Water-soluble tantalum nanoparticles and their preparation method and application

Abstract

The present invention relates to water-soluble tantalum nanoparticles, their preparation method, and applications. This relates to the technical field of tantalum nanoparticles and addresses the problem of poor stability of tantalum nanoparticles prepared by existing methods in high-concentration solutions. The preparation method comprises the following steps: dissolving tantalum powder in water, ultrasonicating, and centrifuging to obtain refined tantalum powder; mixing the refined tantalum powder with metaphosphate to obtain a first mixture; subjecting the first mixture to a first-stage ball milling treatment to obtain a first-stage ball milled mixture; adding an appropriate amount of water to the ball-milled first mixture, then adding an appropriate amount of NaH2PO4 solution to a second-stage ball milling treatment, centrifuging, and washing to obtain the water-soluble tantalum nanoparticles. The water-soluble tantalum nanoparticles prepared by the present invention have a spherical morphology, good water solubility, and are stable for at least 48 hours in a 60 mg / mL aqueous solution.

Description

Technical Field

[0001] The present invention relates to the technical field of tantalum nanomaterials, and in particular to water-soluble tantalum nanoparticles and a preparation method and application thereof. Background Art

[0002] Cancer is the leading cause of death for human health, claiming countless lives each year. Current cancer treatments primarily rely on radiotherapy and chemotherapy. However, the hypoxic environment of tumor cells significantly reduces the effectiveness of radiotherapy. Therefore, there is a need for nanomaterials that can enhance X-ray sensitization to enhance radiotherapy. Furthermore, to more accurately target tumors for treatment, various imaging techniques are needed to locate them. Computed tomography (CT) is a minimally invasive, safe, and reliable imaging technique that provides rapid and accurate information about the patient's condition. It typically requires contrast agents to enhance imaging. Iodine-based contrast agents are currently the most commonly used contrast agents, but their high osmotic pressure and viscosity often cause numerous adverse reactions. Furthermore, their short circulation time in the body limits their ability to provide long-term imaging. Advances in nanotechnology have enabled the design of transition metal nanoparticles in terms of size, shape, and functionality. Due to the nanoscale effect, nanoparticles can prolong their circulation time in the body, offering a solution to addressing the short circulation time and poor imaging quality associated with iodine-based contrast agents. Furthermore, transition metal nanomaterials also possess high X-ray attenuation coefficients, potentially enhancing radiotherapy sensitization.

[0003] Tantalum, a transition metal nanoparticle, possesses excellent biocompatibility and a high radiation attenuation coefficient, enhancing radiosensitization and providing better imaging results. However, current water-soluble tantalum nanoparticles are primarily prepared via microemulsion and hydrothermal methods, which are complex and time-consuming, and also involve the introduction of toxic reagents during the preparation process. Furthermore, tantalum nanoparticles synthesized via microemulsion and hydrothermal methods cannot maintain long-term stability at high molar concentrations, and the resulting morphologies are often irregular.

[0004] Making inorganic tantalum nanoparticles water-soluble will significantly expand their application areas. Numerous methods exist for surface modification of tantalum nanoparticles, including hydrothermal synthesis, microemulsion, and mechanochemical methods. Two main types of surfactants are used for modifying tantalum nanoparticles. Silane coupling agents are used for surface modification in microemulsions or hydrothermal environments. These methods are complex, contain some toxic reagents, and are difficult to clean. Water-soluble tantalum nanoparticles synthesized using hydrothermal synthesis require additional surface treatment, which is time-consuming. Furthermore, silane coupling agents are not listed as medical excipients, which limits the biological applications of tantalum nanoparticles modified with these agents. Alternatively, modification with a single medical adhesive, such as polypyrrolidone, polyethylene glycol, chitosan, polylactic acid, and hydrophilic phospholipids, can result in tantalum nanoparticles that lack stability at high solution concentrations and cannot remain stable for extended periods. Summary of the Invention

[0005] In view of the above analysis, the embodiments of the present invention aim to provide water-soluble tantalum nanoparticles and their preparation method and application, so as to solve the problem that water-soluble tantalum nanoparticles prepared by existing methods have poor stability in high-concentration solutions.

[0006] In one aspect, the present invention provides a method for preparing water-soluble tantalum nanoparticles, comprising the following steps:

[0007] (1) dissolving tantalum powder in water, ultrasonicating, and centrifuging to obtain refined tantalum powder;

[0008] (2) mixing the refined tantalum powder and metaphosphate to obtain a first mixture;

[0009] (3) subjecting the first mixture to a first-stage ball milling treatment to obtain a first-stage ball milled first mixture;

[0010] (4) adding an appropriate amount of water to the first mixture of the first stage ball milling treatment in step (3), then adding NaH2PO4 solution until the pH is 5.5-6.5, performing the second stage ball milling treatment, centrifuging, and washing to obtain the water-soluble tantalum nanoparticles.

