Magnetocaloric radioactive composite particle and preparation method therefor

Abstract

A magnetocaloric radioactive composite particle and a preparation method therefor. The magnetocaloric radioactive composite particle comprises a surrounding layer. An iodine-plated silver rod is wrapped in the surrounding layer. An accommodating area is present between the surrounding layer and the iodine-plated silver rod. The accommodating area is filled with magnetocaloric nanoparticles. The iodine-plated silver rod is located within the mid-section of the surrounding layer. The magnetocaloric radioactive composite particles have magnetocaloric therapy and radioactive therapy functions at the same time; the magnetic medium particles are concentrated in a titanium shell, such that the toxic and side effects can be reduced while effective therapy is guaranteed.

Description

Magnetic-thermal radioactive composite particles and a preparation method thereof TECHNICAL FIELD

[0001] The present disclosure belongs to the technical field of inductive hyperthermia, and particularly relates to magnetic-thermal radioactive composite particles and a preparation method thereof. BACKGROUND

[0002] Magnetic hyperthermia is a physical therapy that selectively kills tumors without damaging normal tissues by implanting or interventional therapy into the target area with magnetic medium, and utilizing the heating characteristics of the magnetic medium under alternating magnetic field. However, in the existing magnetic hyperthermia system, the magnetic medium particles have high fluidity, which can escape into the healthy tissues and organs of the human body, causing toxic side effects to the human body. Moreover, all parts containing the magnetic medium particles will be heated without distinction under the action of the magnetic coil, causing damage to healthy tissues.

[0003] Radioactive particle implantation is one of the effective means for treating cancer, which is to implant radioactive particles into the tumor lesion site, and to kill cancer cells by using the continuous radiation of radioactive particles. This technology has the characteristics of strong targeting and small side effects, and has been widely used. However, due to the radiotherapy resistance of part of the tumor tissue caused by hypoxia and other reasons, the tumor control is not good.

[0004] In the prior art, there are problems of loss of magnetic nanoparticles due to low viscosity and high fluidity of the delivery medium, which cannot achieve the effect of hyperthermia and may damage healthy tissues, and the effective killing range of radioactive particles is limited.

[0005] At present, the existing technology for magnetic nanoparticles and radioactive particles is in the form of, for example, patent publication No. CN209984818U, a dual-function particle with radiotherapy and magnetic hyperthermia, which is constructed by setting a radioactive nuclide source core and a magnetic-thermal medium body in a circular tube, and setting end plates at both ends of the circular tube. The magnetic-thermal medium used in this patent is a millimeter-sized ferromagnetic heat seed, which has a low heat production efficiency, resulting in a long treatment time for magnetic hyperthermia, and the millimeter-sized ferromagnetic heat seed has anisotropy in heat production efficiency, resulting in uneven temperature field, which causes differences in the thermal ablation effect of tumor tissues in all directions around the particle. Moreover, it needs to be heated to 40-70℃, which exceeds the tolerance temperature of normal cells, and needs to be controlled in temperature, otherwise it will cause thermal damage to the normal tissues around the tumor. In addition, this structure will make the composite particles have hot spots at both ends and a cold spot in the middle, which aggravates the unevenness of the temperature field.

[0006] As patent publication No. CN213407506U, a medical particle with dual functions of brachytherapy and magnetic induction hyperthermia, comprising a shell and a core body arranged in the shell, the shell is a titanium tube with sealed ends, the core body is a microsphere or microparticle containing radioactive nuclides, the surface of the microsphere or microparticle is uniformly attached with a radioactive nuclide layer; the magnetic heat medium used in this patent is a microsphere made of traditional ferromagnetic material or Ni-Cu alloy mixed with metal powder, which has low heat production efficiency, resulting in longer magnetic hyperthermia treatment time, and the uniformity of the heat field depends on the uniformity of the microsphere material mixture, which has high requirements for the manufacture of microspheres. In addition, this kind of traditional magnetic heat material also has a large temperature range for hyperthermia, and the temperature rises higher than the tolerance temperature of normal cells, so additional temperature control is needed, otherwise it will cause thermal damage to the normal tissues around the tumor.

