A radiotherapy sensitizer with enhanced radio deposition ability and dispersion stability, and a preparation method and preparation thereof
By employing ball milling and phosphate modification, the problems of insufficient radiation deposition capability and dispersion stability of hafnium oxide nanopowder were solved, achieving more efficient radiation deposition and stability, making it suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SOUTH CHINA UNIV OF TECH
- Filing Date
- 2026-05-12
- Publication Date
- 2026-06-26
AI Technical Summary
Existing hafnium oxide nanoparticles have low radiation deposition capability and dispersion stability, making it difficult to meet the performance requirements of radiotherapy sensitizers.
Radiosensitizers are prepared using a ball milling process to break up agglomerates through strong mechanical force, and are modified with phosphates such as sodium hexametaphosphate. Combined with nanoporous membrane filtration, the particle size uniformity and dispersibility are improved.
It significantly enhances radiation deposition capability and dispersion stability, avoiding the problems of large differences in particle size and dispersibility, complex production, and toxic waste liquid in traditional methods, making it suitable for industrial production.
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Figure CN122272802A_ABST
Abstract
Description
Technical Field
[0001] This application belongs to the field of radiosensitizer technology, and particularly relates to a radiosensitizer that enhances radiation deposition ability and dispersion stability, as well as its preparation method and formulation. Background Technology
[0002] In traditional tumor radiotherapy, while radiation energy kills tumor cells, it also damages the normal cells surrounding the tumor cells. Radiosensitizers are substances that can enhance the sensitivity of tumor cells to radiation. During tumor radiotherapy, radiosensitizers that absorb and deposit radiation can produce reactive oxygen species (ROS) and other substances that kill tumor cells, thus amplifying the killing effect of radiation in the tumor area.
[0003] For the development of radiosensitizers, nanomaterials based on high-Z elements have attracted widespread attention due to their excellent physical properties. These materials can significantly enhance the energy deposition of X-rays or gamma rays in tumor areas, thereby increasing the level of reactive oxygen species (ROS) generated by radiation, increasing DNA damage in tumor cells, and achieving a sensitizing effect. Compared with organic small molecule radiosensitizers, high-Z nanomaterials have advantages such as good physical stability, controllable biological metabolic pathways, and great modification potential. Hafnium oxide (HfO2), as a typical high-Z material, has the characteristics of high atomic number (Z=72), excellent chemical stability, and good biocompatibility. In recent years, radiosensitizers based on hafnium oxide nanoparticles (NBTXR3) have entered clinical trials and obtained marketing approval, verifying the safety and effectiveness of hafnium oxide as a radiosensitizer. These materials can effectively improve the local dose effect during tumor radiation irradiation, thereby achieving the same or even better therapeutic effect while reducing the total radiation dose, and have the clinical value of both enhancing efficacy and reducing toxicity.
[0004] For improving the performance of hafnium oxide, a radiosensitizer, the radiation deposition capability of the radiosensitizer is crucial, as it significantly impacts the generation of reactive oxygen species (ROS) and increases DNA damage in tumor cells. Therefore, it is necessary to develop technologies that enhance the radiation deposition capability of hafnium oxide. Simultaneously, to accommodate intratumoral injection and other administration routes, current radiosensitizer formulations, such as NBTXR3, are aqueous suspensions. Therefore, it is necessary to develop technologies that enhance the dispersibility of hafnium oxide to prevent pre-injection aggregation. However, currently, conventional hafnium oxide nanoparticles exhibit low radiation deposition capability and dispersion stability, making it difficult to meet the performance requirements of radiosensitizers, which demand excellent radiation deposition capability and dispersion stability. Summary of the Invention
[0005] In view of this, this application provides a radiotherapy sensitizer with enhanced radiation deposition capability and dispersion stability, as well as a preparation method and formulation, to solve the technical problem that the radiation deposition capability and dispersion stability of hafnium oxide nanoparticles in the prior art are low, making it difficult to meet the performance requirements of radiotherapy sensitizers.
[0006] The first aspect of this application provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, comprising the following steps:
[0007] The ball milling process involves adding hafnium oxide nanopowder, phosphate, and water as a dispersion medium to a ball mill jar for ball milling to obtain the ball milled product. The ball milling speed is greater than 300 rpm, and the ball-to-material ratio is 30~100:1.
[0008] Purification steps: The ball-milled product was centrifuged and filtered through a nanoporous membrane to obtain a radiosensitizer that enhances radiation deposition ability and dispersion stability.