[0011] Furthermore, the metaphosphate described in step (2) is one or more of sodium trimetaphosphate, sodium tetrametaphosphate or sodium hexametaphosphate.

[0012] Furthermore, in step (2), the mass ratio of the metaphosphate to the refined tantalum powder is 0.1-1.2.

[0013] Furthermore, in the first stage of ball milling in step (3), the ball milling speed is 100-600 r / min, and the ball milling time is 1-3 h.

[0014] Furthermore, medical excipients are added to the water in step (4).

[0015] Furthermore, the medical excipient is one or more of polyvinyl pyrrolidone, polyethylene glycol 4000, polyethylene glycol 6000, betaine, glucoside, polylactic acid, chitosan, phospholipids or Tween.

[0016] Furthermore, the concentration of the medical excipient in water is 0.5-1 g / mL, and the mass ratio of the medical excipient to the refined tantalum powder is 0.5-1.2.

[0017] Furthermore, in the second stage of ball milling in step (4), the ball milling speed is 100-600 r / min, and the ball milling time is 2-6 h;

[0018] The centrifugation is specifically as follows: first centrifuging at a speed of 2000-3000 r / min for 4-6 minutes, and then centrifuging at a speed of 10000-11000 r / min for 10-15 minutes.

[0019] In a second aspect, the present invention provides water-soluble tantalum nanoparticles prepared by the method described above, wherein the water-soluble tantalum nanoparticles are spherical and have a diameter of 30-60 nm.

[0020] Furthermore, the water-soluble tantalum nanoparticles are coated with a hydrophilic film, and the thickness of the hydrophilic film is 4-6 nm.

[0021] In a third aspect, the present invention provides a use of the water-soluble tantalum nanoparticles in the preparation of a radiotherapy sensitizer.

[0022] Compared with the prior art, the present invention can achieve at least one of the following beneficial effects:

[0023] (1) In the preparation of water-soluble tantalum nanoparticles according to the present invention, metaphosphate is added. Under the combined action of metaphosphate and high-energy ball milling in the first ball milling stage, the covalent bonds of tantalum oxide on the surface of tantalum powder are broken to form tantalate, thereby increasing its surface charge and solubility. In the second ball milling stage, an appropriate amount of water is added for wet milling to improve the efficiency of ball milling in crushing large tantalum particles. At the same time, the metaphosphate forms a colloidal state after absorbing water and is coated on the surface of the tantalum nanoparticles, thereby improving its stability in high-water solution. The stability time in an aqueous solution with a concentration of 60 mg / mL is at least 48 hours.

[0024] (2) The method of the present invention enables the prepared water-soluble tantalum nanoparticles to be in a monodisperse state. Through ball milling, the aggregated tantalum nanoparticle polymers are dispersed into small tantalum nanoparticles, and medical excipients are added to coat the tantalum nanoparticles. The medical excipients are macromolecular chains. During the ball milling process, the chain macromolecules are vigorously mixed to form a cross-linked network structure. This network structure has two advantages: first, more medical excipients can be coated on the surface of the tantalum nanoparticles, thereby improving biocompatibility; second, the network structure can be used to load metaphosphate, thereby improving solution stability;

[0025] (3) The pH of the reaction mixture is adjusted to 5.5-6.5 by adding an appropriate amount of NaH2PO4 solution. The acidic inorganic salt solution can inhibit the hydrolysis of metaphosphate, improve the utilization rate of metaphosphate, and increase the surface charge of the water-soluble tantalum nanoparticles;

[0026] (4) The method of the present invention is carried out through two-stage ball milling treatment. The first stage ball milling treatment promotes the formation of a cross-existence mixture of tantalum nanoparticles and metaphosphate. At the same time, the high-energy ball milling treatment activates the surface of the material, promotes the reaction of the phosphate group with the tantalum oxide film on the surface of the tantalum nanoparticles, and breaks the covalent bond of the tantalum oxide film on the surface of the water-soluble tantalum nanoparticles to form tantalate, thereby increasing its surface charge and solubility; an appropriate amount of NaH2PO4 solution is added for the second stage ball milling treatment. The second stage adopts wet milling treatment to improve the efficiency of ball milling for crushing large particles of tantalum. At the same time, metaphosphate will form a colloidal state after absorbing water, presenting a long chain state. This long chain forms a hydrophilic film after coating the surface of the tantalum nanoparticles. This hydrophilic film is negatively charged and reduces the agglomeration phenomenon through the repulsive effect of electrostatic force, thereby improving the stability of the water-soluble tantalum nanoparticles;

