Yttrium 90 glass microsphere for treating liver cancer and preparation method thereof

Abstract

The invention relates to the field of radioactive medical materials, and discloses yttrium 90 glass microspheres for treating liver cancer and a preparation method thereof.The glass microspheres comprise silicon dioxide, aluminum oxide, yttrium oxide and phosphorus pentoxide, the molar weight of the aluminum element is larger than the sum of the molar weights of yttrium and phosphorus elements, and by constructing a charge-compensated aluminosilicate network, the specific surface area of the glass microspheres is larger than that of the yttrium 90 glass microspheres. According to the preparation method, sol step-by-step assembly, azeotropic spray granulation, solvent-assisted aging and graded sintering processes are adopted, the shrinkage densification of liquid drops is regulated and controlled by utilizing solvent volatilization gradient, the surface of the microsphere is subjected to phosphate grafting modification, and the surface of the microsphere is subjected to surface modification. And the material has high negative potential and steric hindrance effects. The microspheres are high in sphericity degree and narrow in particle size distribution, the cumulative leaching rate of yttrium ions in simulated body fluid is lower than 0.0001%, the microspheres have excellent suspension stability in a dispersion medium, and the biological safety of interventional therapy is improved.

Description

Technical Field

[0001] This invention relates to the field of radioactive medical materials, specifically to a yttrium-90 glass microsphere for liver cancer treatment and its preparation method. Background Technology

[0002] Transcatheter radioembolization (TARE) is a key technique for treating advanced primary liver cancer and liver metastases. This therapy utilizes a microcatheter to deliver radioactive yttrium-90 (Yttrium-90) to the affected liver. 90 Yttrium oxide microspheres are delivered to the tumor's blood supply arteries, controlling tumor progression through a dual action of beta-ray radiation killing and vascular embolization. Clinically commonly used carriers mainly include resin microspheres and glass microspheres. Resin microspheres typically adsorb yttrium ions onto a polymer backbone via ion exchange, resulting in a specific gravity close to blood and good suspension properties. However, their specific radioactivity is relatively low, and the bond between yttrium ions and the resin matrix relies primarily on ionic bonds, posing a risk of radionuclide desorption and release in the complex physiological environment of the body. In contrast, glass microspheres integrate yttrium oxide directly into the silicate network structure through high-temperature melting, making yttrium an integral part of the glass structure. Theoretically, this results in higher chemical stability and a higher radionuclide retention rate. Furthermore, glass microspheres can achieve extremely high specific activity, allowing for the achievement of predetermined therapeutic doses with a smaller number of microspheres, thereby reducing the risk of non-targeted embolization of normal liver blood supply arteries and making them more suitable for high-dose fractional radiation therapy.

[0003] Despite the inherent advantages of glass microspheres in terms of radioactivity retention and specific activity, existing silicate glass systems still face significant challenges in pursuing higher therapeutic doses and biocompatibility. When the doping amount of yttrium oxide is significantly increased to enhance radioactivity, yttrium ions, as network exooxides, significantly disrupt the integrity of the silicon-oxygen tetrahedral framework, generating numerous non-bridging oxygen bonds. In traditional formulations lacking effective charge compensation mechanisms, this structural defect leads to a sharp decline in the corrosion resistance of the glass matrix in bodily fluid environments, causing radioactive yttrium ions to leach out and accumulate in non-target organs such as bone marrow via blood circulation, resulting in radiotoxicity. Current technologies primarily focus on simple adjustments to the silicon-to-aluminum ratio, failing to establish a charge balance network at the atomic coordination level for high yttrium content systems, making it difficult to balance high doses with low leaching rates.

[0004] In terms of fabrication processes and microstructure, the production of traditional glass microspheres mainly relies on high-temperature melting-quenching-pulverization or flame spheroidization. Pulverization produces microspheres with irregular shapes, sharp edges that can easily damage the inner walls of blood vessels, and poor rheological properties. While flame spheroidization can improve sphericity, the cooling rate is difficult to control precisely, easily leading to phase separation, crystallization, or hollow structures within the microspheres. These microstructural inhomogeneities are not only weak points in mechanical strength but also preferential pathways for chemical corrosion, further exacerbating the risk of ion leaching.

[0005] In addition, glass microspheres have high density characteristics (typically greater than 3.0 g / cm³). 3 This presents a significant challenge for the suspension and dispersion of high-density glass microspheres in clinical applications. During interventional procedures, the high specific gravity of glass microspheres settles extremely rapidly in contrast agents or saline solution. Furthermore, due to the low surface potential of glass at physiological pH, the microspheres lack sufficient electrostatic repulsion, making them prone to aggregation or blockage within the catheter. This not only increases the complexity of the surgical procedure but may also lead to uneven distribution of the microspheres within the tumor vascular bed. While existing technologies have attempted surface modification, most have failed to construct a stable surface layer with sufficiently long-lasting electrostatic repulsion and steric hindrance effects, thus failing to effectively solve the sedimentation and aggregation problems of high-density microspheres. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides yttrium-90 glass microspheres for liver cancer treatment and their preparation method. The aim is to solve the problems of poor chemical stability and easy leaching of radioactive ions due to the lack of an effective network charge compensation mechanism in high-yttrium glass microspheres in existing technologies, the difficulty in obtaining a uniform and dense amorphous structure by traditional melting or flame preparation processes, and the poor suspension and dispersion of high-density microspheres during clinical interventional delivery, which easily leads to agglomeration and tube blockage.

[0007] To achieve the above objectives, the present invention provides the following technical solution: Firstly, the present invention provides yttrium-90 glass microspheres for liver cancer treatment, employing the following technical solution: A type of yttrium-90 glass microsphere for liver cancer treatment comprises the following oxide components in parts by weight: 26-34 parts silicon dioxide; 23-28 parts aluminum oxide; 35-41 parts yttrium oxide; 5-9 parts phosphorus pentoxide; wherein, the molar amount of aluminum in the glass microspheres is greater than the sum of the molar amounts of yttrium and phosphorus, and is used to form a charge-compensated aluminosilicate network; the glass microspheres are subjected to neutron activation treatment and have a phosphate grafting modification layer on their surface.

