Radioactive silica microspheres wrapped in biomedical polymer materials, preparation method and application thereof

Abstract

The present invention belongs to the field of biomedicine and provides radioactive silica microspheres coated with biomedical polymer materials, as well as a preparation method and application thereof. The method comprises the following steps: S1, mixing silica microspheres, water, and a radioactive nuclide to obtain a radioactive silica microsphere mixture; S2, mixing the radioactive silica microsphere mixture with an alkaline solution and reacting to obtain radioactive silica microspheres; S3, mixing the radioactive silica microspheres with a biomedical polymer solution and coating the mixture to obtain radioactive silica microspheres coated with biomedical polymer materials. The preparation method provided by the present invention is simple, and the prepared radioactive silica microspheres coated with biomedical polymer materials have a high radionuclide labeling rate, a low escape rate, good radiostability, and excellent biosafety, and can be used for the embolization treatment of all solid tumors.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to radioactive silica microspheres wrapped with biomedical polymer materials, and a preparation method and application thereof. Background Art

[0002] Liver cancer is a life-threatening disease. Currently, treatments for liver cancer primarily include surgery, chemotherapy, and radiotherapy. However, most liver cancer patients are diagnosed in the advanced stages of the disease, making surgical treatment ineligible and missing the optimal time for surgical treatment. Transcatheter arterial chemoembolization (TACE) often yields unsatisfactory results, while the dose of external beam radiotherapy is severely limited, making it difficult to control tumor progression. Radioactive microsphere embolization has become a popular research technique because it has minimal effects on normal tissue, only targeting tumor tissue, and offers high precision in drug delivery.

[0003] Currently, some clinical applications use 90Y glass microspheres, which are produced through reactor activation, a complex and difficult process. The radionuclide stability and biocompatibility of 90Y resin microspheres still need to be improved. Therefore, simplifying the preparation of radioactive microspheres and improving their biocompatibility and radiostability are urgent issues to be addressed.

[0004] Biomedical polymers are a class of polymers with excellent biocompatibility and high safety, and are widely used in applied medicine. For example, poly(lactic-co-glycolic acid) is an FDA-approved biomedical polymer for human use. It is composed of lactic acid and glycolic acid monomers polymerized in a specific ratio. Its final degradation products in the body are carbon dioxide and water. It is non-toxic and has good biocompatibility. The polymer can be used to form a thin film on the surface of the microspheres, physically coating the radioactive microspheres and improving the stability of radionuclides. However, there is currently no mature theoretical research or practical technical solutions for encapsulating radioactive microspheres in biomedical polymers for use in the field of medical technology.

[0005] Therefore, how to provide a radioactive microsphere coated with a biomedical polymer material has become an urgent problem to be solved by those skilled in the art. Summary of the Invention

[0006] In view of this, the present invention provides a radioactive silica microsphere wrapped with a biomedical polymer material, a preparation method and an application thereof, the purpose of which is to improve the biocompatibility and radiostability of the radioactive microsphere.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] The present invention provides a method for preparing radioactive silica microspheres coated with biomedical polymer materials, comprising the following steps:

[0009] S1. mixing silica microspheres, water, and radioactive nuclides to obtain a radioactive nuclide silica microsphere mixture;

[0010] S2, mixing the radioactive nuclide silica microsphere mixture and the alkaline solution and reacting them to obtain radioactive silica microspheres;

[0011] S3. Mix the radioactive silica microspheres with a biomedical polymer material solution and then coat them to obtain radioactive silica microspheres coated with the biomedical polymer material.

[0012] Furthermore, in step S1, the mass volume ratio of silica microspheres to water is 0.001-1000 g: 0.1-1000 mL;

[0013] The mass activity ratio of silica microspheres and radionuclides is 0.001 to 1000 g: 1×10 -3 ~1×10 6 mCi;

[0014] The silica microspheres have a diameter of 20 to 500 μm and a density of 1.0 to 2.4 g / cm 3 .

[0015] Furthermore, in step S1, the mixing temperature is 0 to 100° C., and the mixing time is 1 to 100 minutes.

