Active metal microsphere and composite embolic agent based on active metal microsphere

Abstract

To provide a preparation for tumors and a method for preparing the same.SOLUTION: A tumor preparation, characterized in that the tumor preparation comprises active metal microspheres, wherein the active metal microspheres are prepared from an active metal, and the active metal has a metal activity stronger than that of hydrogen and is selected from at least one of magnesium, zinc, gallium, manganese and tin. Preferably, the active metal microsphere has a particle size of 0.1 to 500 microns.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS The present invention belongs to the field of pharmaceutical technology, and particularly relates to an iodine oil-based active metal microsphere or nanohydride composite embolic agent and its preparation method and application.

[0002] The present invention relates to active metal microspheres, composite suppositories based on active metal microspheres, nanohydrides, composite suppositories based on nanohydrides, metal composite structures, and composite suppositories based on metal composite structures. [Background technology]

[0003] Cancer, which kills millions of people worldwide each year, is one of the most dangerous diseases facing humanity today. Among many cancers, liver cancer, in particular, is often incurable through conventional antitumor treatments such as surgical resection, organ transplantation, radiation therapy, and chemotherapy due to its insidious onset, high malignancy, invasiveness, rapid growth, high recurrence rate, and high mortality rate. In recent years, tumor interventional therapy has attracted widespread attention due to its excellent therapeutic efficacy and minimal side effects. Transcatheter arterial embolization (TAE), which efficiently delivers embolic agents and chemotherapy agents to tumor-proximal arteries through superselective arterial perfusion, is one of the most effective methods of targeted drug delivery and is considered the standard treatment for some mid- to late-stage solid tumors. However, the high heterogeneity of HCC and its vasculature hinders the therapeutic response of HCC tissue with a low blood supply. After TAE / TACE (transcatheter chemoembolization) or combined drug therapy, hypoxia-resistant HCC cells and tumor-derived stem cells (CSLCs) accumulate in HCC lesions, leading to the failure of TAE treatment. Furthermore, the hypoxic, weakly acidic, and immunosuppressive microenvironment caused by arterial embolization promotes the rapid proliferation, metastasis, and drug resistance of HCC cells, preventing complete eradication of HCC. Therefore, TAE / TACE treatment is often accompanied by problems such as incomplete tumor necrosis, recurrence, metastasis, and poor patient survival rates, significantly limiting its applicability.

[0004] In recent years, immunotherapy, a therapy that fights cancer by activating the patient's immune system, has shown great promise in the field of tumor treatment. In immunotherapy, cytotoxic T lymphocytes (CTLs) play a key role in attacking tumor cells. However, the complex tumor microenvironment (TME), including vascular abnormalities, acidic pH, hypoxia, and high concentrations of reactive oxygen species (ROS), significantly limits the activity and killing capacity of CTLs within solid tumors. Meanwhile, the above physiological characteristics of the TME promote the infiltration of various immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), tumor antigen receptors (TAMs), and regulatory T cells (Tregs), creating an immunosuppressive microenvironment. The immunosuppressive TME is one of the major barriers that significantly hinders tumor immunotherapy. Therefore, modulating the TME through multiple pathways has been considered an attractive strategy to improve the efficacy of various cancer treatments, especially tumor immunotherapy.

[0005] Hydrogen (H2), an endogenous gas, plays important physiological and pathological regulatory roles. Over the past decade, its high biodiffusion capacity has demonstrated its significant therapeutic benefits in both anti-inflammatory and anti-tumor areas. However, due to its low solubility, current hydrogen delivery methods, such as oral hydrogen water, injectable hydrogen salts, and hydrogen inhalation therapy, are unable to achieve the required doses for effective treatment. This necessitates the development of novel hydrogen carriers and delivery strategies. The reaction of activated metal (potassium, calcium, sodium, magnesium, aluminum, zinc, gallium, iron, manganese, tin, etc.) microspheres or metal hydride materials (calcium, magnesium, lithium, sodium, potassium, strontium, cerium hydride, etc.) with water efficiently releases hydrogen and simultaneously generates hydrides, neutralizing the acidic tumor microenvironment and activating the immune system, thereby achieving microenvironmental modulation through enhanced hydrogen-immune synergy. However, these active metals and metal hydrides are too active in aqueous systems and are unstable, with some even exploding when in direct contact with water, making them generally considered difficult to use in tumor treatment. Summary of the Invention

[0006] To solve the above technical problems, the present invention provides a composite embolic agent and its preparation method and application. After the composite embolic agent provided by the present invention is delivered to liver cancer lesions by interventional procedures, the iodine oil is deposited in the liver cancer tissue to induce embolization therapy, the active metal or hydride releases hydrogen in situ to induce hydrogen therapy, and the hydroxide ions are released to regulate the immune microenvironment and enhance the effect of embolization therapy.