[0008] By adopting the above technical solution and controlling the specific oxide composition range and the molar stoichiometric ratio of aluminum to yttrium and phosphorus, a highly stable glass network structure was constructed. The specific mechanism and effects are as follows: First, a fully connected aluminosilicate framework is formed to suppress ion precipitation. In glass networks, yttrium ions are typically located on the outer layers, which easily leads to the breaking of silicon-oxygen bonds, forming non-bridged oxygen structures and thus reducing chemical stability. This scheme controls the molar amount of aluminum to be greater than the sum of the molar amounts of yttrium and phosphorus, prompting aluminum atoms to preferentially combine with oxygen atoms during glass melting, forming negatively charged [AlO4]. - Tetrahedral structural unit. The localized negative electric field generated by this tetrahedral unit absorbs free yttrium ions (Y).3+ Charge balance is achieved to stabilize yttrium ions in the network voids of aluminum-oxygen tetrahedra, thereby reducing the migration rate and leaching risk of yttrium ions under physiological conditions.

[0009] Second, it suppresses the precipitation of insoluble phosphate crystals. Phosphorus introduced into the system readily combines with yttrium at high temperatures to form chemically heterogeneous yttrium phosphate microcrystals or enriched phases. This scheme utilizes the structural integration effect of excess aluminum in the high-temperature molten state to disperse the yttrium-phosphorus structural units and incorporate them into the silicon-aluminum network. The steric hindrance effect is then used to suppress the independent nucleation of the yttrium-rich phase or yttrium phosphate crystal phase, thereby obtaining a glassy body with uniform composition.

[0010] Third, surface modification enhances dispersion stability. The glass microspheres have a phosphate-grafted modified layer on their surface, which imparts a high density of negative charges to the surface of the microspheres under physiological pH conditions. This surface charge layer generates electrostatic repulsion when the microspheres approach each other, overcoming the van der Waals forces between micron-sized particles, preventing the microspheres from agglomerating or clogging during catheter delivery, and ensuring smooth drug administration in interventional therapy.

[0011] Preferably, the glass microspheres have an amorphous glassy structure with no sharp crystal diffraction peaks in their X-ray diffraction patterns, and the interior of the glass microspheres exhibits a uniform single-phase glass network without microscopically visible yttrium-rich phase separation or flocculent precipitates.

[0012] By employing the above technical solution, it is ensured that there are no grain boundaries or phase boundaries within the microsphere entity. Crystalline or phase-separated structures are usually accompanied by density inhomogeneities and differences in dissolution rates, and phase boundaries are prone to preferential corrosion due to stress concentration or differences in composition gradients. The uniform amorphous single-phase structure endows the microsphere entity with isotropic chemical stability, while ensuring the uniform microscopic distribution of radionuclides in the microsphere matrix after neutron activation, avoiding radioactive hotspots caused by local element enrichment.

[0013] Preferably, the glass microspheres have a particle size distribution range of less than 0.7, a sphericity greater than 0.96, and a tap density of 3.2-3.7 g / cm³. 3 .

[0014] By adopting the above technical solutions, the narrow particle size distribution span and high sphericity improve the flow characteristics of microspheres in blood vessels, enabling them to penetrate deep into the terminal end of tumor-supplying microvessels and form dense emboli, reducing the risk of off-target embolism; the suitable density range gives the microspheres good suspension performance in suspension; the extremely low ion leaching rate ensures the biosafety of in vivo radiotherapy and prevents free radioactive yttrium-90 from entering the blood circulation and causing off-target radiation damage.

[0015] Preferably, the phosphate grafted modified layer on the surface specifically comprises polyphosphate groups chemically bonded to the surface of the glass microspheres.

[0016] By employing the above technical solution, polyphosphate groups are anchored to the glass surface through chemical adsorption or bonding, providing a negative potential much higher than that of ordinary hydroxyl surfaces, forming an electric double-layer repulsion mechanism, and utilizing the spatial extension of the polyphosphate chains to generate a steric hindrance effect. This synergistic mechanism of electrostatics and steric hindrance allows the microspheres to remain monodisperse under long-term static conditions or high-concentration conditions, solving the problem of easy sedimentation and agglomeration of high-density glass microspheres.

[0017] Secondly, the present invention provides a method for preparing yttrium-90 glass microspheres for liver cancer treatment, employing the following technical solution: A method for preparing yttrium-90 glass microspheres for liver cancer treatment, comprising the following steps: S1. Sol-based assembly: Yttrium-phosphorus pre-coordinated cluster solution is mixed with aluminum-chelate precursor solution. The yttrium-phosphorus clusters are encapsulated using an aluminum source. Then, a silicon source and an azeotropic solvent are added, and the mixture is refluxed and aged to form a multi-component precursor sol. S2. Azeotropic spray granulation: The precursor sol is spray-dried, and a spherical framework is constructed by utilizing the solvent evaporation gradient to obtain microsphere green bodies. S3. Solvent-assisted aging: The microsphere green body is placed in a sealed container and heated and aged in a solvent atmosphere to achieve cross-linking and locking of the gel skeleton; S4. Graded sintering: The aged microsphere green body is debinded and sintered at high temperature, and then screened to obtain glass microspheres; S5. Surface treatment and activation: The glass microspheres obtained by sieving are subjected to surface phosphate cleaning and grafting treatment, followed by neutron activation.

[0018] By adopting the above technical solution, this invention establishes a sol-gel combined spray granulation synthesis process for high yttrium content glass microspheres, and the mechanism of each step is as follows: First, stepwise assembly controls reaction kinetics. In the preparation of aluminosilicate sols, the hydrolysis rate of aluminum alkoxides is much faster than that of silanols, easily leading to component stratification. This method first constructs yttrium-phosphorus pre-coordinated clusters, placing them in a metastable state; then, an aluminum source modified with a chelating agent is introduced, utilizing the coordination ability of aluminum ions to encapsulate the yttrium-phosphorus clusters, forming a multi-level intermediate; finally, a silicon source with slower hydrolysis is added. This order of addition balances the condensation rates of yttrium, aluminum, and silicon, promoting simultaneous gelation of different components at the molecular scale, avoiding the precipitation of localized yttrium-rich phases, and laying the foundation for the formation of a uniform glass network.