[0009] Preferably, in the ball milling step, the ball milling speed is 400~600 rpm and the ball-to-material ratio is 80~120:1.
[0010] Preferably, in the ball milling step, the particle size of the hafnium oxide nanoparticles is 2~200 nm.
[0011] Preferably, in the ball milling step, the particle size of the hafnium oxide nanoparticles is 2~10 nm.
[0012] Preferably, the phosphate is selected from at least one of sodium hexametaphosphate, sodium pentamethasone, sodium pyrophosphate, sodium trimetaphosphate, and sodium tripolyphosphate.
[0013] Preferably, in the ball milling step, the mass ratio of the hafnium oxide nanoparticles to the phosphate is 1:0.1~10.
[0014] Preferably, in the ball milling step, the mass ratio of the hafnium oxide nanoparticles to the phosphate is 1:1~3.
[0015] Preferably, in the ball milling step, the sum of the masses of the hafnium oxide nanoparticles and the phosphate is in a mass ratio of 1:1 to 4 with the mass of the dispersion medium water.
[0016] Preferably, in the ball milling step, during intermittent ball milling, the single ball milling time is 10-60 min, the ball milling interval is 5-15 min, and the ball milling time is 1-6 hours;
[0017] For continuous ball milling, the milling time is 1 to 6 hours.
[0018] Preferably, in the purification step, the centrifugation speed is 8000~12000 rpm and the time is 5-15 min.
[0019] Preferably, in the purification step, the process of filtering with the nanopore membrane includes: dispersing the centrifuged ball-milled product into deionized water, and filtering with positive pressure using a filter membrane with a pore size of 20-80 nm to obtain a radiosensitizer that enhances radiation deposition ability and dispersion stability.
[0020] The second aspect of this application provides a radiosensitizer that enhances radiation deposition ability and dispersion stability, prepared by the preparation method described in the first aspect.
[0021] A third aspect of this application provides a radiosensitizer comprising a radiosensitizer that enhances radiation deposition capacity and dispersion stability as described in the second aspect, and a pharmaceutically acceptable carrier.
[0022] Preferably, the pharmaceutically acceptable carrier includes at least one of aqueous carriers, organic solvent carriers, lipid-soluble carriers, and polymer carriers.
[0023] Compared with the prior art, the method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability provided in this application has at least the following beneficial effects:
[0024] 1. The radiosensitizer that enhances radiation deposition ability and dispersion stability provided in this application is prepared by ball milling. During the ball milling process, the aggregates are effectively broken down by strong mechanical force, resulting in finer particle size and more uniform distribution. At the same time, phosphates such as sodium hexametaphosphate are modified, realizing physical pulverization and chemical / physical modification. A radiosensitizer that enhances radiation deposition ability and dispersion stability is obtained in one step.
[0025] 2. The radiosensitizer provided in this application enhances radiation deposition ability and dispersion stability. By improving the ball milling process, such as the ball milling speed, a radiosensitizer with further enhanced radiation deposition ability can be obtained.
[0026] 3. The radiosensitizer with enhanced radiation deposition capacity and dispersion stability provided in this application is prepared by ball milling. This avoids the problems associated with traditional hydrothermal synthesis, which is sensitive to reaction conditions such as temperature, pH, and reaction time, resulting in significant differences in particle size and dispersibility between different batches, making it difficult to ensure the consistency of efficacy of the radiosensitizer in tumor radiotherapy. It also avoids the large amount of toxic waste liquids such as acids and alkalis generated in the traditional hydrothermal synthesis process, which is also quite complex. Therefore, the radiosensitizer with enhanced radiation deposition capacity and dispersion stability prepared by ball milling in this application is a green synthesis process suitable for industrial production. Attached Figure Description
[0027] To more clearly illustrate the technical solutions in the specific embodiments of this application or the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.
[0028] Figure 1 A schematic diagram of the radiosensitizer suspension provided in Example 4 of this application;
[0029] Figure 2 A schematic diagram showing the dispersion stability of the suspension made from the radiosensitizer provided in Example 4 of this application and the commercially available Nanobiotix NBTXR product.
[0030] Figure 3 Transmission electron microscopy image of the radiosensitizer provided in Example 4 of this application;
[0031] Figure 4 X-ray photoelectron spectroscopy analysis (528.0~544.0 eV range) of the radiotherapy sensitizer provided in Example 4 of this application.
