CN114984213A - Copper sulfide/bismuth sulfide/diallyl trisulfide nano composite ball and preparation method and application thereof - Google Patents
Copper sulfide/bismuth sulfide/diallyl trisulfide nano composite ball and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a copper sulfide/bismuth sulfide/diallyl trisulfide nano composite ball as well as a preparation method and application thereof. The nano composite ball comprises protein loaded with copper sulfide and bismuth sulfide and diallyl trisulfide. The preparation method comprises the following steps: 1) sequentially dropwise adding a bismuth nitrate solution and a copper sulfate solution into a protein solution, and stirring to obtain a solution A; 2) adding the diallyl trisulfide solution into the solution A, and stirring to obtain a solution B; 3) and (3) dropwise adding the thioacetamide solution into the solution B, and stirring for reaction to obtain the nano composite ball. In the nano composite sphere, the copper sulfide nano dots and the diallyl trisulfide coordinate to regulate the generation of active oxygen and the consumption of glutathione in tumor cells, so that the radiotherapy sensitization is promoted, and meanwhile, the bismuth sulfide nano dots can sensitize local radiotherapy of tumors, so that efficient radiotherapy sensitization diagnosis and treatment are realized; the dispersion and the biocompatibility are good under physiological conditions, the preparation method is simple and mild, the controllability is good, and the application prospect in the radiotherapy sensitization field is wide.
Description
Technical Field
The invention relates to the technical field of nano composite materials and biochemistry, in particular to a copper sulfide/bismuth sulfide/diallyl trisulfide nano composite ball and a preparation method and application thereof.
Background
2020 there are about 1930 ten thousand new cancer cases and about 1000 cancer patients die worldwide. The physiological complexity of cancer determines that cancer-related mortality remains one of the leading causes of death worldwide. In the clinic of tumor therapy, radiotherapy is widely used as a non-invasive means for the treatment of different types of tumors. Radiotherapy is to generate active oxygen species by utilizing the direct interaction of rays and biological components in tumor cells to cause oxidative damage of the cells; the ray can also ionize water molecules in tissues, and indirectly oxidize intracellular biomacromolecules to cause cell oxidative damage, so that the effect of inhibiting tumor growth is achieved.
The widespread use of nanotechnology has brought new eosins for the effective treatment of cancer. The nano-material has the effects of enhancing permeation and retention, can be selectively enriched at a tumor part, has the advantages of a transport function across a biological barrier, adjustable blood circulation half-life, targeted enrichment in a tumor region and the like, and can be used for effective drug delivery and disease treatment. Radiation therapy is one of the most widely used therapeutic methods in clinical practice. Many types of solid tumors are not sensitive to radiation therapy due to the inertia of the tumor microenvironment. Scientists have done a lot of work on improving the efficiency of radiotherapy by using nanotechnology, such as improving the radiotherapy by using high atomic number elements as radiotherapy sensitizers, improving the yield of active oxygen by supplying exogenous hydrogen peroxide, and the like. The nano-particles with high atomic number have stronger ray attenuation capability, can effectively absorb rays, induce more oxidation active species to generate, and cause reverse damage to biological molecules or organelles in cells, thereby playing a role in sensitizing radiotherapy. Because the abnormal metabolism in the tumor triggers the mutation of the oxidation-reduction steady state, an enhanced antioxidant system (glutathione) in the tumor tissue can effectively eliminate excessive active oxygen in cells, thereby weakening the effect of radiotherapy. During radiotherapy, oxidative damage (DNA double strand damage or lipid peroxidation) caused by ionizing radiation (e.g., X-rays) is easily repaired by cancer cells, thereby causing resistance to radiotherapy. Therefore, a single nano system with the characteristics of enhancing the generation of active oxygen and the consumption of glutathione is urgently needed in the treatment of tumors to destroy the redox balance in tumor cells, and the creation of an environment for oxidative damage caused by ionizing radiation is a promising method for radiosensitization.
Disclosure of Invention
The invention aims to provide a copper sulfide/bismuth sulfide/diallyl trisulfide nano composite sphere and a preparation method and application thereof, which are used for solving the problem of radiotherapy resistance caused by high-expression glutathione in a tumor tissue and realizing effective radiotherapy sensitization.