[0019] Second, solid densification is achieved using a solvent gradient. An azeotropic solvent (such as n-butanol) is introduced during the spray drying process, utilizing the difference in boiling point and evaporation rate between it and the main solvent (ethanol / water) to control the droplet drying process. While water and ethanol rapidly evaporate from the droplet surface, the high-boiling-point azeotropic solvent accumulates on the droplet surface, reducing surface tension and delaying the formation of a hard surface shell, thus maintaining the mass transport channels on the droplet surface. This allows the droplet to shrink and densify during the continuous evaporation of the solvent inside, resulting in solid spheres and reducing defects such as hollow or broken spheres.

[0020] Third, solvent atmosphere-assisted framework strengthening. In step S3, the supercritical or near-critical state of the solvent under high temperature and pressure promotes further condensation of unreacted hydroxyl groups inside the green body and initiates a dissolution-reprecipitation process of the gel particles. This process repairs the microcracks and pores generated during the rapid drying stage, improves the mechanical strength of the green body, and prevents the microspheres from cracking or pulverizing during subsequent high-temperature sintering.

[0021] Preferably, in step S1, the yttrium-phosphorus pre-coordinated cluster solution is prepared by dissolving yttrium salt in an aqueous ethanol solution, adjusting the pH to 2.1-2.3, adding triethyl phosphate dropwise, and reacting at 40-50°C to form yttrium-phosphorus sol clusters; the aluminum-chelate precursor solution is prepared by dissolving aluminum isopropoxide in anhydrous ethanol, adding acetylacetone dropwise, and carrying out a chelation reaction at 25-40°C; wherein the molar ratio of aluminum isopropoxide to acetylacetone is 1:(0.5-1.0).

[0022] By employing the above technical solutions, the reactivity of the precursors can be precisely controlled. For the yttrium-phosphorus system, the pH value is controlled within the range of 2.1-2.3 to inhibit excessive hydrolysis of yttrium ions and promote their coordination with phosphate ester groups to form stable sol clusters. For the aluminum source system, acetylacetone is introduced as a chelating agent, occupying some coordination sites of aluminum atoms through bidentate coordination, increasing the steric hindrance effect, and reducing the hydrolysis rate of aluminum isopropoxide to an order of magnitude comparable to that of tetraethyl orthosilicate, thereby achieving uniform co-hydrolysis and polycondensation of the multi-component system.

[0023] Preferably, in step S1, the silicon source is tetraethyl orthosilicate; the azeotropic solvent is n-butanol, and the amount of n-butanol added accounts for 10-15% of the total volume of the precursor sol-liquid phase; in step S2, the inlet air temperature of the spray dryer is 200-215℃, and the outlet air temperature is 105-112℃; in step S3, the solvent atmosphere is n-butanol atmosphere, the aging temperature is 165-180℃, and the aging time is 3-4 hours.

[0024] By adopting the above technical solution, the optimal solvent system and thermodynamic parameters were determined. n-Butanol, as an azeotropic component, was added in combination with the process temperature to create a drying mode that encourages inward migration of the solute. An addition of 10-15% forms an effective tension-regulating layer on the droplet surface. Combined with an inlet air temperature of 200-215℃, this establishes a steep temperature and concentration gradient, driving the solute to migrate towards the center of the droplet, thus improving the solidity and sphericity of the microspheres.

[0025] Preferably, in step S5, the surface treatment and activation are specifically implemented as follows: the sintered glass microspheres are ultrasonically cleaned with a sodium polyphosphate solution with a concentration of 0.03-0.05 mol / L for 25-40 minutes, followed by washing with water and drying.

[0026] By employing the above-mentioned technical solution, this process combines cleaning and modification functions. On one hand, ultrasonic cavitation effect is used to remove nanoscale dust adhering to the surface of the microspheres during sintering; on the other hand, the complexing ability of polyphosphate groups on metal ions on the glass surface is utilized to construct a negatively charged polyphosphate structure layer in situ on the cleaned surface. This improves the hydrophilicity of the microsphere surface and significantly increases its zeta potential in physiological saline or contrast agents, ensuring excellent suspension and dispersion performance of the product in clinical use.

[0027] This invention provides yttrium-90 glass microspheres for liver cancer treatment and a method for preparing the same. It offers the following advantages: 1. This invention constructs an aluminosilicate glass network with a charge compensation mechanism by controlling the molar amount of aluminum to be greater than the sum of the molar amounts of yttrium and phosphorus. This ratio promotes the formation of negatively charged structural units by aluminum atoms, effectively absorbing and fixing free yttrium ions and inhibiting the precipitation of yttrium-rich phases or insoluble phosphate crystal phases. This uniform single-phase glass structure makes the microspheres exhibit extremely high chemical inertness under physiological conditions. The cumulative leaching rate of yttrium ions after immersion in simulated body fluid for 30 days is less than 0.0001%, thereby avoiding radiation damage to non-target organs caused by radioactive nuclides entering the bloodstream.

[0028] 2. This invention employs a sol-gel stepwise assembly combined with an azeotropic solvent spray granulation process. By utilizing the solvent evaporation gradient to control the droplet shrinkage process, glass microspheres with high solidity and high sphericity are obtained. Combined with solvent-assisted aging, micropores and cracks within the microspheres are eliminated, resulting in a narrow particle size distribution and suitable tap density. This regular physical morphology ensures good fluidity of the microspheres within microvessels, enabling them to penetrate deep into the distal ends of tumor-feeding vessels and form dense accumulations, achieving precise radioembolization therapy.

