CN115920088A - Biomedical polymer material-coated radioactive silica microsphere and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of biomedicine, and provides a radioactive silicon dioxide microsphere wrapped with a biomedical polymer material, a preparation method and application thereof. The method comprises the following steps: S1, mixing the silica microspheres, water and radionuclide to obtain a radionuclide silica microsphere mixture; S2, mixing the radionuclide silica microsphere mixture with an alkaline solution Then carry out the reaction to obtain radioactive silica microspheres; S3, mix the radioactive silica microspheres with the biomedical polymer material solution, and then coat the radioactive silica microspheres to obtain biomedical polymer material-coated radioactive silica microspheres. The preparation method provided by the present invention is simple, and the prepared radioactive silica microspheres wrapped in biomedical polymer materials have high nuclide labeling rate, low escape rate, good radiation stability and good biological safety, and can be used for all solid tumors Treatment of embolism.

Description

A kind of radioactive silica microsphere wrapped by biomedical polymer material and its preparation method and application

technical field

The invention relates to the technical field of biomedicine, in particular to a radioactive silicon dioxide microsphere wrapped with a biomedical polymer material and a preparation method and application thereof.

Background technique

Liver cancer is one of the diseases that threaten human life and health. At present, the treatment methods for liver cancer mainly include surgery, chemotherapy, and radiotherapy. However, most patients with liver cancer are already at an advanced stage when they are diagnosed, and surgery cannot be used, and the best time for surgical treatment has been missed. However, the therapeutic effect of hepatic arterial chemoembolization is often unsatisfactory, and the dose of external beam radiotherapy is very limited, making it difficult to control tumor progression. Because radioactive microsphere embolization has little effect on normal tissues, only has a lethal effect on tumor tissues, and has high drug delivery accuracy, it has become one of the popular research techniques.

At present, 90Y glass microspheres are used in some clinics, which are prepared by reactor activation, and the preparation process is difficult and complicated. The nuclide stability and biocompatibility of 90Y resin microspheres need to be improved. Therefore, simplifying the preparation of radioactive microspheres and improving the biocompatibility and radiostability of radioactive microspheres are urgent problems to be solved.

Biomedical polymer materials (Biomedical materials) are a kind of polymer materials with good biocompatibility and high safety, which are widely used in the field of applied medicine. For example, poly(lactic-co-glycolic acid) is a biomedical polymer material approved by the FDA that can be used in the human body. Lactic acid and glycolic acid monomers are polymerized in a specific ratio, and the final degradation products in the body are carbon dioxide and water, which are non-toxic. Side effects, good biocompatibility, can improve the stability of radionuclides by forming a thin film on the surface of microspheres with polymers and physically coating radioactive microspheres. However, there are no mature theoretical studies and practical technical solutions for encapsulating radioactive microspheres in biomedical polymer materials for use in the field of medical technology.

Therefore, how to provide a radioactive microsphere wrapped with a biomedical polymer material has become an urgent problem to be solved by those skilled in the art.

Contents of the invention

In view of this, the present invention provides a radioactive silicon dioxide microsphere wrapped with a biomedical polymer material and its preparation method and application, with the purpose of improving the biocompatibility and radiation stability of the radioactive microsphere.

In order to achieve the above object, the present invention adopts following technical scheme:

The invention provides a preparation method of radioactive silica microspheres wrapped by biomedical polymer materials, comprising the following steps:

S1. Mixing silica microspheres, water and radionuclides to obtain a mixture of radionuclide silica microspheres;

S2. Mix the mixture of radionuclide silica microspheres and alkaline solution to react to obtain radioactive silica microspheres;

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

Further, in the step S1, the mass volume ratio of silica microspheres and water is 0.001-1000g: 0.1-1000mL;

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

The silicon dioxide microspheres have a diameter of 20-500 μm and a density of 1.0-2.4 g/cm ³ .

