CN113976908A - Bimetallic nanoparticle for tumor diagnosis and treatment and preparation method and application thereof - Google Patents
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
- B22F9/00—Making metallic powder or suspensions thereof
- B22F9/16—Making metallic powder or suspensions thereof using chemical processes
- B22F9/18—Making metallic powder or suspensions thereof using chemical processes with reduction of metal compounds
- B22F9/24—Making metallic powder or suspensions thereof using chemical processes with reduction of metal compounds starting from liquid metal compounds, e.g. solutions
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light
Abstract
The invention discloses a bimetallic nano-particle capable of being used for tumor diagnosis and treatment and a preparation method and application thereof, relates to the field of tumor diagnosis and treatment, and aims to solve the problem that a gold-bismuth bimetallic nano-particle has poor effect in the diagnosis and treatment of photo-thermal/photodynamic cancer, wherein the chemical expression of the bimetallic nano-material is as follows: Au-Bi-SR; wherein the SR is mercaptan. Dissolving bismuth nitrate pentahydrate in ethylene glycol and chloroauric acid in methanol, and mixing; adding methanol-dissolved tetra-n-octyl ammonium bromide, stirring, adding captopril, dissolving in methanol solution, stirring, adding sodium borohydride, dissolving in ice water bath, stirring, removing impurities, washing with ethanol, and drying. The prepared bimetal nano composite material with uniform size, regular shape and good dispersibility is applied to the field of diagnosis and treatment of tumors.
Description
Technical Field
The invention relates to the field of tumor diagnosis and treatment, in particular to a preparation method of a bimetallic nanoparticle for tumor diagnosis and treatment.
Background
Bismuth is a relatively stable element, has a relatively large atomic mass, is relatively inexpensive compared to other heavy metal elements, and has a high X-ray attenuation coefficient among non-radioactive elements. Gold nanoparticles are a very important metal nanomaterial, and not only have the characteristics of nanoparticles, but also have good stability, unique optical effect, electrochemical performance and biological affinity. For example, the gold nano-material can effectively increase the cross section and radiation of the tissue when distributed in the tissue, so that the removal of the nano-material is limited by all tumor tissues; gold nanoparticles have a lower systemic clearance relative to small molecule reagents. It is adsorbed in tumor tissue, can be combined with various biological macromolecules C (such as antibody), and has no influence on its biological activity, and a large quantity of gold atoms can be specifically transferred into tumor tissue.
Cancer has been the leading threat to human life for centuries, and most of the current treatments (such as surgery, photodynamic therapy, chemotherapy and radiotherapy) are inefficient and often cause severe toxic side effects. Recently, in order to achieve therapeutic effects, Near Infrared (NIR) light/X-ray/self-luminescence excitation including deep tissue photodynamic therapy and the like are receiving increasing attention.
Disclosure of Invention
The invention aims to solve the problem that the gold-bismuth bimetallic nanoparticles have poor effect in the diagnosis and treatment of photo-thermal/photodynamic cancer, and provides a preparation method of the bimetallic nanoparticles for tumor diagnosis and treatment. The double-base nano material can combine multimode imaging with various treatment methods, thereby greatly improving the diagnosis and treatment level of tumors. The thiol-protected gold-bismuth bimetallic nanoparticles have good photothermal/photodynamic and CT imaging effects, and can be used for more effectively diagnosing and treating cancers.
The invention relates to a bimetal nano material for tumor diagnosis and treatment, which has the chemical expression: Au-Bi-SR; wherein the SR is mercaptan.
Furthermore, the bimetal nano material is excited by ultraviolet light and visible light.
Furthermore, in the bimetal nano material, the molar ratio of Au to Bi to SR in Au-Bi-SR is 1:1: 10.