[0027] (5) The addition of medical excipients in the present invention enables the synthesized water-soluble tantalum nanoparticles to maintain good dispersibility and stability in the body. The medical excipients are coated on the surface of the tantalum nanoparticles together with the metaphosphate, and the medical excipients are present in a mixed coating form rather than a layer-on-layer form. This coating method combines the advantages of multiple surfactants, improves surface charge repulsion, and also has good biocompatibility, and can maintain better stability in the human body environment;

[0028] (6) The water-soluble tantalum nanoparticles prepared by the present invention can be coated with a hydrophilic film with a thickness of 4-6 nm. This hydrophilic film is a mixed complex of metaphosphate and medical excipients or a single complex of metaphosphate. This complex can improve the biological stability of the water-soluble tantalum nanoparticles and can couple more long metaphosphate chains to increase the surface charge of the water-soluble tantalum nanoparticles.

[0029] In the present invention, the above-mentioned technical solutions can be combined with each other to achieve more preferred combinations. Other features and advantages of the present invention will be described in the following description, and some advantages will become apparent from the description or be learned through practice of the present invention. The objectives and other advantages of the present invention can be realized and obtained through the contents particularly pointed out in the description and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The accompanying drawings are only for the purpose of illustrating particular embodiments and are not to be considered limiting of the present invention. Like reference symbols denote like parts throughout the drawings.

[0031] Figure 1 TEM image of the water-soluble tantalum nanoparticles prepared in Example 1 of the present invention;

[0032] Figure 2 UV images of water-soluble tantalum nanoparticles prepared in Examples 1 and 4 of the present invention;

[0033] Figure 3 The XRD patterns of the water-soluble tantalum nanoparticles prepared in Examples 1 and 4 of the present invention are shown;

[0034] Figure 4 This is the XPS electron spectrum of the tantalum nanoparticles obtained in Example 1;

[0035] Figure 5 This is the XPS electron spectrum of the tantalum nanoparticles obtained in Example 4;

[0036] Figure 6 The infrared spectra of the raw material tantalum powder, the prepared water-soluble tantalum nanoparticles and sodium hexametaphosphate in Test Example 1 are shown;

[0037] Figure 7 TEM images of water-soluble tantalum nanoparticles prepared at a rotation speed of 300 r / min for both the first and second ball milling;

[0038] Figure 8 TEM images of water-soluble tantalum nanoparticles prepared at a rotation speed of 600 r / min for both the first and second ball milling. DETAILED DESCRIPTION

[0039] The preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings, wherein the accompanying drawings constitute a part of the present invention and are used together with the embodiments of the present invention to illustrate the principles of the present invention, but are not used to limit the scope of the present invention.

[0040] A specific embodiment of the present invention discloses a method for preparing water-soluble tantalum nanoparticles, comprising the following steps:

[0041] (1) dissolving tantalum powder in water, ultrasonicating, and centrifuging to obtain refined tantalum powder;

[0042] (2) mixing the refined tantalum powder and metaphosphate to obtain a first mixture;

[0043] (3) subjecting the first mixture to a first-stage ball milling treatment to obtain a first-stage ball milled first mixture;

[0044] (4) adding an appropriate amount of water to the first mixture of the first stage ball milling treatment in step (3), then adding NaH2PO4 solution until the pH is 5.5-6.5, performing the second stage ball milling treatment, centrifuging, and washing to obtain the water-soluble tantalum nanoparticles.

[0045] Compared with the prior art, the preparation method of water-soluble tantalum nanoparticles provided in this embodiment adds metaphosphate. Under the combined action of metaphosphate and high-energy ball milling in the first ball milling stage, the covalent bonds of tantalum oxide on the surface of the water-soluble tantalum powder are broken to form tantalate, thereby improving its surface charge and increasing its solubility. In the second ball milling stage, water is added for wet milling to improve the efficiency of ball milling in crushing large tantalum particles. At the same time, metaphosphate forms a colloidal state after absorbing water and is coated on the surface of the tantalum nanoparticles, thereby improving its stability in high-water solution. The stability time in an aqueous solution with a concentration of 60 mg / mL is at least 48 hours.

[0046] It should be noted that in the present invention, commercially purchased tantalum powder is ultrasonically pretreated to refine the particle size and improve the dispersibility of the water-soluble tantalum nanoparticles. Low-speed centrifugation at 2000-4000 rpm is used to remove larger particles. The refined tantalum powder is then centrifuged at 10,000-11,000 rpm to collect the fine particles. The particle size of the refined tantalum powder is less than 190 nm.

[0047] Specifically, the concentration of the NaH2PO4 solution is 0.02-0.1 g / ml.

[0048] Specifically, the ultrasonic time is 1-2h, such as 1.2h, 1.4h, 1.6h, 1.8h, 2.0h, and the ultrasonic power is 280-320W, such as 280W, 290W, 300W, 310W, 320W.