[0016] Furthermore, in step S1, the radionuclide is scandium 47 Sc, copper 64 Cu, copper 67 Cu, gallium 66 Ga, gallium 67 Ga, gallium 68 Ga, Yttrium 86 Y, yttrium 90 Y, zirconium 89 Zr, Strontium 89 Sr, technetium 99m Tc, palladium 109 Pd, Indium 111 In, terbium 149 Tb, terbium 161 Tb, Samarium 153 Sm, holmium 166 Ho, Lutetium 177 Lu, rhenium 186 Re, rhenium 188 Re, lead 212 Pb, bismuth 212 Bi, bismuth 213Bi, radium 223 Ra, Actinium 225 Ac, actinium 227 Ac, thorium 226 Th and thorium 227 One or more of Th.

[0017] Furthermore, in step S2, the reaction temperature is 0 to 100° C., and the reaction time is 1 to 100 min;

[0018] The mass volume ratio of the silica microspheres in step S1 to the alkaline solution in step S2 is 0.001-1000 g:0.001-100 mL.

[0019] Furthermore, in step S2, the concentration of the alkaline solution is 10 to 100 g / L;

[0020] The alkaline solution is one or more of sodium hydroxide solution, potassium hydroxide solution, ammonium oxalate solution, sodium carbonate solution, sodium bicarbonate solution, ammonia water, potassium carbonate solution, potassium bicarbonate solution, sodium sulfite solution, sodium acetate solution, sodium sulfide solution, sodium silicate solution, sodium phosphate solution, sodium metaaluminate solution, sodium hypochlorite solution, potassium sulfite solution, potassium acetate solution, calcium hydroxide solution and barium hydroxide solution.

[0021] Furthermore, in step S3, the concentration of the biomedical polymer material solution is 0.001 to 2 g / mL;

[0022] The biomedical polymer material is one or more of polylactic acid glycolic acid copolymer, cellulose, chitin, hyaluronic acid, collagen, gelatin, sodium alginate, polyurethane, polyester fiber, polyvinyl pyrrolidone, silicone rubber, polyvinyl alcohol, polylactic acid, polyethylene, polyacrylic acid, povidone, ethylene-vinyl acetate copolymer, polyethylene glycol, polyoxyethylene, polyorthoester, polyorthoacid, polyphosphazene, polyetheretherketone, polymethyl methacrylate, polypropylene, polyacrylate, aromatic polyester, aliphatic polyester, polyamino acid, polycaprolactone, poly-α-cyanoacrylate alkyl ester and dimethicone;

[0023] The solvent of the biomedical polymer material solution is one or more of dichloromethane, chloroform, tetrahydrofuran, acetone, benzene, toluene, xylene, pentane hexane, octane, cyclohexane, cyclohexanone, toluene cyclohexanone, chlorobenzene, dichlorobenzene, methanol, ethanol, isopropanol, ethyl ether, propylene oxide, methyl acetate, ethyl acetate, propyl acetate, methyl butyl ketone, methyl isobutyl ketone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetonitrile, pyridine and phenol.

[0024] Furthermore, in step S3, the coating temperature is 0 to 100° C., and the coating time is 1 to 100 minutes;

[0025] The mass volume ratio of the silica microspheres in step S1 to the biomedical polymer material solution in step S3 is 0.001-1000 g:0.1-1000 mL.

[0026] The present invention provides radioactive silica microspheres wrapped with biomedical polymer materials prepared by the above preparation method.

[0027] The present invention also provides the use of the radioactive silica microspheres coated with the biomedical polymer material in the preparation of medicines for treating tumor embolism.

[0028] It can be seen from the above technical solution that compared with the prior art, the beneficial effects of the present invention are as follows:

[0029] In the present invention, an alkaline solution is used to adjust the pH of the solution, thereby improving the labeling efficiency; by adjusting the concentration of the biomedical polymer material solution, the film thickness of the biomedical polymer material on the surface of the radioactive porous silica microspheres is adjusted, thereby adjusting the radioactivity; and the escape of α-nuclides and the radioactivity of individual microspheres can be controlled to meet the requirements of individualized precision treatment.