The preparation method of the bimetal nano material for tumor diagnosis and treatment is carried out according to the following steps:
dissolving bismuth nitrate pentahydrate in ethylene glycol to obtain a bismuth nitrate pentahydrate ethylene glycol solution; dissolving chloroauric acid in methanol to obtain a chloroauric acid methanol solution; uniformly mixing a bismuth nitrate glycol pentahydrate solution and a chloroauric acid methanol solution according to equal volume to obtain a mixed solution;
step two, adding tetra-n-octyl ammonium bromide dissolved in methanol into the mixed solution obtained in the step one, stirring for 15-20 min, adding a captopril methanol solution, and mixing and stirring for 25-30 min; then adding a sodium borohydride ice-water mixed solution, and mixing and stirring for 60-70 min;
and step three, centrifuging to remove the precipitate, leaving supernatant, repeatedly washing with ethanol, and drying in vacuum to obtain the bimetallic nano-material.
Further, the molar volume (or mole) ratio of bismuth nitrate pentahydrate to ethylene glycol was 1 mmol: 1-0.9 mL;
the molar volume (or mole) ratio of chloroauric acid to methanol was 1 mmol: 1-1.2 mL;
the molar volume (or mole) ratio of tetra-n-octylammonium bromide to methanol was 1 mmol: 2.3-1.2 mL;
the molar volume (or mole) ratio of captopril to methanol was 1 mmol: 10-1.2 mL;
the molar volume (or molar) ratio of the sodium borohydride to the ice-water mixed liquid is 1 mmol: 1-20 mL.
The invention relates to a bimetal nano material for diagnosing and treating tumors, which is used for preparing a medicine for diagnosing and treating photothermal/photodynamic tumors.
The invention has the following beneficial effects:
(1) the bimetal nano composite material can utilize SPR effect to improve the photo-thermal conversion efficiency and the photo-thermal treatment effect; (2) reducing gold bismuth ions in the solution into a simple substance by using a chemical reduction method and using sodium borohydride as a strong reducing agent; (3) thiols are used as protecting agents, and are effectively protected from oxidation due to strong chemisorption between the thiol and the metal, thereby maintaining high stability and long-term near-infrared absorption. The prepared bimetal nano composite material with uniform size, regular shape and good dispersibility is applied to the field of diagnosis and treatment of tumors.
The invention proposes: firstly, preparing a novel Au-Bi-SR bimetallic nano material by adopting a chemical reduction method and taking sodium borohydride as a strong reducing agent; secondly, the mercaptan is used as a protective agent, and due to the strong chemical adsorption effect between the mercaptan and the metal, the mercapto group in the mercaptan is complexed with the simple substance gold and the simple substance bismuth, so that the simple substance gold and the simple substance bismuth are effectively prevented from being oxidized, and the high stability and the near-infrared absorption performance are kept; and thirdly, reducing gold bismuth ions in the solution into a simple substance by using sodium borohydride as a strong reducing agent (double metals are reduced into the simple substance by using the reduction effect of the sodium borohydride, and then mercaptan is used as a protective agent to ensure that the simple substance exists stably for a long time, the shape and the performance of the simple substance are the same as those of the simple substance, and the shape and the performance of the simple substance are proved by a transmission diagram and an ultraviolet absorption diagram of the invention and can be excited by near infrared light).
The invention adopts a chemical reduction method to reduce metal ions into simple substances and uses mercaptan for protection to prepare the bimetal nano composite material which can be used for tumor diagnosis and treatment. The bimetal composite material has the following characteristics that firstly, the preparation method of the bimetal nanocomposite material is simple, the material structure is simple, and the bimetal nanocomposite material can be excited by near infrared light (as can be proved by figure 2, the bimetal material provided by the invention absorbs light at a position of 808 mm). Secondly, the Au-Bi-SR nanocomposite has the photodynamic property of gold and the photothermal property of bismuth, and has higher photothermal conversion efficiency and photodynamic/CT imaging effect by combining the advantages of the Au-Bi-SR nanocomposite and the bismuth (the photothermal property effect can be proved by figure 3, and the photodynamic property effect is proved by figure 4).
