Bismuth oxymethyl acrylic hybrid nanoclusters with bamboo-like structure, preparation method and application thereof
The one-step preparation of bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure solves the problems of low X-ray absorption and difficult structural control of bismuth-based nanomaterials in the prior art, achieving efficient radiosensitization and good biocompatibility, and providing potential nano-formulations for bladder cancer treatment.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-23
- Publication Date
- 2026-03-24
AI Technical Summary
Existing bismuth-based nanomaterials have low X-ray absorption rates and are difficult to control in terms of nanostructure in radiotherapy. They also lack efficient radiosensitizers and may introduce other elements that could negatively affect biocompatibility.
A one-step method was used to prepare bismuth-oxymethyl methacrylate hybrid nanoclusters with a bamboo-like structure. By controlling the reaction conditions and surface modification with hydrophilic polymers, the nanostructure was regulated and biocompatibility was improved. The high X-ray absorption properties of bismuth were used to enhance the tumor cell killing effect.
It achieves efficient inhibition of bladder cancer cell proliferation under X-ray irradiation, provides a highly effective radiosensitizer, and has good biocompatibility and tumor cell killing ability.
Smart Images
Figure CN119874508B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of biomedical material preparation technology, specifically to a bismuth-oxymethyl methacrylate hybrid nanocluster with a bamboo-like structure, its preparation method, and its application. Background Technology
[0002] Cancer remains a significant threat to human health. Radiotherapy is currently one of the most important treatments in clinical practice, used by over 50% of cancer patients. However, due to the low absorption and utilization rate of X-rays by cells, radiotherapy alone is not very effective, often requiring high radiation doses, which inevitably damage normal tissues. Using biocompatible nanomaterials as radiosensitizers can enhance X-ray utilization in the lesion area and strengthen tumor cell killing through the interaction between the material and X-rays, potentially reducing the total X-ray dose while avoiding excessive radiation side effects on surrounding normal tissues. Therefore, developing nanomaterials with high X-ray utilization efficiency is an important direction for improving the field of tumor radiotherapy.
[0003] Bismuth is the heaviest non-radioactive element, exhibiting high absorption and attenuation coefficients for X-rays, with a K-edge absorption energy as high as 90.5 keV, earning it the nickname "green element." As early as the last century, bismuth-containing compounds were used to treat gastrointestinal diseases, demonstrating good therapeutic effects and biocompatibility. Therefore, in recent years, bismuth nanomaterials have been widely used as radiosensitizers and CT contrast agents, showing great potential. However, these materials focus on binary or ternary compounds with defined molecular structures, lacking functional exploration of other bismuth-based materials, thus failing to reveal the crucial properties of bismuth-based materials in radiotherapy. Furthermore, these materials often incorporate other elements not found in the human body, inevitably limiting their application. Studies of the physiological functions of existing bismuth-containing drugs have revealed that the bismuth-oxygen structure is the main component. Therefore, exploring novel bismuth-based materials around the bismuth-oxygen structure is a crucial strategy for developing novel bismuth-based contrast agents. However, only some work has involved the construction of micron-scale cluster structures; research on the controllable preparation and application of nanoscale bismuth-oxygen clusters has not yet been reported.
[0004] Therefore, those skilled in the art have been dedicated to developing bismuth-oxygen nanoclusters with unique structures for use as radiosensitizers, thereby more effectively killing tumor cells. Exploring the construction methods, structure and performance regulation mechanisms of bismuth-oxygen nanoclusters by simulating clinically active ingredients, and revealing more properties of bismuth-based nanomaterials in radiotherapy using a bladder cancer model, is of great significance and has broad application prospects. Summary of the Invention
[0005] Therefore, the purpose of this invention is to provide a bismuth-oxymethacrylic acid hybrid nanocluster with a bamboo-like structure, its preparation method, and its applications. This addresses the current challenges of preparing inorganic-organic hybrid materials and controlling their assembly structures. A one-step method is used to construct bismuth-oxygen clusters composed of methacrylic acid monomers, exhibiting a bamboo-like nanomorphology and a bamboo-like structure. The nanoclusters show significant toxicity after endocytosis by bladder cancer cells and achieve highly efficient inhibition of bladder cancer cell proliferation under X-ray irradiation. This invention is the first to report a bismuth-oxymethacrylic acid hybrid nanocluster with a bamboo-like structure and explores the mechanistic regulation of the nanostructure. It also provides potential nano-formulations for the treatment of bladder cancer, demonstrating extremely high benefits in nanomaterial construction and clinical diagnosis and treatment.