[0030] The radioactive silica microspheres coated with biomedical polymer materials prepared by the present invention are porous silica microspheres with lower density and stronger adsorption capacity. The adsorption rate of radionuclides reaches 100%, the utilization rate of radionuclides is high, and less radioactive waste is generated, which is beneficial to environmental protection. Compared with the existing technology, the product prepared by the present invention has higher radioactivity stability, the release rate of radionuclides in fetal bovine serum (FBS) is less than 1%, and the safety is better.

[0031] The preparation method of the present invention is simple, time-saving, introduces few impurities, has high product purity, and is easy to promote and apply. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The lutetium hydroxide prepared in Example 1 [ 177 Lu(OH)3] porous silica microspheres (MS) and poly (lactic-co-glycolic acid) coated lutetium hydroxide [ 177 Fourier transform infrared spectroscopy characterization of Lu(OH)3] porous silica microspheres (MS@PLGA);

[0033] Figure 2 The lutetium hydroxide prepared in Example 1 [ 177 Lu(OH)3] porous silica microspheres (MS) and poly (lactic-co-glycolic acid) coated lutetium hydroxide [ 177 Thermogravimetric analysis of Lu(OH)3] porous silica microspheres (MS@PLGA);

[0034] Figure 3 The lutetium hydroxide prepared in Example 1 [ 177 Optical microscopy images of Lu(OH)3] porous silica microspheres (MS), scale bar is 50 μm;

[0035] Figure 4 Lutetium hydroxide encapsulated by poly(lactic acid glycolic acid) prepared in Example 1 [ 177 Lu(OH)3] optical microscopy images of porous silica microspheres (MS@PLGA), scale bar is 50 μm;

[0036] Figure 5 The lutetium hydroxide prepared in Example 1 [ 177 Scanning electron micrograph of Lu(OH)3] porous silica microspheres (MS);

[0037] Figure 6 Lutetium hydroxide encapsulated by poly(lactic acid glycolic acid) prepared in Example 1 [ 177 Scanning electron micrograph of Lu(OH)3] porous silica microspheres (MS@PLGA);

[0038] Figure 7 The lutetium hydroxide prepared in Example 1 [ 177 Lu(OH)3] porous silica microspheres (MS) and poly (lactic-co-glycolic acid) coated lutetium hydroxide [ 177 Comparative diagram of the stability of Lu(OH)3] porous silica microspheres (MS@PLGA) in fetal bovine serum (FBS);

[0039] Figure 8 Actinium hydroxide coated with poly(lactic acid glycolic acid) copolymer of different concentrations prepared in Examples 2 to 5 and Comparative Example 1 225 Comparative chart of the stability of [Ac(OH)3] porous silica microspheres in fetal bovine serum (FBS). DETAILED DESCRIPTION

[0040] The present invention provides a method for preparing radioactive silica microspheres coated with biomedical polymer materials, comprising the following steps:

[0041] S1. mixing silica microspheres, water, and radioactive nuclides to obtain a radioactive nuclide silica microsphere mixture;

[0042] S2, mixing the radioactive nuclide silica microsphere mixture and the alkaline solution and reacting them to obtain radioactive silica microspheres;

[0043] S3. Mix the radioactive silica microspheres with a biomedical polymer material solution and then coat them to obtain radioactive silica microspheres coated with the biomedical polymer material.

[0044] In the present invention, in step S1, mixing is performed by oscillation, and the frequency of the oscillation is 200 to 2000 rpm, preferably 400 to 1600 rpm, and more preferably 600 to 1200 rpm.