[0032] Figure 5 X-ray photoelectron spectroscopy (16.0~32.0 eV range) of the radiosensitizer provided in Example 4 of this application.
[0033] Figure 6 Box plot of particle size distribution of 12 batches of radiosensitizers prepared in Example 4 of this application;
[0034] Figure 7 The graph shows the test results of the radiosensitizer provided in Example 4, Nanobiotix's commercially available NBTXR product, and the radiation deposition capability of unmodified hafnium oxide (DCFH-DA probe).
[0035] Figure 8 The graph shows the statistical results of radiation deposition in 5-15 minutes for the radiosensitizer provided in Example 4 and the commercially available NBTXR product from Nanobiotix.
[0036] Figure 9 The graph shows the test results (RhB dye) of the radiosensitizer provided in Example 4, the commercially available NBTXR product from Nanobiotix, and the radiation deposition capability of unmodified hafnium oxide.
[0037] Figure 10The graph shows the test results of the radiation deposition ability of the radiotherapy sensitizers prepared at different ball milling speeds provided in Examples 4-12 and Comparative Examples 2-7, and the radiotherapy sensitizer prepared by the hydrothermal method in Comparative Example 1. In the graph, SHMP is sodium hexametaphosphate, TSPP is sodium pyrophosphate, and STPP is sodium tripolyphosphate.
[0038] Figure 11 The graph shows the test results of the radiation deposition capacity of the radiosensitizers prepared with different phosphate dosages at the same rotation speed provided in Examples 4, 13-20. Detailed Implementation
[0039] This application provides a radiosensitizer that enhances radiation deposition capability and dispersion stability, as well as a preparation method and formulation, to solve the technical problem that the radiation deposition capability and dispersion stability of hafnium oxide nanopowder in the prior art are low, making it difficult to meet the performance requirements of radiosensitizers.
[0040] The technical solutions of this application will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this application. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.
[0041] Example 1
[0042] This embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0043] The steps for preparing raw materials include:
[0044] Weigh 1g of commercially available hafnium oxide nanoparticles (particle size approximately 50nm) and 0.1g of sodium hexametaphosphate at a mass ratio of 1:0.1; weigh 33g of agate grinding balls at a ball-to-material ratio of 30:1; and measure 2mL of deionized water at approximately 1.8 times the mass of the powder.
[0045] The steps of ball milling include:
[0046] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 300rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0047] The ball milling was performed intermittently, with each milling session lasting 20 minutes, followed by a 10-minute interval, and the milling process was completed in 2 hours.
[0048] The purification steps include:
[0049] First, the ball-milled product was centrifuged at 10,000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 20 mL of deionized water and filtered under positive pressure using a 50 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0050] Example 2
[0051] This embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0052] The steps for preparing raw materials include:
[0053] Weigh 2g of commercially available hafnium oxide nanoparticles (particle size approximately 100nm) and 0.6g of sodium hexametaphosphate at a mass ratio of 1:0.3; weigh 130g of agate grinding balls at a ball-to-material ratio of 50:1; and measure 4mL of deionized water at approximately 1.5 times the mass of the powder.
[0054] The steps of ball milling include:
[0055] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 400rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0056] The ball milling operation was continuous, and the ball milling was completed after 4 hours.
[0057] The purification steps include:
[0058] First, the ball-milled product was centrifuged at 12,000 rpm for 15 min to remove unbound sodium hexametaphosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 30 mL of deionized water and filtered under positive pressure using a 20 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0059] Example 3
[0060] This embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0061] The steps for preparing raw materials include:
[0062] Weigh 0.5g of commercially available hafnium oxide nanoparticles (particle size approximately 150nm) and 1g of sodium hexametaphosphate at a mass ratio of 1:2; weigh 150g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 2mL of deionized water at approximately 1.3 times the mass of the powder.