[0007] Of course, for patent publication No. CN108373174A, a preparation method of high-heat self-controlled temperature type magnetic nanoparticles. First, ZnCl2, CoCl2·6H2O, CrCl3·6H2O and FeCl3·6H2O metal salt ion solution and NaOH aqueous solution are co-precipitated to form a precursor solution, and then transferred to an autoclave for hydrothermal reaction at 250-450℃ for 2-24 hours to form high-heat self-controlled temperature type magnetic nanoparticles; that is, the prepared magnetic heat nanoparticles; such as direct installation in the existing way, such as CN209984818U and CN213407506U through the titanium tube or titanium shell, only the magnetic heat medium exists, only magnetic induction hyperthermia can be performed, the curative effect is limited, and other tumor treatment methods cannot be combined to synergistically enhance the effect; and the above two wrapping structures themselves will also cause the non-uniformity of the temperature field, resulting in the difference in curative effect in each direction. SUMMARY

[0008] In a first aspect, the present application provides a magnetic heat radioactive composite particle.

[0009] The present application is realized by the following scheme:

[0010] A magnetic heat radioactive composite particle, comprising a surrounding layer, a silver rod plated with iodine is wrapped in the surrounding layer, there is a containing area between the surrounding layer and the silver rod plated with iodine, and magnetic heat nanoparticles are filled in the containing area; the silver rod plated with iodine is in the middle of the containing area.

[0011] In some publications, the particle size of the magnetic heat radioactive composite particle is 0.8mm, and the length is 4.5mm.

[0012] In some publications, the material of the surrounding layer is one of titanium, stainless steel and ceramic.

[0013] In some publications, the thickness of the surrounding layer is 0.05-0.1mm.

[0014] In some embodiments, the ratio between the volume of the containing area and the volume of the iodine-coated silver rod is 6:1 to 12:1.

[0015] In some embodiments, the filling degree of the magnetic heat nanoparticles in the containing area is ≥70%.

[0016] In some embodiments, the particle size of the magnetic heat nanoparticles is 10-300 nm.

[0017] In some embodiments, the magnetic heat nanoparticles comprise: dissolving NaOH into deionized water, stirring to completely dissolve, forming an alkaline solution with a concentration of 3.5-4.5 mol, as a precipitant;

[0018] Dissolving 6.3-6.5 parts by weight of FeCl3·6H2O, 2.3-2.5 parts by weight of CrCl3·6H2O, 1.7-1.9 parts by weight of CoCl2·6H2O and 1.1-1.3 parts by weight of ZnCl2 into 78-85 parts by weight of deionized water to form a metal salt ion solution;

[0019] Slowly drop the precipitant into the metal salt ion solution at room temperature to carry out a preliminary co-precipitation reaction to generate a precursor suspension; the mixed solution needs to be continuously stirred during the addition of the precipitant to ensure uniform mixing of the solution;

[0020] The precursor suspension is moved to a high-pressure kettle and sealed, and after setting the rotation speed and hydrothermal temperature, heating is started. After the temperature in the high-pressure kettle rises to the set heating temperature, it is maintained at this temperature for 6 hours, and then naturally cooled to room temperature. Then the high-pressure kettle is opened, and the formed magnetic nanoparticle suspension is taken out; the rotation speed of the high-pressure kettle is set to 200 rad / min, and the hydrothermal temperature is 350°C.

[0021] The obtained magnetic nanoparticle suspension is washed to neutral;

[0022] After the washing is completed, the obtained precipitate is vacuum dried at a temperature of 80°C for 6 hours, and then naturally cooled to room temperature to obtain a magnetic solid; the magnetic solid is fully ground to obtain magnetic nanoparticles.

[0023] In a second aspect, the application provides a method for preparing the magnetic heat radioactive composite particles of the first aspect, comprising: placing the surrounding layer in the groove of the magnetic base, and then filling the magnetic heat nanoparticles in the bottom of the containing area;

[0024] The iodine-coated silver rod is placed in the containing area;

[0025] The filling of the magnetic heat nanoparticles is continued until the iodine-coated silver rod is completely wrapped and the containing area of the titanium shell is completely filled; and the surrounding layer is closed.