In order to solve the technical problem, the invention adopts the following technical scheme:
provided is a copper sulfide/bismuth sulfide/diallyl trisulfide nanocomposite ball, which comprises a protein supporting copper sulfide and bismuth sulfide and diallyl trisulfide.
According to the scheme, the nano composite sphere is assembled based on the interaction between protein and diallyl trisulfide through hydrophilic and hydrophobic water, and is formed through induction in the presence of a sulfur ion donor. Specifically, the protein chelated with bismuth ions and copper ions and diallyl trisulfide are assembled through hydrophilic-hydrophobic interaction, thioacetamide is used as a sulfur source, sulfur ions are provided to induce copper sulfide/bismuth sulfide nanodots to grow, and finally copper sulfide/bismuth sulfide/diallyl trisulfide nano composite spheres are formed.
According to the scheme, the protein is bovine serum albumin.
According to the scheme, the particle size of the nano composite sphere is 60-90nm, for example, 60nm, 70nm, 80nm and 90 nm.
According to the scheme, the hydrated particle size of the nano composite sphere is 65-259nm, for example, 65nm, 80nm, 130nm, 150nm, 180nm and 220 nm.
According to the scheme, the mass ratio of the copper element to the bismuth element in the nano composite ball is preferably 1 to (8.6-12.8).
According to the scheme, the mass fraction of the protein in the nano composite sphere is preferably 25-35%, and the mass fraction of the diallyl trisulfide is preferably 6-10%.
The preparation method of the copper sulfide/bismuth sulfide/diallyl trisulfide nano composite ball comprises the following steps:
1) sequentially dropwise adding a bismuth nitrate pentahydrate solution and a copper sulfate trihydrate solution into a protein solution, and stirring to obtain a solution A;
2) adding the diallyl trisulfide solution into the solution A obtained in the step 1), and stirring to obtain a solution B;
3) and dropwise adding the thioacetamide solution into the solution B, and stirring for reaction to obtain the copper sulfide/bismuth sulfide/diallyl trisulfide nano composite ball.
According to the scheme, the mass ratio of the bismuth nitrate pentahydrate to the copper nitrate trihydrate to the protein is (8-10): (1.6-3): (3-6); the mass ratio of the bismuth nitrate pentahydrate to the copper nitrate trihydrate to the diallyl trisulfide is (8-10): (1.6-3): (4-6); the mass ratio of the bismuth nitrate pentahydrate to the copper nitrate trihydrate to the thioacetamide is (8-10): (1.6-3): (1.2-2).
According to the scheme, the concentration of the protein is 0.375-0.75 mg/mL; the concentration of the bismuth nitrate pentahydrate solution is 20-25 mg/mL; the concentration of the copper nitrate trihydrate solution is 4-7.5 mg/mL; in the step 2), the concentration of the diallyl trisulfide solution is 0.1-0.15 mg/mu L; in the step 3), the concentration of the thioacetamide solution is 3-5 mg/mL.
According to the scheme, the solvent in the protein solution in the step 1) is water; the solvent of the copper nitrate solution in the step 1) is water; the solvent of the thioacetamide solution in the step 3) is water.
According to the scheme, in the step 1), the protein is bovine serum albumin.
According to the scheme, the solvent of the bismuth nitrate pentahydrate solution in the step 1) is a nitric acid solution; the concentration of the nitric acid solution is preferably 1-2 mol/L.
According to the scheme, the solvent of the diallyl trisulfide solution in the step 2) is dimethyl sulfoxide.
According to the scheme, in the step 1), stirring is carried out for 10-30 min; in the step 2), stirring is carried out for 10-30 min.
According to the scheme, in the step 3), the stirring reaction temperature is 20-40 ℃, and preferably 20-30 ℃; the reaction time is 5-12h, preferably 6 h.
Provides an application of the nano composite ball in preparing a tumor radiotherapy sensitizer.