[0063] The steps of ball milling include:
[0064] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0065] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0066] The purification steps include:
[0067] First, the ball-milled product was centrifuged at 8000 rpm for 5 min to remove unbound sodium hexametaphosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 15 mL of deionized water and filtered under positive pressure using an 80 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0068] Example 4
[0069] This embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0070] The steps for preparing raw materials include:
[0071] Weigh 3g of commercially available hafnium oxide nanoparticles (particle size approximately 5nm) and 5g of sodium hexametaphosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0072] The steps of ball milling include:
[0073] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0074] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0075] The purification steps include:
[0076] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0077] Example 5
[0078] To investigate the effect of ball milling speed on radiation deposition capability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition capability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0079] The steps for preparing raw materials include:
[0080] Weigh 3g of commercially available hafnium oxide nanoparticles (particle size approximately 5nm) and 5g of sodium hexametaphosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0081] The steps of ball milling include:
[0082] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 600rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0083] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0084] The purification steps include:
[0085] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0086] Example 6
[0087] To investigate the effect of ball milling speed on radiation deposition capability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition capability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0088] The steps for preparing raw materials include:
[0089] Weigh 3g of commercially available hafnium oxide nanoparticles (particle size approximately 5nm) and 5g of sodium hexametaphosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0090] The steps of ball milling include:
[0091] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 400rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0092] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0093] The purification steps include:
[0094] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0095] Example 7
[0096] To investigate the effect of phosphate type on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0097] The steps for preparing raw materials include:
[0098] Weigh 3g of commercially available hafnium oxide nanopowder (particle size approximately 5nm) and 5g of sodium pyrophosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0099] The steps of ball milling include:
[0100] Weigh out hafnium oxide nanopowder, sodium pyrophosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm and ball mill. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0101] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0102] The purification steps include:
[0103] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium pyrophosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium pyrophosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0104] Example 8
[0105] To investigate the effect of phosphate type on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0106] The steps for preparing raw materials include:
[0107] Weigh 3g of commercially available hafnium oxide nanopowder (particle size approximately 5nm) and 5g of sodium pyrophosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0108] The steps of ball milling include:
[0109] Weigh out hafnium oxide nanopowder, sodium pyrophosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 600rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0110] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0111] The purification steps include:
[0112] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium pyrophosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium pyrophosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0113] Example 9
[0114] To investigate the effect of phosphate type on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0115] The steps for preparing raw materials include:
[0116] Weigh 3g of commercially available hafnium oxide nanopowder (particle size approximately 5nm) and 5g of sodium pyrophosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0117] The steps of ball milling include:
[0118] Weigh out hafnium oxide nanopowder, sodium pyrophosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 400rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0119] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0120] The purification steps include:
[0121] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium pyrophosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium pyrophosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0122] Example 10
[0123] To investigate the effect of phosphate type on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0124] The steps for preparing raw materials include:
[0125] Weigh 3g of commercially available hafnium oxide nanoparticles (approximately 5nm in particle size) and 5g of sodium tripolyphosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0126] The steps of ball milling include:
[0127] Weigh out hafnium oxide nanopowder, sodium tripolyphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm and ball mill. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0128] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0129] The purification steps include:
[0130] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium tripolyphosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium tripolyphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0131] Example 11
[0132] To investigate the effect of phosphate type on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0133] The steps for preparing raw materials include:
[0134] Weigh 3g of commercially available hafnium oxide nanoparticles (approximately 5nm in particle size) and 5g of sodium tripolyphosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0135] The steps of ball milling include:
[0136] Weigh out hafnium oxide nanopowder, sodium tripolyphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 600rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0137] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0138] The purification steps include:
[0139] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium tripolyphosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium tripolyphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0140] Example 12
[0141] To investigate the effect of phosphate type on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0142] The steps for preparing raw materials include:
[0143] Weigh 3g of commercially available hafnium oxide nanoparticles (approximately 5nm in particle size) and 5g of sodium tripolyphosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0144] The steps of ball milling include:
[0145] Weigh out hafnium oxide nanopowder, sodium tripolyphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 400rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0146] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0147] The purification steps include:
[0148] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium tripolyphosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium tripolyphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0149] Example 13
[0150] To investigate the effect of phosphate dosage on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0151] The steps for preparing raw materials include:
[0152] Weigh 3g of commercially available hafnium oxide nanoparticles (approximately 5nm in particle size) and 30g of sodium hexametaphosphate at a mass ratio of 1:10; weigh 800g of agate grinding balls; and measure 15mL of deionized water.
[0153] The steps of ball milling include:
[0154] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0155] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0156] The purification steps include:
[0157] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0158] Example 14
[0159] To investigate the effect of phosphate dosage on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0160] The steps for preparing raw materials include:
[0161] Weigh 3g of commercially available hafnium oxide nanoparticles (approximately 5nm in particle size) and 15g of sodium hexametaphosphate in a mass ratio of 1:5; weigh 800g of agate grinding balls; and measure 15mL of deionized water.