[0029] 3. This invention introduces polyphosphate groups onto the surface of glass microspheres through surface phosphate grafting modification, constructing a stable surface layer with a high negative potential. This results in the absolute value of the zeta potential of the microspheres being greater than 40mV under physiological pH conditions. By utilizing strong electrostatic repulsion and steric hindrance, the inherent van der Waals attraction between high-density glass microspheres is overcome, effectively preventing the microspheres from agglomerating during standing or transportation. This improves the dispersion stability of the product in clinical contrast agents or physiological saline and reduces the risk of catheter blockage in interventional procedures. Detailed Implementation

[0030] Preparation Examples 1-3: Preparation Example 1: This preparation example provides an aluminum-acetylacetone chelate precursor solution A1, comprising the following steps: Preparation: Weigh each component according to the following weight proportions: Aluminum isopropoxide: 204.2 parts Acetylacetone: 50.1 parts Anhydrous ethanol: 800.0 parts Dissolution: Under the protection of dry nitrogen at room temperature, 204.2 parts of aluminum isopropoxide were added to 800.0 parts of anhydrous ethanol and magnetically stirred until the solid was completely dissolved to obtain a colorless and transparent aluminum alkoxide solution.

[0031] Chelation reaction: Under vigorous stirring, 50.1 parts of acetylacetone were slowly added dropwise to the above aluminum alkoxide solution.

[0032] Aging: After the addition was complete, the mixture was sealed and stirred at 25°C for 60 minutes to obtain a light yellow, transparent aluminum-acetylacetone chelate precursor solution A1. The theoretical concentration of aluminum in this solution (as Al2O3) was approximately 5.0 wt%.

[0033] Preparation Example 2: This preparation example provides an aluminum-acetylacetone chelate precursor solution A2 for verifying hydrolysis behavior under high coordination inhibition, including the following steps: Preparation: Weigh each component according to the following weight proportions: Aluminum isopropoxide: 204.2 parts Acetylacetone: 100.2 parts Anhydrous ethanol: 800.0 parts Dissolution: Under the protection of dry nitrogen at room temperature, add 204.2 parts of aluminum isopropoxide to 800.0 parts of anhydrous ethanol and stir until completely dissolved.

[0034] Chelation reaction: Under vigorous stirring, 100.2 parts of acetylacetone were slowly added dropwise to the above solution.

[0035] Aging: After the addition is complete, the system will turn a deep yellow color. Reflux and stir at 40°C for 30 minutes, then allow to cool naturally to room temperature to obtain aluminum-acetylacetone chelate precursor solution A2.

[0036] Preparation Example 3: This preparation example provides a yttrium-phosphorus (YP) pre-coordinated cluster solution B1, comprising the following steps: Solvent preparation: Mix 400.0 parts of anhydrous ethanol with 80.0 parts of deionized water to obtain an alcohol-water mixed solvent.

[0037] Dissolving the main salt: Add 135.2 parts of yttrium acetate tetrahydrate to the mixed solvent and stir until the solid completely disappears to obtain a clear solution.

[0038] pH adjustment: Add 2.0 mol / L nitric acid solution dropwise to the solution while monitoring with a pH meter until the pH value of the solution stabilizes within the range of 2.2 ± 0.1.

[0039] Pre-assembly reaction: Raise the solution temperature to 45°C.

[0040] 18.2 parts of triethyl phosphate (TEP) were slowly added dropwise while stirring at 600 rpm.

[0041] The reaction was carried out at a constant temperature for 90 minutes, using Y... 3+ Nucleophilic attack or solvation effect on phosphate ester groups leads to the formation of metastable [YOP] sol clusters.

[0042] Finished product: After stopping heating and allowing it to cool naturally, a colorless and transparent YP pre-coordinated cluster solution B1 is obtained. The molar ratio of yttrium to phosphorus in this solution is designed to be 4:1, which is suitable for preparing glass microspheres with low or standard phosphorus content. If it is necessary to prepare microspheres with high phosphorus content, the amount of triethyl phosphate can be increased proportionally in this preparation example.

[0043] Examples 1-6: In the preparation process of this invention, the precursor raw materials used are converted into corresponding oxides after high-temperature sintering to construct a glass network. The specific correspondence is as follows: Tetraethyl orthosilicate is converted to silicon dioxide (SiO2), aluminum isopropoxide / acetylacetone chelate is converted to Al2O3, yttrium acetate is converted to Y2O3Y2, and triethyl phosphate is converted to P2O5.

[0044] Based on stoichiometric calculations, the raw material feed amounts in the examples and preparation examples correspond to the following oxide glass compositions: Preparation Example 1: The aluminum content in the aluminum-acetylacetone chelate precursor solution A1 is approximately 5.0 wt% based on Al2O3.

[0045] Preparation Example 3: In yttrium-phosphorus pre-coordinated cluster solution B1, based on 100% conversion, each 100 parts of solution contains approximately 7.1 parts of Y2O3 and 1.1 parts of P2O5 (this is just an example, and accurate calculation based on molecular weight is required).

[0046] Final microsphere composition: Each embodiment aims to obtain the oxide composition within the scope of the claims by controlling the proportions of each precursor solution. For example, the feed amounts in Example 1 correspond to approximately 30.1 wt% SiO2, approximately 24.6 wt% Al2O3, approximately 37.0 wt% Y2O3, and approximately 8.2 wt% P2O5 (normalized data).

[0047] Example 1: This embodiment provides yttrium-90 glass microspheres for liver cancer treatment, and the specific preparation steps are as follows: Sol-gel step-by-step assembly: Take 538.4 parts of the yttrium-phosphorus (YP) pre-coordinated cluster solution B1 obtained in Preparation Example 3; Add an additional 6.4 parts of triethyl phosphate (TEP); After stirring at 45°C for 30 minutes, 27.2 parts of the aluminum-acetylacetone chelate precursor solution A15 prepared in Example 1 were slowly added dropwise. After stirring and wrapping for 60 minutes, add 108.3 parts of tetraethyl orthosilicate (TEOS); Add 160.0 parts of n-butanol (approximately 12% of the total liquid volume); Heat to 60°C and reflux for 4 hours, then cool and age.

[0048] Azeotropic spray granulation: Inlet air temperature 215℃, outlet air temperature 112℃.

[0049] Solid green bodies with a particle size of approximately 40-50 μm were prepared by utilizing the volatilization gradient of ethanol / water / n-butanol.

[0050] Solvent-assisted aging: The green body was placed in a high-pressure autoclave and aged at a constant temperature of 165°C for 3 hours under a n-butanol atmosphere.