Description of the drawings:
FIG. 1(a) is an X-ray diffraction pattern of Au-Bi-SR nanoparticles;
(b) XPS plots of Au-Bi-SR nanoparticles;
(c) TEM image of Au-Bi-SR nanoparticles;
(d) HRTEM image of Au-Bi-SR nanoparticles;
FIG. 2 is a graph of the UV absorption and photoluminescence emission spectra of Au-Bi-SR nanoparticles; wherein, the left image is an ultraviolet absorption spectrogram, and the right image is a photoluminescence emission spectrogram; in the left figure, A is Au-Bi-SR, B is Au-SR, and C is Bi-SR;
FIG. 3 photo-thermal intensity plots of Au-Bi-SR nanoparticles at different irradiation times; wherein A is 400. mu.g/mL-1B is 200. mu.g.mL-1C is 100. mu.g.mL-1D is 50. mu.g.mL-1E is 25. mu.g.mL-1F is 0. mu.g/mL-1；
FIG. 4 is a graph of the fluorescence intensity of DCF at different illumination times; wherein A is 10min, B is 6min, C is 3min, D is 1min, and E is 0 min.
The specific implementation mode is as follows:
in order to better understand the present invention, the technical solutions and effects of the present invention are further described below with reference to examples.
Example 1
The preparation method of the bimetal nano material for tumor diagnosis and treatment of the embodiment is as follows:
the preparation method comprises the following steps of: dissolving 0.15 mmol-0.25 mmol of bismuth nitrate pentahydrate in 5mL of ethylene glycol, then dissolving 0.15 mmol-0.25 mmol of chloroauric acid in 5mL of methanol, and stirring the two solutions according to the weight ratio of 1: dissolving in a proportion of 1, changing the solution into light yellow, then adding 0.20-0.25mmol of tetra-n-octyl ammonium bromide into the solution, changing the solution into deep red, stirring for 15-20 min, then dissolving 0.80-1.2mmol of captopril (mercaptan) into 5mL of methanol solution, quickly adding the solution into the solution, mixing and stirring, changing the solution color into milk white, stirring for 20-30 min, then dissolving 1.80-2.2mmol of sodium borohydride, namely corresponding to the ratio of the mercaptan to the sodium borohydride being 1:2, into an ice water bath, adding the solution into the solution, stirring for 60-70min, firstly removing unreacted impurities by using a low revolution, then repeatedly washing for several times by using ethanol, and drying the prepared nanoparticles by using a vacuum drying oven to obtain the Au-Bi-SR nanomaterial.
The Au-Bi-SR nanomaterial prepared in the example is subjected to performance characterization:
the structure and the appearance of the Au-Bi-SR nano material are as follows: by chemical reductionThe double-core metal nano-particles with gold and bismuth protected by mercaptan are synthesized, wherein raw materials comprise bismuth nitrate pentahydrate, chloroauric acid, captopril, sodium borohydride and the like, and solvents comprise ethylene glycol, methanol and purified water. The Au-Bi-SR nanoparticles synthesized by the method have high contrast with the background, uniform size, regular appearance, spherical shape and good dispersibility by analyzing the Au/Bi bimetallic nanoparticles (figures 1c and d) through a transmission electron microscope. Meanwhile, as shown in FIG. 1a, the XRD diffraction pattern of the Au-Bi-SR nanoparticle is shown, and the phase composition and the structure of a sample are analyzed by the X-ray diffraction powder diffraction technology. The diffraction peaks of the Au-Bi-SR nanoparticles respectively correspond to standard cards of Au (JCPDS 04-0784) and Bi (JCPDS 44-1246), and the diffraction peaks of the Au-Bi-SR nanoparticles are well corresponding to the standard cards, and clear diffraction peaks also indicate that the sample has good crystallinity, thereby confirming the successful synthesis of the Au-Bi-SR nanoparticles. Particularly, the XRD pattern of the Au-Bi-SR nanoparticle sample just corresponds to the hexagonal crystal system structure of bismuth and the tetragonal crystal system structure of gold, and the characteristic peaks of the hexagonal crystal system structure and the tetragonal crystal system structure of gold coexist. This further confirmed the formation of bimetallic nanoparticles and formed Au-Bi-SR nanoparticles instead of Au/Bi nanocomposites or Au2Bi nanocrystals and the like. Furthermore, the chemical state and the elemental composition of the Au-Bi-SR surface element are verified through X-ray photoelectron spectroscopy. As shown in FIG. 1b, the analysis of the full spectrum of Au-Bi-SR can result in that Au-Bi-SR contains Au, Bi, C and O, i.e. contains all the major elements of the sample prepared in this example.