[0162] The steps of ball milling include:
[0163] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0164] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0165] The purification steps include:
[0166] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0167] Example 15
[0168] To investigate the effect of phosphate dosage on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0169] The steps for preparing raw materials include:
[0170] Weigh 3g of commercially available hafnium oxide nanoparticles (particle size approximately 5nm) and 7.5g of sodium hexametaphosphate in a mass ratio of 2:5; weigh 800g of agate grinding balls; and measure 15mL of deionized water.
[0171] The steps of ball milling include:
[0172] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0173] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0174] The purification steps include:
[0175] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0176] Example 16
[0177] This embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0178] The steps for preparing raw materials include:
[0179] Weigh 3g of commercially available hafnium oxide nanoparticles (approximately 5nm in particle size) and 3.75g of sodium hexametaphosphate in a mass ratio of 4:5; weigh 800g of agate grinding balls; and measure 15mL of deionized water.
[0180] The steps of ball milling include:
[0181] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0182] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0183] The purification steps include:
[0184] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0185] Example 17
[0186] This embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0187] The steps for preparing raw materials include:
[0188] Weigh 3g of commercially available hafnium oxide nanoparticles (approximately 5nm in particle size) and 3g of sodium hexametaphosphate in a 1:1 mass ratio; weigh 800g of agate grinding balls; and measure 15mL of deionized water.
[0189] The steps of ball milling include:
[0190] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0191] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0192] The purification steps include:
[0193] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0194] Example 18
[0195] To investigate the effect of phosphate dosage on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0196] The steps for preparing raw materials include:
[0197] Weigh 6g of commercially available hafnium oxide nanoparticles (approximately 5nm in particle size) and 5g of sodium hexametaphosphate in a mass ratio of 6:5; weigh 800g of agate grinding balls; and measure 15mL of deionized water.
[0198] The steps of ball milling include:
[0199] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0200] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0201] The purification steps include:
[0202] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0203] Example 19
[0204] To investigate the effect of phosphate dosage on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0205] The steps for preparing raw materials include:
[0206] Weigh 7g of commercially available hafnium oxide nanoparticles (particle size approximately 5nm) and 5g of sodium hexametaphosphate in a mass ratio of 7:5; weigh 800g of agate grinding balls; and measure 15mL of deionized water.
[0207] The steps of ball milling include:
[0208] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0209] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0210] The purification steps include:
[0211] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0212] Example 20
[0213] To investigate the effect of phosphate dosage on radiation deposition ability, this embodiment provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0214] The steps for preparing raw materials include:
[0215] Weigh 8g of commercially available hafnium oxide nanoparticles (approximately 5nm in particle size) and 5g of sodium hexametaphosphate in a mass ratio of 8:5; weigh 800g of agate grinding balls; and measure 15mL of deionized water.
[0216] The steps of ball milling include:
[0217] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 500rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0218] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0219] The purification steps include:
[0220] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0221] Comparative Example 1
[0222] This comparative example provides a method for preparing a radiosensitizer. The difference between this method and the example is that a hydrothermal synthesis process is used. The process of hydrothermally synthesizing the radiosensitizer includes the following steps:
[0223] A solution was prepared by mixing tetramethylammonium hydroxide (TMAOH) with 40g of hafnium tetrachloride (HfCl4) and slowly mixing it under stirring conditions, controlling the pH between 7 and 8, to obtain a white precipitate;
[0224] The resulting white precipitate was transferred to a high-pressure reactor and initially heated at about 120°C for 5 hours. Then, the temperature was increased to 300°C for hydrothermal treatment for 3 hours. After the reaction was completed, the product was allowed to cool naturally. The product was washed multiple times with deionized water (softened water) to remove residual ions and impurities, and pure nanocrystalline particles were obtained.
[0225] A solution containing sodium hexametaphosphate was added to the washed precipitate to adjust the pH of the system to 6.5-7.0, ultimately forming a uniform and stable nanoparticle suspension.
[0226] Unbound modifiers and impurities were removed by centrifugation at 8000 rpm for 10 minutes to obtain the radiosensitizer.
[0227] Comparative Example 2
[0228] To investigate the effect of ball milling speed on radiation deposition capability, this comparative example provides a method for preparing a radiosensitizer that enhances radiation deposition capability and dispersion stability, including steps for raw material preparation, ball milling, and purification.