[0006] The technical solution provided by this invention is as follows:
[0007] <First Aspect>
[0008] A method for preparing bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure includes the following steps:
[0009] S1. Dissolve a bismuth-containing compound in an organic solvent at a certain temperature to form a bismuth-containing organic solution;
[0010] S2. Add sodium methacrylate to a bismuth-containing organic solution and react at a certain temperature for a period of time; collect the reaction product to obtain bismuth-oxygen organic hybrid nanoclusters with a bamboo-like structure.
[0011] In step S1, the bismuth-containing compound includes one or more of bismuth nitrate, bismuth chloride, and bismuth acetate.
[0012] Furthermore, the bismuth-containing compound includes bismuth nitrate. Preferably, the bismuth nitrate is hydrated bismuth nitrate. Even further, the hydrated bismuth nitrate includes pentahydrate bismuth nitrate.
[0013] In step S1, the concentration of the bismuth-containing compound in the bismuth-containing organic solution is 0.06~0.03 g / mL;
[0014] And / or, in step S1, the organic solvent includes one or more of dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, diethyl ether, and N,N-dimethylformamide.
[0015] And / or, in step S1, the temperature condition is 70-90°C. o C.
[0016] The mass ratio of the bismuth-containing compound to sodium methacrylate is 1.5:1 to 3:1.
[0017] In step S2, the step of collecting the reaction product from the reaction solution is to centrifuge the reaction solution, collect the precipitate, wash, centrifuge, and dry it to obtain the bismuth-oxygen organic hybrid nanoclusters with a bamboo-like structure.
[0018] In step S2, the reaction temperature is 70-90℃ and the reaction time is 10-12 hours.
[0019] In step S2, the centrifugation conditions are: 10000-12000 rpm for 5-10 minutes.
[0020] <Second aspect>
[0021] This invention provides a bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure prepared by the preparation method described above.
[0022] <Third aspect>
[0023] A method for preparing polymer-modified bismuth-oxymethylacrylic acid hybrid nanoclusters with a bamboo-like structure includes the following steps: dispersing the bismuth-oxymethylacrylic acid hybrid nanoclusters with a bamboo-like structure in an organic solvent A to form dispersion A; adding a phospholipid compound solution to dispersion A and then sonicating for a period of time; centrifuging, collecting the material deposited at the bottom of the centrifuge tube, washing, and redispersing in solvent B to form dispersion B; adding a polymer hydrophilic modifier to dispersion B, stirring for a period of time, and obtaining the polymer hydrophilic modified bismuth-oxygen organic hybrid nanocluster material with a bamboo-like structure after solvent evaporation.
[0024] In dispersion A, the concentration of bismuth-oxygen organic hybrid nanoclusters with a bamboo-like structure is 10-20 mg / mL.
[0025] The phospholipid compounds include sodium 1,2-dioleoyl-sn-glycerol-3-phosphate (DOPA).
[0026] The method for preparing phospholipid compound solutions is as follows: dissolve phospholipid compounds in an organic solvent (such as chloroform) to prepare a phospholipid compound solution with a mass concentration of 2-5 mg / mL.
[0027] The hydrophilic polymeric modifier includes one or more of distearylphosphatidylethanolamine-methoxy polyethylene glycol 5000 (DSPE-mPEG5000), methoxy polyethylene glycol 2000 derivative (mPEG2000), chitosan, and polydopamine.
[0028] The ratio of bismuth-oxymethyl methacrylate hybrid nanoclusters with a bamboo-like structure to phospholipid compounds is 2:1-10:1.
[0029] In step S3, the mass ratio of the bismuth-oxymethyl methacrylate hybrid nanoclusters with a bamboo-like structure, the phospholipid compound, and the hydrophilic polymeric modifier is 2:1:1 to 10:1:1.
[0030] The present invention relates to a polymer-modified bismuth-oxymethyl methacrylate hybrid nanocluster material with a bamboo-like structure.
