CN112707853B - Tellurium-containing compound, method for preparing tellurium gold nanoparticles by using tellurium-containing compound and application of tellurium gold nanoparticles in preparing antitumor drugs - Google Patents
Tellurium-containing compound, method for preparing tellurium gold nanoparticles by using tellurium-containing compound and application of tellurium gold nanoparticles in preparing antitumor drugs Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C395/00—Compounds containing tellurium
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- 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
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B19/00—Selenium; Tellurium; Compounds thereof
- C01B19/007—Tellurides or selenides of metals
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- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention discloses a tellurium-containing compound, a method for preparing tellurium gold nanoparticles by using the same and application of the tellurium gold nanoparticles in preparing antitumor drugs. The method utilizes a tellurium compound and a chlorine ion complex of gold to prepare tellurium-gold nanoparticles; the nanoparticles can realize stimulus response under the action of an oxidizing agent. The tellurium gold nano-particles and tumor cells are incubated together, and the obvious reduction of the cell survival rate can be observed; the tellurium gold nano-particles and normal cells are incubated together, and the survival state of the cells is good. According to the invention, based on the reducibility and coordination interaction of tellurium elements, a tellurium-containing compound is used as a reducing agent and a stabilizing agent at the same time, and tellurium and gold nanoparticles are prepared by adopting different material synthesis methods while regulating the molecular structure of the tellurium compound. The prepared material has oxidation stimulation responsiveness, is a potential selective antitumor drug and has good clinical application prospect.
Description
Technical Field
The invention relates to the field of nano biomedicine, in particular to a tellurium-containing compound, a method for preparing tellurium gold nanoparticles by using the tellurium-containing compound and application of the tellurium gold nanoparticles in antitumor drugs.
Background
Cancer is one of common malignant diseases, and causes serious economic and psychological burden to patients due to the characteristics of rapid development, low cure rate and high recurrence rate.
The + 4-valent tellurium-containing functional structure has potential anti-tumor activity, and the compound can destroy intracellular redox balance to induce cells to apoptosis by inhibiting the intracellular selenol structure active site. AS101 is a + 4-valent tellurium-containing molecule entering the second phase of clinical trials, however, further clinical trials cannot be achieved due to its low stability and poor selectivity. The key to the development of novel antitumor drugs is to overcome the defects of low stability and poor selectivity of a tellurium-containing structure.
The development of nano materials and nano technology develops a brand new system for the diagnosis and treatment of cancer. Among them, gold nanoparticles are receiving wide attention due to their diverse functionalities — based on their photothermal effect, gold nanoparticles can be used as a thermal medium for photothermal therapy and a contrast agent for photoacoustic imaging; based on the high atomic number, the gold nanoparticles can be used as a radiation sensitizer for radiotherapy and a contrast agent for CT imaging; based on the larger specific surface area of the nano structure, the gold nano particles can be used as a carrier of chemotherapeutic drugs. However, such nano-drugs have the disadvantages of complex material structure and complicated synthesis steps, and it is difficult to achieve effective economic benefits through industrial production. Meanwhile, the nano-drugs have large toxic and side effects on normal cells while killing tumor cells, and selective treatment can be realized only by modifying targeted small molecules or specific proteins on the surfaces, which causes the problems of high price and harsh storage conditions in clinical application of the drugs.
Therefore, how to further develop and prepare the nano-drug which is convenient and has selective killing effect has great application prospect and biomedical significance.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and discloses a tellurium-containing compound, a method for preparing tellurium-gold nanoparticles by using the tellurium-gold compound and application of the tellurium-gold nanoparticles in antitumor drugs. The invention improves and expands the existing preparation method of gold nanoparticles, designs various tellurium-containing compounds which can be used as a reducing agent and a stabilizing agent simultaneously by regulating and controlling the molecular structure based on the reducibility and the coordination of the tellurium-containing compounds, and prepares the tellurium-gold nanoparticles by adopting a one-pot method for in-situ reduction and coordination. The invention develops the biomedical application of the prepared nano material, the material can ensure the activity of normal cells while causing the apoptosis of tumor cells, and is a potential selective antitumor drug.
In order to achieve the purpose, the invention adopts the following technical scheme:
the tellurium-containing compound provided by the first aspect of the invention is characterized in that the structural formula of the tellurium-containing compound is (HO-EG)X-CY)2-Te, wherein, HO-EGY-is a hydrophilic segment, EG-is an oxyethyl group, the number X of repeating units is 2 to 6; cY-is a hydrophobic chain segment, and the number Y of carbon atoms is 2-6.
The second aspect of the present invention provides a method for preparing tellurium gold nanoparticles by using the above tellurium-containing compound, which is characterized by comprising the following steps:
(1) and (3) mixing the tellurium-containing compound with a gold-containing reagent according to a molar ratio of 2-12: 1, uniformly mixing in a solvent to obtain a uniform mixing system with the molar concentration of gold element of 0.1-1 mmol/L;
(2) and (2) removing the solvent from the uniform mixed system prepared in the step (1), and then rinsing and drying to obtain powdery tellurium gold nanoparticles.
Further, the gold-containing reagent in the step (1) adopts any one or a mixture of two of chloroauric acid and aurous chloride.
Further, in the step (1), the solvent is any one or more of deionized water, dimethylformamide, dimethyl sulfoxide, ethylene glycol, ethanol and methanol.
The third aspect of the invention provides an application of the prepared tellurium gold nanoparticles in preparation of antitumor drugs.
Further, the tumor types targeted by the antitumor drugs are liver cancer, breast cancer, lung gland and pancreatic cancer.
The invention has the characteristics and beneficial effects that:
the tellurium-containing compound used in the invention has two characteristics of reducibility and coordination, wherein the reducibility can reduce the free gold element into a simple gold substance; the coordination of the gold-silver-containing complex is based on a soft and hard acid-base theory, a tellurium-containing compound is used as a stabilizer, the surface energy of the simple substance gold is reduced through tellurium-metallographic interaction, the simple substance gold is uniformly dispersed in a nanometer size, and agglomeration is effectively avoided. In addition, the obtained tellurium gold nanoparticles have oxidation stimulation responsiveness, can further increase the concentration of active oxygen substances over-expressed in tumor cells through a cascade amplification mechanism, and can cause the apoptosis of the tumor cells while not influencing the healthy growth of normal cells. The invention is based on tellurium-metallographical interaction, endows the tellurium-containing functional structure with good thermodynamic stability; the selective treatment effect of the tellurium-gold nanoparticles is realized based on the oxidation-reduction stimulation responsiveness of the tellurium-containing functional structure and the microenvironment with high active oxygen concentration inside the tumor. The invention overcomes the defects of poor stability and low selectivity of a tellurium-containing functional structure, can be used for preparing selective anti-tumor nano-drugs, and has potential clinical application prospects.