The application provides a copper sulfide/bismuth sulfide/diallyl trisulfide nano composite ball, which comprises a protein carrier and diallyl trisulfide, wherein the protein carrier is used for loading copper sulfide and bismuth sulfide; wherein the copper sulfide nano-dots can act with hydrogen peroxide and glutathione overexpressed in a tumor microenvironment to eliminate the glutathione and generate active oxygen; the diallyl trisulfide can induce the active oxygen level in the tumor cells to be increased, the consumption of glutathione is further promoted, and the copper sulfide nano-dots and the diallyl trisulfide can synergistically regulate the active oxygen and the glutathione in the tumor cells; the bismuth sulfide nano-dots can enhance local radiotherapy of the tumor; therefore, the purposes of promoting the radiotherapy sensitization based on the generation of active oxygen and the consumption of glutathione and realizing efficient radiotherapy sensitization diagnosis and treatment are achieved.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention provides a copper sulfide/bismuth sulfide/diallyl trisulfide nano composite sphere, wherein copper sulfide nano dots and diallyl trisulfide cooperate to regulate active oxygen generation and glutathione consumption in tumor cells, so that radiotherapy sensitization is promoted, and meanwhile, the bismuth sulfide nano dots can sensitize local radiotherapy of tumors, so that efficient radiotherapy sensitization diagnosis and treatment are realized.
2. The invention provides a method for synthesizing copper sulfide/bismuth sulfide/diallyl trisulfide nano composite spheres by a one-step method, in a water phase, a protein chelated with bismuth particles and copper ions is assembled with diallyl trisulfide through hydrophilic-hydrophobic interaction, thioacetamide is used as a donor of sulfur ions to induce copper sulfide/bismuth sulfide nano dots to grow, and the copper sulfide/bismuth sulfide/diallyl trisulfide nano composite spheres are formed through reaction; the obtained nano composite ball has good dispersibility and biocompatibility under physiological conditions, the preparation method is simple and mild, the controllability is good, and the application prospect in the field of radiotherapy sensitization is wide.
Drawings
FIG. 1 is a TEM image of the Cu sulfide/Bi sulfide/diallyl trisulfide nanocomposite ball prepared in example 1.
Fig. 2 is a distribution diagram of the hydrated particle size of the copper sulfide/bismuth sulfide/diallyl trisulfide nanocomposite spheres prepared in example 1.
Fig. 3 is an X-ray photoelectron spectrum of copper element (fig. a) and bismuth element (fig. b) in the copper sulfide/bismuth sulfide/diallyl trisulfide nanocomposite ball prepared in example 1.
Fig. 4 is an infrared spectrum of the copper sulfide/bismuth sulfide/diallyl trisulfide nanocomposite ball prepared in example 1.
Fig. 5 is a thermogravimetric plot of the copper sulfide/bismuth sulfide/diallyl trisulfide nanocomposite spheres prepared in example 1.
FIG. 6 is a transmission electron micrograph of the nanocomposite prepared in comparative example 1.
FIG. 7 is a transmission electron micrograph of the nanocomposite prepared in comparative example 2.
FIG. 8 shows the intracellular active oxygen content (panel a) and glutathione/glutathione oxide content (panel b) of the copper sulfide/bismuth sulfide/diallyl trisulfide nanocomposite ball prepared in example 1.
FIG. 9 is a clonal clone viability assay of the resulting nanocomposite spheres of example 1 and a control group.
FIG. 10 is a graph showing tumor growth curves of mice in the groups treated with radiotherapy, direct radiotherapy and control using the nanocomposite spheres obtained in example 1.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
The implementation provides a preparation method of a nano composite sphere for sensitizing tumor radiotherapy, which comprises the following specific steps:
(1) dissolving 48mg of bismuth nitrate pentahydrate in 2mL of nitric acid solution (1.5M) to obtain solution I;
(2) dissolving 12mg of copper nitrate trihydrate in 2mL of deionized water to obtain a solution II;
(3) dissolving 15mg of bovine serum albumin in 40mL of deionized water to obtain a solution III;
(4) dissolving 20mg of diallyl trisulfide in 200 mu L of dimethyl sulfoxide to obtain a solution IV;
(5) dissolving 8mg of thioacetamide in 2mL of deionized water to obtain a solution V;
(6) sequentially dropwise adding the solutions I and II into the solution III to obtain a solution VI; after stirring the solution VI for 30min, immediately injecting the solution IV into the solution VI to obtain a solution VII;
(7) stirring the solution VII for 30min, dropwise adding the solution V into the solution VII to obtain a reaction system A,
(8) stirring the reaction system A for 6 hours at 25 ℃ to obtain a system B;
(9) and centrifuging and washing the system B at 12000rpm, and collecting precipitates to obtain the copper sulfide/bismuth sulfide/diallyl trisulfide nano composite ball.