[0031] The bismuth-oxymethyl methacrylate hybrid nanoclusters with a bamboo-like structure have an average length of 80-200 nm and a width of 40-50 nm. They also exhibit good dispersibility, and their specific dimensions can be controlled through experimental conditions.
[0032] The nanoclusters of this invention spontaneously form a bamboo-like structure during the preparation process.
[0033] The nanoclusters are subsequently surface-modified with hydrophilic polymer methoxy polyethylene glycol 2000 derivatives to improve biocompatibility.
[0034] The bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure prepared by the aforementioned method are also within the scope of protection of this invention.
[0035] Compared with the prior art, the present invention has the following beneficial effects:
[0036] 1. First, there is currently no method for constructing bismuth-oxymethyl methacrylate hybrid nanoclusters with a bamboo-like structure. The present invention first proposes a stable preparation strategy and reveals that the length and dimensions of the nanostructures can be adjusted.
[0037] 2. This invention solves the current problems of difficult preparation and difficult control of assembly structure of inorganic-organic hybrid materials. It realizes the construction of bismuth oxygen clusters composed of methacrylic acid monomers in one step, which has a nano-morphology similar to bamboo and has a bamboo joint structure.
[0038] 3. Using bismuth, an element with high X-ray responsiveness, as the matrix material and sodium methacrylate monomer as a structure modifier, bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure were prepared in a single step at appropriate temperature and feed concentration. The morphology of this nanostructure was reproducible by adjusting the reaction concentration. After surface modification with a hydrophilic polymer, the nanoclusters were able to be phagocytosed by bladder cancer cells, exhibiting certain biotoxicity, and the proliferation of bladder cancer cells was further inhibited under X-ray irradiation. Attached Figure Description
[0039] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings:
[0040] Figure 1This is a schematic diagram of the preparation route of the polymer-modified bismuth oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure in Example 4 of the present invention;
[0041] Figure 2 This is a transmission electron microscope image of the bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure from Example 1.
[0042] Figure 3 This is a transmission electron microscope image of the bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure from Example 2;
[0043] Figure 4 This is a transmission electron microscope image of the bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure from Example 3.
[0044] Figure 5 This is a transmission electron microscope image of the bismuth-oxymethacrylic acid hybrid nanoclusters of Comparative Example 1.
[0045] Figure 6 This is a transmission electron microscope image of the bismuth-oxymethacrylic acid hybrid nanoclusters of Comparative Example 2.
[0046] Figure 7 This is a transmission electron microscope image of the bismuth-oxymethacrylic acid hybrid nanoclusters of Comparative Example 3.
[0047] Figure 8 In the performance test example, the cell survival rate of polymer-modified bismuth oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure after endocytosis in bladder cancer cells;
[0048] Figure 9 In the performance test example, the cell survival rate of bladder cancer cells after X-ray irradiation before and after endocytosis was measured by polymer-modified bismuth-oxymethyl methacrylate hybrid nanoclusters with a bamboo-like structure. Detailed Implementation
[0049] The present invention will be described in detail below with reference to embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make several adjustments and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention.
[0050] Example 1
[0051] Dissolve 0.9 g of bismuth nitrate pentahydrate in dimethyl sulfoxide (15 mL) at 80 °C. oHeat at C until completely dissolved, then add 0.3 g of sodium methacrylate under stirring and continue the reaction for 12 hours (reaction temperature 80℃). After cooling to room temperature, centrifuge at 10,000 rpm for 5 minutes, and wash successively with dimethyl sulfoxide, water and anhydrous ethanol. After vacuum drying at 80℃ for 1 hour, a white powder is obtained.
[0052] like Figure 2 As shown, this embodiment prepared bismuth oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure, with a length of approximately 200 nm and a width of approximately 50 nm.
[0053] Example 2
[0054] Dissolve 0.7 g of bismuth nitrate pentahydrate in dimethyl sulfoxide (15 mL) at 80 °C. o Heat to C until completely dissolved, then add 0.3 g of sodium methacrylate under stirring and continue the reaction for 12 hours (reaction temperature 80°C). After cooling to room temperature, centrifuge at 10,000 rpm for 5 minutes, wash repeatedly (same as in Example 1), and dry under vacuum at 80°C for 1 hour to obtain a white powder.