[0049] Specifically, the metaphosphate described in step (2) is one or more of sodium trimetaphosphate, sodium tetrametaphosphate or sodium hexametaphosphate.

[0050] It should be noted that the first mixture in step (2) can be prepared by directly mixing the metaphosphate with the refined tantalum powder, or by dissolving the metaphosphate in an appropriate amount of secondary water and then mixing it with the refined tantalum powder.

[0051] Specifically, in step (2), the mass ratio of the metaphosphate to the refined tantalum powder is 0.1-1.2.

[0052] Exemplarily, the mass ratio of metaphosphate to refined tantalum powder is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, or 1.2.

[0053] It should be noted that the inventors have found through a large number of experiments that when the mass ratio of metaphosphate to refined tantalum powder is lower than 0.1, the modification effect is not obvious and the stability in aqueous solution is relatively poor. In the range of 0.1-1.2, the modification effect first increases and then decreases, reaching a peak at 1:1. When the ratio is greater than 1.2, the modification effect is still relatively good, but not as good as the previous range. The comprehensive selection of the mass ratio is 0.1-1.2.

[0054] Specifically, the ball milling speed in the first stage of ball milling in step (3) is 100-600 r / min, and the ball milling time is 1-3 h.

[0055] Illustratively, the ball milling speed in the first stage ball milling treatment is 100 r / min, 200 r / min, 300 r / min, 400 r / min, 500 r / min, 600 r / min, and the ball milling time is 1 h, 1.5 h, 2 h, 2.5 h, 3 h.

[0056] It should be noted that under the ball milling conditions of the first stage of the present invention, the extrusion pressure of the ball milling beads causes the tantalum nanoparticles and metaphosphate to form a cross-existing mixture. At the same time, the high-energy ball milling method activates the surface of the material, promotes the reaction of the phosphate groups with the tantalum oxide film on the surface of the tantalum nanoparticles, and breaks the covalent bonds of the tantalum oxide film on the surface of the water-soluble tantalum nanoparticles to form tantalate, thereby increasing its surface charge and solubility.

[0057] Specifically, medical excipients are also added to the water in step (4).

[0058] Specifically, the medical excipient is one or more of polyvinyl pyrrolidone, polyethylene glycol 4000, polyethylene glycol 6000, betaine, glucoside, polylactic acid, chitosan, phospholipids or Tween.

[0059] Biocompatible medical excipients enable the synthesized water-soluble tantalum nanoparticles to maintain good dispersibility and stability in the body. The medical excipients are coated on the surface of the tantalum nanoparticles together with metaphosphate. When multiple medical excipients are selected, they exist in a mixed coating form rather than a layer-on-layer form. This coating method combines the advantages of multiple medical excipients, improving surface charge repulsion while also having good biocompatibility.

[0060] Specifically, in step (4), the concentration of the medical excipient in water is 0.5-1 g / mL, and the mass ratio of the medical excipient to the refined tantalum powder is 0.5-1.2.

[0061] Exemplarily, the concentration of the medical excipient in the second mixture is 0.5 g / mL, 0.6 g / mL, 0.7 g / mL, 0.8 g / mL, 0.9 g / mL, and 1.0 g / mL, and the mass ratio of the medical excipient to the refined tantalum powder is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, and 1.2.

[0062] A large number of experiments have shown that the addition of medical excipients can improve the stability of tantalum nanoparticles in PBS buffer, and can stably exist in PBS buffer for at least 8 hours. The inventors have found through a large number of experiments that when too little medical excipient is added, the stability of tantalum nanoparticles in PBS solution is not obvious, and when too much is added, the agglomeration phenomenon will be accelerated. After comprehensive selection, the concentration of medical excipients in water is 0.5-1g / mL.

[0063] Specifically, the ball milling speed in the second stage ball milling treatment in step (4) is 100-600 r / min, and the ball milling time is 2-6 h.

[0064] Illustratively, the ball milling speed in the second stage ball milling treatment is 100 r / min, 200 r / min, 300 r / min, 400 r / min, 500 r / min, and 600 r / min, and the ball milling time is 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, and 6 h.

[0065] It should be noted that the appropriate amount of water in step (4) refers to water added to fully soak the first mixture of the first stage ball milling treatment. Under the second stage ball milling treatment conditions of the present invention, by adding an appropriate amount of inorganic salt solution (NaH2PO4 solution) to a pH of 5.5-6.5, the hydrolysis of metaphosphate can be inhibited, the utilization rate of metaphosphate can be improved, the agglomeration phenomenon can be reduced, the stability of the solution can be improved, and the surface charge of the water-soluble tantalum nanoparticles can be increased. The biocompatible medical excipient is a macromolecular chain. During the ball milling process, the chain macromolecules are vigorously mixed to form a cross-linked network structure.