[0229] The steps for preparing raw materials include:
[0230] Weigh 3g of commercially available hafnium oxide nanoparticles (particle size approximately 5nm) and 5g of sodium hexametaphosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0231] The steps of ball milling include:
[0232] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 300rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0233] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0234] The purification steps include:
[0235] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0236] Comparative Example 3
[0237] To investigate the effect of ball milling speed on radiation deposition capability, this comparative example provides a method for preparing a radiosensitizer that enhances radiation deposition capability and dispersion stability, including steps for raw material preparation, ball milling, and purification.
[0238] The steps for preparing raw materials include:
[0239] Weigh 3g of commercially available hafnium oxide nanoparticles (particle size approximately 5nm) and 5g of sodium hexametaphosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0240] The steps of ball milling include:
[0241] Weigh out hafnium oxide nanopowder, sodium hexametaphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 200rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0242] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0243] The purification steps include:
[0244] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium hexametaphosphate and impurities. Then, the hafnium oxide obtained by centrifugation was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium hexametaphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0245] Comparative Example 4
[0246] To investigate the effect of phosphate type on radiation deposition ability, this comparative example provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0247] The steps for preparing raw materials include:
[0248] Weigh 3g of commercially available hafnium oxide nanopowder (particle size approximately 5nm) and 5g of sodium pyrophosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0249] The steps of ball milling include:
[0250] Weigh out hafnium oxide nanopowder, sodium pyrophosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 300rpm and ball mill. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0251] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0252] The purification steps include:
[0253] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium pyrophosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium pyrophosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0254] Comparative Example 5
[0255] To investigate the effect of phosphate type on radiation deposition ability, this comparative example provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0256] The steps for preparing raw materials include:
[0257] Weigh 3g of commercially available hafnium oxide nanopowder (particle size approximately 5nm) and 5g of sodium pyrophosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0258] The steps of ball milling include:
[0259] Weigh out hafnium oxide nanopowder, sodium pyrophosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 200rpm and ball mill. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0260] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0261] The purification steps include:
[0262] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium pyrophosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium pyrophosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0263] Comparative Example 6
[0264] To investigate the effect of phosphate type on radiation deposition ability, this comparative example provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0265] The steps for preparing raw materials include:
[0266] Weigh 3g of commercially available hafnium oxide nanoparticles (approximately 5nm in particle size) and 5g of sodium tripolyphosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0267] The steps of ball milling include:
[0268] Weigh out hafnium oxide nanopowder, sodium tripolyphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 300rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0269] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0270] The purification steps include:
[0271] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium tripolyphosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium tripolyphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0272] Comparative Example 7
[0273] To investigate the effect of phosphate type on radiation deposition ability, this comparative example provides a method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, including steps of raw material preparation, ball milling, and purification.
[0274] The steps for preparing raw materials include:
[0275] Weigh 3g of commercially available hafnium oxide nanoparticles (approximately 5nm in particle size) and 5g of sodium tripolyphosphate at a mass ratio of 3:5; weigh 800g of agate grinding balls at a ball-to-material ratio of 100:1; and measure 15mL of deionized water at approximately 1.9 times the mass of the powder.
[0276] The steps of ball milling include:
[0277] Weigh out hafnium oxide nanopowder, sodium tripolyphosphate and agate grinding balls and add them to a 1000mL agate ball mill jar. Set the speed to 200rpm for ball milling. Add measured deionized water during the ball milling process to assist in particle dispersion and surface modification.
[0278] The ball milling was performed intermittently, with each milling session lasting 30 minutes, followed by a 15-minute interval, and the milling process lasting 6 hours.
[0279] The purification steps include:
[0280] First, the ball-milled product was centrifuged at 8000 rpm for 10 min to remove unbound sodium tripolyphosphate and impurities. Then, the centrifuged hafnium oxide was dispersed in 15 mL of deionized water and filtered under positive pressure using a 30 nm pore size filter membrane to remove agglomerates caused by centrifugation or particles with large particle sizes, resulting in uniformly dispersed sodium tripolyphosphate-modified hafnium oxide nanoparticles, which are radiosensitizers that enhance radiation deposition ability and dispersion stability.
[0281] Experimental Example 1
[0282] This experimental example demonstrates the structural characterization and performance testing of the radiosensitizers prepared using the methods provided in Examples 1-4 and Comparative Example 1, as well as Nanobiotix's commercially available NBTXR product and unmodified hafnium oxide.