[0007] In this invention, magnesium microspheres or nano-calcium hydride were selected as the formulations under investigation and dispersed in clinical iodine oil suppositories. The resulting composite embolic agent has excellent chemical stability, a slower reaction rate when mixed with an aqueous solution, and can gently and continuously generate hydrogen gas. When used in tumor interventional embolization therapy, this invention provides iodine oil microspheres or nano-calcium hydride composite embolic agents that can synchronously and continuously generate hydrogen gas within the tumor, thereby achieving the function of hydrogen therapy and further improving the tumor microenvironment by neutralizing the acidic environment of the tumor, resulting in significantly improved therapeutic effects compared to iodine oil perfusion alone.

[0008] The first objective of the present invention is to provide an iodine oil-based metal microsphere or nano-hydride composite embolic agent, which comprises active metal microspheres or nano-hydride material and iodine oil as a dispersing and protecting agent, where the mass percentage of the active metal microspheres or nano-hydride material in the composite embolic agent is 0.1-10%. The iodine oil is a medical embolic agent, and the iodine oil has dispersing and protecting functions. The iodine oil protects the active metal and hydride and slows the reaction rate with water, thereby achieving sustained release of hydrogen and hydride, and fulfilling the function of long-term treatment.

[0009] In one embodiment of the present invention, the active metal microspheres have a size of 0.1 to 20 microns.

[0010] In one embodiment of the present invention, the active metal microspheres have a size of 20 to 500 microns.

[0011] In one embodiment of the present invention, the active metal microspheres have a size of 0.1 microns or greater, 5 microns or greater, 10 microns or greater, 20 microns or greater, 50 microns or greater, 100 microns or greater, 150 microns or greater, 200 microns or greater, 250 microns or greater, 300 microns or greater, 350 microns or greater, 400 microns or greater, 450 microns or greater, up to 500 microns.

[0012] In one embodiment of the present invention, the nano-hydride has a particle size of 5 to 200 nanometers.

[0013] In one embodiment of the present invention, 5 to 200 nm corresponds to 0.005 to 0.2 microns.

[0014] In one embodiment of the present invention, the nano-hydride material has a particle size of 0.2 to 500 microns.

[0015] In one embodiment of the present invention, the active metal microspheres have a size of 0.1 microns or greater, 0.005 microns or greater, 0.01 microns or greater, 0.05 microns or greater, 0.1 microns or greater, 0.5 microns or greater, 1 micron or greater, 5 microns or greater, 10 microns or greater, 20 microns or greater, 50 microns or greater, 100 microns or greater, 150 microns or greater, 200 microns or greater, 250 microns or greater, 300 microns or greater, 350 microns or greater, 400 microns or greater, 450 microns or greater, up to 500 microns.

[0016] If the particle size of the microspheres is too large, they cannot be dispersed well in the dispersing agent and cannot be applied well in clinical practice.

[0017] In one embodiment of the present invention, the active metal microspheres are prepared by an aerosolization powdering method, that is, an active metal ingot is heated and melted, and then atomized and cooled to obtain active metal microspheres.

[0018] In one embodiment of the present invention, the nano-hydride material is prepared by a liquid-phase exfoliation method, i.e., ultrasonically dispersing a metal hydride in an exfoliation solvent for 0.2 to 4 hours, followed by centrifugation to obtain the nano-hydride material.

[0019] In one embodiment of the present invention, the ultrasonic power is 50-100W and the operating temperature is 10-20°C.

[0020] In one embodiment of the present invention, the ratio of the amount of the metal hydride to the amount of the stripping solvent (M 質量(mg) :V 体積(mL) ) is 0.1:1 to 10:1.