[0066] This reticular structure has two advantages: first, it allows for the coating of more medical excipients onto the tantalum nanoparticles, improving biocompatibility; second, it allows for the loading of metaphosphate through the reticular structure, enhancing solution stability. The second stage of wet milling improves the efficiency of ball milling for breaking up large tantalum particles. Furthermore, upon absorbing water, the metaphosphate forms a colloidal state, forming long chains. These long chains coat the surface of the tantalum nanoparticles, forming a negatively charged hydrophilic film that, through electrostatic repulsion, reduces agglomeration and improves the stability of the water-soluble tantalum nanoparticles.

[0067] Specifically, the centrifugation in step (4) is as follows: first centrifuging at a speed of 2000-3000 r / min for 4-6 min, and then centrifuging at a speed of 10000-11000 r / min for 10-15 min.

[0068] It should be noted that low-speed centrifugation is used to remove unstable large water-soluble tantalum nanoparticles, and then high-speed centrifugation is used to remove unmodified medical excipients or metaphosphates.

[0069] Specifically, the tantalum nanoparticles prepared in the present invention are stored by adding an appropriate amount of sodium hyaluronate and freeze-drying for later use.

[0070] Another embodiment of the present invention provides water-soluble tantalum nanoparticles prepared by the method described above, wherein the water-soluble tantalum nanoparticles are spherical and have a diameter of 30-60 nm.

[0071] It should be noted that the water-soluble tantalum nanoparticles prepared in the present invention are spherical at the nanoscale, with a size between 30-60 nm and a monodisperse state.

[0072] Specifically, the water-soluble tantalum nanoparticles are coated with a hydrophilic film, and the thickness of the hydrophilic film is 4-6 nm.

[0073] It should be noted that this hydrophilic membrane is a mixed complex of metaphosphate and medical excipients or a single complex of metaphosphate. This complex can improve the biological stability of water-soluble tantalum nanoparticles, and at the same time can couple more long metaphosphate chains to increase the surface charge of water-soluble tantalum nanoparticles.

[0074] Another embodiment of the present invention provides a use of the water-soluble tantalum nanoparticles in preparing a radiotherapy sensitizer.

[0075] The water-soluble tantalum nanoparticles of the present invention are stable in aqueous solution for at least 48 hours and in PBS buffer for at least 8 hours. They also have good biocompatibility and a high X-ray attenuation coefficient, enabling them to enhance radiotherapy sensitization.

[0076] Example 1

[0077] A method for preparing water-soluble tantalum nanoparticles in this embodiment includes the following steps:

[0078] (1) 5 g of purchased commercial tantalum powder was dissolved in 500 mL of water and ultrasonically dispersed for 1 h to obtain a tantalum powder solution. 0.5 L of water was then added to the tantalum powder solution and ultrasonicated at a power of 300 W for 1 h. The solution was centrifuged at a low speed of 2000-4000 r / min to remove large-sized tantalum nanoparticles, and then centrifuged at a high speed of 10000-11000 r / min to obtain refined tantalum powder.

[0079] (2) mixing 2.5 g of refined tantalum powder and 1.0 g of sodium hexametaphosphate to obtain a first mixture;

[0080] (3) placing the first mixture in an agate jar and ball milling at 600 r / min for 1 h to obtain the first mixture after the first stage of ball milling;

[0081] (4) 4 mL of secondary water was added to the first mixture of the first stage ball milling treatment described in step (3), and then an appropriate amount of 0.1 g / ml NaH2PO4 solution was added, the pH was adjusted to 5.5-6.5, and ball milling was performed at 600 r / min for 3 h. The unstable water-soluble tantalum nanoparticles were first removed by low-speed centrifugation at 2000 r / min for 6 min, and then the mixture was washed by high-speed centrifugation at 10000 r / min for 15 min. After washing 3-4 times, the mixture was dissolved in secondary water. During the centrifugation process, water and alcohol were used for cross-cleaning to ensure that impurities were cleaned, thereby obtaining the water-soluble tantalum nanoparticles.

[0082] The water-soluble nanoparticles prepared in this example were dissolved in an appropriate amount of water, uniformly dispersed under 300W ultrasound, and an appropriate amount of sodium hyaluronate was added. After uniform ultrasonic mixing, the mixture was freeze-dried to obtain freeze-dried water-soluble nanoparticle powder, which was placed in a constant temperature and moisturizing cabinet for later use.

[0083] The TEM image of the water-soluble tantalum nanoparticles prepared in this example is as follows: Figure 1 As shown in the figure, it can be seen that the water-soluble tantalum nanoparticles prepared in this embodiment are spherical, with a size between 30-60 nm, and are monodispersed. The water-soluble tantalum nanoparticles in this embodiment are coated with a hydrophilic film with a thickness of 4-6 nm.