[0026] In some embodiments,

[0027] Place the titanium shell in the groove of the magnetic base; fill the magnetic heat nanoparticles at the bottom of the titanium shell;

[0028] Continue to fill the magnetic heat nanoparticles until the iodine-coated silver rod is completely wrapped and the inner cavity of the titanium shell is completely filled;

[0029] Install the titanium shell cover at the gap of the titanium shell for packaging.

[0030] The beneficial effects of the present disclosure are:

[0031] The composite particle has both magnetic heat therapy and radiotherapy functions, and has better killing and inhibiting effect on diseased cells;

[0032] The required implantation and interventional magnetic medium particles are concentrated in the titanium shell, which can reduce toxic side effects while ensuring effective treatment;

[0033] The composite particle has CT / MR dual imaging capability, and the external imaging means for implantation and intervention into the human body is rich. BRIEF DESCRIPTION OF DRAWINGS

[0034] In order to more clearly illustrate the technical solutions of the embodiments of the present disclosure or the prior art, the drawings needed to be used in the embodiment or prior art description will be briefly introduced below. Obviously, for those skilled in the art, other drawings can also be obtained without creative labor on the basis of these drawings.

[0035] Figure 1 is a flow chart of a material preparation method of a magnetic heat radioactive composite particle according to an embodiment of the present application;

[0036] Figure 2 is a flow chart of a preparation and assembly method of a magnetic heat radioactive composite particle according to an embodiment of the present application;

[0037] Figure 3 is a schematic diagram of the structure of a magnetic heat radioactive composite particle according to an embodiment of the present application. DETAILED DESCRIPTION

[0038] The combination of nanoparticles and iodine-coated silver rods obtains a magnetic heat radioactive composite particle, which has both magnetic heat therapy and radiotherapy effects, can more efficiently kill diseased tissues, and improve treatment effect. The magnetic nanoparticles of the composite particle are wrapped in a titanium shell and do not directly contact with human tissues, which can reduce toxic side effects. The material properties of the composite particle can satisfy multiple imaging methods such as CT and MR, and the external imaging means for implantation and intervention into the human body is rich. As shown in Figure 3, the surrounding layer 1, the iodine-coated silver rod 2 and the magnetic heat nanoparticles 3.

[0039] In some cases, the size of the magnetocaloric radioactive composite particle can be selected as a conventional size, such as a particle diameter of 0.8 mm and a length of 4.5 mm.

[0040] In some cases, the material of the surrounding layer is titanium, and in addition to the titanium shell, ceramic or other low-atomic-number metals such as stainless steel and aluminum can also be selected.

[0041] In some cases, the thickness of the surrounding layer is 0.05-0.1 mm, which ensures that the composite particle containing area is sufficient and at the same time ensures that the structural strength meets the requirements of the particle implantation operation.

[0042] The ratio between the volume of the containing area and the volume of the iodine-coated silver rod is 6:1-12:1, which ensures that the ratio of magnetocaloric nanoparticles and radionuclides is balanced, and the two treatment methods can be synergistically sensitized.

[0043] The filling degree of the magnetocaloric nanoparticles located in the containing area is ≥70%, which ensures that the number of magnetocaloric nanoparticles is sufficient, otherwise it will lead to a long magnetocaloric therapy time and poor efficacy.

[0044] The iodine-coated silver rod is located in the middle of the containing area, and the height deviation is <0.5 mm and the radial deviation is <0.15 mm. The attitude deviation will cause uneven distribution of magnetic nanoparticles in the composite particle and uneven temperature field formation, but the slight deviation has a weak impact.

[0045] As shown in FIG. 1 or FIG. 2, in the present application, the particle size of the magnetocaloric nanoparticles is 10-300 nm, which is determined by the preparation method. For example, for the preparation of magnetocaloric nanoparticles, the purpose is to form magnetocaloric nanoparticles with a heat production efficiency >15 W / g and a magnetocaloric therapy temperature of 42-45°C, such as the patent "Preparation of high-heat self-controlled temperature type magnetic nanoparticles" (CN108373174A). The magnetocaloric nanoparticles comprise: dissolving NaOH into deionized water, stirring to completely dissolve it, forming an alkaline solution with a concentration of 3.5-4.5 mol as a precipitating agent;