Further, in the step S1, the mixing temperature is 0-100° C., and the mixing time is 1-100 min.

Further, in the step S1, the radionuclides are 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 ²¹³ Bi, radium ²²³ Ra, actinium ²²⁵ Ac, actinium ²²⁷ Ac, thorium ²²⁶ Th and thorium ²²⁷ Th.

Further, in the step S2, the reaction temperature is 0-100°C, and the reaction time is 1-100 min;

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.

Further, in the step S2, the concentration of the alkaline solution is 10-100 g/L;

Described alkaline solution is sodium hydroxide solution, potassium hydroxide solution, ammonium oxalate solution, sodium carbonate solution, sodium bicarbonate solution, ammoniacal liquor, potassium carbonate solution, potassium bicarbonate solution, sodium sulfite solution, sodium acetate solution, sodium sulfide solution , one or more of 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.

Further, in the step S3, the concentration of the biomedical polymer material solution is 0.001-2 g/mL;

The biomedical polymer material is poly(lactic-co-glycolic acid), cellulose, chitin, hyaluronic acid, collagen, gelatin, sodium alginate, polyurethane, polyester fiber, polyvinylpyrrolidone, silicone rubber, polyethylene Alcohol, polylactic acid, polyethylene, polyacrylic acid, povidone, ethylene-vinyl acetate copolymer, polyethylene glycol, polyoxyethylene, polyorthoester, polyorthoacid, polyphosphazene, polyether ether ketone, poly One or more of methyl methacrylate, polypropylene, polyacrylate, aromatic polyester, aliphatic polyester, polyamino acid, polycaprolactone, polyalkyl α-cyanoacrylate, and simethicone ;

The solvent of the biomedical polymer material solution is 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 butanone, methyl isobutyl ketone, ethylene glycol monomethyl One or more of ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetonitrile, pyridine and phenol.

Further, in the step S3, the coating temperature is 0-100°C, and the coating time is 1-100 min;

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

The invention provides radioactive silicon dioxide microspheres wrapped with biomedical polymer materials prepared by the above preparation method.

The present invention also provides the application of the radioactive silicon dioxide microspheres wrapped by the biomedical macromolecule material in the preparation of a drug for treating tumor embolism.

Via the above-mentioned technical scheme, it can be seen that compared with the prior art, the beneficial effects of the present invention are as follows:

In the present invention, the alkaline solution is used to adjust the pH of the solution, which improves 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 microsphere is adjusted, and then Adjust the radiation stability; and can control the escape of α nuclide progeny, and can also control the radioactivity of a single microsphere to meet the requirements of individualized precision treatment.

The radioactive silica microspheres wrapped by biomedical polymer materials prepared by the present invention are porous silica microspheres with lower density and stronger adsorption capacity; and the adsorption rate of radionuclides reaches 100%. Utilization rate is high, radioactive waste is produced few, is conducive to environmental protection; Compared with prior art, the radiation stability of the product prepared by the present invention is higher, and the release rate of radionuclide in fetal bovine serum (FBS) is lower than 1 %, better security.

The preparation method of the invention is simple, time-consuming, less impurities are introduced, the product has high purity, and is convenient for popularization and application.

Description of drawings

Figure 1 shows the lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres (MS) prepared in Example 1 and the lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres (MS) coated with poly(lactic-co-glycolic acid) copolymer. Fourier transform infrared spectrum characterization of silica microspheres (MS@PLGA);

Figure 2 shows the lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres (MS) prepared in Example 1 and the lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres wrapped by poly(lactic-co-glycolic acid) copolymer. Thermogravimetric analysis of silica microspheres (MS@PLGA);

Fig. 3 is the optical micrograph of the lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres (MS) prepared in Example 1, and the scale bar is 50 microns;

Fig. 4 is an optical micrograph of lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres (MS@PLGA) wrapped in poly(lactic-co-glycolic acid) prepared in Example 1, and the scale bar is 50 microns;

5 is a scanning electron micrograph of lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres (MS) prepared in Example 1;

6 is a scanning electron micrograph of lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres (MS@PLGA) wrapped in poly(lactic-co-glycolic acid) prepared in Example 1;

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

Fig. 8 is the actinium hydroxide [ ²²⁵ Ac(OH) ₃ ] porous silica microspheres coated with different concentrations of poly(lactic-co-glycolic acid) prepared in Examples 2-5 and Comparative Example 1 in fetal bovine serum (FBS) The stability comparison chart.