The method firstly synthesizes the compound containing tellurium, and then prepares the tellurium gold nanoparticles by a one-pot method. The CCK-8 detection and flow cytometry detection results show that the tellurium gold nanoparticles have obvious cytotoxicity to tumor cells and have no obvious cytotoxicity to normal cells under the condition of not modifying the targeting groups.
In conclusion, compared with the traditional chemotherapeutic drug, the tellurium gold nanoparticles reported by the invention have the advantages of simple preparation and low toxic and side effects on normal cells, and have wide application prospects in the field of cancer treatment.
Drawings
Fig. 1 is a schematic diagram of a tellurium-containing compound, a method for preparing tellurium gold nanoparticles by using the compound, and an application of the tellurium gold nanoparticles in preparing an anti-tumor drug.
In FIG. 2, (a) to (e) are (HO-EG)6-C6)2-molecular formula of Te (bis (17-hydroxy-3, 6,9,12, 15-pentoxyacetyl) 4,4' -telluro-dihexanoate), nmr hydrogen spectrum, nmr carbon spectrum, nmr tellurium spectrum, and electrospray ionization mass spectrum.
In FIG. 3, (a) to (e) are (HO-EG)4-C6)2-molecular formula of Te (bis (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) 4,4' -telluro-dihexanoate), nmr hydrogen spectra, nmr carbon spectra, nmr tellurium spectra and electrospray ionization mass spectra.
In FIG. 4, (a) to (e) are (HO-EG)2-C6)2-molecular formula of Te (bis (2- (2-hydroxyethoxy) ethyl) 6,6' -telluro-dihexanoate), nmr hydrogen spectrum, nmr carbon spectrum, nmr tellurium spectrum and electrospray ionization mass spectrum.
In FIG. 5, (a) to (e) are (HO-EG)6-C4)2Molecular formula of-Te (bis (17-hydroxy-3, 6,9,12, 15-pentoxyacetyl) 4,4' -tellurodibutyrate), hydrogen spectrum by nuclear magnetic resonance, carbon spectrum by nuclear magnetic resonance, tellurium spectrum by nuclear magnetic resonance, and electrospray ionizationAnd (4) mass spectrometry.
In FIG. 6, (a) to (e) are (HO-EG)4-C4)2-molecular formula of Te (bis (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) 4,4' -tellurodibutyrate), nmr hydrogen spectra, nmr carbon spectra, nmr tellurium spectra, and electrospray ionization mass spectra.
In FIG. 7, (a) to (e) are (HO-EG)2-C4)2-molecular formula of Te (bis (2- (2-hydroxyethoxy) ethyl) 4,4' -tellurodibutyrate), nmr hydrogen spectrum, nmr carbon spectrum, nmr tellurium spectrum, and electrospray ionization mass spectrum.
Fig. 8 is an energy dispersive X-ray spectrum of a tellurium gold nanoparticle.
FIG. 9 is an X-ray photoelectron spectroscopy analysis chart of tellurium element and gold element in the tellurium-gold nanoparticles.
Fig. 10 is a transmission electron microscope image of tellurium gold nanoparticles.
FIG. 11 is a dynamic light scattering diagram of the tellurium gold nanoparticles prepared at 40, 60 and 80 ℃.
FIG. 12 is the UV-visible absorption diagram of the tellurium-gold nanoparticles prepared at 40, 60 and 80 ℃.
FIG. 13 is a transmission electron microscope photograph of tellurium and gold nanoparticles as a function of time under the action of hydrogen peroxide.
FIG. 14 is an X-ray photoelectron spectroscopy analysis chart of tellurium and gold nanoparticles under the action of hydrogen peroxide along with the change of time.
Fig. 15 (a) and (b) are flow cytometry detection results of human normal hepatocytes (L02) and human hepatoma cells (HepG2) incubated with different concentrations of tellurium and gold nanoparticles for 24h, respectively, and stained with an apoptosis kit.
FIG. 16 shows the result of enzyme-linked immunosorbent assay (ELISA) detection by CCK-8 kit staining after human normal liver cells (L02) and human liver cancer cells (HepG2) and traditional gold nanoparticles (AuNP/Citrate) with different concentrations are incubated for 24 h.
FIG. 17 shows the results of different concentrations of compounds containing tellurium ((HO-EG) in human normal hepatocytes (L02) and human hepatoma cells (HepG2)4-C6)2-Te) incubation for 24h, and detecting result of enzyme linked immunosorbent assay detector stained by CCK-8 kit。
FIG. 18 shows the detection results of enzyme-linked immunosorbent assay (ELISA) detector obtained by incubating human normal hepatocytes (L02) and human hepatoma cells (HepG2) with selenium gold nanoparticles (AuNP-Se) of different concentrations for 24h and staining the cells with CCK-8 kit.
FIG. 19 shows the results of detection in an ELISA detector stained with CCK-8 kit after incubation of human normal hepatocytes (L02) and human hepatoma cells (HepG2) with different concentrations of Tellurium-Gold nanoparticles (TG NP) for 24 h.
FIG. 20 shows the detection results of an ELISA detector in which human normal mammary epithelial cells (MCF-10A), human breast cancer cells (MCF-7), human breast cancer cells (MDA-MB-231), human non-small cell lung cancer cells (A549) and pancreatic cancer cells (Panc-1) are incubated with different concentrations of tellurium and gold nanoparticles for 24h and stained with a CCK-8 kit.
FIG. 21 shows mouse tumors injected with Phosphate Buffered Saline (PBS) into tail vein, traditional gold nanoparticles (AuNP/Citrate) in PBS, and tellurium-containing compound ((HO-EG) into tail vein4-C6)2-Te), PBS solution of seleno-Gold nanoparticles (AuNP-Se), PBS solution of Tellurium-Gold nanoparticles (TG NP) in tail vein.
FIG. 22 shows mouse tumors injected with Phosphate Buffered Saline (PBS) into tail vein, traditional gold nanoparticles (AuNP/Citrate) in PBS, and tellurium-containing compound ((HO-EG) into tail vein4-C6)2-Te), PBS solution of seleno-Gold nanoparticles (AuNP-Se), PBS solution of Tellurium-Gold nanoparticles (TG NP) injected in tail vein, mouse body weight change curves after PBS solution of TG NP).