The nanocomposite balls prepared in this example were subjected to the following relevant performance tests:
1) the nano-composite spheres prepared in this example were characterized by using a transmission electron microscope (TEM, TaLos F200X), and as a result, as shown in fig. 1, the particle size of the nano-composite spheres was between 60nm and 90nm, and the particle size distribution was relatively uniform.
2) The nanocomposite balls prepared in this example were characterized in terms of particle size using a dynamic light scattering instrument (DLS, MaLvern Instruments), and the average hydrated particle size was 60 to 259nm, as shown in fig. 2.
3) The valence states of the copper element, the bismuth element and the sulfur element in the nano composite sphere prepared in this example were characterized by using an X-ray photoelectron spectrometer (XPS, AXIS-ULTRA DLD-600W), and as a result, as shown in fig. 3, characteristic peaks of Cu 2p, Bi 4f and S2 p respectively exist, which proves that copper sulfide and bismuth sulfide exist in the nano composite sphere prepared in this example, wherein the valence state of the copper element is +2 and the valence state of the bismuth element is + 3.
4) The nanocomposite spheres prepared in this example were characterized using infrared spectroscopy (FTIR, NicoLet iS50R) and the characteristic groups-CH ═ CH and ═ CH, respectively, of diallyl trisulfide are shown in fig. 4 2 The absorption peak indicates that the prepared nano composite sphere is successfully loaded with diallyl trisulfide.
5) As a control, the nanocomposite ball without the addition of the diallyl trisulfide was synthesized according to the procedure (1-3, 5-9) of example 1, and the content of the diallyl trisulfide in the nanocomposite ball was calculated by thermogravimetric analysis. The organic content of the nanocomposite spheres prepared in this example and the control group containing no diallyl trisulfide were analyzed by using a thermogravimetric analyzer (Diamond TG/DTA), and the results are shown in fig. 5, in which the mass fraction of bovine serum albumin in the nanocomposite spheres is 29% and the mass fraction of diallyl trisulfide is 8%.
6) The content of copper element and bismuth element in the nano composite ball is analyzed by using an inductively coupled plasma mass spectrometer, and the result shows that the mass ratio of the copper element to the bismuth element is 1: 9.
7) The effect of the nanocomposite balls in this example on intracellular reactive oxygen species and glutathione in 4T1 was evaluated as follows:
after co-culturing 4T1 cells with the nano-composite spheres (100. mu.g/mL) for 18h, the cells were washed three times, stained with 2',7' -dichlorodihydrofluorescein diacetate (10. mu.M), incubated at 37 ℃ in the dark for 30min, and then the intracellular reactive oxygen levels were measured using a flow cytometer.
4T1 cells after co-culturing 4T1 cells with nanocomposite spheres (100. mu.g/mL) for 12h, the cells were collected. The protein removal reagent solution was mixed with the treated cells and vortexed rapidly, then subjected to two rapid freeze-thaw cycles in liquid nitrogen and 37 ℃ water bath. Centrifuging at 10000g for 10min, and collecting supernatant. And detecting the GSH and the GSSG in the sample according to the detection scheme of the GSH/GSSG detection kit.
As shown in fig. 8, compared with the blank control group, the nanocomposite ball can significantly increase the reactive oxygen species level in 4T1 cells, and after the nanocomposite ball is used for treating tumor cells, the amount of glutathione in the cells is reduced by 43%, and glutathione in 4T1 cells is effectively consumed.
8) The ability of the nanocomposite ball prepared in this example to perform sensitization radiotherapy was evaluated as follows:
4T1 cells were co-cultured with nanocomposite balls (100. mu.g/mL) for 12h, the co-cultured cells were collected, seeded onto 6-well plates at 2000 cells per well, irradiated at doses of 0Gy,2Gy,4Gy,6Gy and 8Gy after 24h of culture, and after 7 days, the cells were fixed, stained, and cell colonies were counted.
As shown in fig. 9, the sensitivity of the tumor cells treated with the nanocomposite balls to radiation therapy was significantly enhanced, and the tumor cells in the material-treated group had significantly fewer colonies compared to the blank control group.
