflammation of RA rats and reduce the injury of the inflammation to joint bone tissues and cartilage tissues, and the R-DHLA-AuNCs-Ce is an effective medicament for preventing and treating RA.
3. ELISA detection of laboratory animals
After blood was collected from the fundus of the SD rat, the whole blood was left at room temperature for 45 minutes. Without violent shaking to avoid hemolysis, after the whole blood is naturally coagulated and the serum is separated out, centrifuging at the temperature of 4 ℃ at 2000g for 10 minutes, taking yellow supernatant to obtain the serum, and paying attention not to suck white or light yellow precipitate. The prepared serum needs to be placed on ice for standby. Preparing an appropriate amount of standard dilution: the standard dilution (5 minutes) was diluted to 1 use with deionized water, wash (20 washes) was diluted to 1 use with deionized water, and incubated for 15 minutes at room temperature. The standards were then gently mixed and blown several times with a pipette to dissolve completely. Then, the final concentration of the standard product is 2000pg/ml, and the standard product is combined and mixed evenly for use. 250 mul of standard dilution liquid is added in each tube in advance, and the standard is diluted by times to finally obtain six standard concentrations of 2000, 1000, 500, 250, 125 and 62.5 pg/ml. And finally, sequentially adding the diluted standard substance into the holes of the pre-coated plate, and directly adding the standard substance diluent as the concentration of 0pg/ml, wherein the total concentration of seven standard substances is seven. Samples or standards of different concentrations were added to the corresponding wells at 100. mu.l/well, the reaction wells were sealed with a sealing plate (clear), and incubated at room temperature for 120 minutes. The plate was washed 5 times and the last time was patted dry on thick absorbent paper. Biotinylated antibody was added at 100. mu.l/well. The reaction wells were sealed with a plate-sealing membrane (clear) and incubated at room temperature for 1 hour. The plate was washed 5 times and the last time was patted dry on thick absorbent paper. 100. mu.l/well of Streptavidin was labeled with horseradish peroxidase. The reaction wells were sealed with a sealing plate (white) and incubated at room temperature in the dark for 20 min. The plate was washed 5 times and the last time was patted dry on thick absorbent paper. Add stop solution 50. mu.l/well and measure A450 value immediately after mixing.
As shown in FIGS. 8-9, serum samples from positive control rats showed significantly increased expression of TNF-serum and PGE2 compared to the Sham group. Compared with the positive control group, the expression of TNF-s and PGE2 in the R-DHLA-AuNCs-Ce group is obviously reduced. In addition, TNF-s and PGE2 expression was also reduced in the R-DHLA-AuNCs-Ce group compared to the methotrexate treated group. The above results suggest that R-DHLA-AuNCs-Ce reduces systemic inflammatory response in RA rats.
4. Arthritis index detection in laboratory animals
The condition and joint swelling were observed daily and rats were scored for arthritis on days 12, 16, 20, 24 and 28 after the second immunization according to the following criteria: 0 is normal; 1 is mild, but has obvious red swelling of ankle or wrist joints or obvious red swelling of single toes, and has no relation with the number of affected toes; 2, moderate redness and swelling of the ankle or wrist; severe redness of the entire paw, including the toes; maximum inflammation of the affected limb at multiple joints.
As shown in FIG. 10, the arthritis index was significantly decreased in the R-DHLA-AuNCs-Ce group compared to the positive control group. In addition, the arthritis index was significantly decreased in the R-DHLA-AuNCs-Ce group compared to the methotrexate-treated group.
5. In vivo toxicity testing in laboratory animals
SD rats were obtained from heart, liver, lung, spleen and kidney, fixed with 10% Paraformaldehyde (PFA) for 3 days, dehydrated with 10% Paraformaldehyde (PFA) containing 30% sucrose for 3 days, soaked and washed with PBS, embedded in a microtome, sectioned in sagittal position (10 μm), and subjected to conventional HE staining in a fume hood (distilled water washing 5 minutes × Stachys lignin staining solution for 45 seconds → water washing 25 minutes → Stachys% hydrochloric acid ethanol differentiation 10 seconds → distilled water washing 5 minutes 3 minutes eosin staining solution for 1 minute → distilled water washing 5 minutes × Stachys water washing% ethanol 5 minutes → Stachys% ethanol 5 minutes → anhydrous ethanol 5 minutes → xylene 10 minutes × Stachys benzene neutral coversheet placed in the fume hood overnight and observed under a microscope.
As shown in FIG. 11, the important organs in 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 without toxicity.
The foregoing shows and describes the general principles, essential 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, which are merely illustrative of the principles of the invention, but that various changes and modifications may be made without departing from the spirit and scope of the invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (9)
1. A preparation method of a cerium modified gold nanocluster is characterized by comprising the following steps: dissolving lipoic acid and chloroauric acid, mixing, sequentially adding cerium salt and sodium borohydride under the condition of pH10-12, stirring to react, and purifying the obtained reaction liquid 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;
the molar ratio of the cerium salt to the chloroauric acid is 0.5-3: 100.
2. The method of preparing a cerium modified gold nanocluster of claim 1, wherein said lipoic acid is R-lipoic acid, S-lipoic acid or α -lipoic acid.
3. The method of preparing a cerium-modified gold nanocluster according to claim 2, wherein the cerium salt is cerium nitrate, cerium sulfate, cerium carbonate, cerium oxalate or cerium acetate.
4. The method of preparing a cerium-modified gold nanocluster according to claim 1, wherein said reaction is a continuous reaction for 20 to 36 hours.
5. The method of claim 4, wherein the purification is dialysis for 20-30h using a dialysis bag or centrifugation at 2000-10000rpm for 5-30 min.
6. A cerium-modified gold nanocluster prepared according to the method of any one of claims 1 to 5.
7. Use of the cerium-modified gold nanoclusters of claim 6 in preparation of medicaments for anti-inflammation, anti-rheumatism and repair of damaged joints.
8. The use according to claim 7, wherein the cerium-modified gold nanoclusters are used for the preparation of inhibitors of TNF-a and/or PGE 2.
9. A pharmaceutical preparation for treating rheumatoid arthritis, comprising the cerium-modified gold nanoclusters of claim 6, 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 |
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| CN114767851A (en) * | 2022-04-06 | 2022-07-22 | 中国科学院遗传与发育生物学研究所 | Gold nanocluster, preparation method thereof and application of gold nanocluster in preparation of medicine for treating tumors through radiation dynamics |
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