[0021] In one embodiment of the present invention, the active metal is one or more of potassium, calcium, sodium, magnesium, aluminum, zinc, gallium, iron, manganese and tin.

[0022] In one embodiment of the present invention, the metal hydride is one or more of calcium hydride, magnesium hydride, lithium hydride, sodium hydride, potassium hydride, strontium hydride, and cerium hydride.

[0023] In one embodiment of the present invention, the stripping solvent is one or more of N-methylpyrrolidone, dimethyl sulfoxide or polyethylene glycol 200, pyrrole and N,N-dimethylformamide.

[0024] A second object of the present invention is to provide a method for preparing an iodine oil-based active metal microsphere or nanohydride composite embolic agent, the method comprising the steps of mixing active metal microspheres or nanohydride material with iodine oil and uniformly dispersing them by ultrasonic treatment to obtain the iodine oil-based active metal microsphere or nanohydride composite embolic agent.

[0025] The third object of the present invention is to provide the application of said iodine oil-based active metal microspheres or nanohydride composite embolic agent in preparing an embolization therapeutic agent for liver cancer.

[0026] A fourth object of the present invention is to provide active metal microspheres, which have a stronger metal activity than hydrogen.

[0027] Furthermore, the active metal microspheres have a particle size of 0.1 to 500 microns.

[0028] Furthermore, the metal of the active metal microspheres is one or more selected from potassium, calcium, sodium, magnesium, aluminum, zinc, gallium, iron, manganese, and tin.

[0029] Furthermore, the shape of the active metal microspheres may be spherical, mesoporous, urchin-like, or polyhedral.

[0030] A fifth object of the present invention is to provide a composite embolic agent containing active metal microspheres.

[0031] Furthermore, the composite embolic agent further comprises a dispersing agent.

[0032] Furthermore, the mass ratio of the active metal microspheres to the dispersant is 0.1:100 to 50:100.

[0033] Furthermore, the dispersant is an organic phase.

[0034] Furthermore, the dispersant is an oil phase.

[0035] Further, the dispersant is selected from one or more of iodine oil, poppy seed oil, soybean oil and olive oil.

[0036] A sixth object of the present invention is to provide a nano-hydride, the nano-hydride having a particle size of 0.005 to 1 micron.

[0037] Further, the nanohydrides are selected from one or more of calcium hydride, magnesium hydride, lithium hydride, sodium hydride, potassium hydride, strontium hydride and cerium hydride.

[0038] A seventh object of the present invention is to provide a composite embolic agent, which comprises a nanohydride.

[0039] Furthermore, the composite embolic agent further comprises a dispersing agent.

[0040] Furthermore, the mass ratio of the nano-hydride to the dispersant is 0.1:100 to 50:100.

[0041] Furthermore, the dispersant is an organic phase.

[0042] Furthermore, the dispersant is an oil phase.

[0043] Further, the dispersant is selected from one or more of iodine oil, poppy seed oil, soybean oil and olive oil.

[0044] An eighth object of the present invention is to provide an anti-tumor preparation comprising active metal microspheres.

[0045] A ninth object of the present invention is to provide a tumor preparation comprising a composite embolic agent, said composite embolic agent comprising activated metal microspheres.

[0046] A tenth object of the present invention is to provide an anti-tumor preparation comprising nanohydrides.

[0047] An eleventh object of the present invention is to provide a tumor preparation comprising a composite embolic agent, said composite embolic agent comprising said nanohydride.

[0048] A twelfth object of the present invention is to provide a metal composite structure, the metal composite structure comprising a core structure and a bonding layer bonded to a surface of the core structure, the core structure being a first metal, the bonding layer being a second metal, and the first metal being an active metal different from the second metal.

[0049] Furthermore, the core structure has a spherical shape, a polyhedral shape, a porous structure, or a rod shape.

[0050] Furthermore, the first metal has a metal activity that is stronger than hydrogen activity, ie, the first metal reacts with water to produce hydrogen.

[0051] Furthermore, the first metal is selected from at least one of potassium, calcium, sodium, magnesium, aluminum, zinc, gallium, iron, manganese, and tin.

[0052] Furthermore, the second metal has a metal activity that is less than the activity of hydrogen.