[0045] In the present invention, in step S1, the mass volume ratio of silica microspheres to water is 0.001-1000 g:0.1-1000 mL, preferably 0.1-500 g:1-500 mL, and more preferably 1-100 g:5-100 mL;

[0046] The mass activity ratio of silica microspheres and radionuclides is 0.001 to 1000 g: 1×10 -3 ~1×10 6 mCi, preferably 0.1 to 500 g: 1×10 -2 ~1×10 5 mCi, more preferably 1 to 100 g: 1×10 -1 ~1×10 4 mCi;

[0047] The diameter of the silica microspheres is 20 to 500 μm, preferably 20 to 100 μm, and more preferably 20 to 50 μm; the density is 1.0 to 2.4 g / cm 3 , preferably 1.0 to 1.5 g / cm 3 , more preferably 1.0 to 1.3 g / cm 3 .

[0048] In the present invention, in step S1, the mixing temperature is 0-100° C., preferably 20-80° C., more preferably 40-60° C.; the mixing time is 1-100 min, preferably 10-90 min, more preferably 20-80 min.

[0049] In the present invention, in step S1, the radioactive nuclide is scandium 47 Sc, copper 64 Cu, copper 67 Cu, gallium 66 Ga, gallium 67 Ga, gallium 68 Ga, Yttrium 86 Y, yttrium 90 Y, zirconium 89 Zr, Strontium 89 Sr, technetium 99m Tc, palladium 109Pd, Indium 111 In, terbium 149 Tb, terbium 161 Tb, Samarium 153 Sm, holmium 166 Ho, Lutetium 177 Lu, rhenium 186 Re, rhenium 188 Re, lead 212 Pb, bismuth 212 Bi, bismuth 213 Bi, radium 223 Ra, Actinium 225 Ac, actinium 227 Ac, thorium 226 Th and thorium 227 One or more of Th, preferably scandium 47 Sc, copper 64 Cu, copper 67 Cu, gallium 66 Ga, gallium 67 Ga, gallium 68 Ga, Yttrium 86 Y, yttrium 90 Y, Lutetium 177 Lu, rhenium 186 Re, rhenium 188 Re, lead 212 Pb, bismuth 212 Bi, bismuth 213 Bi, radium 223 Ra, Actinium 225 Ac, actinium 227 Ac, thorium 226 Th and thorium 227 One or more of Th, more preferably scandium 47 Sc, copper 64 Cu, gallium 67 Ga, gallium 68 Ga, Yttrium 86 Y, yttrium 90 Y, Lutetium 177 Lu, rhenium 186 Re, rhenium 188 Re, lead 212 Pb, bismuth 212 Bi, bismuth 213 Bi, radium 223 Ra, Actinium 225 Ac, actinium 227 Ac, thorium 226 Th and thorium 227 One or more of Th.

[0050] In the present invention, in step S2, the reaction temperature is 0-100°C, preferably 20-80°C, more preferably 40-60°C; the reaction time is 1-100 min, preferably 10-90 min, more preferably 20-80 min.

[0051] In the present invention, in step S2, the reaction pH is 7-14, preferably 8-12, and more preferably 9-10.

[0052] In the present invention, the mass volume ratio of the silica microspheres in step S1 to the alkaline solution in step S2 is 0.001-1000 g:0.001-100 mL, preferably 0.01-800 g:0.01-80 mL, and more preferably 1-500 g:1-50 mL.

[0053] In the present invention, in step S2, the concentration of the alkaline solution is 10 to 100 g / L, preferably 20 to 80 g / L, and more preferably 40 to 60 g / L;

[0054] The alkaline solution is one or more of sodium hydroxide solution, potassium hydroxide solution, ammonium oxalate solution, sodium carbonate solution, sodium bicarbonate solution, ammonia water, potassium carbonate solution, potassium bicarbonate solution, sodium sulfite solution, sodium acetate solution, sodium sulfide solution, sodium silicate solution, sodium phosphate solution, sodium metaaluminate solution, sodium hypochlorite solution, potassium sulfite solution, potassium acetate solution, calcium hydroxide solution and barium hydroxide solution, preferably one or more of sodium hydroxide solution, potassium hydroxide solution, ammonium oxalate solution, sodium carbonate solution, calcium hydroxide solution and barium hydroxide solution, further preferably one or more of sodium hydroxide solution, potassium hydroxide solution, ammonium oxalate solution, sodium carbonate solution and barium hydroxide solution.

