An embolization microsphere preparation carrying multi-core platinum drugs, a preparation method and application thereof

Abstract

The application provides an embolization microsphere preparation loaded with multi-core platinum drugs and a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The application aims to solve the problems of poor adaptability, low drug loading efficiency and easy burst release of traditional single-core platinum drugs and anionic embolization microspheres, and high systemic toxicity and lack of effective local delivery form of cationic multi-core platinum drugs. The embolization microsphere preparation comprises anionic drug-loaded embolization microspheres and cationic multi-core platinum drugs adsorbed in the embolization microspheres; the embolization microspheres contain anionic groups capable of ion exchange and / or electrostatic adsorption with cationic drugs. Taking CalliSpheres microspheres as an example, the drug loading efficiency of multi-core platinum under the same drug preparation conditions is higher than that of oxaliplatin and cisplatin, and in a serum-containing release medium, the multi-core platinum shows low early release and sustained release, and the particle size and morphology of the microspheres remain stable after drug loading and release. The preparation is suitable for preparing a local treatment drug for liver malignant tumor for transcatheter arterial chemoembolization.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to an embolic microsphere formulation carrying a multinucleated platinum-based drug, its preparation method, and its application. Background Technology

[0002] Transcatheter arterial chemoembolization (TACE) is an important local treatment for malignant tumors such as liver cancer and uterine fibroids. This technique delivers embolic material and chemotherapeutic drugs to the tumor's feeding artery via a catheter, blocking blood supply to the tumor while increasing local drug exposure and reducing the rapid entry of drugs into systemic circulation. Drug-loaded embolic microspheres combine vascular embolization with local drug release, and their therapeutic performance largely depends on the compatibility between the drug and the microspheres.

[0003] Existing drug-loadable embolization microspheres include polyvinyl alcohol (PVA) microspheres and gelatin microspheres. CalliSpheres and 8Spheres microspheres are PVA microspheres, while Embosphere® microspheres are gelatin microspheres. PVA microspheres can utilize anion exchange sites to load positively charged drugs. Clinically, PVA microspheres are used to load doxorubicin (a positively charged chemotherapy drug) for embolization chemotherapy.

[0004] Platinum-based drugs are first-line treatments for most cancers in clinical practice. However, traditional platinum-based drugs such as oxaliplatin and cisplatin have low overall charge, limiting their ion exchange with anionic microspheres. In the comparative experiments of this application, both drugs showed low drug loading efficiency on CalliSpheres microspheres. Oxaliplatin also exhibited significant early rapid release, limiting its ability to form highly drug-loaded, sustained-release microsphere formulations.

[0005] Polynuclear platinum is a class of platinum compounds consisting of two or more platinum centers linked by ligands. Dinuclear platinum (BBR3005) and trinuclear platinum (BBR3464) exist as polyvalent cations, exhibiting DNA-binding characteristics and strong in vitro antitumor activity unlike traditional mononuclear platinum. BBR3464 has been studied in clinical trials, but its systemic administration is limited by dose-limiting toxicities such as neutropenia and limited efficacy in certain tumor types, preventing its routine clinical application.

[0006] This invention utilizes the ion exchange and / or electrostatic adsorption between cationic polynuclear platinum and anionic drug-loaded embolization microspheres to load BBR3005 and BBR3464 into the microspheres, thereby improving drug loading efficiency, reducing early release, and forming a formulation suitable for local delivery via TACE. Existing technologies have not yet provided specific technical solutions for directly loading the aforementioned polynuclear platinum onto these embolization microspheres for TACE treatment of malignant liver tumors. Summary of the Invention

[0007] This invention aims to address the problems of low drug loading efficiency and rapid early release caused by the limited ion exchange between traditional mononuclear platinum drugs (such as oxaliplatin and cisplatin) and anionic embolic microspheres due to their low overall charge. Simultaneously, it overcomes the limitations of highly active cationic multinuclear platinum drugs (such as BBR3005 and BBR3464) due to significant systemic toxicity, which hinders their clinical application. The invention provides an embolic microsphere formulation carrying cationic multinuclear platinum drugs that achieves high drug loading efficiency, low early release, and sustained release behavior without additional surface modification of the microspheres. This provides a drug composition that combines highly efficient local delivery and sustained release for transcatheter arterial chemoembolization (TACE) treatment of liver malignancies.