FIG. 23 shows mouse tumors injected with Phosphate Buffered Saline (PBS) into tail vein, traditional gold nanoparticles (AuNP/Citrate) in PBS, and tellurium-containing compound ((HO-EG) into tail vein4-C6)2-Te), PBS solution of seleno-Gold nanoparticles (AuNP-Se), PBS solution of Tellurium-Gold nanoparticles (TG NP) injected into tail vein.
Fig. 24 (a) and (b) show the contents of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) in blood 18 days after the mice were injected with the drug, respectively.
Fig. 25 (a) and (b) are contents of Creatine Kinase (CK, Creatine Kinase) and Lactate Dehydrogenase (LDH) in blood, respectively, 18 days after injection of the drug into mice.
FIGS. 26 (a) and (b) are the levels of UREA (UREA) and Blood UREA Nitrogen (BUN, Blood UREA Nitrogen) in the Blood of mice 18 days after drug injection, respectively.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention. In addition, all reagents used in the following examples are commercially available or can be synthesized according to methods herein or known, and are readily available to those skilled in the art for reaction conditions not listed, if not explicitly stated.
Referring to FIG. 1, the invention provides a tellurium-containing compound with a structural formula of (HO-EG)X-CY)2-Te, wherein HO-EGY-is a hydrophilic segment, EG-is an oxyethyl group, the number X of repeating units thereof is 2 to 6; cY-is a hydrophobic chain segment, and the number Y of carbon atoms is 2-6.
The invention also provides a method for preparing the tellurium gold nanoparticles by using the tellurium-containing compound, which comprises the following steps:
(1) mixing the tellurium-containing compound with a gold-containing reagent according to a molar ratio of 2-12: 1, uniformly mixing in a solvent to obtain a uniform mixing system with the molar concentration of gold element of 0.1-1 mmol/L; the gold-containing reagent adopts chloroauric acid or gold chloride or a mixture of two of chloroauric acid and gold chloride; the solvent is any one or a mixture of more of deionized water, dimethylformamide, dimethyl sulfoxide, ethylene glycol, ethanol and methanol;
(2) and (2) removing the solvent from the uniformly mixed system prepared in the step (1) through freeze-drying, vacuum oven drying or rotary evaporation, rinsing, vacuum oven drying, and nitrogen blow-drying or freeze-drying to obtain powdery tellurium gold nanoparticles.
The invention also provides a method for applying the prepared tellurium gold nanoparticles to an anti-tumor drug, and the invention discovers that significant apoptosis of tumor cells can be observed by co-incubating the low-concentration tellurium gold nanoparticles with the tumor cells, namely human liver cancer cells (HepG2), human breast cancer cells (MDA-MB-231, MCF-7), human lung adenocarcinoma cells (A549) and pancreatic cancer cells (Panc-1), for 24 hours through cell experiments; by co-incubating tellurium gold nanoparticles with healthy cells, human normal liver cells (L02) and human normal mammary cells (MCF-10A), at the same concentration for 24 hours, there was no significant cytotoxicity. Further analysis of BALB/c nude mouse experiments shows that the low-concentration tellurium gold nanoparticles can inhibit tumor growth in mice without liver, kidney and heart toxicity.
Examples of the present invention are described below:
example 1: based on (HO-EG)6-C6)2Preparation of tellurium gold nanoparticles of (bis (17-hydroxy-3, 6,9,12, 15-pentaoxoacetyl) 4,4' -tellurodihexanoate) and chloroauric acid and application of tellurium gold nanoparticles in preparation of antitumor drugs
(1) Mixing 88.7mg (HO-EG)6-C6)2-Te was dissolved in 1mL of deionized water to give component A, and 9.6mg of chloroauric acid was dissolved in 1mL of deionized water to give component B. And (3) fully and uniformly mixing the component A and the component B in a 5mL reaction bottle to obtain a uniform mixing system. And (3) freeze-drying the mixed system, rinsing for 3 times by using 2mL of dichloromethane, and drying by using nitrogen to obtain the tellurium gold nanoparticles. Wherein (HO-EG)6-C6)2The synthesis of the-Te molecule is as follows:
5.64g of hexaethylene glycol was dissolved in a round-bottomed flask containing 100mL of methylene chloride, and 4.27g of 6-bromohexanoyl chloride was added dropwise to the round-bottomed flask through an isopiestic dropping funnel while stirring in an ice-water bath. 0.24g of N, N-lutidine was added dropwise to the system, and the reaction was carried out at room temperature for 4 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the product is purified by a silica gel chromatographic column to obtain HO-EG6-C6-Br (17-hydroxy-3, 6,9,12, 15-pentoxyacetyl 6-bromohexanoate). 0.64g of tellurium powder and 1.13g of sodium borohydride were charged into a 250mL round-bottom flask, and 50mL of deionized water was added thereto. Reacting at 40 ℃ for 30min under the nitrogen atmosphere to obtain a light purple transparent solution, and recovering to room temperature for later use. 4.59gHO-EG6-C6dissolving-Br in 10mL of tetrahydrofuran, adding the light purple transparent solution, and reacting at room temperature for 30min under a nitrogen atmosphere. After the reaction was completed, the reaction system was extracted three times with 20mL of dichloromethane, and the organic phases were combined and dried by adding anhydrous sodium sulfate. Filtering to remove anhydrous sodium sulfate, removing solvent by rotary evaporation, and purifying the product with silica gel column chromatography to obtain (HO-EG)6-C6)2-Te。
(2) And (3) reacting the uniformly mixed system at room temperature for 5min, freeze-drying to remove the solvent, rinsing with dichloromethane, and drying to obtain powdery tellurium gold nanoparticles.
(3) The tellurium gold nanoparticles were dispersed in a cell culture medium and incubated with L02 cells, and a good cell survival state was observed.
(4) And (4) dispersing the tellurium and gold nanoparticles with the medium mass concentration in the step (3) in a cell culture medium, and incubating with HepG2 cells, so that the cells can be observed to undergo obvious apoptosis.
(5) And (4) dispersing the tellurium and gold nanoparticles with the medium mass concentration in the step (3) in a cell culture medium, and incubating the cell culture medium with MCF-10A cells, so that the cell survival state is observed to be good.
(6) And (4) dispersing the tellurium and gold nanoparticles with the medium mass concentration in the step (3) in a cell culture medium, and incubating the cell culture medium with MCF-7 cells, so that the cells can be observed to obviously die.
(7) And (4) dispersing the tellurium and gold nanoparticles with the medium mass concentration in the step (3) in a cell culture medium, and incubating the cell culture medium with MDA-MB-231 cells, so that the cells can be observed to obviously die.
(8) And (4) dispersing the tellurium and gold nanoparticles with medium mass concentration in the step (3) in a cell culture medium, and incubating the cell culture medium and the A549 cells together, so that the cells can be observed to undergo obvious apoptosis.