9) The tumor inhibition effect of the nano composite sphere prepared in the embodiment in vivo is evaluated by the following method:
tumors were inoculated into the right thigh groin of BALB/c mice, each mouse was inoculated with 2X 106 4T1 cells, and when the tumor volume reached 60mm 3 The treatment is started. The nano composite spheres are prepared into 4mg/mL PBS solution, and the PBS solution is administered to tumor-bearing mice through tail veins, and the dosage is50 mu L/10 g. After 18h of administration, a radiation dose of 6Gy was received. The control group is tumor-bearing mice without treatment, and the radiotherapy group is tumor-bearing mice receiving 6Gy ray irradiation. The length and width of the mouse tumor were measured every other day with a vernier caliper, the tumor volume was recorded, and the tumor-suppressing effect was monitored.
Fig. 10 shows a tumor growth curve, and the tumor growth of the mice treated by the nano composite spheres combined with radiotherapy is obviously inhibited, and has significant difference with that of a single radiotherapy group, which shows that the composite nano particles have good radiotherapy sensitization effect.
Comparative example 1
The preparation method comprises the following specific steps:
(1) dissolving 48mg of bismuth nitrate pentahydrate in 2mL of nitric acid solution (1.5M) to obtain solution I;
(2) dissolving 12mg of copper nitrate trihydrate in 2mL of deionized water to obtain a solution II;
(3) dissolving 8mg of bovine serum albumin in 40mL of deionized water to obtain a solution III;
(4) dissolving 20mg of diallyl trisulfide in 200 mu L of dimethyl sulfoxide to obtain a solution IV;
(5) dissolving 8mg of thioacetamide in 2mL of deionized water to obtain a solution V;
(6) sequentially dropwise adding the solutions I and II into the solution III to obtain a solution VI; after stirring the solution VI for 30min, immediately injecting the solution IV into the solution VI to obtain a solution VII;
(7) stirring the solution VII for 30min, dropwise adding the solution V into the solution VII to obtain a reaction system A,
(8) stirring the reaction system A for 6 hours at 25 ℃ to obtain a system B;
(9) and centrifuging and washing the system B at 12000rpm, and collecting precipitates to obtain the copper sulfide/bismuth sulfide/diallyl trisulfide nano composite ball.
FIG. 6 is a photograph of a transmission electron microscope (TEM, TaLos F200X) of the composite material prepared in this example (scale 50nm), from which it can be seen that the composite material prepared in this example has small unassembled nanoparticles.
Comparative example 2
The preparation method comprises the following specific steps:
(1) 48mg of bismuth nitrate pentahydrate were dissolved in 2mL of nitric acid solution (1.5M) to give solution I
(2) Dissolving 12mg of copper nitrate trihydrate in 2mL of deionized water to obtain a solution II;
(3) dissolving 15mg of bovine serum albumin in 40mL of deionized water to obtain a solution III;
(4) dissolving 50mg of diallyl trisulfide in 200 mu L of dimethyl sulfoxide to obtain a solution IV;
(5) dissolving 8mg of thioacetamide in 2mL of deionized water to obtain a solution V;
(6) sequentially dropwise adding the solutions I and II into the solution III to obtain a solution VI; after stirring the solution VI for 30min, immediately injecting the solution IV into the solution VI to obtain a solution VII;
(7) stirring the solution VII for 30min, dropwise adding the solution V into the solution VII to obtain a reaction system A,
(8) stirring the reaction system A for 6 hours at 25 ℃ to obtain a system B;
(9) and centrifuging and washing the system B at 12000rpm, and collecting precipitates to obtain the copper sulfide/bismuth sulfide/diallyl trisulfide nano composite ball.
Fig. 7 is a photograph of the composite material prepared in this example under a transmission electron microscope (TEM, TaLos F200X), and it can be seen that the composite material prepared in this example is crosslinked and has a large amount of plate-like impurities.
In the nano composite ball, the mass fraction of the protein is preferably 25-35%, and the mass fraction of the diallyl trisulfide is preferably 6-10%.
Claims (10)
1. The copper sulfide/bismuth sulfide/diallyl trisulfide nanocomposite ball is characterized by comprising copper sulfide and bismuth sulfide loaded protein and diallyl trisulfide.