[0283] The yield and stability results of the radiosensitizers prepared by the methods provided in Examples 1-4 and Comparative Example 1 are shown in Table 1.
[0284] Table 1: Yield and Stability
[0285]
[0286] As can be seen from Table 1, compared with the preparation method provided in Comparative Example 1, the yield of the radiosensitizer synthesized by hydrothermal synthesis is only 65%, and the amount of sodium hexametaphosphate modified with hafnium oxide nanoparticles is relatively small, with a negative potential of -20mV. The electrostatic repulsion between hafnium oxide nanoparticles is generally weak, and obvious precipitation can be observed with the naked eye after 90 hours. In contrast, the preparation method provided in this application can achieve a higher yield of 77% through ball milling, and the negative potential can reach -34mV. The electrostatic repulsion between hafnium oxide nanoparticles is generally strong, and precipitation only occurs after 120 hours. Thus, when suspended in an aqueous carrier, it can form a stable suspension-type radiosensitizer, avoiding aggregation before intratumoral injection and improving the sensitizing efficacy of the radiosensitizer.
[0287] The radiosensitizer (hafnium oxide nanoparticles modified with sodium hexametaphosphate) provided in Example 4 was further prepared into a suspension, such as... Figure 1 As shown, it can be seen that it has good dispersion stability as a radiosensitizer; at the same time, the dispersion stability of the suspension prepared with the radiosensitizer provided in Example 4 was compared with that of Nanobiotix's commercially available NBTXR product, and the results are as follows. Figure 2 As shown, from Figure 2It can be seen that the absorbance of the suspension prepared by the radiosensitizer provided in Example 4 decreases more slowly, indicating that the suspension prepared by the radiosensitizer provided in Example 4 does not easily settle, which makes the particle concentration and absorbance in the supernatant of the suspension decrease more slowly. From the above experiments, it can be seen that the preparation process provided in the embodiments of this application prepares a radiosensitizer with excellent dispersion stability through ball milling.
[0288] Meanwhile, the radiosensitizer provided in Example 4 was analyzed by transmission electron microscopy and X-ray photoelectron spectroscopy, and the results are as follows: Figure 3-5 As shown, from Figure 4-5 The X-ray photoelectron spectroscopy analysis diagram shown indicates that the radiosensitizer was successfully synthesized in this embodiment of the application. Figure 3 The transmission electron microscopy (TEM) images shown indicate that the particle size is approximately 5–20 nm. Particle size analysis was also performed on 12 batches of the radiosensitizer provided in Example 4, and the box plots of the particle size distribution for these 12 batches are shown below. Figure 6 As shown, from Figure 6 It can be seen that the radiosensitizer provided in Example 4 has a stable particle size, avoiding the defects of hydrothermal synthesis processes, such as those in the comparative example, which are sensitive to reaction conditions such as temperature, pH, and reaction time, resulting in large differences in particle size and dispersibility between different batches, making it difficult to guarantee the stability of industrial production. This shows that the ball milling preparation process provided in the embodiments of this application can prepare radiosensitizers with stable dispersion and particle size, which is beneficial to ensuring that the radiosensitizers prepared subsequently have excellent efficacy consistency and improve the therapeutic effect of tumor radiotherapy.
[0289] For radiosensitizers, it is also necessary to demonstrate excellent radiation deposition effects during tumor radiotherapy. This experimental example compares the radiation deposition capabilities of unmodified hafnium oxide (control group), the radiosensitizer provided in Example 4, and Nanobiotix's commercially available NBTXR product. The ROS results detected by the DCFH-DA (2',7'-dichlorofluorescein diacetate) probe are as follows: Figure 7 As shown; from Figure 7 It can be seen that unmodified hafnium oxide has low radiodeposition capacity and produces low ROS levels detected by the DCFH-DA probe, making it difficult to use as a radiosensitizer. In contrast, the radiosensitizer provided in Example 4 has higher radiodeposition capacity than Nanobiotix's commercially available NBTXR product. Furthermore, the radiodeposition amounts of the radiosensitizer provided in Example 4 and Nanobiotix's commercially available NBTXR product were compared between 5 and 15 minutes, and the results are as follows: Figure 8 As shown, from Figure 8It can be seen that the radiosensitizer provided in Example 4 has a stronger radiation deposition ability, indicating that the radiosensitizer provided in Example 4 has an enhanced radiation deposition ability; in addition, the results of the radiation deposition ability of the radiosensitizer provided in Example 4 reacting with RhB dye (Rhodamine B), the commercially available NBTXR product from Nanobiotix, and unmodified hafnium oxide are as follows: Figure 9 As shown, from Figure 9 It can be seen that the radiosensitizer provided in Example 4 has enhanced radiation deposition ability, can generate more ROS, and promotes a decrease in the signal intensity of RhB dye.