Detailed ways

The invention provides a preparation method of radioactive silica microspheres wrapped by biomedical polymer materials, comprising the following steps:

S1. Mixing silica microspheres, water and radionuclides to obtain a mixture of radionuclide silica microspheres;

S2. Mix the mixture of radionuclide silica microspheres and alkaline solution to react to obtain radioactive silica microspheres;

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

In the present invention, in the step S1, the mixing method is oscillating, and the frequency of the oscillating is 200-2000 rpm, preferably 400-1600 rpm, more preferably 600-1200 rpm.

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

The mass activity ratio of silica microspheres and radionuclides is 0.001-1000g: 1× ^10-3-1 ×10 ⁶ mCi, preferably 0.1-500g: 1× ^10-2-1 ×10 ⁵ mCi, further Preferably 1 to 100g: 1×10 ^-1 to 1×10 ⁴ mCi;

The silica microspheres have a diameter of 20-500 μm, preferably 20-100 μm, more preferably 20-50 μm; a density of 1.0-2.4 g/cm ³ , preferably 1.0-1.5 g/cm ³ , more preferably 1.0～1.3g/cm ³ .

In the present invention, in the step S1, the mixing temperature is 0-100°C, preferably 20-80°C, more preferably 40-60°C; the mixing time is 1-100min, preferably 10-90min, further Preferably it is 20 to 80 minutes.

In the present invention, in the step S1, the radionuclides are 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 One or more of ²¹² Bi, bismuth ²¹³ Bi, radium ²²³ Ra, actinium ²²⁵ Ac, actinium ²²⁷ Ac, thorium ²²⁶ Th and thorium ²²⁷ 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, One or more of actinium ²²⁷ Ac, thorium ²²⁶ Th and thorium ²²⁷ Th, more preferably scandium ⁴⁷ Sc, copper ⁶⁴ Cu, gallium ⁶⁷ Ga, gallium ⁶⁸ Ga, yttrium ⁸⁶ Y, yttrium ⁹⁰ Y, lutetium ¹⁷⁷ Lu, One or more of 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 Th.

In the present invention, in the step S2, the reaction temperature is 0-100°C, preferably 20-80°C, more preferably 40-60°C; the reaction time is 1-100min, preferably 10-90min, further Preferably it is 20 to 80 minutes.

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

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

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

Described alkaline solution is sodium hydroxide solution, potassium hydroxide solution, ammonium oxalate solution, sodium carbonate solution, sodium bicarbonate solution, ammoniacal liquor, potassium carbonate solution, potassium bicarbonate solution, sodium sulfite solution, sodium acetate solution, sodium sulfide solution , one or more of 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 sodium hydroxide solution, potassium hydroxide solution, ammonium oxalate solution, sodium carbonate solution, calcium hydroxide solution and barium hydroxide solution, more preferably sodium hydroxide solution, potassium hydroxide solution, ammonium oxalate solution, carbonate One or more of sodium solution and barium hydroxide solution.