Measurement of photothermal effect: 808 laser irradiation is used for researching the photo-thermal property of the gold-bismuth bimetal. The concentrations were 0, 10, 20, 50, 100, 200. mu.g.mL-1The Au-Bi-SR nano material and irradiating the culture medium by laser. The temperature rises rapidly within 0-180 s, the temperature rises slowly from 180 s-600 s along with the time, and the temperature rise of the pure culture medium is not obvious. Concentration (0, 10, 20, 50, 100, 200. mu.g.mL) within 600s-1) The temperature of the Au-Bi-SR nanomaterial is increased along with the temperature, which shows that the Au-Bi-SR nanomaterial has a concentration-dependent effect. Within 0-250 s, the temperature of the sample solution is rapidly increased, and the temperature of the sample is not obviously increased within 250-480s along with the time. The results are shown in the figure3, it can be seen from fig. 3 that the photothermal effect of the sample has a certain concentration dependence, but the higher the concentration is, the faster the temperature rises with longer exposure time, indicating that the best photothermal effect can be obtained by selecting the most suitable concentration and exposure time.
(II) detection of Reactive Oxygen Species (ROS) in photodynamic therapy: ROS were determined chemically using 2, 7-Dichlorofluorescein (DCFH) as a probe. Briefly, DCFH (0.5mL, 1 mmol. multidot.mL)-1) And NaOH (0.01 mol/mL)-12mL) was stirred in a methanol solution for 30 minutes in the dark, and DCFH (2mL, 25 mmol. multidot.mL) was added-1) And 2mL of Au-Bi-SR nanoparticle solution is irradiated by 808nm near-infrared laser for different time, and the amount of ROS under different conditions is distinguished through different measurement results of fluorescence spectra. The results are shown in FIG. 4, from which it can be derived that the emission intensity of the sample is gradually increased with the increase of the light irradiation time, which can indicate that the sample can generate active oxygen under the light irradiation. At the same time, it can be seen that the production of active oxygen by these samples increases with the increase in emission intensity.
Example 2
This example prepares Bi-SR, Au-SR and Au-Bi-SR nanoparticles, and compares the UV absorption and photoemission spectra of the nanoparticles:
(1) synthesis of Bi-SR
0.0970g of bismuth nitrate pentahydrate is dissolved in 5mL of ethylene glycol, and when the bismuth nitrate pentahydrate is completely dissolved, 0.23mmol of tetraoctylammonium bromide dissolved in 5mL of methanol is added, and the mixture is vigorously stirred for 20 min. 1mmol of captopril was dissolved in 5mL of methanol, and the solution was stirred for 30min, changing the color of the solution from deep red to milky yellow. Then 2mmol of sodium borohydride (completely dissolved in 5mL of ice-water bath) were rapidly injected into the reaction mixture with vigorous stirring, the color of the solution immediately turning black. After about 1h of reaction, unreacted impurities were removed with a lower number of revolutions to give the product.
(2) Synthesis of Au-Bi-SR
0.10mmol of bismuth nitrate pentahydrate and 0.10mmol of chloroauric acid were dissolved in 5mL of ethylene glycol solvent, and after complete dissolution, 0.1268g of tetraoctylammonium bromide completely dissolved in 5mL of methanol was added, followed by vigorous stirring for 20 min. 0.2172g of captopril dissolved in 5mL of methanol was added and stirring was continued for 30min, the solution changed color from light red to cream yellow. 2mmol of sodium borohydride (completely dissolved in 5mL of ice-water bath) was added rapidly to the reaction mixture with vigorous stirring, and the color of the solution immediately turned black. After about 1h of reaction, unreacted impurities were removed with a lower number of revolutions to give the product.