[0055] In the present invention, after the reaction in step S2 is completed, centrifugation is performed, and the obtained solid is washed with water. The centrifugal speed is 1000-14000 rpm, preferably 2000-12000 rpm, and more preferably 5000-10000 rpm; the centrifugal time is 1-30 min, preferably 5-25 min, and more preferably 10-20 min. The number of washings is 2-5 times, and preferably 3-4 times.

[0056] In the present invention, in step S3, the concentration of the biomedical polymer material solution is 0.001 to 2 g / mL, preferably 0.1 to 1.5 g / mL, and more preferably 1 to 1 g / mL;

[0057] The biomedical polymer material is one or more of polylactic acid glycolic acid copolymer, cellulose, chitin, hyaluronic acid, collagen, gelatin, sodium alginate, polyurethane, polyester fiber, polyvinyl pyrrolidone, silicone rubber, polyvinyl alcohol, polylactic acid, polyethylene, polyacrylic acid, povidone, ethylene-vinyl acetate copolymer, polyethylene glycol, polyoxyethylene, polyorthoester, polyorthoacid, polyphosphazene, polyetheretherketone, polymethyl methacrylate, polypropylene, polyacrylate, aromatic polyester, aliphatic polyester, polyamino acid, polycaprolactone, poly-α-cyanoacrylate alkyl ester and dimethicone, preferably Selected from one or more of polylactic acid glycolic acid copolymer, cellulose, chitin, hyaluronic acid, collagen, gelatin, sodium alginate, polyurethane, polyester fiber, polyvinyl pyrrolidone, silicone rubber, polyvinyl alcohol, polylactic acid, polyethylene, polyacrylic acid, povidone, ethylene-vinyl acetate copolymer, polyethylene glycol, polyoxyethylene, and dimethicone, more preferably one or more of polylactic acid glycolic acid copolymer, cellulose, silicone rubber, polyvinyl alcohol, polylactic acid, polyethylene, polyacrylic acid, povidone, ethylene-vinyl acetate copolymer, polyethylene glycol, polyoxyethylene, and dimethicone;

[0058] The solvent of the biomedical polymer material solution is one or more of dichloromethane, chloroform, tetrahydrofuran, acetone, benzene, toluene, xylene, pentane hexane, octane, cyclohexane, cyclohexanone, toluene cyclohexanone, chlorobenzene, dichlorobenzene, methanol, ethanol, isopropanol, ether, propylene oxide, methyl acetate, ethyl acetate, propyl acetate, methyl butyl ketone, methyl isobutyl ketone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetonitrile, pyridine and phenol, preferably dichloromethane, tetrahydrofuran, acetone, benzene, toluene, xylene, One or more of pentane hexane, methanol, ethanol, isopropanol, diethyl ether, propylene oxide, methyl acetate, ethyl acetate, propyl acetate, methyl butyl ketone, methyl isobutyl ketone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetonitrile, pyridine and phenol, and more preferably one or more of dichloromethane, tetrahydrofuran, toluene, xylene, pentane hexane, methanol, ethanol, isopropanol, diethyl ether, propylene oxide, methyl acetate, methyl isobutyl ketone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetonitrile, pyridine and phenol.

[0059] In the present invention, in step S3, the coating temperature is 0-100°C, preferably 20-80°C, more preferably 40-60°C; the coating time is 1-100 min, preferably 10-90 min, more preferably 20-80 min.

[0060] In the present invention, after the coating in step S3 is completed, centrifugation is performed, and the obtained solid is washed with water. The centrifugal speed is 1000-14000 rpm, preferably 2000-12000 rpm, and more preferably 5000-10000 rpm; the centrifugal time is 1-30 min, preferably 5-25 min, and more preferably 10-20 min. The number of washings is 2-5 times, and preferably 3-4 times.

[0061] In the present invention, the mass volume ratio of the silica microspheres in step S1 to the biomedical polymer material solution in step S3 is 0.001-1000 g:0.1-1000 mL, preferably 0.01-100 g:1-800 mL, and more preferably 0.1-80 g:10-500 mL.