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

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

The biomedical polymer material is poly(lactic-co-glycolic acid), cellulose, chitin, hyaluronic acid, collagen, gelatin, sodium alginate, polyurethane, polyester fiber, polyvinylpyrrolidone, silicone rubber, polyethylene Alcohol, polylactic acid, polyethylene, polyacrylic acid, povidone, ethylene-vinyl acetate copolymer, polyethylene glycol, polyoxyethylene, polyorthoester, polyorthoacid, polyphosphazene, polyether ether ketone, poly One or more of methyl methacrylate, polypropylene, polyacrylate, aromatic polyester, aliphatic polyester, polyamino acid, polycaprolactone, polyalkyl α-cyanoacrylate, and simethicone , preferably polylactic-co-glycolic acid, cellulose, chitin, hyaluronic acid, collagen, gelatin, sodium alginate, polyurethane, polyester fiber, polyvinylpyrrolidone, silicone rubber, polyvinyl alcohol, polylactic acid, One or more of polyethylene, polyacrylic acid, povidone, ethylene-vinyl acetate copolymer, polyethylene glycol, polyoxyethylene, and simethicone, more preferably polylactic-co-glycolic acid copolymer, cellulose , silicone rubber, polyvinyl alcohol, polylactic acid, polyethylene, polyacrylic acid, povidone, ethylene-vinyl acetate copolymer, polyethylene glycol, polyoxyethylene, and one or more of simethicone;

The solvent of the biomedical polymer material solution is 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 butanone, methyl isobutyl ketone, ethylene glycol monomethyl One or more of ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetonitrile, pyridine and phenol, preferably dichloromethane, tetrahydrofuran, acetone, benzene, toluene, xylene, pentane hexane , methanol, ethanol, isopropanol, ether, propylene oxide, methyl acetate, ethyl acetate, propyl acetate, methyl butanone, methyl isobutyl ketone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether , ethylene glycol monobutyl ether, acetonitrile, pyridine and phenol, more preferably dichloromethane, tetrahydrofuran, toluene, xylene, pentane hexane, methanol, ethanol, isopropanol, ether One or more of propylene oxide, methyl acetate, methyl isobutyl ketone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetonitrile, pyridine and phenol.

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

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

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 0.001-1000g: 0.1-1000mL, preferably 0.01-100g: 1-800mL, more preferably 0.1-80g: 10-500mL.

The invention provides radioactive silicon dioxide microspheres wrapped with biomedical polymer materials prepared by the above preparation method.

The present invention also provides the application of the above-mentioned radioactive silica microspheres coated with biomedical polymer materials in the preparation of drugs for the treatment of 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 body cancer, prostate cancer, ovarian cancer, skin cancer, nasopharyngeal cancer, gallbladder cancer, lip and mouth cancer, laryngeal cancer, testicular cancer, osteosarcoma and chondrosarcoma.

The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present invention, but not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Example 1

Disperse 10 mg of porous silica microspheres in 0.5 mL of pure water, add 0.1 mCi of ¹⁷⁷ LuCl ₃ solution, and mix in a constant temperature mixer for 5 minutes at 25 ° C to prepare a mixture of radionuclide silica microspheres;

Dissolve 40 g of solid sodium hydroxide in 1 L of deionized water to prepare a sodium hydroxide solution with a pH of 14. Dissolve 120 mg of poly(lactic-co-glycolic acid) in 5 mL of dichloromethane to prepare a solution of poly(lactic-co-glycolic acid) with a concentration of 24 mg/mL in dichloromethane. Add 0.1 mL of sodium hydroxide solution dropwise to the radionuclide silica microsphere mixture, react at 20°C for 30 minutes, centrifuge at 5000 rpm for 20 minutes, and wash with pure water for 3 times after solid-liquid separation , after solid-liquid separation, the radioactive silica microspheres were prepared; the radioactivity of the radioactive silica microspheres was measured with a radioactivity meter, and the lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] silica microspheres were The adsorption rate of lutetium-177 reaches 100%.

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

Example 2

In this example, 1 μCi of ²²⁵ AcCl ₃ solution was used to replace the 0.1 mCi of ¹⁷⁷ LuCl ₃ solution in Example 1 to prepare poly(lactic-co-glycolic acid)-coated actinium hydroxide [ ²²⁵ Ac(OH) ₃ ] porous silica microparticles. Ball, other steps are the same as in Example 1.