(3) Synthesis of Au-SR
0.20mmol of chloroauric acid and 0.23mmol of tetraoctylammonium bromide were completely dissolved in 10mL of methanol. 0.2172g of captopril dissolved in 5mL of methanol were added and stirring was continued for 30 min. 2mmol of sodium borohydride (completely dissolved in 5mL of ice-water bath) was added rapidly to the reaction mixture with vigorous stirring, and the color of the solution immediately turned black. After about 1h of reaction, unreacted impurities were removed with a lower number of revolutions to give the product.
The prepared Bi-SR, Au-SR and Au-Bi-SR nanoparticles are subjected to ultraviolet absorption and photoluminescence spectrum investigation, and the results are shown in FIG. 2: these samples all had a broad light absorption capability in the range of 250-850 nm. Meanwhile, the light absorption effect of the bimetallic sample and the Bi-SR is obviously lower than that of the Au-SR. However, the difference in absorption in the near infrared region is limited for all samples and not very different. Since these samples all absorb well in the near infrared region, it is presumed that these samples should also have good photothermal properties, and thus can be well used for near infrared light-induced phototherapy, and thus, the photothermal properties of the sample materials are laid for the next study.
The fluorescence spectrum of Au-Bi-SR is shown in FIG. 4, and two different light-emitting regions were found, the emission peaks were at 413nm and 800nm, respectively, and the emission peak at 413nm was strong. And the fluorescence property can be used for researching the interaction between the nano particles and the tumor cells. In addition, good sample dispersion is an important prerequisite for the application of tumor therapy. As shown in the inset of FIG. 4, the Au-Bi-SR aqueous solution is very stable and has good dispersibility.
Claims (6)
1. A bimetallic nanomaterial for tumor diagnosis and treatment, characterized in that the bimetallic nanomaterial has the chemical expression: Au-Bi-SR; wherein the SR is mercaptan.
2. The bimetallic nanomaterial of claim 1, wherein the bimetallic nanomaterial is excited by ultraviolet and visible light.
3. The bimetallic nanomaterial for tumor diagnosis and treatment according to claim 1, wherein the molar ratio of Au: Bi: SR in the bimetallic nanomaterial is 1:1: 10.
4. The method for preparing the bimetallic nanomaterial for tumor diagnosis and treatment according to claim 1, characterized in that it is carried out according to the following steps:
dissolving bismuth nitrate pentahydrate in ethylene glycol to obtain a bismuth nitrate pentahydrate ethylene glycol solution; dissolving chloroauric acid in methanol to obtain a chloroauric acid methanol solution; uniformly mixing a bismuth nitrate glycol pentahydrate solution and a chloroauric acid methanol solution according to equal volume to obtain a mixed solution;
step two, adding tetra-n-octyl ammonium bromide dissolved in methanol into the mixed solution obtained in the step one, stirring for 15-20 min, adding a captopril methanol solution, and mixing and stirring for 25-30 min; then adding a sodium borohydride ice-water mixed solution, and mixing and stirring for 60-70 min;
and step three, centrifuging to remove the precipitate, leaving supernatant, repeatedly washing with ethanol, and drying in vacuum to obtain the bimetallic nano-material.
5. The method for preparing bimetallic nano-material for tumor diagnosis and treatment according to claim 1,
the molar volume (or molar) ratio of bismuth nitrate pentahydrate to ethylene glycol is 1 mmol: 1-0.9 mL;
the molar volume (or mole) ratio of chloroauric acid to methanol was 1 mmol: 1-1.2 mL;
the molar volume (or mole) ratio of tetra-n-octylammonium bromide to methanol was 1 mmol: 2.3-1.2 mL;
the molar volume (or mole) ratio of captopril to methanol was 1 mmol: 10-1.2 mL;
the molar volume (or molar) ratio of the sodium borohydride to the ice-water mixed liquid is 1 mmol: 1-20 mL.
6. The use of the bimetallic nanomaterial of claim 1 for diagnosis and therapy of tumors, characterized in that it is used for the preparation of a drug for the diagnosis and therapy of photothermal/photodynamic tumors.
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