[0051] Staged sintering: Remove the binder at 600℃ and sinter at 1380℃ for 2 hours.

[0052] Surface treatment: After sieving, the sample was ultrasonically cleaned with a 0.03 mol / L sodium polyphosphate solution for 25 minutes.

[0053] Example 2: This embodiment provides yttrium-90 glass microspheres for liver cancer treatment, and the specific preparation steps are as follows: Sol-gel step-by-step assembly: Take 506.7 parts of the yttrium-phosphorus (YP) pre-coordinated cluster solution B1 obtained in Preparation Example 3; No additional triethyl phosphate is added; 506.1 parts of the aluminum-acetylacetone chelate precursor solution A1 prepared in Example 1 were slowly added dropwise; Add 116.6 parts of tetraethyl orthosilicate (TEOS); Add 150.0 parts of n-butanol; The subsequent process is the same as in Example 1.

[0054] Example 3: This embodiment provides yttrium-90 glass microspheres for liver cancer treatment, and the specific preparation steps are as follows: Take 1.7 parts of the yttrium-phosphorus (YP) pre-coordinated cluster solution B1 obtained in Preparation Example 3; Add an additional 4.6 parts of triethyl phosphate (TEP); Add dropwise 596.4 parts of the high chelation ratio solution A2 prepared in Example 2; Add 100.0 parts of tetraethyl orthosilicate (TEOS); Add 180.0 parts of n-butanol; Due to the increased organic content in the aluminum source, the heating rate during the debinding stage decreased to 1℃ / min; The remaining steps are the same as in Example 1.

[0055] Example 4: This embodiment provides yttrium-90 glass microspheres for liver cancer treatment, and the specific preparation steps are as follows: The specific preparation steps are the same as in Example 1, except for the following changes: Sol-gel step-by-step assembly: The amount of n-butanol added was reduced to 120.0 parts; The inlet air temperature is reduced to 200℃, and the outlet air temperature is 105℃.

[0056] Example 5: This embodiment provides yttrium-90 glass microspheres for liver cancer treatment, and the specific preparation steps are as follows: The specific preparation steps are the same as in Example 1, except for the following changes: Solvent-assisted aging: The green body was placed in a high-pressure autoclave and aged at a constant temperature of 180°C for 4 hours under a n-butanol atmosphere.

[0057] Staged sintering: The temperature is set to 1400℃.

[0058] Example 6: This embodiment provides yttrium-90 glass microspheres for liver cancer treatment, and the specific preparation steps are as follows: The specific preparation steps are the same as in Example 1, except for the following changes: Surface treatment: Ultrasonic cleaning with 0.05 mol / L sodium polyphosphate solution for 40 minutes.

[0059] Comparative Examples 1-5: Comparative Example 1: Compared with Example 1, the difference lies in the sol preparation steps, which are as follows: A mixed solvent was pre-added to a reaction vessel: 740.0 parts anhydrous ethanol, 68.0 parts deionized water, and 160.0 parts n-butanol; Add 25.0 parts of acetylacetone and an appropriate amount of nitric acid (to adjust the pH to 2.0). While vigorously stirring, add all of the following ingredients simultaneously: Yttrium acetate tetrahydrate: 115.0 parts; Triethyl phosphate: 21.9 parts; Aluminum isopropoxide: 102.1 parts; Ethyl orthosilicate: 108.3 parts; Reflux and stir at 60°C for 6 hours.

[0060] The remaining steps are the same as in Example 1.

[0061] Comparative Example 2: The difference compared to Example 1 is as follows: The sol formulation is different: 160.0 parts n-butanol in the formulation is replaced with 160.0 parts anhydrous ethanol. The solvent system consists entirely of ethanol and water.

[0062] The azeotropic spray granulation parameters are different: due to the lack of high-boiling-point solvents, in order to prevent the droplets from bursting too quickly, the inlet air temperature is adjusted to 180℃ and the outlet air temperature is 90℃.

[0063] The remaining steps are the same as in Example 1.

[0064] Comparative Example 3: The difference compared to Example 1 is as follows: The solvent-assisted aging step is omitted, and after collecting the solid green body, it is not subjected to solvent aging treatment in a high-pressure autoclave at 165°C.

[0065] The collected green blanks were directly fed into a tube furnace and subjected to debinding at 600°C and sintering at 1380°C, as in Example 1.

[0066] The remaining steps are the same as in Example 1.

[0067] Comparative Example 4: Compared with Example 1, the difference lies in the raw material ratio, and the specific weight proportions are adjusted as follows: The feed amount in the sol-gel step assembly is changed to: Solution B1 of Example 3: 500.0 parts; Additional triethyl phosphate (TEP): 5.9 parts; Solution A1 of Preparation Example 1: 338.0 parts; Tetraethyl orthosilicate (TEOS): 125.0 parts; n-Butanol: 160.0 parts; The remaining steps are the same as in Example 1.

[0068] Comparative Example 5: The difference compared to Example 1 lies in the surface treatment steps: The sintered and sieved microspheres were dispersed in pure deionized water (not sodium polyphosphate solution) and ultrasonically cleaned under the same conditions (25 minutes), followed by filtration and drying.

[0069] The remaining steps are the same as in Example 1.

[0070] Test Example 1-3: Test Example 1: Process Stability and Microsphere Physical Properties Test Test method: The final glass microsphere samples prepared in Examples 1 to 5 were selected and characterized according to the following standard methods: Particle size distribution determination: The median diameter of the microspheres was determined using a laser particle size analyzer (Malvern Mastersizer 3000) with deionized water as the dispersion medium. The particle size distribution width of the microspheres is determined by the span. The characterization, its calculation formula is: ; The smaller the value, the narrower the particle size distribution.

[0071] Sphericity characterization: Projected images of at least 200 microspheres were randomly acquired using an optical microscope equipped with image analysis software. The projected area of ​​the particles was calculated using the software. and perimeter The sphericity coefficient is calculated using the formula calculate. The closer the value is to 1.0, the higher the roundness.