Example 3

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

Example 4

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

Example 5

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

Example 6

In this example, 100 μCi of ⁹⁰ YCl ₃ solution was used to replace the 0.1 mCi of ¹⁷⁷ LuCl ₃ solution in Example 1 to prepare poly(lactic-co-glycolic acid)-coated yttrium hydroxide [ ⁹⁰ Y(OH) ₃ ] porous silica microparticles. Ball, other steps are the same as in Embodiment 1. The radioactivity of radioactive silica microspheres was measured by a radioactivity meter, and the adsorption rate of yttrium-90 by yttrium hydroxide [ ⁹⁰ Y(OH) ₃ ] silica microspheres reached 100%.

Comparative example 1

In this example, the actinium hydroxide [ ²²⁵ Ac(OH) ₃ ] porous silica microspheres are prepared without using the biomedical polymer material solution, and other steps are the same as in Example 2.

Performance Characterization

Infrared spectrum: the powdered lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres prepared in Example 1 and the lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] wrapped by poly(lactic-co-glycolic acid) copolymer The porous silica microspheres are respectively placed on the sample stage of the Fourier transform infrared spectrometer, and the infrared spectrum is measured. The results are shown in Figure 1. Poly(lactic-co-glycolic acid)-coated lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres have both poly(lactic-co-glycolic acid) and lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] Characteristic peaks of porous silica microspheres.

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

Optical microscope: the powdered lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres prepared in Example 1 and lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] wrapped by poly(lactic-co-glycolic acid) copolymer The porous silica microspheres were respectively placed on glass slides and observed with an optical microscope. The results are shown in Figures 3-4, the appearance of the microspheres has no obvious change, and they are all monodisperse microspheres.

Scanning electron microscope: the powdered lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres prepared in Example 1 and the lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] coated with poly(lactic-co-glycolic acid) copolymer ] The porous silica microspheres were respectively placed in the electron microscope stage, and observed with a scanning electron microscope. The results are shown in Figures 5-6, the appearance of the microspheres has no obvious change, and they are all monodisperse microspheres.

In vitro stability: Lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres prepared in Example 1 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 with a gamma radioimmunocounter after solid-liquid separation at 2, 4, 24, 48, and 96 hours respectively. The results are shown in Figure 7. Within 96 hours, the release rate of lutetium-177 from lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres in fetal bovine serum (FBS) was nearly 20%. The lutetium hydroxide [ ¹⁷⁷ Lu(OH) ₃ ] porous silica microspheres encapsulated by the copolymer have a lutetium-177 release rate of less than 2% in fetal bovine serum (FBS), and the radiation stability of the microspheres is obviously improved.

In vitro stability: soak the products prepared in Examples 2 to 5 and Comparative Example 1 with fetal bovine serum (FBS) respectively, and irradiate them with gamma after solid-liquid separation at 2, 4, 24, 48, 96, and 192 hours respectively The radioactivity of the microspheres was measured by an immunocounter. The results are shown in Figure 8, within 192 hours, the release rate of actinium-225 in fetal bovine serum (FBS) from actinium hydroxide [ ²²⁵ Ac(OH) ₃ ] porous silica microspheres coated with poly(lactic-co-glycolic acid) copolymer The minimum is about 17%. With the increase of the concentration of the poly(lactic-co-glycolic acid) copolymer, the radiation stability of the microspheres is obviously improved, and the escape of daughter nuclides is reduced.

Each embodiment in this specification is described in a progressive manner, each embodiment focuses on the difference from other embodiments, and the same and similar parts of each embodiment can be referred to each other.