[0055] like Figure 3 As shown, this embodiment prepared bismuth oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure, with a length of approximately 280 nm and a width of approximately 50 nm.
[0056] Example 3
[0057] Dissolve 0.5 g of bismuth nitrate pentahydrate in dimethyl sulfoxide (15 mL) at 80 °C. o Heat to C until completely dissolved, then add 0.3 g of sodium methacrylate under stirring and continue the reaction for 12 hours (reaction temperature 80°C). After cooling to room temperature, centrifuge at 10,000 rpm for 5 minutes, wash repeatedly (same as in Example 1), and dry under vacuum at 80°C for 1 hour to obtain a white powder.
[0058] like Figure 4 As shown, this embodiment prepared bismuth oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure, with a length of approximately 230 nm and a width of approximately 50 nm.
[0059] Example 4
[0060] 20 mg of the bismuth oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure obtained in Example 1 were weighed and dispersed in 1 mL of chloroform. The mixture was then mixed with 1 mL of a chloroform solution of sodium 1,2-dioleoyl-sn-glycerol-3-phosphate at a concentration of 2 mg / mL under ultrasonic conditions (120 W ultrasonic mixing for 20 minutes) to prepare a suspension. The suspension was centrifuged at 8000 rpm for 5 minutes, and the material deposited at the bottom of the centrifuge tube was collected. The mixture was washed (using dimethyl sulfoxide, water, and anhydrous ethanol successively) and redispersed in 1 mL of chloroform. Then, 4 mL of a chloroform solution of distearylphosphatidylethanolamine-methoxypolyethylene glycol at a concentration of 2 mg / mL was added, and the mixture was magnetically stirred at 300 rpm for 8 hours. Finally, the chloroform solvent was evaporated to dryness to obtain the polymer-modified bismuth oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure.
[0061] like Figure 1 The diagram shown is a schematic of the preparation route for polymer-modified bismuth-oxymethylacrylic acid hybrid nanoclusters with a bamboo-like structure in this embodiment.
[0062] Comparative Example 1
[0063] Dissolve 0.3 g of bismuth nitrate pentahydrate in dimethyl sulfoxide at 80 °C. o Heat to C until completely dissolved, then add 0.3 g of sodium methacrylate under stirring, and continue the reaction for 12 hours (reaction temperature 80°C). After cooling to room temperature, centrifuge at 10,000 rpm for 5 minutes, wash repeatedly (same as Example 1), and vacuum dry at 80°C for 1 hour to obtain a white powder, such as... Figure 5 As shown, it is impossible to obtain bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure.
[0064] Comparative Example 2
[0065] Dissolve 0.3 g of bismuth nitrate pentahydrate in dimethyl sulfoxide at 60 °C. o Heat to C until completely dissolved, then add 0.3 g of sodium methacrylate under stirring and continue the reaction for 12 hours (reaction temperature 60°C). After cooling to room temperature, centrifuge at 10,000 rpm for 5 minutes, wash repeatedly (same as Example 1), and vacuum dry at 80°C for 1 hour to obtain a white powder, such as... Figure 6 As shown, it is impossible to obtain bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure.
[0066] Comparative Example 3
[0067] like Figure 7 As shown, 0.3 g of bismuth nitrate pentahydrate was dissolved in dimethyl sulfoxide at 100 °C. oHeat to C until completely dissolved, then add 0.3 g of sodium methacrylate under stirring and continue the reaction for 12 hours (reaction temperature 100℃). After cooling to room temperature, centrifuge at 10,000 rpm for 5 minutes, wash repeatedly (same as Example 1), and vacuum dry at 80℃ for 1 h to obtain a white powder. It is not possible to obtain bismuth oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure.
[0068] Performance test examples
[0069] The polymer-modified bismuthoxymethacrylic acid hybrid nanoclusters with a bamboo-like structure prepared in Example 4 were incubated at different concentrations (0, 50, 100, 200, 400 μg / mL). -1 Dispersed in DMEM medium solution, the nanoclusters were co-incubated with bladder cancer cells MB49 at a density of 10,000 cells / well in a 96-well plate. Cell viability was then tested. The viability data showed that the nanoclusters exhibited significant tumor cell killing ability after endocytosis (e.g., ...). Figure 8 This study confirmed the antitumor value of the bismuth-oxygen cluster. After co-incubating the nanoclusters with MB49 bladder cancer cells at a concentration of 100 μg / mL and irradiating them with different doses of X-rays, cell viability was tested. The viability data revealed that the nanoclusters exhibited significant tumor cell killing ability after endocytosis and irradiation (e.g., ...). Figure 9 This study confirmed the radiosensitizing properties of the bismuth-oxygen cluster.