[0008] To achieve the above-mentioned technical objectives of this invention, the following technical solution is adopted: In a first aspect, the present invention provides an embolization microsphere formulation carrying a cationic polynuclear platinum drug, comprising anionic drug-loaded embolization microspheres and a cationic polynuclear platinum drug adsorbed in the embolization microspheres; the embolization microspheres contain anionic groups capable of ion exchange and / or electrostatic adsorption with the cationic drug.

[0009] Preferably, the anionic drug-loaded embolization microspheres are selected from one or more of polyvinyl alcohol microspheres and gelatin microspheres; more preferably, the embolization microspheres are polyvinyl alcohol microspheres; more preferably, the embolization microspheres are CalliSpheres microspheres or 8Spheres microspheres. When the microsphere carrier is CalliSpheres microspheres, the single-load efficiency of the multinuclear platinum drugs (dianuclear platinum BBR3005, trinuclear platinum BBR3464) at the prepared drug dosage and concentration is 85%-98%, 55%-85% at 0.50 mg (5 mg / ml), 40%-60% at 0.75 mg (5 mg / ml), and 30%-46% at 1.00 mg (5 mg / ml), all of which are 1-2 times higher than those of oxaliplatin (OXA) and cisplatin at different prepared drug dosages. Based on the common adsorption mechanism of the microsphere carrier, other carriers selected from 8Spheres microspheres can achieve comparable drug loading efficiency when carrying the multinuclear platinum drugs.

[0010] When the microsphere carrier is CalliSpheres microspheres, the cumulative release of oxaliplatin (OXA) in PBS and 10% FBS is 85%-95% over 1-2 hours, exhibiting burst release; while dinuclear platinum BBR3005 and trinuclear platinum BBR3464 show a cumulative release of 15-20% over 1-2 hours and 60%-70% over 72 hours, exhibiting sustained release; based on the common adsorption mechanism of the microsphere carriers, other carriers selected from 8Spheres microspheres can achieve a similar sustained release effect when carrying the multinuclear platinum drugs.

[0011] Preferably, the cationic multinuclear platinum drug contains two or three platinum centers, selected from one or both of dinuclear platinum BBR3005 and trinuclear platinum BBR3464; preferably trinuclear platinum BBR3464.

[0012] Preferably, the particle size of the embolization microspheres is 100-300 μm.

[0013] More preferably, the cationic polynuclear platinum drug is loaded into the embolization microspheres via ion exchange and / or electrostatic adsorption, and the particle size change of the microspheres after loading is ≤5%.

[0014] In a further preferred embodiment, in a serum-containing release medium, the cumulative release of the cationic polynuclear platinum drug is 15%-20% within 1-2 hours and 55%-70% within 72 hours, exhibiting low early release and sustained release characteristics.

[0015] Secondly, the present invention provides a method for preparing the embolic microsphere formulation, comprising the following steps: Step 1: Pre-treat the anionic drug-loaded microspheres to remove the preservative solution; Step 2: Dissolve the cationic polynuclear platinum drug in water to prepare a drug solution; Step 3: Mix the pretreated embolization microspheres with the drug solution and incubate them to allow the drug to be adsorbed onto the microspheres; Step 4: Separate and wash the microspheres to remove free drug and obtain the embolization microsphere formulation.

[0016] Specifically, Step 1: Microsphere pretreatment: Take 100 μL of the embolic microspheres, centrifuge, discard the supernatant, and drain for later use; Step 2: Drug solution preparation: Dissolve the platinum-based drug in pure water to prepare a drug solution with a concentration of 5 mg / mL; Step 3: Incubation: Mix the pretreated embolic microspheres with different drug volumes (50, 100, 150, 200 μL) and incubate for a total of 30 min, shaking once every 5 min; Step 4: Purification: Centrifuge to collect the microspheres, wash with physiological saline 2-3 times to remove free drug, and obtain the formulation.

[0017] Preferably, the concentration of the drug solution in step 2 is 1-10 mg / mL; and the incubation time in step 3 is 10-60 minutes.

[0018] In a third aspect, the present invention provides the use of an embolization microsphere formulation carrying a cationic multinuclear platinum drug in the preparation of a drug for transcatheter arterial chemoembolization (TACE) for the treatment of malignant liver tumors.