[0290] Furthermore, to investigate the effect of ball milling on the radiodeposition ability of radiosensitizers, this application, based on the radiosensitizer preparation process with enhanced radiodeposition ability and dispersion stability provided in Example 4, adjusted the ball milling speed to 200 rpm, 300 rpm, 400 rpm, and 600 rpm, obtaining radiosensitizers prepared at different ball milling speeds. Different radiosensitizers were obtained by treating hafnium oxide with different phosphates, and their radiodeposition abilities were compared. The results are as follows: Figure 10 As shown, from Figure 10 It can be seen that for the three phosphates, increasing the ball mill speed by more than 300 rpm can yield radiosensitizers with stronger radiodeposition capabilities, indicating that the ball mill speed has a significant impact on the radiodeposition capability of radiosensitizers. The method proposed in this application, which improves the radiodeposition capability of radiosensitizers by increasing the ball mill speed, has universal applicability.
[0291] Furthermore, to investigate the effect of phosphate dosage on the radiodeposition ability of radiosensitizers, this application also treated hafnium oxide with different phosphates to obtain different radiosensitizers, and compared their radiodeposition abilities. The results are as follows: Figure 11 As shown, from Figure 11 It can be seen that the amount of phosphate has little effect on the radiation deposition ability of the radiosensitizer. Combined with Examples 1-4 and Table 1, it can be seen that the amount of phosphate mainly affects the dispersibility of the radiosensitizer.
[0292] The experimental results above show that this application has prepared multiple batches of radiosensitizers with uniform particle size and enhanced radiation deposition ability and dispersion stability through ball milling, which can provide a high-performance radiosensitizer for tumor radiotherapy.
[0293] The above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.
Claims
1. A method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability, characterized in that, Includes the following steps: The ball milling process involves adding hafnium oxide nanopowder, phosphate, and water as a dispersion medium to a ball mill jar for ball milling to obtain the ball milled product. The ball milling speed is greater than 300 rpm, and the ball-to-material ratio is 30~100:
1. Purification steps: The ball-milled product was centrifuged and filtered through a nanoporous membrane to obtain a radiosensitizer that enhances radiation deposition ability and dispersion stability.
2. The method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability according to claim 1, characterized in that, In the ball milling step, the ball milling speed is 400~600 rpm and the ball-to-material ratio is 80~120:
1.
3. The method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability according to claim 1, characterized in that, In the ball milling step, the particle size of the hafnium oxide nanoparticles is 2~200nm.
4. The method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability according to claim 1, characterized in that, The phosphate is selected from at least one of sodium hexametaphosphate, sodium pentamethasone, sodium pyrophosphate, sodium trimetaphosphate, and sodium tripolyphosphate.
5. The method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability according to claim 1, characterized in that, In the ball milling step, the mass ratio of the hafnium oxide nanoparticles to the phosphate is 1:0.1~10.
6. The method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability according to claim 1, characterized in that, In the ball milling step, the sum of the masses of the hafnium oxide nanopowder and the phosphate is in a mass ratio of 1:1 to 4 with the mass of the dispersion medium water.
7. The method for preparing a radiosensitizer that enhances radiation deposition ability and dispersion stability according to claim 1, characterized in that, In the ball milling process, during intermittent ball milling, the single milling time is 10-60 minutes, the intermittent milling time is 5-15 minutes, and the total milling time is 1-6 hours. For continuous ball milling, the milling time is 1 to 6 hours.
8. A radiosensitizer that enhances radiation deposition ability and dispersion stability, characterized in that, It is prepared by the preparation method according to any one of claims 1-7.
9. A radiosensitizing agent, characterized in that, Includes a radiosensitizer and a pharmaceutically acceptable carrier for enhancing radiation deposition ability and dispersion stability as described in claim 8.
10. A radiosensitizing agent according to claim 9, characterized in that, The pharmaceutically acceptable carriers include at least one of the following: aqueous carriers, organic solvent carriers, lipid-soluble carriers, and polymer carriers.