(9) And (4) dispersing the tellurium and gold nanoparticles with the medium mass concentration in the step (3) in a cell culture medium, and incubating with Panc-1 cells, so that the cells can be observed to undergo obvious apoptosis.
(10) Tellurium and gold nanoparticles were dispersed in Phosphate Buffered Saline (PBS) and injected into tumor-bearing mice via tail vein, and it was observed that tumor volume was significantly inhibited.
Example 2: based on (HO-EG)4-C6)2Preparation of tellurium gold nanoparticles of (-Te) (bis (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) 4,4' -telluro dihexanoate) and chloroauric acid and application of tellurium gold nanoparticles in preparation of antitumor drugs
The difference between this example and example 1 lies in the preparation of tellurium-gold nanoparticles, and the rest of the steps are the same as those in example 1, specifically:
142.0mg (HO-EG)4-C6)2-Te was dissolved in 1mL of ethylene glycol to give component A, and 2.6mg of chloroauric acid was dissolved in 1mL of dimethyl sulfoxide to give component B. And (3) fully and uniformly mixing the component A and the component B in a 5mL reaction bottle to obtain a uniform mixing system. And (3) drying the mixed system in a vacuum oven, rinsing with 2mL of tetrahydrofuran for 3 times, and drying in the vacuum oven to obtain the tellurium-gold nanoparticles. Wherein (HO-EG)4-C6)2The synthesis of the-Te molecule is as follows:
3.88g of tetraethylene glycol was dissolved in a round-bottomed flask containing 100mL of methylene chloride, and 4.27g of 6-bromohexanoyl chloride was added dropwise to the round-bottomed flask through an isopiestic dropping funnel with stirring in an ice-water bath. 0.24g of N, N-lutidine was added dropwise to the system, and the reaction was carried out at room temperature for 4 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the product is purified by a silica gel chromatographic column to obtain HO-EG4-C6-Br (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl 6-bromohexanoate). 0.64g of tellurium powder and 1.13g of sodium borohydride were charged into a 250mL round-bottom flask, and 50mL of deionized water was added thereto. Reacting at 40 ℃ for 30min under the nitrogen atmosphere to obtain a light purple transparent solution, and recovering to room temperature for later use. Mixing 3.71gHO-EG4-C6dissolving-Br in 10mL of tetrahydrofuran, adding the light purple transparent solution, and reacting at room temperature for 30min under a nitrogen atmosphere. After the reaction was completed, the reaction system was extracted three times with 20mL of dichloromethane, and the organic phases were combined and dried by adding anhydrous sodium sulfate. FiltrationRemoving anhydrous sodium sulfate, removing solvent by rotary evaporation, and purifying the product with silica gel column chromatography to obtain (HO-EG)4-C6)2-Te。
Example 3: based on (HO-EG)2-C6)2Preparation of tellurium gold nanoparticles of (-Te (bis (2- (2-hydroxyethoxy) ethyl) 6,6' -telluro dihexanoate) and chloroauric acid and application of tellurium gold nanoparticles in preparation of antitumor drugs
The difference between this example and example 1 lies in the preparation of tellurium-gold nanoparticles, and the rest of the steps are the same as those in example 1, specifically:
17.8mg of (HO-EG)2-C6)2-Te was dissolved in 1mL of methanol to give component A, and 2.0mg of aurous chloride was dissolved in 1mL of ethylene glycol to give component B. And (3) fully and uniformly mixing the component A and the component B in a 5mL reaction bottle to obtain a uniform mixing system. And drying the mixed system by using a vacuum oven to remove the solvent, rinsing for 3 times by using 2mL ethyl acetate, and drying by using nitrogen to obtain the tellurium-gold nanoparticles. Wherein (HO-EG)2-C6)2The synthesis of the-Te molecule is as follows:
2.12g of diethylene glycol was dissolved in a round-bottomed flask containing 100mL of methylene chloride, and 4.27g of 6-bromohexanoyl chloride was added dropwise to the round-bottomed flask through an isopiestic dropping funnel with stirring in an ice-water bath. 0.24g of N, N-lutidine was added dropwise to the system, and the reaction was carried out at room temperature for 4 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the product is purified by a silica gel chromatographic column to obtain HO-EG2-C6-Br (2-hydroxyethoxy) ethyl 6-bromohexanoate). 0.64g of tellurium powder and 1.13g of sodium borohydride were charged into a 250mL round-bottom flask, and 50mL of diethylene glycol was added thereto. Reacting at 40 ℃ for 30min under the nitrogen atmosphere to obtain a light purple transparent solution, and recovering to room temperature for later use. 2.83gHO-EG2-C6dissolving-Br in 10mL of tetrahydrofuran, adding the light purple transparent solution, and reacting at room temperature for 30min under a nitrogen atmosphere. After the reaction was completed, the reaction system was extracted three times with 20mL of dichloromethane, and the organic phases were combined and dried by adding anhydrous sodium sulfate. Filtering to remove anhydrous sodium sulfate, removing solvent by rotary evaporation, and purifying the product with silica gel column chromatography to obtain (HO-EG)2-C6)2-Te。
Example 4: based on (HO-EG)6-C4)2Preparation of tellurium gold nanoparticles of (bis (17-hydroxy-3, 6,9,12, 15-pentaoxoacetyl) 4,4' -tellurodibutyrate) and chloroauric acid and application of tellurium gold nanoparticles in preparation of antitumor drugs
The difference between this example and example 1 lies in the preparation of tellurium-gold nanoparticles, and the rest of the steps are the same as those in example 1, specifically:
103.0mg of (HO-EG)6-C4)2-Te was dissolved in 1mL of dimethylformamide to give component A, and 4.7mg of aurous chloride was dissolved in 1mL of ethanol to give component B. And (3) fully and uniformly mixing the component A and the component B in a 5mL reaction bottle to obtain a uniform mixing system. And drying the mixed system in a vacuum oven, rinsing for 3 times by using 2mL of tetrahydrofuran/dichloromethane mixed solvent, and drying in the vacuum oven to obtain the tellurium-gold nanoparticles. Wherein (HO-EG)6-C4)2The synthesis of the-Te molecule is as follows:
5.64g of hexaethylene glycol was dissolved in a round-bottomed flask containing 100mL of methylene chloride, and 3.71g of 4-bromobutyryl chloride was added dropwise to the round-bottomed flask through an isobaric dropping funnel with stirring in an ice-water bath. 0.25g of N, N-diisopropylethylamine was added dropwise to the system, and the reaction was carried out at room temperature for 4 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the product is purified by a silica gel chromatographic column to obtain HO-EG6-C4-Br (17-hydroxy-3, 6,9,12, 15-pentoxyacetyl 4-bromobutyrate). 0.64g of tellurium powder and 1.13g of sodium borohydride were charged into a 250mL round-bottom flask, and 50mL of deionized water was added thereto. Reacting at 40 ℃ for 30min under the nitrogen atmosphere to obtain a light purple transparent solution, and recovering to room temperature for later use. 4.31gHO-EG6-C4dissolving-Br in 10mL of tetrahydrofuran, adding the light purple transparent solution, and reacting at room temperature for 30min under a nitrogen atmosphere. After the reaction was completed, the reaction system was extracted three times with 20mL of dichloromethane, and the organic phases were combined and dried by adding anhydrous sodium sulfate. Filtering to remove anhydrous sodium sulfate, removing solvent by rotary evaporation, and purifying the product with silica gel column chromatography to obtain (HO-EG)6-C4)2-Te。
Example 5: based on (H)O-EG4-C4)2Preparation of tellurium gold nanoparticles of (-Te) (bis (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) 4,4' -tellurodibutyrate) and chloroauric acid and application of tellurium gold nanoparticles in preparation of antitumor drugs
The difference between this example and example 1 lies in the preparation of tellurium-gold nanoparticles, and the rest of the steps are the same as those in example 1, specifically:
65.4mg of (HO-EG)4-C4)2-Te in 1mL of methanol gave component A, and 1.9mg of chloroauric acid in 1mL of ethylene glycol gave component B. And (3) fully and uniformly mixing the component A and the component B in a 5mL reaction bottle to obtain a uniform mixing system. And (3) carrying out rotary evaporation on the mixed system to remove the solvent, rinsing for 3 times by using 2mL of ethyl acetate/dichloromethane mixed solvent, and drying by blowing nitrogen to obtain the tellurium-gold nanoparticles. Wherein (HO-EG)4-C4)2The synthesis of the-Te molecule is as follows:
3.88g of tetraethylene glycol was dissolved in a round-bottomed flask containing 100mL of methylene chloride, and 3.71g of 4-bromobutyryl chloride was added dropwise to the round-bottomed flask through an isobaric dropping funnel with stirring in an ice-water bath. 0.25g of N, N-diisopropylethylamine was added dropwise to the system, and the reaction was carried out at room temperature for 4 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the product is purified by a silica gel chromatographic column to obtain HO-EG4-C4-Br (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl 4-bromobutyrate). 0.64g of tellurium powder and 1.13g of sodium borohydride were charged into a 250mL round-bottom flask, and 50mL of deionized water was added thereto. Reacting at 40 ℃ for 30min under the nitrogen atmosphere to obtain a light purple transparent solution, and recovering to room temperature for later use. Mixing 3.43gHO-EG4-C4dissolving-Br in 10mL of tetrahydrofuran, adding the light purple transparent solution, and reacting at room temperature for 30min under a nitrogen atmosphere. After the reaction was completed, the reaction system was extracted three times with 20mL of dichloromethane, and the organic phases were combined and dried by adding anhydrous sodium sulfate. Filtering to remove anhydrous sodium sulfate, removing solvent by rotary evaporation, and purifying the product with silica gel column chromatography to obtain (HO-EG)4-C4)2-Te。
Example 6: based on (HO-EG)2-C4)2-Te (bis (2- (2-hydroxyethyl)Oxy) ethyl) 4,4' -tellurodibutyrate) and chloroauric acid, and application thereof in preparation of antitumor drugs
The difference between this example and example 1 lies in the preparation of tellurium-gold nanoparticles, and the rest of the steps are the same as those in example 1, specifically:
27.8mg of (HO-EG)2-C4)2-Te was dissolved in 1mL of deionized water to give component A, and 1.9mg of chloroauric acid was dissolved in 1mL of dimethylformamide to give component B. And (3) fully and uniformly mixing the component A and the component B in a 5mL reaction bottle to obtain a uniform mixing system. And drying the mixed system in a vacuum oven, rinsing for 3 times by using 2mL of ethyl acetate/tetrahydrofuran mixed solvent, and drying in the vacuum oven to obtain the tellurium-gold nanoparticles. Wherein (HO-EG)2-C4)2The synthesis of the-Te molecule is as follows:
2.12g of diethylene glycol was dissolved in a round-bottomed flask containing 100mL of methylene chloride, and 3.71g of 4-bromobutyryl chloride was added dropwise to the round-bottomed flask through an isopiestic dropping funnel with stirring in an ice-water bath. 0.25g of N, N-diisopropylethylamine was added dropwise to the system, and the reaction was carried out at room temperature for 4 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the product is purified by a silica gel chromatographic column to obtain HO-EG2-C4-Br (ethyl 2- (2-hydroxyethoxy) 4-bromobutyrate). 0.64g of tellurium powder and 1.13g of sodium borohydride were charged into a 250mL round-bottom flask, and 50mL of deionized water was added thereto. Reacting at 40 ℃ for 30min under the nitrogen atmosphere to obtain a light purple transparent solution, and recovering to room temperature for later use. 2.55gHO-EG2-C4dissolving-Br in 10mL of tetrahydrofuran, adding the light purple transparent solution, and reacting at room temperature for 30min under a nitrogen atmosphere. After the reaction was completed, the reaction system was extracted three times with 20mL of dichloromethane, and the organic phases were combined and dried by adding anhydrous sodium sulfate. Filtering to remove anhydrous sodium sulfate, removing solvent by rotary evaporation, and purifying the product with silica gel column chromatography to obtain (HO-EG)2-C4)2-Te。
Example 7: based on (HO-EG)6-C2)2Preparation of tellurium gold nanoparticles of (bis (17-hydroxy-3, 6,9,12, 15-pentaoxoacetyl) 2,2' -tellurodiacetate) and chloroauric acid and preparation thereofApplication of antitumor drug
The difference between this example and example 1 lies in the preparation of tellurium-gold nanoparticles, and the rest of the steps are the same as those in example 1, specifically:
77.4mg of (HO-EG)6-C2)2-Te in 1mL ethanol gave component A, and 4.0mg chloroauric acid in 1mL methanol gave component B. And (3) fully and uniformly mixing the component A and the component B in a 5mL reaction bottle to obtain a uniform mixing system. And (3) freeze-drying the mixed system, rinsing for 3 times by using a 2mL ethyl acetate/tetrahydrofuran/dichloromethane mixed solvent, and drying by using nitrogen to obtain the tellurium gold nanoparticles. Wherein (HO-EG)6-C2)2The synthesis of the-Te molecule is as follows:
5.64g of hexaethylene glycol was dissolved in a round-bottomed flask containing 100mL of tetrahydrofuran, and 4.04g of bromoacetyl bromide was added dropwise to the round-bottomed flask through an isobaric dropping funnel with stirring in an ice-water bath. 0.20g of triethylamine was added dropwise to the system, and the reaction was carried out at room temperature for 4 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the product is purified by a silica gel chromatographic column to obtain HO-EG6-C2-Br (17-hydroxy-3, 6,9,12, 15-pentoxyacetyl 2-bromoacetate). 0.64g of tellurium powder and 1.13g of sodium borohydride were charged into a 250mL round-bottom flask, and 50mL of deionized water was added thereto. Reacting at 40 ℃ for 30min under the nitrogen atmosphere to obtain a light purple transparent solution, and recovering to room temperature for later use. 4.03gHO-EG6-C2dissolving-Br in 10mL of tetrahydrofuran, adding the light purple transparent solution, and reacting at room temperature for 30min under a nitrogen atmosphere. After the reaction was completed, the reaction system was extracted three times with 20mL of dichloromethane, and the organic phases were combined and dried by adding anhydrous sodium sulfate. Filtering to remove anhydrous sodium sulfate, removing solvent by rotary evaporation, and purifying the product with silica gel column chromatography to obtain (HO-EG)6-C2)2-Te。
Example 8: based on (HO-EG)4-C2)2Preparation of tellurium gold nanoparticles of (-Te) (bis (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) 4,4' -telluro diacetate) and chloroauric acid and application of tellurium gold nanoparticles in preparation of antitumor drugs
The difference between this example and example 1 lies in the preparation of tellurium-gold nanoparticles, and the rest of the steps are the same as those in example 1, specifically:
59.8mg of (HO-EG)4-C2)2-Te was dissolved in 1mL of dimethyl sulfoxide to give component A, and 1.6mg of aurous chloride was dissolved in 1mL of dimethylformamide to give component B. And (3) fully and uniformly mixing the component A and the component B in a 5mL reaction bottle to obtain a uniform mixing system. And drying the mixed system in a vacuum oven, rinsing for 3 times by using 2mL of ethyl acetate solvent, and freeze-drying to obtain the tellurium-gold nanoparticles. Wherein (HO-EG)4-C2)2The synthesis of the-Te molecule is as follows:
3.88g of tetraethylene glycol was dissolved in a round-bottomed flask containing 100mL of tetrahydrofuran, and 4.04g of bromoacetyl bromide was added dropwise to the round-bottomed flask through an isobaric dropping funnel with stirring in an ice-water bath. 0.20g of triethylamine was added dropwise to the system, and the reaction was carried out at room temperature for 4 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the product is purified by a silica gel chromatographic column to obtain HO-EG4-C2-Br (2- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl 2-bromoacetate). 0.64g of tellurium powder and 1.13g of sodium borohydride were charged into a 250mL round-bottom flask, and 50mL of deionized water was added thereto. Reacting at 40 ℃ for 30min under the nitrogen atmosphere to obtain a light purple transparent solution, and recovering to room temperature for later use. Mixing 3.15gHO-EG4-C2dissolving-Br in 10mL of tetrahydrofuran, adding the light purple transparent solution, and reacting at room temperature for 30min under a nitrogen atmosphere. After the reaction was completed, the reaction system was extracted three times with 20mL of dichloromethane, and the organic phases were combined and dried by adding anhydrous sodium sulfate. Filtering to remove anhydrous sodium sulfate, removing solvent by rotary evaporation, and purifying the product with silica gel column chromatography to obtain (HO-EG)4-C2)2-Te。
Example 9: based on (HO-EG)2-C2)2Preparation of tellurium gold nanoparticles of (-Te (bis (2- (2-hydroxyethoxy) ethyl) 2,2' -tellurodiacetate) and chloroauric acid and application of tellurium gold nanoparticles in preparation of antitumor drugs
The difference between this example and example 1 lies in the preparation of tellurium-gold nanoparticles, and the rest of the steps are the same as those in example 1, specifically:
84.4mg of (HO-EG)2-C2)2-Te in 1mL of ethylene glycol gave component A, and 1.6mg of chloroauric acid in 1mL of ethylene glycol gave component B. And (3) fully and uniformly mixing the component A and the component B in a 5mL reaction bottle to obtain a uniform mixing system. And (3) freeze-drying the mixed system, rinsing for 3 times by using 2mL of tetrahydrofuran solvent, and drying by using nitrogen to obtain the tellurium-gold nanoparticles. Wherein (HO-EG)2-C2)2The synthesis of the-Te molecule is as follows:
2.12g of diethylene glycol was dissolved in a round-bottomed flask containing 100mL of methylene chloride, and 4.04g of bromoacetyl bromide was added dropwise to the round-bottomed flask through an isopiestic dropping funnel with stirring in an ice-water bath. 0.20g of triethylamine was added dropwise to the system, and the reaction was carried out at room temperature for 4 hours. After the reaction is finished, the solvent is removed by rotary evaporation, and the product is purified by a silica gel chromatographic column to obtain HO-EG2-C2-Br (ethyl 2- (2-hydroxyethoxy) 2-bromoacetate). 0.64g of tellurium powder and 1.13g of sodium borohydride were charged into a 250mL round-bottom flask, and 50mL of deionized water was added thereto. Reacting at 40 ℃ for 30min under the nitrogen atmosphere to obtain a light purple transparent solution, and recovering to room temperature for later use. 2.27gHO-EG2-C2dissolving-Br in 10mL of tetrahydrofuran, adding the light purple transparent solution, and reacting at room temperature for 30min under a nitrogen atmosphere. After the reaction was completed, the reaction system was extracted three times with 20mL of dichloromethane, and the organic phases were combined and dried by adding anhydrous sodium sulfate. Filtering to remove anhydrous sodium sulfate, removing solvent by rotary evaporation, and purifying the product with silica gel column chromatography to obtain (HO-EG)2-C2)2-Te。
The validity of the embodiments of the present invention is verified as follows:
1. structural characterization of tellurium-containing compounds
And dissolving the prepared tellurium-containing compound in a deuterated nuclear magnetic reagent, and performing structural characterization on the compound through a nuclear magnetic resonance hydrogen spectrum, a nuclear magnetic resonance carbon spectrum, a nuclear magnetic resonance tellurium spectrum and an electrospray ionization mass spectrum. The characterization results are shown in fig. 2-7, which demonstrate that the target tellurium-containing compound can be obtained by the relevant synthesis steps provided by the present invention.