[0019] The malignant liver tumor is primary liver cancer or metastatic liver tumor; the embolization microsphere formulation is delivered locally via the tumor-supplying artery to simultaneously achieve vascular embolization and local sustained release of multinucleated platinum drugs.

[0020] Compared with the prior art, the present invention achieves the following technical effects: 1. Improved drug loading efficiency: Taking 100 μL CalliSpheres wet microspheres, 5 mg / mL drug solution, and 30 min incubation as an example, the drug loading efficiencies of BBR3005 at preparation amounts of 0.25, 0.50, 0.75, and 1.00 mg were 93.39%, 59.78%, 42.81%, and 31.15%, respectively; while those of BBR3464 were 97.01%, 87.61%, 58.97%, and 45.79%, respectively, all of which were higher than those of oxaliplatin and cisplatin under the same conditions.

[0021] 2. Optimized Release Behavior: In PBS and release media containing 20% ​​fetal bovine serum, BBR3005 and BBR3464 drug-loaded microspheres cumulatively released approximately 15%-20% within 1-2 hours and approximately 60%-70% cumulatively after 72 hours; oxaliplatin drug-loaded microspheres released approximately 85%-90% in the early stages. Multinuclear platinum drug-loaded microspheres thus exhibited lower early release and sustained release characteristics.

[0022] 3. Stable microsphere structure: The average particle size change of CalliSpheres microspheres before and after drug loading is less than 5%, and they still maintain an intact spherical shape and a particle size range that is compatible with TACE operation after 72 h of release; SEM / EDS results show that platinum is distributed in the microsphere region, and no obvious microsphere breakage was observed.

[0023] 4. Clear electrical evidence: Apparent Zeta potential measurements performed under the same aqueous phase conditions allow for comparison of the electromigration trends of different platinum-based drugs. BBR3005 and BBR3464 exhibit a positive electrical trend, which is consistent with their high drug loading efficiency on anionic microspheres, providing supplementary evidence for ion exchange and electrostatic adsorption mechanisms.

[0024] 5. In vitro effects exhibit sustained-release characteristics: At the same total drug dosage, the cytotoxicity of the BBR3005 and BBR3464 drug-loaded microsphere groups appeared later than that of the free drug, consistent with the characteristic of gradual drug release from the microspheres. This application therefore describes this as a reduction in early free drug exposure and does not directly equate this in vitro result with a proven reduction in in vivo systemic toxicity.

[0025] 6. Simple preparation operation: The formulation can be prepared by directly incubating commercially available embolization microspheres with a drug aqueous solution without additional modification to the surface of the microspheres, which is convenient to connect with conventional drug loading operations. Attached Figure Description

[0026] For ease of explanation, the present invention will be described in detail below with reference to specific embodiments and accompanying drawings.

[0027] Figure 1 Structure, proton NMR spectrum, and mass spectra of dinuclear and trinuclear platinum compounds; Figure 2 Comparison of drug loading capacity and drug loading efficiency of different platinum-based drugs on CalliSpheres microspheres; Figure 3 SEM / EDS characterization images of CalliSpheres microspheres without drug loading and loaded with different platinum drugs; Figure 4 : Morphology and particle size changes of CalliSpheres microspheres before drug loading, after drug loading, and 72 h after release; Figure 5 Cumulative release curves of different platinum-based drug-loaded CalliSpheres microspheres in PBS and release media containing 20% ​​FBS; Figure 6 Figure: In vitro cytotoxicity results of free platinum drugs and CalliSpheres drug-loaded microspheres on HepG2 and AML12 cells. Detailed Implementation

[0028] The following are specific embodiments of the present invention, described in conjunction with the accompanying drawings, to further illustrate the technical solutions of the present invention. However, the present invention is not limited to these embodiments. Specific details, such as particular configurations, are provided in the following description merely to aid in a comprehensive understanding of the embodiments of the present invention. Therefore, those skilled in the art should understand that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of the present invention.

[0029] It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other.

[0030] Unless otherwise specified, the materials, practices, and experimental equipment involved in the embodiments of this invention are all commercially available products in the relevant chemical and biotechnology fields.