[0046] 6.3-6.5 parts by weight of FeCl3·6H2O, 2.3-2.5 parts by weight of CrCl3·6H2O, 1.7-1.9 parts by weight of CoCl2·6H2O, and 1.1-1.3 parts by weight of ZnCl2 are dissolved into 78-85 parts by weight of deionized water to form a metal salt ion solution;

[0047] The precipitating agent is slowly added dropwise into the metal salt ion solution at room temperature to perform a preliminary co-precipitation reaction to generate a precursor suspension; during the addition of the precipitating agent, the mixed solution needs to be continuously stirred to ensure uniform mixing of the solution;

[0048] The precursor suspension liquid is moved into a high-pressure kettle for sealing. After setting the rotation speed and hydrothermal temperature, the heating is started. When the temperature in the high-pressure kettle reaches the set heating temperature, the temperature is kept for 6 hours. Then, the high-pressure kettle is naturally cooled to room temperature. Then, the magnetic nanoparticle suspension liquid is taken out. The rotation speed of the high-pressure kettle is set to 200 rad / min, and the hydrothermal temperature is 350℃.

[0049] The obtained magnetic nanoparticle suspension liquid is washed to be neutral.

[0050] After the washing is completed, the obtained precipitate is vacuum dried at a temperature of 80℃ for 6 hours. Then, the magnetic solid is naturally cooled to room temperature. The magnetic nanoparticle is obtained by fully grinding the magnetic solid.

[0051] For the preparation method of the above-mentioned magnetic-thermal radioactive composite particles, the surrounding layer is placed in the groove of the magnetic base, and then the magnetic-thermal nanoparticles are filled at the bottom of the containing area. The weight of the filled magnetic-thermal nanoparticles is greater than or equal to 1.05 mg. If the filling amount is too small, the magnetic-thermal treatment time will be increased, the operation efficiency will be reduced, and the tumor thermal ablation area will be smaller. The iodine-coated silver rod is placed in the containing area. The magnetic-thermal nanoparticles are continuously filled until the iodine-coated silver rod is completely wrapped and the containing area of the titanium shell is completely filled. The surrounding layer is closed. Specifically, in some embodiments, the titanium shell is placed in the groove of the magnetic base. The magnetic-thermal nanoparticles are filled at the bottom of the titanium shell. The magnetic-thermal nanoparticles are continuously filled until the iodine-coated silver rod is completely wrapped and the inner cavity of the titanium shell is completely filled. The titanium shell cover is installed at the gap of the titanium shell for packaging.

[0052] Example 1:

[0053] Preparation process of magnetic-thermal nanoparticles:

[0054] First step, preparation of precipitant. 24 g of NaOH is dissolved in 150 mL of deionized water. A glass rod is used for stirring to make it completely dissolved, and an alkaline solution is prepared as a precipitant.

[0055] Second step, preparation of metal salt ion solution. 6.467 g of FeCl3·6H2O (≥99%), 2.418 g of CrCl3·6H2O (≥99%), 1.805 g of CoCl2·6H2O (≥99%) and 1.214 g of ZnCl2 (≥98%) are dissolved in 80 mL of deionized water to form a metal salt ion solution.

[0056] Third step, dropwise addition of precipitant to generate precursor suspension liquid. The precipitant prepared in the first step is slowly added dropwise to the metal salt ion solution prepared in the second step at room temperature to generate a preliminary co-precipitation reaction to generate a precursor suspension liquid. It should be noted that the mixed solution needs to be continuously stirred during the dropwise addition of the precipitant to make the solution uniform.

[0057] Fourth step, hydrothermal reaction to generate magnetic nanoparticles suspension. The third step of the prepared precursor suspension is moved to the autoclave sealed. Set the speed and hydrothermal temperature after heating. When the temperature in the autoclave rises to the set heating temperature, keep it at this temperature for a certain time. Then naturally cooled to room temperature, then open the autoclave, take out the formed magnetic nanoparticles suspension. The speed is set to 200 rad / min, the hydrothermal temperature is 350℃, and the holding time is 6 hours;

[0058] Fifth step, post-processing. The magnetic nanoparticles suspension obtained in the fourth step is repeatedly washed with deionized water and anhydrous ethanol several times until it is neutral. After washing, the obtained precipitate is vacuum dried at a temperature of 80℃ for 6 hours, and then naturally cooled to room temperature. The obtained magnetic solid is ground with a jade mortar to obtain magnetic nanoparticles.