[0070] This invention discloses a method for preparing bismuth-oxymethyl methacrylate hybrid nanoclusters with a bamboo-like structure. By overcoming the current challenges of preparing inorganic-organic hybrid materials and controlling their assembly structure, this method achieves the one-step construction of bismuth-oxygen clusters composed of methacrylic acid monomers. These clusters exhibit a bamboo-like nanomorphology and a bamboo-like structure, with a length of 80–200 nm and a width of approximately 40 nm. The specific dimensions can be adjusted by regulating reaction parameters. The nanoclusters show significant toxicity after endocytosis by bladder cancer cells and achieve highly efficient inhibition of bladder cancer cell proliferation under X-ray irradiation. This invention is the first to report bismuth-oxymethyl methacrylate hybrid nanoclusters with a bamboo-like structure and explores the mechanistic regulation of the nanostructure. It also provides potential nano-formulations for the treatment of bladder cancer, demonstrating significant advantages in nanomaterial construction and clinical diagnosis.
[0071] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.
Claims
1. A method for preparing bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure, characterized in that, Includes the following steps: S1, bismuth-containing compounds are heated at 70-90°C. o The bismuth-containing organic solution is formed by dissolving the bismuth compound in an organic solvent at temperature C; the bismuth-containing compound includes one or more of bismuth nitrate, bismuth chloride, and bismuth acetate; the concentration of the bismuth-containing compound in the bismuth-containing organic solution is 0.03~0.06 g / mL; S2. Add sodium methacrylate to the bismuth-containing organic solution and react at 70-90℃ for 10-12 hours; centrifuge the reaction solution, collect the precipitate, wash, centrifuge, and dry to obtain the bismuth-oxygen organic hybrid nanoclusters with a bamboo-like structure; the mass ratio of bismuth-containing compound to sodium methacrylate is 1.5:1-3:
1.
2. The method for preparing bismuth-oxymethyl methacrylate hybrid nanoclusters with a bamboo-like structure according to claim 1, characterized in that, In step S1, the organic solvent includes one or more of dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, diethyl ether, and N,N-dimethylformamide.
3. The method for preparing bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure according to claim 2, characterized in that, In step S2, the centrifugation conditions are: 10000-12000 rpm for 5-10 minutes.
4. A bismuth-oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure prepared by the preparation method according to any one of claims 1-3.
5. A method for preparing a polymer-modified bismuth-oxymethacrylic acid hybrid nanocluster material with a bamboo-like structure, characterized in that, The process includes the following steps: dispersing the bismuth oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure obtained by the preparation method according to any one of claims 1-3 or the bismuth oxymethacrylic acid hybrid nanoclusters with a bamboo-like structure as described in claim 4 in an organic solvent A to form a dispersion A; adding a phospholipid compound solution to the dispersion A and then sonicating for a period of time. Centrifuge, collect the material deposited at the bottom of the centrifuge tube, wash, and redisperse in solvent B to form dispersion B; add a polymer hydrophilic modifier to dispersion B, stir for a period of time, and after the solvent evaporates, obtain a bismuth-oxygen organic hybrid nanocluster material with a bamboo-like structure modified by a polymer hydrophilic modification; the phospholipid compound is sodium salt of 1,2-dioleoyl-sn-glycerol-3-phosphate.
6. The preparation method according to claim 5, characterized in that, In dispersion A, the concentration of bismuth-oxygen organic hybrid nanoclusters with a bamboo-like structure is 10-20 mg / mL; And / or, the polymeric hydrophilic modifier includes one or more of distearylphosphatidylethanolamine-methoxy polyethylene glycol 5000, methoxy polyethylene glycol 2000, chitosan, and polydopamine.
7. A polymer-modified bismuthoxymethacrylic acid hybrid nanocluster material with a bamboo-like structure prepared by the preparation method of claim 5 or 6.