[0062] The present invention provides radioactive silica microspheres wrapped with biomedical polymer materials prepared by the above preparation method.

[0063] The present invention also provides the use of the radioactive silica microspheres coated with the above-mentioned biomedical polymer material in the preparation of a drug for treating tumor embolism. The tumors include lung cancer, gastric cancer, esophageal cancer, liver cancer, colorectal cancer, breast cancer, cervical cancer, pancreatic cancer, thyroid cancer, lymphoma, bladder cancer, kidney cancer, uterine corpus cancer, prostate cancer, ovarian cancer, skin cancer, nasopharyngeal cancer, gallbladder cancer, lip and oral cancer, laryngeal cancer, testicular cancer, osteosarcoma and chondrosarcoma.

[0064] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0065] Example 1

[0066] 10 mg of porous silica microspheres were dispersed in 0.5 mL of pure water and 0.1 mCi of 177 LuCl3 solution was mixed in a thermomixer at 25°C for 5 min to prepare a radionuclide silica microsphere mixture;

[0067] 40g of sodium hydroxide solid was dissolved in 1L of deionized water to prepare a sodium hydroxide solution with a pH of 14. 120mg of poly(lactic-co-glycolic acid) copolymer was dissolved in 5mL of dichloromethane to prepare a dichloromethane solution of poly(lactic-co-glycolic acid) copolymer with a concentration of 24mg / mL. 0.1mL of sodium hydroxide solution was added dropwise to the above radioactive nuclide silica microsphere mixture, reacted at 20°C for 30min, centrifuged at 5000rpm for 20min, and after solid-liquid separation, washed with pure water 3 times. After solid-liquid separation, radioactive silica microspheres were obtained; the radioactivity of the radioactive silica microspheres was measured using a radioactivity meter. Lutetium hydroxide [ 177 The adsorption rate of Lu(OH)3] silica microspheres for lutetium-177 reached 100%.

[0068] The prepared radioactive porous silica microspheres were evenly dispersed in 1 mL of 24 mg / mL poly(lactic-co-glycolic acid) copolymer dichloromethane solution, coated at 25 °C for 5 min, centrifuged at 8000 rpm for 30 min, and then washed with pure water three times after solid-liquid separation. After solid-liquid separation, poly(lactic-co-glycolic acid) copolymer-encapsulated lutetium hydroxide was obtained. 177 Lu(OH)3] porous silica microspheres.

[0069] Example 2

[0070] In this embodiment, 1 μCi 225 The AcCl3 solution replaces the 0.1 mCi in Example 1. 177 LuCl3 solution, prepared poly (lactic acid glycolic acid copolymer) coated with actinium hydroxide [ 225 Ac(OH)3] porous silica microspheres, and other steps are the same as in Example 1.

[0071] Example 3

[0072] In this example, the concentration of the dichloromethane solution of poly(lactic-co-glycolic acid) copolymer was adjusted to 12 mg / mL to prepare poly(lactic-co-glycolic acid) copolymer-encapsulated actinium hydroxide [ 225 Ac(OH)3] porous silica microspheres, and other steps are the same as in Example 2.

[0073] Example 4

[0074] In this example, the concentration of the dichloromethane solution of poly(lactic-co-glycolic acid) copolymer was adjusted to 6 mg / mL to prepare poly(lactic-co-glycolic acid) copolymer-encapsulated actinium hydroxide [ 225 Ac(OH)3] porous silica microspheres, and other steps are the same as in Example 2.

[0075] Example 5

[0076] In this example, the concentration of the dichloromethane solution of poly(lactic-co-glycolic acid) copolymer was adjusted to 3 mg / mL to prepare poly(lactic-co-glycolic acid) copolymer-encapsulated actinium hydroxide [ 225 Ac(OH)3] porous silica microspheres, and other steps are the same as in Example 2.