[0053] Furthermore, the second metal is selected from one or more of copper, silver, platinum and gold.

[0054] Furthermore, the metal composite structure has a minor axis of 0.1 to 500 microns.

[0055] Furthermore, the metal composite structure has a minor axis of 0.1 microns or more, 0.005 microns or more, 0.01 microns or more, 0.05 microns or more, 0.1 microns or more, 0.5 microns or more, 1 micron or more, 5 microns or more, 10 microns or more, 20 microns or more, 50 microns or more, and 100 microns or less, 150 microns or more, 200 microns or more, 250 microns or more, 300 microns or more, 350 microns or more, 400 microns or more, 450 microns or more, and 500 microns or less.

[0056] When the core structure of the metal composite structure has a spherical shape, the minor axis of the metal composite structure is the particle diameter.

[0057] Furthermore, the grain size of the metal composite structure is uniformly distributed.

[0058] A thirteenth object of the present invention is to provide a composite embolic agent, which comprises the metal composite structure and a dispersing agent, and the metal composite structure is dispersed in the dispersing agent.

[0059] Furthermore, the metal composite structure is uniformly dispersed in the dispersant.

[0060] Furthermore, the mass ratio of the metal composite structure to the dispersant is 0.1:100 to 50:100, that is, the mass fraction of the metal composite structure in the dispersant is 0.1% to 50%.

[0061] Furthermore, the mass fraction of the metal composite structure in the organic phase is 0.1% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, and 50% or less.

[0062] Furthermore, the dispersant is an organic phase.

[0063] Furthermore, the organic phase is an oil phase.

[0064] Furthermore, the oil phase is selected from at least one of iodine oil, poppy seed oil, soybean oil, and olive oil.

[0065] A fourteenth object of the present invention is to provide a method for preparing a metal composite structure comprising the step of bonding said second metal to the surface of said first metal.

[0066] Additionally, physical or chemical methods are used to bond the second metal to the surface of the first metal.

[0067] Furthermore, said chemical method is selected from substitution methods.

[0068] The substitution method further comprises subjecting the first metal to a solution containing ions of a higher valence state of the second metal.

[0069] Furthermore, the solution containing the high-valent ions of the second metal contains one or more of chloroaurate ions, chloroplatinate ions, copper ions, and silver ions. In the method for preparing the metal composite structure, the efficiency of the metal substitution can be promoted by shaking, ultrasonication, or the like.

[0070] Furthermore, the physical method is a mechanical stirring method.

[0071] Specifically, the mechanical stirring method comprises mixing and stirring the second metal in a solid state and the first metal in a liquid state.

[0072] Furthermore, the physical method may be a vapor deposition method.

[0073] A fifteenth object of the present invention is to provide a method for preparing a composite embolic agent, which comprises a step of dispersing the metal composite structure in the dispersing agent.

[0074] Furthermore, the method for preparing the composite embolic agent of the present invention further comprises an ultrasonic dispersion step.

[0075] A sixteenth object of the present invention is to provide alloy metal particles, which contain at least two metals with different activities, and the two metals with different activities are mixed in an alloy state.

[0076] Furthermore, the alloying metal particles include at least one active metal monomer and at least one inactive metal monomer, the active metal monomer being alloyingly mixed with the inactive metal monomer.

[0077] Furthermore, the active metal monomer has a metal activity greater than its hydrogen activity.

[0078] Furthermore, the active metal monomer is selected from one or more of potassium, calcium, sodium, magnesium, aluminum, zinc, gallium, iron, manganese, and tin.

[0079] Furthermore, the inert metal monomer has a metal activity that is less than its hydrogen activity.

[0080] Furthermore, the inert metal monomer is selected from at least one of copper, silver, platinum, and gold.

[0081] Furthermore, the alloying metal particles have a spherical shape, a polyhedral shape, a porous structure, a sea urchin shape, or a rod shape.

[0082] Furthermore, the alloy metal particles have a minor axis of 0.1 to 500 microns.

[0083] Furthermore, the alloying metal particles have a minor axis of 0.1 microns or greater, 0.005 microns or greater, 0.01 microns or greater, 0.05 microns or greater, 0.1 microns or greater, 0.5 microns or greater, 1 micron or greater, 5 microns or greater, 10 microns or greater, 20 microns or greater, 50 microns or greater, and 100 microns or less, 150 microns or greater, 200 microns or greater, 250 microns or greater, 300 microns or greater, 350 microns or greater, 400 microns or greater, 450 microns or greater, and 500 microns or less.