2. Elemental composition characterization of tellurium and gold nanoparticles
The prepared tellurium-gold nanoparticles were dispersed in deionized water, 20 μ L was placed in a copper mesh and dried, and the composition was characterized by energy dispersive X-ray spectroscopy (EDS), as shown by the results in fig. 8, the constituent elements of the obtained nanoparticles were tellurium and gold. Dispersing the prepared tellurium-gold nanoparticles in an aqueous solution, taking 20 mu L of the prepared tellurium-gold nanoparticles, placing the solution in a smooth silicon wafer, airing the smooth silicon wafer, carrying out further research on the valence states of tellurium element and gold element in the tellurium-gold nanoparticles through X-ray photoelectron spectroscopy (XPS), and knowing that tellurium is in a valence state of +2 (figure 9 left) and gold is in a valence state of 0 (figure 9 right) according to characteristic peaks. The formation of the elemental gold of valence 0 demonstrates the effect of the tellurium-containing compound as a reducing agent. EDS results show that tellurium-containing compounds as stabilizers coexist with nanoscale elemental gold.
3. Morphology characterization of tellurium-gold nanoparticles
Dispersing the prepared tellurium gold nanoparticles in deionized water, placing 20 mu L of aqueous solution in a copper mesh for airing, and characterizing the morphology of the solution by an electron projection microscope (TEM). As shown in FIG. 10, the prepared tellurium gold nanoparticles have regular and uniform shapes. The result shows that the tellurium-containing compound avoids the agglomeration of the nano-gold and has good stabilizing effect.
4. Tellurium gold nanoparticle thermodynamic stability test
Tellurium gold nanoparticles were prepared at 40, 60, 80 ℃ respectively. The resulting hydrated particle size of the nanoparticles was characterized by Dynamic Light Scattering (DLS). As can be seen from fig. 11, the hydrated particle size of the nanoparticles obtained at different temperatures does not significantly change, which proves the thermodynamic stability of the tellurium-gold nanostructure, and the relevant conclusion can be also confirmed by UV-VIS (fig. 12).
5. Tellurium gold nanoparticle oxidation stimulation responsiveness test
Dispersing tellurium and gold nanoparticles in an aqueous solution, and adding a small amount of hydrogen peroxide solution. And (3) taking 20 mu L of aqueous solution at 6 and 24 hours respectively, placing the aqueous solution in a copper mesh for airing, and characterizing the appearance of the solution by an electron projection microscope (TEM). As shown in fig. 13, the tellurium gold nanoparticles gradually agglomerated with the lapse of time. Placing 20 μ L of the obtained product on a smooth silicon wafer for drying at 0, 6, 12, 18 and 24 hours respectively. The valence state change of tellurium element in tellurium-gold nanoparticles was characterized by X-ray photoelectron spectroscopy (XPS), see fig. 14. Wherein is located at 5Tellurium element 3d at 74keV5/2The peak gradually decreases and a new 3d at 576keV5/2The gradual increase of the peak proves the process of changing the valence of tellurium element from +2 to +4 in the process. The + 4-valent tellurium element does not have coordination with the gold element, so the surface energy of the nano-sized simple substance gold cannot be reduced, and the aggregation of tellurium gold nanoparticles is caused.
6. Tellurium gold nanoparticle apoptosis test
The effect of tellurium-gold nanoparticles on HepG2 cell activity was investigated by flow cytometry. Meanwhile, the CCK-8 experiment shows that the tellurium gold nanoparticles generate cytotoxicity on HepG2 cells, and do not show obvious cytotoxicity on L02 cells.
The normal cell lines used in the apoptosis experiment are human normal liver cells (L02) and human normal mammary cells (MCF-10A), and the tumor cell lines are human liver cancer cells (HepG2), human breast cancer cells (MDA-MB-231, MCF-7), human lung adenocarcinoma cells (A549) and pancreatic cancer cells (Panc-1).
Preparation of a culture medium for L02 cells: respectively adding a tellurium-containing compound, traditional gold nanoparticles (AuNP/Citrate), selenium gold nanoparticles (AuNP-Se) and tellurium gold nanoparticles (TG NP) into a culture medium suitable for L02 cells, so as to respectively obtain the final concentration of the tellurium-containing compound of 0 mu g mL-1、2μg mL-1、5μg mL-1、10μg mL-1、15μg mL-1、20μg mL-1The culture medium of (1); the final concentration of traditional gold nanoparticles was 0 μ g mL-1、2μg mL-1、5μg mL-1、10μg mL-1、15μg mL-1、20μg mL-1The culture medium of (1); the final concentration of tellurium and gold nanoparticles is 0 mu g mL-1、2μg mL-1、5μg mL-1、10μg mL-1、15μg mL-1、20μg mL-1The medium of (1).
Preparation of a medium for HepG2 cells: respectively adding a tellurium-containing compound, traditional gold nanoparticles and tellurium gold nanoparticles into a culture medium suitable for HepG2 cells, so as to respectively obtain the final concentration of the tellurium-containing compound of 0 mu g mL-1、2μg mL-1、5μg mL-1、10μg mL-1、15μg mL-1、20μg mL-1The culture medium of (1); the final concentration of conventional gold nanoparticles is 0. mu.g mL-1、2μg mL-1、5μg mL-1、10μg mL-1、15μg mL-1、20μg mL-1The culture medium of (1); the final concentration of tellurium and gold nanoparticles is 0 mu g mL-1、2μg mL-1、5μg mL-1、10μg mL-1、15μg mL-1、20μg mL-1The medium of (1).
Preparation of MCF-10A cell culture medium: adding tellurium gold nanoparticles into a culture medium suitable for MCF-10A cells to obtain the final concentration of the tellurium gold nanoparticles of 0 mu g mL-1、2μg mL-1、5μg mL-1、10μg mL-1、15μg mL-1、20μg mL-1The medium of (1).
Preparation of MCF-7 cell culture medium: adding tellurium gold nanoparticles into a culture medium suitable for MCF-7 cells to obtain the final concentration of the tellurium gold nanoparticles of 0 mu g mL-1、2μg mL-1、5μg mL-1、10μg mL-1、15μg mL-1、20μg mL-1The medium of (1).
Preparation of a culture medium for MDA-MB-231 cells: adding tellurium gold nanoparticles into a culture medium suitable for MDA-MB-231 cells to obtain tellurium gold nanoparticles with the final concentration of 0 mu g mL-1、2μg mL-1、5μg mL-1、10μg mL-1、15μg mL-1、20μg mL-1The medium of (1).