The above description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those 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 invention. Therefore, the present invention will not be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (10)

1. A preparation method of a radioactive silicon dioxide microsphere wrapped by a biomedical polymer material is characterized by comprising the following steps:

s1, mixing silicon dioxide microspheres, water and radionuclide to obtain a radionuclide-silicon dioxide microsphere mixture;

s2, mixing the radionuclide-silica microsphere mixture and an alkaline solution, and reacting to obtain radioactive silica microspheres;

and S3, mixing the radioactive silica microspheres with the biomedical polymer material solution, and then coating to obtain the radioactive silica microspheres coated by the biomedical polymer material.

2. The preparation method according to claim 1, wherein in the step S1, the mass-to-volume ratio of the silica microspheres to the water is 0.001 to 1000g: 0.1-1000 mL;

the mass activity ratio of the silicon dioxide microspheres to the radioactive nuclide is 0.001-1000 g:1 x 10 ^-3 ～1×10 ⁶ mCi；

The diameter of the silicon dioxide microsphere is 20 to 500 mu m, and the density is 1.0 to 2.4g/cm ³ 。

3. The method according to claim 2, wherein the mixing temperature in step S1 is 0 to 100 ℃ and the mixing time is 1 to 100min.

4. The method according to claim 2 or 3, wherein the radionuclide in step S1 is scandium ⁴⁷ Sc, copper ⁶⁴ Cu, copper ⁶⁷ Cu, gallium ⁶⁶ Ga. Gallium (Ga) compound ⁶⁷ Ga. Gallium (Ga) compound ⁶⁸ Ga. Yttrium salt ⁸⁶ Y, Y ⁹⁰ Y, zirconium ⁸⁹ Zr, sr ⁸⁹ Sr, technetium ^99m Tc, palladium ¹⁰⁹ Pd, indium ¹¹¹ In, terbium ¹⁴⁹ Tb, terbium ¹⁶¹ Tb, samarium ¹⁵³ Sm and holmium ¹⁶⁶ Ho, lu ¹⁷⁷ Lu, re ¹⁸⁶ Re, re ¹⁸⁸ Re, lead ²¹² Pb and Bi ²¹² Bi. Bismuth (Bi) ²¹³ Bi. Laser ²²³ Ra, actinium ²²⁵ Ac. Actinium ²²⁷ Ac. Thorium (Th) ²²⁶ Th and thorium ²²⁷ One or more of Th.

5. The method according to claim 4, wherein in step S2, the reaction temperature is 0-100 ℃, and the reaction time is 1-100 min;

the mass-volume ratio of the silicon dioxide microspheres in the step S1 to the alkaline solution in the step S2 is 0.001-1000 g:0.001 to 100mL.

6. The production method according to claim 1 or 5, wherein in the step S2, the concentration of the alkaline solution is 10 to 100g/L;

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

7. The method according to claim 2, 3 or 5, wherein in the step S3, the concentration of the biomedical polymer material solution is 0.001-2 g/mL;

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, polyvinylpyrrolidone, silicone rubber, polyvinyl alcohol, polylactic acid, polyethylene, polyacrylic acid, povidone, ethylene-vinyl acetate copolymer, polyethylene glycol, polyoxyethylene, polyorthoester, polyortho acid, polyphosphazene, polyether ether ketone, polymethyl methacrylate, polypropylene, polyacrylate, aromatic polyester, aliphatic polyester, polyamino acid, polycaprolactone, poly alpha-alkyl cyanoacrylate and dimethicone;

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

8. The method according to claim 7, wherein in step S3, the temperature of coating is 0-100 ℃, and the time of coating is 1-100 min;

the mass-volume ratio of the silicon dioxide microspheres in the step S1 to the biomedical polymer material solution in the step S3 is 0.001-1000 g: 0.1-1000 mL.

9. The biomedical polymer material-coated radioactive silica microspheres prepared by the preparation method of any one of claims 1 to 8.

10. Use of the biomedical polymer material-coated radioactive silica microspheres of claim 9 in the preparation of a medicament for treating tumor embolization.

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