[0077] Example 6

[0078] This example uses 100 μCi 90 YCl3 solution replaces 0.1mCi in Example 1 177 LuCl3 solution, prepared poly (lactic acid glycolic acid copolymer) coated yttrium hydroxide [ 90 The other steps are the same as those in Example 1. The radioactivity of the radioactive silica microspheres is measured by radioactivity meter. 90 The adsorption rate of yttrium-90 by silica microspheres [Y(OH)3] reached 100%.

[0079] Comparative Example 1

[0080] This example does not use biomedical polymer material solution to prepare actinium hydroxide [ 225 Ac(OH)3] porous silica microspheres, and other steps are the same as in Example 2.

[0081] Performance Characterization

[0082] Infrared spectrum: The powdered lutetium hydroxide prepared in Example 1 [ 177 Lu(OH)3] porous silica microspheres and poly (lactic-co-glycolic acid) coated lutetium hydroxide [ 177 Lu(OH)3] porous silica microspheres were placed on the sample stage of the Fourier transform infrared spectrometer and the infrared spectrum was measured. Figure 1 As shown, poly (lactic-co-glycolic acid)-coated lutetium hydroxide [ 177 Lu(OH)3] porous silica microspheres have both poly (lactic acid glycolic acid copolymer) and lutetium hydroxide [ 177 characteristic peaks of porous silica microspheres.

[0083] Thermogravimetric analysis: The powdered lutetium hydroxide prepared in Example 1 [ 177 Lu(OH)3] porous silica microspheres and poly (lactic-co-glycolic acid) coated lutetium hydroxide [ 177 Lu(OH)3] porous silica microspheres were placed in crucibles, and the crucibles were placed in a synchronous thermal analyzer for thermogravimetric analysis. The results are shown in Figure 2. Figure 2 As shown, with lutetium hydroxide [ 177 Compared with porous silica microspheres, poly (lactic acid glycolic acid copolymer)-encapsulated lutetium hydroxide [177 The quality of Lu(OH)3 porous silica microspheres decreases significantly in the range of 280-360℃.

[0084] Optical microscope: The powdered lutetium hydroxide prepared in Example 1 [ 177 Lu(OH)3] porous silica microspheres and poly (lactic-co-glycolic acid) coated lutetium hydroxide [ 177 Lu(OH)3] porous silica microspheres were placed on glass slides and observed using an optical microscope. Figures 3-4 As shown, there is no obvious change in the appearance of the microspheres, and all of them are monodispersed microspheres.

[0085] Scanning electron microscope: The powdered lutetium hydroxide prepared in Example 1 [ 177 Lu(OH)3] porous silica microspheres and poly (lactic-co-glycolic acid) coated lutetium hydroxide [ 177 Lu(OH)3] porous silica microspheres were placed on the electron microscope table and observed using a scanning electron microscope. The results are as follows Figures 5-6 As shown, there is no obvious change in the appearance of the microspheres, and all of them are monodispersed microspheres.

[0086] In vitro stability: The lutetium hydroxide prepared in Example 1 [ 177 Lu(OH)3] porous silica microspheres and poly (lactic-co-glycolic acid) coated lutetium hydroxide [ 177 Lu(OH)3] porous silica microspheres were soaked in fetal bovine serum (FBS) and the radioactivity of the microspheres was measured using a γ-radioimmunoassay counter after solid-liquid separation at 2, 4, 24, 48, and 96 hours. Figure 7 As shown, within 96 hours, lutetium hydroxide [ 177 The release rate of lutetium-177 from porous silica microspheres in fetal bovine serum (FBS) was nearly 20%, and the release rate of lutetium hydroxide [ 177 The release rate of lutetium-177 from porous silica microspheres prepared from Lu(OH)3 in fetal bovine serum (FBS) was less than 2%, and the radiostability of the microspheres was significantly improved.