[0084] When the alloying metal particles are spherical, the minor axis of the alloying metal particles is the particle diameter.

[0085] Here, the alloy metal nanoparticles can be purchased commercially or can be prepared by an existing alloy preparation method.

[0086] A seventeenth object of the present invention is to provide a composite embolic agent comprising the alloy metal particles and a dispersant, wherein the alloy metal particles are dispersed in the dispersant.

[0087] Furthermore, the alloying metal particles are uniformly dispersed in the dispersant.

[0088] Furthermore, the dispersant is an organic phase.

[0089] Furthermore, the organic phase is an oil phase.

[0090] Furthermore, the oil phase is one or more selected from iodine oil, poppy seed oil, soybean oil and olive oil.

[0091] Furthermore, the mass fraction of the alloy metal particles in the dispersant is 0.1% to 50%.

[0092] An eighteenth object of the present invention is to provide a method for preparing a composite embolic agent, comprising the step of mixing said alloying metal particles with said dispersing agent.

[0093] Furthermore, the preparation method further comprises an ultrasonic dispersion step.

[0094] A nineteenth object of the present invention is to provide a method for treating tumors using a composite embolic agent comprising a metal composite structure for tumor embolization therapy.

[0095] A twentieth object of the present invention is to provide a method for treating tumors using a composite embolic agent containing alloy metal particles for tumor embolization therapy.

[0096] The inventors have experimentally confirmed that metal microspheres, nanohydrides, metal composite structures, and alloy metal particles cannot be effectively dispersed when their mass fraction in the dispersant exceeds 50%, making catheter injection for practical use difficult.

[0097] A twenty-first object of the present invention is to provide a method for tumor therapy using a composite embolic agent containing metal microspheres for the treatment of liver cancer, kidney cancer, pancreatic cancer, lung cancer, and pelvic malignant tumors.

[0098] A twenty-second object of the present invention is to provide a tumor treatment method using a composite embolic agent containing a metal composite structure for the treatment of liver cancer, kidney cancer, pancreatic cancer, lung cancer, and pelvic malignant tumors.

[0099] A twenty-third object of the present invention is to provide a tumor treatment method using a composite embolic agent containing alloy metal particles for the treatment of liver cancer, kidney cancer, pancreatic cancer, lung cancer, and pelvic malignant tumors.

[0100] A twenty-fourth object of the present invention is to provide a tumor treatment kit containing a composite embolic agent comprising metal microspheres, metal composite structures or alloy metal particles.

[0101] Compared with the prior art, the beneficial effects of the above technical solution provided by the present invention include, but are not limited to:

[0102] The present invention provides a composite embolic agent and a method for preparing it, in which active metal microspheres or nano-metal hydride are dispersed in different ratios in an iodine oil embolic agent. The resulting composite embolic agent has excellent chemical stability. Even when mixed with an aqueous solution, the reaction rate is slower, resulting in gentle, continuous hydrogen generation, thereby solving the problem of uncontrollable violent reactions between active metal microspheres or nano-metal hydride materials and water. In this invention, the iodine oil microspheres or nano-metal hydride composite embolic agent is administered locally to liver cancer tissue via interventional procedures, and iodine oil is deposited in the liver cancer tissue to perform embolization therapy. The active metal microspheres or nano-metal hydride continuously generate hydrogen within the tumor, achieving the function of hydrogen therapy. At the same time, the released hydride neutralizes the weakly acidic tumor microenvironment, improving the tumor microenvironment and amplifying the effects of embolization therapy, significantly improving the therapeutic effect compared to iodine oil perfusion alone.

[0103] In this invention, magnesium microspheres or nano calcium hydride were selected as the preparations to be investigated and dispersed in clinical suppository iodine oil, and the obtained composite preparations have good chemical stability.