[0031] Example 1: Preparation of different platinum-based drug embolization microsphere formulations Materials: Commercially available CalliSpheres microspheres (particle size 100-300 μm); oxaliplatin (OXA), cisplatin, dinuclear platinum BBR3005, and trinuclear platinum BBR3464; physiological saline, ultrapure water, and PBS buffer. The structures of BBR3005 and BBR3464 were confirmed by ¹H-NMR and MS, and the characterization results are shown below. Figure 1 (Laboratory synthesis, such as) Figure 1 The product BBR3464, as shown in the spectrum, has a base peak of 100% abundance at m / z 329.90, which is a single platinum characteristic fragment resulting from the complete breakage of the trinuclear framework, reflecting a strong degree of fragmentation within the ion source. The next most abundant main peak at m / z 532.90 corresponds to the +2 hydrated / dechlorinated derivative ion of the intact trinuclear platinum parent nucleus. The peaks at m / z 461.70, 517.25, and 556.95 are binuclear characteristic fragments generated from the breakage of the Pt-Cl bonds at both ends. The high m / z peaks in the range of 697.20 to 1237.95 are high-order fragmented ions that retain most of the trinuclear framework. The distribution of all fragments is completely consistent with the fragmentation pattern of BBR3464 in the literature. The few impurities at the baseline are trace impurities. Based on the comprehensive analysis, it is determined that the target product BBR3464 was successfully synthesized in this study. The dinuclear platinum complex BBR3005 exhibits a 100% abundance base peak at m / z 706.95, which perfectly matches the theoretical mass-to-charge ratio of the intact dinuclear cation [M]²⁺, indicating it is the intact ion peak of the target molecule and confirming that the dinuclear platinum skeleton is the main component of the sample. The series of peaks in the m / z range of 535.55–680.95 represent characteristic fragments resulting from unilateral fracture of the dinuclear skeleton and the stepwise removal of ammonia / chlorine ligands. The high m / z peaks from 757.00–961.70 represent hydrated and sodium-derived ions from the parent compound. The distribution of all fragments matches the ESI fragmentation pattern of the dinuclear platinum-amine-chlorine-bridged complex. The low-abundance baseline impurities represent trace amounts of synthetic intermediates. Based on these findings, the target product BBR3005 was successfully synthesized.

[0032] Microsphere pretreatment: Take a CalliSpheres microsphere suspension containing 100 μL of wet microsphere deposition volume, place it in a 1.5 mL centrifuge tube, centrifuge at 1200 rpm for 4 min, discard the supernatant and drain for later use.

[0033] Drug solution preparation: Take OXA, cisplatin, BBR3005 and BBR3464 respectively and prepare 5 mg / mL drug solutions with ultrapure water; if necessary, use short-term sonication or vortexing to fully disperse or dissolve them.

[0034] Drug loading incubation: Add 50, 100, 150 or 200 μL of drug solution, corresponding to drug preparation amounts of 0.25, 0.50, 0.75 or 1.00 mg; incubate with 100 μL of pretreated microspheres for 30 min, gently shaking once every 5 min.

[0035] Purification and collection: After incubation, the microspheres were collected by centrifugation at 1200 rpm for 4 min; washed three times with physiological saline, and the supernatant and washing solution were combined for drug loading efficiency determination to obtain CalliSpheres-OXA, CalliSpheres-cisplatin, CalliSpheres-BBR3005 and CalliSpheres-BBR3464.

[0036] Subsequent experiments: The drug-loaded microspheres were suspended in physiological saline or the appropriate release medium as needed for the experiment, and characterization and release experiments were carried out as soon as possible after preparation.

[0037] Example 2 Physicochemical characterization of the formulation 1. Measurement of apparent Zeta potential in platinum-based drug solutions Measurement Method: OXA, cisplatin, BBR3005, and BBR3464 were prepared into 5 mg / mL solutions with ultrapure water. After equilibration at 25°C for 2 min, the apparent Zeta potential was measured using the same model of Zeta potential analyzer and the same capillary sample cell. Each sample was measured independently in triplicate, and the results are expressed as mean ± standard deviation. Given that the analytes are small molecules or ionic complexes, this embodiment describes the result as "apparent Zeta potential" for comparing their electromigration trends under the same conditions.

[0038] Table 1. Apparent Zeta potentials of different platinum-based drugs in ultrapure water.