[0084] Example 2

[0085] A method for preparing water-soluble tantalum nanoparticles in this embodiment includes the following steps:

[0086] (1) The purchased commercial tantalum powder was dissolved in water and ultrasonically dispersed for 1.5 h at an ultrasonic power of 320 W. The large-sized tantalum nanoparticles were removed by low-speed centrifugation at 2000-4000 r / min, and the refined tantalum powder was obtained by high-speed centrifugation at 10000-11000 r / min.

[0087] (2) mixing the refined tantalum powder and sodium tetrametaphosphate, wherein the mass ratio of sodium tetrametaphosphate to the refined tantalum powder is 0.1, to obtain a first mixture;

[0088] (3) placing the first mixture in an agate jar and ball milling at 100 r / min for 3 h to obtain the first mixture after the first stage of ball milling;

[0089] (4) 4 mL of secondary water was added to the first mixture of the first stage ball milling treatment described in step (3), and then an appropriate amount of 0.05 g / ml NaH2PO4 solution was added, the pH was adjusted to 5.5-6.5, and ball milling was performed at 100 r / min for 6 hours. The unstable water-soluble tantalum nanoparticles were first removed by low-speed centrifugation at 2500 r / min for 5 minutes, and then the mixture was washed by high-speed centrifugation at 10500 r / min for 13 minutes. After washing 3-4 times, it was dissolved in secondary water. During the centrifugation process, water and alcohol were used for cross-cleaning to ensure that impurities were cleaned, thereby obtaining the water-soluble tantalum nanoparticles.

[0090] The water-soluble nanoparticles prepared in this example were dissolved in an appropriate amount of water, uniformly dispersed under 300W ultrasound, and an appropriate amount of sodium hyaluronate was added. After uniform ultrasonic mixing, the mixture was freeze-dried to obtain freeze-dried water-soluble nanoparticle powder, which was placed in a constant temperature and moisturizing cabinet for later use.

[0091] The water-soluble tantalum nanoparticles prepared in this embodiment are spherical, with a size between 30-60 nm and are monodispersed. The water-soluble tantalum nanoparticles in this embodiment are coated with a hydrophilic film with a thickness of 4-6 nm.

[0092] Example 3

[0093] A method for preparing water-soluble tantalum nanoparticles in this embodiment includes the following steps:

[0094] (1) The purchased commercial tantalum powder was dissolved in water and ultrasonically dispersed for 2 h at an ultrasonic power of 280 W. The large-sized tantalum nanoparticles were removed by low-speed centrifugation at 2000-4000 r / min, and the refined tantalum powder was obtained by high-speed centrifugation at 10000-11000 r / min.

[0095] (2) mixing the refined tantalum powder and sodium trimetaphosphate, wherein the mass ratio of sodium trimetaphosphate to the refined tantalum powder is 0.6, to obtain a first mixture;

[0096] (3) placing the first mixture in an agate jar and ball milling at 350 r / min for 2 h to obtain the first mixture subjected to the first stage of ball milling;

[0097] (4) 4 mL of secondary water was added to the first mixture of the first stage ball milling treatment described in step (3), and then an appropriate amount of 0.02 g / ml NaH2PO4 solution was added, the pH was adjusted to 5.5-6.5, and ball milling was performed at 350 r / min for 4 hours. The unstable water-soluble tantalum nanoparticles were first removed by low-speed centrifugation at 3000 r / min for 4 minutes, and then the mixture was washed by high-speed centrifugation at 11000 r / min for 10 minutes. After washing 3-4 times, it was dissolved in secondary water. During the centrifugation process, water and alcohol were used for cross-cleaning to ensure that impurities were cleaned, thereby obtaining the water-soluble tantalum nanoparticles.

[0098] The water-soluble nanoparticles prepared in this example were dissolved in an appropriate amount of water, uniformly dispersed under 300W ultrasound, and an appropriate amount of sodium hyaluronate was added. After uniform ultrasonic mixing, the mixture was freeze-dried to obtain freeze-dried water-soluble nanoparticle powder, which was placed in a constant temperature and moisturizing cabinet for later use.

[0099] The water-soluble tantalum nanoparticles prepared in this embodiment are spherical, with a size between 30-60 nm and are monodispersed. The water-soluble tantalum nanoparticles in this embodiment are coated with a hydrophilic film with a thickness of 4-6 nm.

[0100] Example 4

[0101] The water-soluble nanoparticles of this embodiment are prepared in the same manner as in Example 1, except that polyvinyl pyrrolidone is added to the secondary water in step (4). Specifically, 2 g of polyvinyl pyrrolidone is added to 4 mL of secondary water, ultrasonically treated at 300 W until completely dissolved, and then NaH2PO4 solution is added.