[0087] In vitro stability: The products prepared in Examples 2 to 5 and Comparative Example 1 were soaked in fetal bovine serum (FBS) and the radioactivity of the microspheres was measured using a γ-radioimmunoassay counter after solid-liquid separation at 2, 4, 24, 48, 96, and 192 hours. The results are shown in Table 1. Figure 8 As shown, within 192 hours, poly (lactic acid co-glycolic acid)-coated actinium hydroxide [ 225The lowest actinium-225 release rate of poly(Ac(OH)3) porous silica microspheres in fetal bovine serum (FBS) was about 17%. With the increase of poly(lactic-co-glycolic acid) concentration, the radiostability of the microspheres was significantly improved, and the escape of daughter nuclides was reduced.

[0088] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referenced to each other.

[0089] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing radioactive silica microspheres coated with biomedical polymer materials, characterized in that: The following steps are involved: S1. mixing silica microspheres, water, and radioactive nuclides to obtain a radioactive nuclide silica microsphere mixture; S2, mixing the radioactive nuclide silica microsphere mixture and the alkaline solution and reacting them to obtain radioactive silica microspheres; S3, mixing the radioactive silica microspheres with a biomedical polymer material solution and then coating the mixture to obtain radioactive silica microspheres coated with the biomedical polymer material; In step S1, the mass volume ratio of silica microspheres to water is 0.001-1000 g:0.1-1000 mL; The mass volume ratio of the silica microspheres in step S1 to the biomedical polymer material solution in step S3 is 0.001-1000 g: 0.1-1000 mL; In step S1, the mass activity ratio of the silica microspheres to the radioactive nuclides is 0.001 to 1000 g: 1×10 -3 ~1×10 6 mCi; The silica microspheres have a diameter of 20 to 500 μm and a density of 1.0 to 2.4 g / cm 3 ; In step S3, the concentration of the biomedical polymer material solution is 0.001-2 g / mL, the biomedical polymer material is poly(lactic acid co-glycolic acid), and the solvent of the biomedical polymer material solution is dichloromethane.

2. The preparation method according to claim 1, characterized in that In the step S1, the mixing temperature is 0 to 100° C., and the mixing time is 1 to 100 minutes.

3. The preparation method according to claim 1 or 2, characterized in that In step S1, the radioactive nuclide is one or more of scandium 47Sc, copper 64Cu, copper 67Cu, gallium 66Ga, gallium 67Ga, gallium 68Ga, yttrium 86Y, yttrium 90Y, zirconium 89Zr, strontium 89Sr, technetium 99mTc, palladium 109Pd, indium 111In, terbium 149Tb, terbium 161Tb, samarium 153Sm, holmium 166Ho, lutetium 177Lu, rhenium 186Re, rhenium 188Re, lead 212Pb, bismuth 212Bi, bismuth 213Bi, radium 223Ra, actinium 225Ac, actinium 227Ac, ​​thorium 226Th and thorium 227Th.

4. The preparation method according to claim 3, characterized in that In step S2, the reaction temperature is 0 to 100° C., and the reaction time is 1 to 100 minutes; The mass volume ratio of the silica microspheres in step S1 to the alkaline solution in step S2 is 0.001-1000 g:0.001-100 mL.

5. The preparation method according to claim 1 or 4, characterized in that In step S2, the concentration of the alkaline solution is 10 to 100 g / L; The alkaline solution is one or more of sodium hydroxide solution, potassium hydroxide solution, ammonium oxalate solution, sodium carbonate solution, sodium bicarbonate solution, ammonia water, potassium carbonate solution, potassium bicarbonate solution, sodium sulfite solution, sodium acetate solution, sodium sulfide solution, sodium silicate solution, sodium phosphate solution, sodium metaaluminate solution, sodium hypochlorite solution, potassium sulfite solution, potassium acetate solution, calcium hydroxide solution and barium hydroxide solution.

6. The preparation method according to claim 5, characterized in that In step S3, the coating temperature is 0-100° C., and the coating time is 1-100 minutes.

7. Radioactive silica microspheres coated with biomedical polymer materials prepared by the preparation method according to any one of claims 1 to 6.

8. Use of the radioactive silica microspheres coated with the biomedical polymer material according to claim 7 in the preparation of a drug for treating tumor embolism.

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