[0072] Tap density: Measured according to the tap density determination method proposed in GB / T5162-2021, the ratio of powder mass to volume is measured after vibrating the tap density meter 3000 times. This index is used to indirectly reflect the density (solidity) of the microspheres.

[0073] Product yield: Calculate the percentage of the mass of microspheres with a particle size range of 20-35μm after sieving to the total theoretical mass of the input raw material oxides.

[0074] Test results: The physical performance test data of Examples 1-5 are summarized in the table below.

[0075] Table 1. Summary of physical property test data of glass microspheres in Examples 1-5 ; Results Analysis and Conclusions: Process adaptability and microsphere quality: Data from Examples 1 to 3 show that the D50 of the microspheres prepared by this process is stable between 25-32 μm, and the Span value is controlled below 0.7, exhibiting good monodispersity. In particular, the tap density of Example 3 (high yttrium formulation) reaches 3.68 g / cm³. 3 The sphericity was higher than that of Example 2 (high-silica formulation), which is related to the relatively large atomic mass of yttrium atoms and their high filling rate in the glass network. The average sphericity of all components remained above 0.965, confirming that the rheological properties of the precursor sol are suitable for spray granulation requirements.

[0076] The effect of azeotropic solvents on particle size distribution: In Example 4, reducing the n-butanol content to 10% resulted in an increase in the Span value to 0.89 and a decrease in sphericity to 0.941. As a high-boiling-point component, n-butanol created an inward-outward evaporation gradient during droplet drying, delaying the premature formation of a surface hard shell. When the proportion of n-butanol decreased, the solvent evaporation rate increased, disturbing the capillary force balance during droplet shrinkage, leading to a wider particle size distribution and a decrease in the sphericity of some microspheres. This result conversely demonstrates the necessity of azeotropic gradient drying technology in controlling morphology.

[0077] Effect of heat treatment process on yield: Example 5 employed a higher aging temperature (180°C) and sintering temperature (1400°C). Although the density of the microspheres (3.46 g / cm³) was [not specified in the original text], [the following text is incomplete and likely refers to a different process:] 3 The microspheres maintained excellent shape (sphericity 0.979), but the yield decreased to 62.1%. The high-temperature environment increased the probability of diffusion at contact points between green body particles, causing some microspheres to neck and agglomerate during sintering. These agglomerates were removed as oversized particles during sieving. This data indicates that the upper limit of the aging temperature in the process parameters is reasonable, and a balance needs to be struck between ensuring structural locking and preventing particle adhesion.

[0078] Test Example 2: Chemical Stability and Yttrium Ion Leaching Characteristics Test This test case aims to evaluate the chemical stability of the glass microspheres prepared in Example 1 under simulated physiological conditions, and to compare them with Comparative Examples 1, 3, and 4, to verify the effects of stepwise assembly process, solvent-assisted aging, and charge compensation ratio on blocking yttrium ions (Yttrium). 3+ The role of precipitation.

[0079] Test method: Ion leaching tests were conducted using the simulated body fluid (SBF) immersion method, in accordance with the medical device biological evaluation standards proposed in ISO 10993-14.

[0080] Preparation of soaking solution: Prepare a modified simulated body fluid with a pH of 7.4, whose ion concentration is similar to that of human blood plasma.

[0081] Sample preparation: Accurately weigh 100.0 mg of the microsphere sample to be tested, place it in a polypropylene container, and add 50.0 mL of modified simulated body fluid solution.

[0082] Immersion conditions: Seal the container and place it in a constant temperature shaking chamber. Set the temperature to 37±0.5℃ and the shaking frequency to 60rpm.

[0083] Sampling and Detection: Supernatant was collected on day 1, day 7, and day 30 of soaking. After filtration through a 0.22 μm microporous membrane, the concentration of yttrium in the solution (unit: ng / mL) was determined using inductively coupled plasma mass spectrometry (ICP-MS, Agilent 7900).

[0084] Data processing: The measured concentration is converted into cumulative leaching mass, and its percentage of the total mass of yttrium in the microspheres is calculated (cumulative leaching rate).

[0085] Test results: Table 2 shows the cumulative leaching rate of yttrium ions in microspheres prepared under different process conditions.

[0086] Table 2. Comparison of cumulative yttrium ion leaching rates between the examples and comparative samples ; Note: The detection limit in Table 2 is approximately 1×10⁻⁶. -6 %, the value is retained to the number of significant digits.

[0087] Results Analysis and Conclusions: The inhibitory effect of stepwise assembly process on initial burst release: Comparing the data of Example 1 and Comparative Example 1, Comparative Example 1 showed a leaching rate as high as 0.0682% on the first day, exhibiting typical "burst release" characteristics. This is because during the one-pot mixing process, yttrium ions preferentially combine with phosphate ions to form tiny yttrium phosphate enriched phases, which are not completely encapsulated by the silicon-aluminum network. After sintering, part of the enriched phase is exposed on the surface of the microspheres and dissolves rapidly upon contact with water. In contrast, Example 1, which uses stepwise assembly and pre-encapsulates yttrium-phosphorus clusters with aluminum-oxygen octahedra, achieved a leaching rate of only 4.2 × 10⁻⁶ on the first day. -5 The percentage (at an extremely low level) confirms that the process effectively eliminates the free yttrium phase on the surface.

[0088] The effect of green body aging on microstructure uniformity: Comparative Example 3 omitted the solvent-assisted aging step at 165°C, and its cumulative leaching rate reached 0.0589% on day 30, showing a continuous increasing trend over time. This indicates that without high-pressure solvent aging, component migration occurred inside the microspheres during the drying stage, with some yttrium ions migrating to the shallow surface layer with solvent evaporation. Example 1 locked the gel skeleton at low temperature through the aging step, preventing the formation of component gradients and thus ensuring long-term chemical stability.