[0102] The water-soluble tantalum nanoparticles prepared in this embodiment are spherical, with a size between 30-60 nm and are monodispersed. The water-soluble tantalum nanoparticles in this embodiment are coated with a hydrophilic film with a thickness of 4-6 nm.

[0103] Example 5

[0104] The water-soluble nanoparticles of this embodiment are prepared in the same manner as in Example 1, except that polylactic acid is added to the secondary water in step (4). Specifically, the concentration of polylactic acid in water is 1 g / mL, the mass ratio of polylactic acid to refined tantalum powder is 1.2, and NaH2PO4 solution is added after 300W ultrasonic treatment until completely dissolved.

[0105] The water-soluble tantalum nanoparticles prepared in this embodiment are spherical, with a size between 30-60 nm and are monodispersed. The water-soluble tantalum nanoparticles in this embodiment are coated with a hydrophilic film with a thickness of 4-6 nm.

[0106] Example 6

[0107] The water-soluble nanoparticles of this embodiment are prepared in the same manner as in Example 1, except that polyethylene glycol 4000 is added to the secondary water in step (4). Specifically, the concentration of polyethylene glycol 4000 in water is 0.5 g / mL, the mass ratio of polylactic acid to refined tantalum powder is 0.5, and NaH2PO4 solution is added after 300W ultrasonic treatment until completely dissolved.

[0108] The water-soluble tantalum nanoparticles prepared in this embodiment are spherical, with a size between 30-60 nm and are monodispersed. The water-soluble tantalum nanoparticles in this embodiment are coated with a hydrophilic film with a thickness of 4-6 nm.

[0109] Comparative Example 1

[0110] The preparation method of the tantalum nanoparticles in this comparative example is the same as that in Example 1, except that in step (4), the first mixture and water are directly mixed, and only one ball milling treatment is performed, that is, ball milling is performed at 600 r / min for 1 hour, and the second stage ball milling treatment is not performed.

[0111] Test Example 1

[0112] 1. UV images of water-soluble tantalum nanoparticles prepared in Example 1 and Example 4 are as follows: Figure 2 As shown, from Figure 2 It can be seen that the infrared light absorption of tantalum nanoparticles after adding PVP is better than that of single-modified tantalum nanoparticles. The absorbance of PVP-modified tantalum nanoparticles in the infrared range is about 1.5 times that of single-modified tantalum nanoparticles, and has better photothermal conversion ability, which means that better photothermal treatment effect can be obtained after adding PVP.

[0113] 2. The XRD patterns of the water-soluble tantalum nanoparticles and the raw tantalum powder prepared in Example 1 and Example 4 are as follows: Figure 3 As shown, XRD analysis shows that the composition and structure of the nanoparticles after water solubilization treatment do not change significantly compared with the original nanoparticles, and the original composition and structure are maintained, indicating that the method of the present invention will not change the composition and structure of the tantalum nanoparticles.

[0114] 3. Figure 4 This is the XPS electron spectrum of the tantalum nanoparticles obtained in Example 1. Figure 5This is the XPS electron spectrum of the tantalum nanoparticles obtained in Example 4. XPS electron spectrum is used to analyze the surface composition of the material. Ta4f is the most commonly used peak in XPS analysis. Ta4f5 / 2 and Ta4f7 / 2 are the two splitting peaks of Ta4f. The valence state and composition of the tantalum element can be determined by the binding energy of the splitting peak position. Figure 4 and 5 The results show that its composition is Ta2O5 and TaO3 - It shows that changes occur in the chemical bonds on the surface of tantalum nanoparticles, and the tantalum oxide on the surface reacts with sodium hexametaphosphate to achieve improved water solubility.

[0115] 4. The infrared spectra of the raw material tantalum powder, the prepared water-soluble tantalum nanoparticles and sodium hexametaphosphate in Test Example 1 are as follows: Figure 6 As shown in the figure, the spectrum of the tantalum nanoparticles after ball milling has the characteristics of both the spectrum of tantalum before ball milling and the spectrum of sodium hexametaphosphate. The change in the external spectrum of the water-soluble tantalum nanoparticles obtained by the method of the present invention indicates that sodium hexametaphosphate has been successfully modified on the tantalum nanoparticles.

[0116] Test Example 2

[0117] The water-soluble tantalum nanoparticles prepared in Examples 1-6 and Comparative Example 1 were added with water and PBS buffer to prepare solutions with a concentration of 60 mg / mL, and the concentration was observed over time. When the concentration dropped rapidly, it indicated that the stability of the solution decreased. The time for the solution to stabilize was determined, and the stability time of each group was examined. The results are shown in Table 1.