Preparation of a549 cell culture medium: adding tellurium gold nanoparticles into a culture medium suitable for A549 cells to obtain tellurium gold nanoparticles with the final concentration of 0 mu g mL-1、2μg mL-1、5μg mL-1、10μg mL-1、15μg mL-1、20μg mL-1The medium of (1).
Preparation of culture medium for Panc-1 cells: adding tellurium gold nanoparticles into a culture medium suitable for Panc-1 cells to obtain tellurium gold nanoparticles with the final concentration of 0 mu g mL-1、2μg mL-1、5μg mL-1、10μg mL-1、15μg mL-1、20μg mL-1The medium of (1).
Culturing L02 cells by respectively adopting the prepared L02 cell culture medium; culturing HepG2 cells by adopting the prepared culture medium of the HepG2 cells; culturing the MCF-10A cell by adopting the prepared MCF-10A cell culture medium; culturing the MCF-7 cells by adopting the prepared MCF-7 cell culture medium; culturing the MDA-MB-231 cells by adopting the culture medium of the MDA-MB-231 cells prepared by the preparation method; culturing the A549 cells by adopting the culture medium of the A549 cells prepared by the method; panc-1 cells were cultured in the Panc-1 cell culture medium prepared as described above.
The viability of L02 cells and HepG2 cells incubated with tellurium gold nanoparticles for 24 hours was stained by an apoptosis kit and characterized using a flow cytometer, and the results are shown in fig. 15. The viability of L02 cells and HepG2 cells incubated with conventional gold nanoparticles for 24 hours was characterized by CCK-8 kit staining and using an enzyme linked immunosorbent assay, and the results are shown in fig. 16. The viability of L02 cells and HepG2 cells incubated with a tellurium-containing compound for 24 hours was characterized by CCK-8 kit staining and using an enzyme linked immunosorbent assay, and the results are shown in FIG. 17. The viability of L02 cells and HepG2 cells incubated with selenium gold nanoparticles for 24 hours was characterized by CCK-8 kit staining and using an enzyme linked immunosorbent assay, and the results are shown in fig. 18. The viability of L02 cells and HepG2 cells incubated with tellurium gold nanoparticles for 24 hours was characterized by CCK-8 kit staining and using an enzyme linked immunosorbent assay, and the results are shown in fig. 19. The survival rates of MCF-10A cells, MCF-7 cells, MDA-MB-231 cells, A549 cells and Panc-1 cells incubated with the tellurium gold nanoparticles for 24 hours were characterized by CCK-8 kit staining and using an enzyme linked immunosorbent assay (ELISA), and the results are shown in FIG. 20.
The above results show that the tellurium gold nanoparticles have significant cytotoxicity to tumor cells and no significant cytotoxicity to normal cells. The tellurium-containing compound, the traditional gold nanoparticles and the selenium gold nanoparticles do not show obvious cytotoxicity to normal cells and tumor cells. The tellurium-gold nanoparticles, the selenium-gold nanoparticles, the traditional gold nanoparticles and the tellurium-containing compound are proved to have completely different biochemical properties, and the compound is a potential selective anti-tumor chemotherapeutic drug.
7. Mouse experiments with tellurium and gold nanoparticles
In the mouse experiment, BALB/c nude mice are used, HepG2 cells are planted for nodulation, and PBS buffer solution is adopted to prepare blank solution, tellurium-containing compound solution, traditional gold nanoparticle solution, selenium gold nanoparticle solution and tellurium gold nanoparticle solution respectively. The solution is injected into tail vein once every 3 days, and the dosage of the drug for tumor mice is 1 mg/kg. The relative volume of the tumor and the weight of the mouse are measured every three days, the result of the tumor growth curve is shown in fig. 21, the result shows that the tellurium-containing compound, the traditional gold nanoparticles and the selenium gold nanoparticles have no obvious inhibition effect on the solid tumor, and the tellurium gold nanoparticles have obvious inhibition effect on the solid tumor; the change of the body weight of the mouse is shown in fig. 22, and the result shows that the tellurium-containing compound, the traditional gold nanoparticles, the selenium gold nanoparticles and the tellurium gold nanoparticles have good biocompatibility and have no obvious influence on the health of the mouse. After 18 days of treatment, the tumor picture of the mice is shown in fig. 23, and the result shows that the tumor volume of the mice in the tellurium gold nanoparticle treatment group is obviously smaller than that of the other treatment groups. Meanwhile, after 18 days, the biochemical indexes of the Blood of the mice are glutamic pyruvic Transaminase (ALT), glutamic oxaloacetic Transaminase (AST), Creatine Kinase (CK), Lactate Dehydrogenase (LDH), UREA (UREA) and Blood UREA Nitrogen (BUN, Blood UREA Nitrogen). The detection result shows that the tellurium gold nanoparticles have no hepatotoxicity, cardiotoxicity and nephrotoxicity (fig. 24-26), and have good clinical application prospect.
Furthermore, in the description herein, reference to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (8)
1. A tellurium-containing compound, which is characterized in that the structural formula is (HO-EG)X-CY)2-Te, wherein, HO-EGY-is a hydrophilic segment, EG-is an oxyethyl group, the number X of repeating units is 2 to 6; cY-is a hydrophobic chain segment, and the number Y of carbon atoms is 2-6.
2. A method for preparing tellurium gold nanoparticles using the tellurium-containing compound as claimed in claim 1, comprising the steps of:
(1) and (3) mixing the tellurium-containing compound with a gold-containing reagent according to a molar ratio of 2-12: 1, uniformly mixing in a solvent to obtain a uniform mixing system with the molar concentration of gold element of 0.1-1 mmol/L;
(2) and (2) removing the solvent from the uniform mixed system prepared in the step (1), and then rinsing and drying to obtain powdery tellurium gold nanoparticles.
3. The method of claim 2, wherein the gold-containing reagent of step (1) employs any one or a mixture of two of chloroauric acid and gold chlorite chloride.
4. The method according to claim 2, wherein the solvent in step (1) is a mixture of one or more selected from deionized water, dimethylformamide, dimethylsulfoxide, ethylene glycol, ethanol and methanol.
5. The method of claim 2, wherein the solvent is removed in step (2) by lyophilization, vacuum oven drying, or rotary evaporation.
6. The method according to claim 2, wherein the drying in step (2) is performed by vacuum oven drying, nitrogen blow drying or freeze drying.
7. Use of tellurium and gold nanoparticles prepared according to any one of claims 2 to 6 in the preparation of an anti-tumor medicament.
8. The use according to claim 7, wherein the antineoplastic drugs are directed against tumors of the type liver cancer, breast cancer, lung gland and pancreatic cancer.
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