[0089] The decisive role of charge compensation ratio in network stability: Comparative Example 4 showed the worst performance, with a leaching rate as high as 1.247% on day 30, which was four orders of magnitude higher than that of Example 1. The aluminum content in Comparative Example 4 was insufficient to cover all Y... 3+ and P 5+ Providing sufficient charge balance causes some yttrium ions to break the silicon-oxygen bonds (Si-O-Si) as modified ions, forming a non-bridged oxygen bond structure. This structure is highly susceptible to hydrolytic corrosion in SBF solution, leading to the collapse of the glass network. Conversely, Example 1 maintains an excess of aluminum, ensuring that the yttrium element is stably bound within the rigid cage structure of the aluminosilicate.

[0090] In summary, the technical solution adopted in Example 1 successfully controlled the leaching rate of radionuclides to the level of one part per million by precisely controlling the stoichiometry (charge compensation) and locking the microstructure through process control (stepwise assembly and aging). Compared with samples with defects in traditional processes or formulations, this solution improves the chemical inertness of microspheres under physiological conditions, meeting the stringent requirements for biosafety of implantable materials.

[0091] Test Example 3: Suspension Dispersion Stability and Surface Charge Characteristics Test This test case aims to evaluate the dispersion performance of glass microspheres in a clinical catheter delivery environment, focusing on comparing the anti-agglomeration ability of surface phosphate-modified samples (Examples 1 and 6) and untreated samples (Comparative Example 5) in suspension.

[0092] Test method: To simulate drug administration conditions during clinical interventional procedures, the following tests were conducted using physiological saline as the dispersion medium: Surface potential (Zeta potential) determination: The microsphere sample to be tested was dispersed in a 0.01 mol / L NaCl solution at pH 7.4 to prepare a dilute suspension with a concentration of 0.1 mg / mL. The Zeta potential of the particle surface was measured at 25°C using an electrophoretic light scattering instrument (Malvern Zetasizer Nano ZS). Each sample was measured three times and the average value was taken.

[0093] Sedimentation and redispersion performance: 500 mg of microspheres were placed in a 10 mL medical vial, 5 mL of physiological saline was added, and the mixture was shaken vigorously for 30 seconds and then allowed to stand. The natural sedimentation and stratification of the particles were observed. After standing for 24 hours, the mixture was shaken by hand again to observe whether the bottom precipitate could be redispersed into a homogeneous suspension, and to record whether there were any hard clumps that could not be dispersed by shaking.

[0094] Statistical analysis of micro-aggregates: 20 μL of the redispersed suspension was dropped onto a glass slide and scanned under an optical microscope (100x magnification). The number of multi-particle aggregates with a diameter greater than 50 μm in the field of view was counted.

[0095] Test results: Test data from Example 1 (standard treatment), Example 6 (enhanced treatment), and Comparative Example 5 (no chemical treatment) are summarized in Table 3.

[0096] Table 3. Dispersion stability test data of glass microspheres under different surface treatment conditions ; Results Analysis and Conclusions: The stabilization mechanism of surface charge in the dispersion system: The absolute values ​​of the Zeta potentials in Examples 1 and 6 both exceeded 40 mV (-43.2 mV and -46.8 mV, respectively), falling within the high-stability colloidal range. This indicates that after treatment with sodium polyphosphate, phosphate groups were successfully grafted or adsorbed onto the glass surface, constructing a high-density negative charge layer. This strong negative charge generates a significant electrostatic repulsion force when the microspheres approach each other. This repulsion force is greater than the van der Waals attraction between particles, thus preventing the physical contact and adhesion of the microspheres.

[0097] Risk of aggregation due to lack of surface treatment: Comparative Example 5 was only washed with water, and its Zeta potential was only -7.5mV, close to the zero charge point. Without electrostatic repulsion protection, the microspheres settled and accumulated under gravity during static placement, resulting in close contact between particles. This made them highly susceptible to forming irreversible, dense aggregates under van der Waals forces. Microscopic examination revealed 18 aggregates larger than 50μm within a single field of view in Comparative Example 5. Such large aggregates are highly likely to clog microcatheters (typically with an inner diameter of 500-700μm, but the tip may be even finer) in clinical applications, leading to surgical failure or off-target embolism.

[0098] Saturation effect of the treatment process: Comparing Example 1 (0.03M treatment solution) and Example 6 (0.05M treatment solution), the Zeta potentials were not significantly different (-43.2mV vs -46.8mV), and no aggregates were found in either case. This indicates that a treatment concentration of 0.03M is sufficient to achieve saturation coverage of the adsorption sites on the microsphere surface. Although Example 6 provided a slightly higher potential value, from the perspective of engineering cost and efficiency, the process parameters of Example 1 already meet the clinical requirements for dispersion stability.

[0099] In summary, the polyphosphate surface modification process introduced in this invention is a necessary step to ensure the safety of microsphere formulations. This treatment imparts a strong negative charge to the microsphere surface, ensuring that it exists in a monodisperse state in saline or contrast agents, thus avoiding the risk of catheter blockage caused by aggregation.

[0100] Test Example 4: Microstructure and Crystal Phase Analysis This test case aims to verify, by X-ray diffraction (XRD) and scanning electron microscopy (SEM), whether the microspheres prepared in Example 1 formed a uniform single-phase glass network, and to investigate the effect of formulation defects (Comparative Example 4, insufficient aluminum content) on the microstructure.

[0101] Test method: XRD phase analysis: The microsphere sample to be tested was ground into a fine powder and scanned using an X-ray diffractometer (Bruker D8 Advance). Test conditions: Cu-Kα ray source, tube voltage 40kV, tube current 40mA, scanning range ( 10° to 80°, scanning speed 5° / min.

[0102] Microscopic morphology and phase separation observation: The microsphere samples were embedded in resin and polished. They were then lightly etched with dilute hydrofluoric acid solution for 10 seconds to expose the phase boundaries. After gold sputtering, the cross-sectional morphology was observed using a field emission scanning electron microscope (SEM, Hitachi S-4800), and surface mapping was performed using an energy dispersive spectroscopy (EDS) instrument to analyze the uniformity of yttrium distribution.

[0103] Test results: Table 4. Characterization results of the crystal phase structure and microscopic morphology of the microspheres ; Result analysis and conclusion: Confirmation of the amorphous glass state: The XRD patterns of Examples 1 and 5 showed only broad diffuse scattering bulges in the range of =28° - 35°, and no crystallization peaks were detected. This confirmed that through the charge compensation ratio and azeotropic rapid cooling process of the present invention, the tendency of crystallization was successfully suppressed, and a high content of Y2O3 (∼37 wt%) was completely dissolved in the aluminosilicate glass network, forming a thermodynamically metastable homogeneous vitreous body.