[0039] Results: The apparent Zeta potentials of OXA, cisplatin, BBR3005, and BBR3464 were 1.396 ± 0.63, 5.96 ± 0.25, 24.76 ± 0.79, and 38.84 ± 0.39 mV, respectively. Both BBR3005 and BBR3464 exhibited a positive electromigration trend; this result is consistent with their high drug loading efficiency on anionic CalliSpheres microspheres.

[0040] 2. Drug loading and efficiency determination: The supernatant and washing solution after drug loading were collected, and the microspheres and liquid phase samples were digested separately. The platinum content was determined by ICP-MS. Drug loading was calculated as the difference between the total amount of drug loaded and the amount of unloaded drug in the liquid phase, and drug loading efficiency was calculated as the percentage of drug loaded to the total amount of drug loaded. The results are as follows: Figure 2As shown, the drug loading efficiencies of OXA at ​​preparation doses of 0.25, 0.50, 0.75, and 1.00 mg were 48.40%, 30.95%, 26.35%, and 24.43%, respectively; those of cisplatin were 33.48%, 21.23%, 15.65%, and 14.96%; those of BBR3005 were 93.39%, 59.78%, 42.81%, and 31.15%; and those of BBR3464 were 97.01%, 87.61%, 58.97%, and 45.79%.

[0041] 3. SEM / EDS characterization: Unloaded microspheres and small amounts of each drug-loaded microsphere were taken, naturally dried, and then observed and analyzed using scanning electron microscopy and elemental surface distribution. Results are as follows: Figure 3 As shown, the microspheres generally maintain their spherical shape after drug loading; the Pt elemental signals of the BBR3005 and BBR3464 groups are distributed in the microsphere region, indicating that polynuclear platinum has been loaded onto the microspheres. This result is used to demonstrate morphological preservation and platinum elemental distribution, and is not used to infer specific chemical bond types.

[0042] 4. Particle size determination: The particle size of unloaded microspheres, loaded microspheres, and microspheres after 72 hours of release was determined using a microscope. Results are as follows: Figure 4 As shown, the average particle size of the unloaded microspheres was 256.73 ± 31.66 μm; the average particle sizes of CalliSpheres-OXA, CalliSpheres-BBR3005, and CalliSpheres-BBR3464 after drug loading were 266.58 ± 35.03, 262.09 ± 28.06, and 264.20 ± 26.06 μm, respectively; and after 72 h of release, the average particle sizes were 260.99 ± 27.87, 260.56 ± 27.90, and 255.79 ± 36.92 μm, respectively. The changes in average particle size before and after drug loading and release were all less than 5%, indicating that the microspheres remained generally stable.

[0043] Example 3 Drug Release Experiment Experimental groups: A PBS group and a PBS group containing 20% ​​fetal bovine serum were set up. Each group included CalliSpheres-OXA, CalliSpheres-BBR3005 and CalliSpheres-BBR3464, and three parallel samples were set up for each formulation.

[0044] Experimental Methods: Drug-loaded microspheres were placed in an inner tube that allowed for the exchange of release medium but prevented microsphere escape. 3 mL of release medium was added to the outer tube, and the mixture was incubated at 37°C and 100 rpm. Samples of 300 μL were taken at 0.25, 0.5, 1, 4, 8, 12, 24, 36, 48, and 72 h, and an equal volume of fresh medium was added. After sample digestion, the platinum content was determined by ICP-MS. Correction was performed based on the sample replenishment, and the cumulative release rate was calculated.

[0045] The results are as follows Figure 5 As shown, CalliSpheres-OXA achieved approximately 85%-90% cumulative release in the initial release phase, exhibiting a significantly rapid release; CalliSpheres-BBR3005 and CalliSpheres-BBR3464 showed approximately 15%-20% cumulative release within 1-2 hours and approximately 60%-70% cumulative release after 72 hours. Both polynuclear platinum-containing formulations showed a sustained release trend in both PBS and media containing 20% ​​FBS.

[0046] Example 4: In vitro cytotoxicity assay (MTT assay) Cell culture: HepG2 hepatocellular carcinoma cells and AML12 normal hepatocytes were seeded in 96-well plates, 1 × 10⁶ cells per well. 4 Cells were cultured at 37°C and 5% CO2 for 12 h.

[0047] Drug treatment: Free OXA, cisplatin, BBR3005, BBR3464 and the corresponding multinuclear platinum drug-loaded microspheres were added to make the final platinum concentrations calculated based on the total amount of drugs 3.125, 6.25, 12.5, 25, 50, 100 and 200 μM respectively; culture medium control and unloaded microsphere control were set up, with 3 parallel wells in each group.