[0118] Table 1

[0119]

[0120] As can be seen from Table 1, the water-soluble tantalum nanoparticles prepared by the present invention have good stability in both aqueous solution and high concentration PBS buffer. The stabilization time of Comparative Example 1 is significantly lower than that of Example 1. This is because the secondary ball milling improves the efficiency of ball milling in crushing large tantalum particles. At the same time, the metaphosphate forms a colloidal state after absorbing water and is coated on the surface of the tantalum nanoparticles, thereby improving the stability of the tantalum nanoparticles in aqueous solution.

[0121] In addition, compared with Example 1, the stability time of the tantalum nanoparticles in aqueous solution in Examples 4-5 is similar, indicating that the addition ratio of the medical excipient according to the present invention does not affect the stability of the tantalum nanoparticles in water. However, compared with Examples 1-3, the stability time of the tantalum nanoparticles in PBS buffer was significantly improved in Examples 4-6. This is because the addition of the medical excipient enables the synthesized water-soluble tantalum nanoparticles to maintain good dispersibility and stability in vivo. The medical excipient is coated on the surface of the tantalum nanoparticles together with the metaphosphate, and the medical excipient is present in a mixed coating form, rather than a layer-on-layer coating. This coating method combines the advantages of multiple surfactants, improving surface charge repulsion while also having good biocompatibility, which can meet the needs of using water-soluble tantalum nanoparticles in PBS buffer.

[0122] Test Example 3

[0123] Only the first and second ball milling speeds were changed, and the mass ratio of the refined tantalum powder to sodium hexametaphosphate was 1:1. Other conditions were the same as in Example 1 to prepare water-soluble tantalum nanoparticles.

[0124] Tantalum nanoparticles were prepared into a 60 mg / mL aqueous solution. The stability time of the water-soluble tantalum nanoparticles in the aqueous solution was measured in the same manner as in Experimental Example 2. The results are shown in Table 2.

[0125] Table 2

[0126]

[0127] It can be seen from Table 2 that the stability increases with the increase of the rotation speed. However, the TEM images of the water-soluble tantalum nanoparticles prepared at 300 r / min and 600 r / min are as follows: Figure 7 and 8 As shown, from Figure 7 and 8 It can be seen from the figure that as the rotation speed increases, the proportion of nanoparticles decreases. Taking into account the stability and the proportion of spherical particles, the optimal speed for the first and second ball milling processes in the present invention is 300 r / min.

[0128] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by any technician familiar with this technical field within the technical scope disclosed by the present invention should be covered by the scope of protection of the present invention.

Claims

1. A method for preparing water-soluble tantalum nanoparticles, characterized in that: The steps include: (1) dissolving tantalum powder in water, ultrasonicating, and centrifuging to obtain refined tantalum powder; (2) mixing the refined tantalum powder and metaphosphate, wherein the mass ratio of the metaphosphate to the refined tantalum powder is 0.1-1.2, to obtain a first mixture; (3) subjecting the first mixture to a first-stage ball milling treatment to obtain a first-stage ball milled first mixture; (4) adding an appropriate amount of water to the first mixture of the first stage ball milling treatment in step (3), then adding NaH2PO4 solution until the pH is 5.5-6.5, performing a second stage ball milling treatment, centrifuging, and washing to obtain the water-soluble tantalum nanoparticles; Wherein, a medical excipient is further added to the water in step (4), and the medical excipient is one or more of polyvinyl pyrrolidone, polyethylene glycol 4000, polyethylene glycol 6000, betaine, glucoside, polylactic acid, chitosan, phospholipids or Tween; The concentration of the medical excipient in water is 0.5-1 g / mL, and the mass ratio of the medical excipient to the refined tantalum powder is 0.5-1.2; The water-soluble tantalum nanoparticles are coated with a hydrophilic film, and the thickness of the hydrophilic film is 4-6 nm.

2. The method for preparing water-soluble tantalum nanoparticles according to claim 1, wherein: The metaphosphate described in step (2) is one or more of sodium trimetaphosphate, sodium tetrametaphosphate or sodium hexametaphosphate.

3. The method for preparing water-soluble tantalum nanoparticles according to claim 1, wherein: The ball milling speed in the first stage of ball milling in step (3) is 100-600 r / min, and the ball milling time is 1-3 h.

4. The method for preparing water-soluble tantalum nanoparticles according to claim 1, wherein: In the second stage of ball milling in step (4), the ball milling speed is 100-600 r / min, and the ball milling time is 2-6 h; The centrifugation is specifically as follows: first centrifuging at a speed of 2000-3000 r / min for 4-6 minutes, and then centrifuging at a speed of 10000-11000 r / min for 10-15 minutes.

5. Water-soluble tantalum nanoparticles prepared by the method according to any one of claims 1 to 4, characterized in that: The water-soluble tantalum nanoparticles are spherical and have a diameter of 30-60 nm.

6. Use of water-soluble tantalum nanoparticles prepared by the method according to any one of claims 1 to 4 in the preparation of a radiotherapy sensitizer.

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