[0104] Mechanism of charge compensation for suppressing phase separation: SEM backscattered electron images (BSE) are sensitive to the atomic number (the larger the atomic number, the brighter). The cross-section of Example 1 showed uniform gray scale, indicating that the heavy element yttrium was highly uniformly distributed in the glass network. In contrast, weak diffraction peaks of the Y2Si2O7 (yttrium silicate) crystal phase were detected in the XRD pattern of Comparative Example 4 (aluminum deficiency), and obvious sea-island-like phase separation structures were observed in the SEM cross-section, with white island regions (yttrium-rich phase) separated from the gray matrix (silicon-rich phase). This confirmed that when Al < Y + P, there was a lack of sufficient - tetrahedra in the network to balance the charge of Y 3+ , forcing yttrium ions to dissociate from the network, forming yttrium-rich microdomains or crystallization. These yttrium-rich microdomains were the root cause of the extremely poor chemical stability (high leaching rate) in Test Example 2.

[0105] The microspheres prepared by the present invention have a typical single-phase amorphous structure, without microscopically visible phase separation or crystal precipitation inside. This homogeneous microstructure is the material basis for ensuring that the microspheres have both a high radiation dose (high yttrium content) and high biosecurity (low leaching).

Claims

1. A yttrium-90 glass microsphere for liver cancer treatment, characterized in that, It contains the following oxide components in parts by weight: Silica: 26-34 parts; Alumina: 23-28 parts; Yttrium oxide: 35-41 parts; Phosphorus pentoxide: 5-9 parts; The glass microspheres contain an aluminum molar amount greater than the sum of the molar amounts of yttrium and phosphorus, which is used to form a charge-compensated aluminosilicate network. The glass microspheres are neutron-activated and have a phosphate grafting modification layer on their surface.

2. The yttrium-90 glass microspheres for liver cancer treatment according to claim 1, characterized in that, The glass microspheres have a single-phase amorphous glass structure; in the aluminosilicate network, aluminum atoms form negatively charged [AlO4] through tetracoordination. - Tetrahedral structural units, with yttrium ions filling the network voids formed by silicon-oxygen tetrahedra and aluminum-oxygen tetrahedra.

3. The yttrium-90 glass microspheres for liver cancer treatment according to claim 1, characterized in that, The glass microspheres are solid spheres with a dense, non-porous interior structure, and their tap density is 3.2-3.7 g / cm³. 3 .

4. The yttrium-90 glass microspheres for liver cancer treatment according to claim 1, characterized in that, The phosphate grafted modified layer contains polyphosphate groups, which are chemically bonded to metal ions on the surface of the glass microspheres through coordination bonds.

5. A method for preparing yttrium-90 glass microspheres for liver cancer treatment, characterized in that, The preparation of the yttrium 90 glass microspheres for liver cancer treatment according to any one of claims 1-4 comprises the following steps: S1. Sol-based assembly: Yttrium-phosphorus pre-coordinated cluster solution is mixed with aluminum-chelate precursor solution. The yttrium-phosphorus clusters are encapsulated using an aluminum source. Then, a silicon source and an azeotropic solvent are added, and the mixture is refluxed and aged to form a multi-component precursor sol. S2. Azeotropic spray granulation: The precursor sol is spray-dried, and a spherical framework is constructed by utilizing the solvent evaporation gradient to obtain microsphere green bodies. S3. Solvent-assisted aging: The microsphere green body is placed in a sealed container and heated and aged in a solvent atmosphere to achieve cross-linking and locking of the gel skeleton; S4. Graded sintering: The aged microsphere green body is debinded and sintered at high temperature, and then screened to obtain glass microspheres; S5. Surface treatment and activation: The glass microspheres obtained by sieving are subjected to surface phosphate cleaning and grafting treatment, followed by neutron activation.

6. The method for preparing yttrium-90 glass microspheres for liver cancer treatment according to claim 5, characterized in that, In step S1, the yttrium-phosphorus pre-coordinated cluster solution is prepared as follows: Yttrium salts were dissolved in an aqueous ethanol solution, the pH was adjusted to 2.1-2.3, and triethyl phosphate was added dropwise. The reaction was carried out at 40-50℃ to form yttrium-phosphorus sol clusters. The method for preparing the aluminum-acetylacetone chelate precursor solution is as follows: aluminum isopropoxide is dissolved in anhydrous ethanol, acetylacetone is added dropwise, and a chelation reaction is carried out at 25-40℃; wherein the molar ratio of aluminum isopropoxide to acetylacetone is 1:(0.5-1.0).

7. The method for preparing yttrium-90 glass microspheres for liver cancer treatment according to claim 5, characterized in that, In step S1, the silicon source is tetraethyl orthosilicate; the azeotropic solvent is n-butanol, and the amount of n-butanol added accounts for 10-15% of the total volume of the precursor sol-liquid phase.

8. The method for preparing yttrium-90 glass microspheres for liver cancer treatment according to claim 5, characterized in that, In step S2, the inlet air temperature of the spray dryer is 200-215℃, and the outlet air temperature is 105-112℃. In step S3, the solvent atmosphere is n-butanol atmosphere, the aging temperature is 165-180℃, and the aging time is 3-4 hours.

9. A method for preparing yttrium-90 glass microspheres for liver cancer treatment according to claim 5, characterized in that, In step S4, the high-temperature sintering temperature is 1380-1400℃, the holding time is 1.5-2 hours, and the sintering atmosphere contains a hydrogen-argon mixture.

10. A method for preparing yttrium-90 glass microspheres for liver cancer treatment according to claim 5, characterized in that, The specific implementation methods of surface treatment and activation are as follows: The sintered glass microspheres were ultrasonically cleaned with a sodium polyphosphate solution with a concentration of 0.03-0.05 mol / L for 25-40 minutes, followed by washing with water and drying.