[0104] The active metal composite structure or alloy metal particles, with their large particle size, have a high reaction efficiency, and the composite embolic agent combined with iodine oil significantly improves the tumor microenvironment and enhances the efficacy of embolization therapy. Selecting different metals to prepare the metal composite structure or alloy particles has additional effects, such as improving the immune microenvironment and increasing retention. The use of active metal composite structures or alloy metal particles mixed with a dispersing agent in embolization therapy allows for the combination of embolization therapy and hydrogen therapy, significantly improving the efficacy of embolization therapy while resolving the problem of the instability of active metals in physiological environments and improving the safety of active metals in tumor treatment. The composite embolic agent described in the present invention is easy to prepare and clinically applicable. [Brief explanation of the drawings]

[0105] In order to make the contents of the present invention more clearly understandable, the present invention will be described in more detail below according to specific embodiments of the present invention in conjunction with the accompanying drawings. [Figure 1] 1 is a micrograph of the magnesium metal microspheres obtained in Example 1 of the present invention. [Figure 2] 1 shows photographs of hydrogen release evaluation of the metallic magnesium microspheres obtained in Example 1 of the present invention in different buffer solutions. [Figure 3] 1 is a transmission electron microscope (TEM) photograph of calcium hydride nanoparticles obtained in Example 2 of the present invention. [Figure 4] 1 is an X-ray diffraction diagram (XRD) of calcium hydride nanoparticles obtained in Example 2 of the present invention. [Figure 5] 1 is an optical photograph of the magnesium metal microsphere-iodine oil composite embolic agent obtained in Example 1 of the present invention. [Figure 6] 1 is an optical photograph of the nano-calcium hydride-iodine oil composite embolic agent obtained in embodiment 2 of the present invention. [Figure 7] 1 shows an evaluation of hydrogen release from the calcium hydride-iodine oil composite bolus preparation obtained in Example 2 of the present invention. [Figure 8]FIG. 1 is a schematic diagram of an interventional procedure for rabbit liver cancer in Application Example 1 of the present invention. [Figure 9] 10 is a DSA image of a liver cancer lesion during an interventional procedure in a rabbit in Application Example 1 of the present invention. [Figure 10] 1 shows CT images of liver cancer lesions in rabbits before and after embolization using the magnesium microsphere-iodine oil composite embolic agent obtained in Application Example 1 of the present invention. [Figure 11] 10 shows CT images of liver cancer lesions in a rabbit before and after embolization using the nano-calcium hydride-iodine oil composite embolic agent obtained in the second embodiment of the present invention. [Figure 12] 18F-FDG PET images of a liver cancer lesion in a rabbit before and after embolization using the nano-calcium hydroxide-iodine oil composite embolic agent obtained in embodiment 2 of the present invention. [Figure 13] 18 shows the 18F-FDG intensity of liver cancer lesions in rabbits before and after embolization using the nano-calcium hydride-iodine oil composite embolic agent obtained in embodiment 2 of the present invention. [Figure 14] 1 shows an immunohistochemical analysis of an isolated liver cancer lesion 7 days after embolization of a rabbit using the nano-calcium hydride-iodine oil composite embolic agent obtained in embodiment 2 of the present invention. [Figure 15] 10 shows the apoptosis level in a solitary focus of hepatocellular carcinoma 7 days after embolization of a rabbit using the nano-calcium hydride-iodine oil composite embolic agent obtained in embodiment 2 of the present invention. [Figure 16] 1 shows the proliferation activity in a solitary focus of hepatocellular carcinoma 7 days after embolization using the nano-calcium hydride-iodine oil composite embolic agent obtained in embodiment 2 of the present invention in a rabbit. [Figure 17] 1 shows the particle size distribution of the magnesium-platinum metal composite structure described in Example 3 of the present invention. [Figure 18] 1 is a graph of hydrogen yield statistics in 96% ethanol solution of magnesium microspheres tested in Example 4 and the Mg@Pt composite structure obtained in Example 3 of the present invention. [Figure 19]1 is a graph showing tumor growth curves of mice statistically obtained in Example 6 of the present invention using the Mg@Pt metal composite structure-iodine oil composite embolization therapy prepared in Example 3 for tumor treatment in mice. [Figure 20] 10 is a scanning electron microscope image of raw magnesium microspheres and Mg@Pt composite structure in Example 7 of the present invention. [Figure 21] 1 is an XRD powder diffraction spectrum of the magnesium-platinum metal composite structure prepared in Example 8 of the present invention. [Figure 22] 10 is a graph showing the measurement of the total amount of hydrogen evolution in a phosphate buffer solution for the Mg@platinum metal composite structure prepared by testing in Example 8 in Example 9 of the present invention. [Figure 23] 1 is a statistical graph of particle size distribution of large magnesium microspheres in Example 15 of the present invention. [Figure 24] 16 is a graph showing the total hydrogen generation curves determined when the magnesium microspheres in Example 15 of the present invention are placed in buffer solutions under different pH conditions and detected by gas chromatography in Example 16 of the present invention. [Figure 25] 1 is a graph showing the particle size distribution of magnesium microspheres in Example 18 of the present invention. [Figure 26] 10 is a graph of the amount of hydrogen produced by magnesium microspheres in buffer solutions of different pH as a function of time in Example 18 of the present invention. [Figure 27] 19 shows detection images of the rabbit liver cancer model after establishment of the rabbit liver cancer model in Example 19 and after application of a composite embolic agent to the rabbit liver cancer model. The image on the left is a detection image of the rabbit liver cancer model in Example 19 after establishment of the rabbit liver cancer model, and the image on the right is a detection image of the rabbit liver cancer model showing vascular embolism after application of a composite embolic agent to the rabbit liver cancer model. [Figure 28] 10 shows ultrasound images before and after delivery of magnesium microspheres to the lesion site in Example 19 of the present invention. [Figure 29] CT image data at various times before and after treatment in Example 19.1 of the present invention and corresponding Example 19.2. [Figure 30] 1 is an X-ray diffraction pattern of the manganese-platinum metal composite structure of the present invention. [Figure 31] 1 is a statistical graph of hydrogen production content of the manganese metal and metal composite structure of the present invention at different time points in phosphate buffer solution. [Figure 32] 1 shows tumor growth curves of different groups of mice in Example 22 of the present invention. [Figure 33] 10 is a statistical graph showing the residual magnesium content at different time points in the tumor site of mice after intratumoral injection of the magnesium microsphere-iodine oil composite embolic agent in Example 23 of the present invention. [Figure 34] 1 is a graph showing the time course of intratumoral pH in mice in Example 24 of the present invention. [Figure 35] 10 is a graph showing statistics of the amount of hydrogen produced by magnesium-platinum metal composite structures with different ratios in solution for 24 hours in Example 25 of the present invention. [Figure 36] 10 is a graph showing statistics of the amount of hydrogen produced by manganese-platinum metal composite structures with different ratios in solution for 24 hours in Example 26 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0106] The present invention will now be further described in connection with the accompanying drawings and specific embodiments so that those skilled in the art can better understand and practice the present invention, but the cited embodiments should not be construed as limiting the present invention.