[0059] Iodine-coated silver rod preparation process:

[0060] ①Halogenation: Move the silver particles and the mixed solution of hydrochloric acid and sodium chlorate into the reaction bottle, rotate the reaction for about 2 hours, take out the halogenated silver particles and dry them.

[0061] ②Coating core: Put the dried silver particles into the reaction bottle, move KI-NaOH solution, iodine [125I] source and NaOH solution into the reaction bottle, react for 10-18 hours. After the reaction is completed, take out the radioactive silver particles and dry them.

[0062] Titanium shell and titanium shell cover are prepared by mechanical processing:

[0063] After the preparation of magnetic nanoparticles, iodine-coated silver rods, titanium shells and titanium shell covers, the magnetic and radioactive composite particles are assembled. As shown in Figure 2, a. Install the titanium shell in the groove of the magnetic base, then fill the magnetic and thermal nanoparticles at the bottom of the titanium shell. Due to the influence of the magnetic base, the magnetic and thermal nanoparticles are adsorbed at the bottom of the titanium shell; b. Put the iodine-coated silver rod into the titanium shell; c. Continue to fill the magnetic and thermal nanoparticles until the iodine-coated silver rod is completely wrapped and the inner cavity of the titanium shell is completely filled; d. Install the titanium shell cover at the gap of the titanium shell, and weld or glue to seal the composite particles. After the assembly of the magnetic and radioactive composite particles is completed, the welding or glue will exist on the surface of the titanium shell, so the surface of the composite particles needs to be polished.

[0064] For the convenience of verification, the present application selects the magnetic heat radioactive composite particles with a particle size of 0.8 mm and a length of 4.5 mm; the material of the surrounding layer is titanium; the thickness of the surrounding layer is 0.1 mm; the ratio between the volume of the containing area and the volume of the iodine-coated silver rod is 7.2:1; the filling degree of the magnetic heat nanoparticles in the containing area is 100%, and generally, the iodine-coated silver rod is located at the center position; the particle size of the magnetic heat nanoparticles is 13.3 nm.

[0065] Verification Example One: The composite particles have both magnetic heat treatment and radioactive treatment functions, and the killing and inhibiting effect on the diseased cells is better

[0066] Under the condition that other conditions are the same, as shown in Table 1, the magnetic heat nanoparticles are loaded in the titanium shell alone to perform magnetic heat treatment; the iodine-coated silver rod is loaded in the titanium shell alone to perform radioactive treatment; and the combination of the magnetic heat nanoparticles and the radioactive particles of the iodine-coated silver rod improves the killing range (radius) relative to the single magnetic heat nanoparticle.

[0067] Table 1

[0068]

[0069] Verification Example Two: The required interventional magnetic medium particles are concentrated in the titanium shell, which can reduce the toxic side effects while ensuring effective treatment

[0070] Under the condition that other conditions are the same, as shown in Table 2, the magnetic medium particles are concentrated in the titanium shell, which can reduce the toxic side effects while ensuring effective treatment.

[0071] Table 2

[0072]

[0073] Verification Example Three:

[0074] Under the condition that other conditions are the same, the magnetic heat nanoparticles are loaded in the titanium shell alone, as shown in Table 3, wherein the titanium shell only loads the magnetic heat nanoparticles, and the killing range (radius) is 1.8 mm; and the killing range (radius) of the structure of the present application is 2.4 mm, that is, the combination of the magnetic heat nanoparticles and the radioactive particles of the iodine-coated silver rod improves the killing range (radius) relative to the single magnetic heat nanoparticle.

[0075] Table 3

[0076]

[0077] Verification Example Four:

[0078] Under the same conditions, as shown in Table 4, the structure of the present application, but the filling degree of the magnetic nano-particles is different; the higher the filling degree, the greater the killing range (radius) and the higher the heat production efficiency (J / S).