2. The nanocomposite ball of claim 1, wherein the nanocomposite ball has a particle size of 60-90 nm; the hydrated particle size of the nano composite sphere is 65-259 nm.
3. The nanocomposite ball according to claim 1, wherein the nanocomposite ball comprises 25 to 35% by mass of the protein and 6 to 10% by mass of the diallyl trisulfide; the mass ratio of the copper element to the bismuth element is 1: 8.6-12.8.
4. The nanocomposite ball of claim 1, wherein the protein is bovine serum albumin.
5. A method for preparing the copper sulfide/bismuth sulfide/diallyl trisulfide nanocomposite ball as claimed in any one of claims 1 to 4, comprising the steps of:
1) sequentially dropwise adding a bismuth nitrate pentahydrate solution and a copper sulfate trihydrate solution into a protein solution, and stirring to obtain a solution A;
2) adding the diallyl trisulfide solution into the solution A obtained in the step 1), and stirring to obtain a solution B;
3) and dropwise adding the thioacetamide solution into the solution B, and stirring for reaction to obtain the copper sulfide/bismuth sulfide/diallyl trisulfide nano composite ball.
6. The preparation method according to claim 5, wherein the mass ratio of the bismuth nitrate pentahydrate, the copper nitrate trihydrate and the protein is (8-10): (1.6-3): (3-6); the mass ratio of the bismuth nitrate pentahydrate to the copper nitrate trihydrate to the diallyl trisulfide is (8-10): (1.6-3): (4-6); the mass ratio of the bismuth nitrate pentahydrate to the copper nitrate trihydrate to the thioacetamide is (8-10): (1.6-3): (1.2-2).
7. The method according to claim 5, wherein in the step 1), the concentration of the protein is 0.375 to 0.75 mg/mL; the concentration of the bismuth nitrate solution is 20-25 mg/mL; the concentration of the copper nitrate solution is 4-7.5 mg/mL; in the step 2), the concentration of the diallyl trisulfide solution is 0.1-0.15 mg/mu L; in the step 3), the concentration of the thioacetamide solution is 3-5 mg/mL.
8. The preparation method according to claim 5, wherein the solvent in the protein solution in step 1) is water, the solvent in the copper nitrate solution is water, and the solvent in the bismuth nitrate solution is a nitric acid solution; the solvent of the diallyl trisulfide solution in the step 2) is dimethyl sulfoxide; the solvent of the thioacetamide solution in the step 3) is water.
9. The method according to claim 5, wherein in the step 1), the stirring is performed for 10 to 30 min; in the step 2), stirring for 10-30 min; in the step 3), the stirring reaction temperature is 20-40 ℃; the reaction time is 5-12 h.
10. The use of the copper sulfide/bismuth sulfide/diallyl trisulfide nanocomposite ball of any one of claims 1 to 4 in the preparation of tumor radiotherapy sensitizers.
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| CN106729713A (en) * | 2017-02-28 | 2017-05-31 | 中南大学 | A kind of preparation method and applications of protein coated metallic sulfide nano-particle |
| CN107551279A (en) * | 2017-09-14 | 2018-01-09 | 苏州大学 | Extra small albumen composite nano-granule near infrared light fuel factor and multi-modality imaging function and its preparation method and application |
| CN108478796A (en) * | 2018-05-15 | 2018-09-04 | 浙江大学 | It is a kind of it is extra small can kidney be metabolized multi-functional copper sulfide nano material and its preparation method and application |
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| US20020015679A1 (en) * | 2000-06-01 | 2002-02-07 | Kotov Nicholas A. | Bioconjugates of nanoparticles as radiopharmaceuticals |
| CN106729713A (en) * | 2017-02-28 | 2017-05-31 | 中南大学 | A kind of preparation method and applications of protein coated metallic sulfide nano-particle |
| CN107551279A (en) * | 2017-09-14 | 2018-01-09 | 苏州大学 | Extra small albumen composite nano-granule near infrared light fuel factor and multi-modality imaging function and its preparation method and application |
| CN108478796A (en) * | 2018-05-15 | 2018-09-04 | 浙江大学 | It is a kind of it is extra small can kidney be metabolized multi-functional copper sulfide nano material and its preparation method and application |
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