[0048] Incubation and detection: After 48 h or 72 h of treatment, MTT solution was added and incubation continued for 4 h. The supernatant was discarded, and DMSO was added to dissolve and crystallize the cells. The absorbance at 490 nm was measured, and cell viability and IC50 were calculated. 50 .

[0049] The results are as follows Figure 6 As shown. For HepG2 cells, the IC50 values ​​of free OXA, cisplatin, BBR3005, and BBR3464 at 48 h were [indicative of the desired effect]. 50 The concentrations were 25, 10.67, 6.3, and 3.9 μM, respectively; the drug-loaded microspheres of BBR3005 and BBR3464 did not reach the IC50 threshold within 48 h. 50 , in 72 h IC 50 The concentrations were 87.55 and 41.03 μM, respectively. For AML12 cells, the IC50 values ​​of free OXA, cisplatin, BBR3005, and BBR3464 at 48 h were... 50The concentrations were 15, 7.9, 3.3, and 2.2 μM, respectively; the IC50 values ​​of BBR3005 and BBR3464 drug-loaded microspheres at 48 h were [missing information]. 50 The concentrations were 81 and 61.36 μM, respectively, and 59.62 and 33.81 μM at 72 h. Compared with the free drug, the cytotoxicity of the drug-loaded microsphere group was delayed, consistent with the characteristics of sustained release.

[0050] Those skilled in the art to which this application pertains may modify or supplement the specific embodiments described or use similar methods to replace them, but without departing from the inventive concept of this application or exceeding the scope defined by the appended claims.

Claims

1. An embolic microsphere formulation carrying a multinuclear platinum-based drug, characterized in that, The invention includes anionic drug-loaded embolization microspheres and cationic polynuclear platinum drugs adsorbed in the embolization microspheres; the embolization microspheres contain anionic groups capable of ion exchange and / or electrostatic adsorption with the cationic drugs.

2. The embolic microsphere formulation according to claim 1, characterized in that, The anionic drug-loaded embolization microspheres are selected from one or more of polyvinyl alcohol microspheres and gelatin microspheres.

3. The embolic microsphere formulation according to claim 1 or 2, characterized in that, The cationic multinuclear platinum-based drug contains two or three platinum centers, selected from one or both of dinuclear platinum BBR3005 and trinuclear platinum BBR3464.

4. The embolic microsphere formulation according to any one of claims 1-3, characterized in that, The embolization microspheres have a particle size of 100-300 μm.

5. The embolic microsphere formulation according to any one of claims 1-4, characterized in that, The cationic multinuclear platinum drug is loaded into the embolization microspheres via ion exchange and / or electrostatic adsorption, and the particle size change of the microspheres after loading is ≤5%.

6. The embolic microsphere formulation according to any one of claims 1-5, characterized in that, In a serum-containing release medium, the cumulative release of the cationic polynuclear platinum drug is 15%-20% within 1-2 hours and 60%-70% within 72 hours, exhibiting low early release and sustained release characteristics.

7. A method for preparing the embolic microsphere formulation according to any one of claims 1-6, characterized in that, Includes the following steps: Step 1: Pre-treat the anionic drug-loaded microspheres to remove the preservative solution; Step 2: Dissolve the cationic polynuclear platinum drug in water to prepare a drug solution; Step 3: Mix the pretreated embolization microspheres with the drug solution and incubate them to allow the drug to be adsorbed onto the microspheres; Step 4: Separate and wash the microspheres to remove free drug and obtain the embolization microsphere formulation.

8. The method according to claim 7, characterized in that, The concentration of the drug solution in step 2 is 1-10 mg / mL; the incubation time in step 3 is 10-60 minutes.

9. The use of the embolization microsphere formulation according to any one of claims 1-6 or the embolization microsphere formulation prepared by the method according to any one of claims 7-8 in the preparation of a medicament for the treatment of malignant liver tumors by transcatheter arterial chemoembolization.

10. The application according to claim 9, characterized in that, The malignant liver tumor is primary liver cancer or metastatic liver tumor; the embolization microsphere formulation is delivered locally via the tumor-supplying artery to simultaneously achieve vascular embolization and local sustained release of multinucleated platinum drugs.

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