[0079] Table 4

[0080]

[0081] In the description of the present specification, the description referring to the terms "one embodiment", "an example", "a specific example" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present disclosure. In the present specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Also, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0082] The basic principles, main features and advantages of the present disclosure are shown and described above. It should be understood by those skilled in the art that the present disclosure is not limited by the above embodiments, and the above embodiments and descriptions in the specification are only to illustrate the principles of the present disclosure. Without departing from the spirit and scope of the present disclosure, various changes and improvements of the present disclosure can be made, and these changes and improvements all fall within the scope of the claimed present disclosure.

Claims

1. A magnetocalorically active radioactive composite particle comprising a surrounding layer, characterized in that The iodine-coated silver rod is wrapped in the surrounding layer, and a containing area exists between the surrounding layer and the iodine-coated silver rod, and the containing area is filled with magnetic heat nanoparticles; the iodine-coated silver rod is in the middle of the containing area.

2. The magnetocalorically active radioactive composite particle according to claim 1, characterized in that The magnetic heat radioactive composite particle has a particle size of 0.8 mm and a length of 4.5 mm.

3. The magnetocalorically active radioactive composite particle according to claim 1, characterized in that The surrounding layer is made of one of titanium, stainless steel and ceramic.

4. The magnetocalorically active radioactive composite particle according to claim 1, characterized in that The thickness of the surrounding layer is 0.05-0.1 mm.

5. The magnetocalorically active radioactive composite particle according to claim 1, characterized in that The volume ratio between the containing area and the iodine-coated silver rod is 6:1-12:

1.

6. The magnetocalorically active radioactive composite particle according to claim 1, characterized in that The filling degree of the magnetic heat nanoparticles in the containing area is greater than or equal to 70%.

7. The magnetocalorically active radioactive composite particle according to claim 1, characterized in that The particle size of the magnetic heat nanoparticles is 10-300 nm.

8. The magnetocalorically active radioactive composite particle according to claim 1, characterized in that The magnetic heat nanoparticles comprise: dissolving NaOH into deionized water, stirring to completely dissolve, forming an alkaline solution with a concentration of 3.5-4.5 mol as a precipitant; 6.3-6.5 parts by weight of FeCl3·6H2O, 2.3-2.5 parts by weight of CrCl3·6H2O, 1.7-1.9 parts by weight of CoCl2·6H2O and 1.1-1.3 parts by weight of ZnCl2 are dissolved into 78-85 parts by weight of deionized water to form a metal salt ion solution; The precipitant is slowly added drop by drop into the metal salt ion solution at room temperature to perform a preliminary co-precipitation reaction to generate a precursor suspension; the mixed solution needs to be continuously stirred during the addition of the precipitant to make the solution uniform; The precursor suspension is moved into a high-pressure kettle for sealing, and the rotation speed and hydrothermal temperature are set before heating starts; after the temperature in the high-pressure kettle rises to the set heating temperature, the temperature is maintained at the set temperature for 6 hours, and then the high-pressure kettle is opened, and the formed magnetic nanoparticle suspension is taken out; the rotation speed of the high-pressure kettle is set to 200 rad / min, and the hydrothermal temperature is 350℃. The obtained magnetic nanoparticle suspension is washed to neutral; After the washing is completed, the obtained precipitate is vacuum dried at a temperature of 80℃ for 6 hours, and then naturally cooled to room temperature to obtain a magnetic solid; the magnetic solid is fully ground to obtain magnetic nanoparticles.

9. A method of producing the magnetocalorically active radioactive composite particles according to any one of claims 1 to 8, characterized in that It comprises: The surrounding layer is placed in the groove of the magnetic base, and then the containing area is filled with magnetic heat nanoparticles at the bottom; The iodine-coated silver rod is placed in the containing area; Continue to fill the magnetic heat nanoparticles until the iodine-coated silver rod is completely wrapped and the containing area of the titanium shell is completely filled; and the surrounding layer is closed.

10. The method of claim 9, wherein, It comprises: The titanium shell is placed in the groove of the magnetic base; the containing area is filled with magnetic heat nanoparticles at the bottom; Continue to fill the magnetic heat nanoparticles until the iodine-coated silver rod is completely wrapped and the inner cavity of the titanium shell is completely filled; The titanium shell cover is installed at the gap of the titanium shell for packaging.

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