[0107] In order to more precisely describe the technical solutions of the above invention, specific embodiments are given below to demonstrate the technical effects. However, it should be emphasized that these embodiments are for the purpose of illustrating the present invention and do not limit the scope of the present invention.

[0108] As used herein and in the claims, the terms "a," "one," "one," and / or "the" do not specifically refer to the singular and may include the plural, unless the context clearly suggests otherwise. The terms "comprising" and "consisting of" merely imply the inclusion of the specifically identified elements and do not constitute an exclusive list; the device may include other elements. The term "one embodiment" means "at least one embodiment," and the term "another embodiment" means "at least one other embodiment." Relevant definitions of other terms are provided below.

[0109] The test equipment and test method used in the embodiments of this specification are as follows. Morphological characterization: transmission electron microscope (FEI Tecnai F20 TEM), scanning electron microscope (ZEISS Sigma); Elemental analysis: powder X-ray diffractometer (PANalytical X-ray diffractometer); Hydrogen production efficiency measurement: gas chromatograph (SIEMENS MAXUM II); In vivo angiography to detect embolism: DAS digital subtraction angiography (PHILIPS FD20); In vivo angiography to detect tumor size: (1) CT (PHILIPS Access CT): Evaluation of treatment effects using CT imaging with Optiray contrast agent; (2) PET-CT (GEMINI TF PET / CT): Using positron emission tomography (PET) / CT images as a nuclide probe. 18 To evaluate the efficacy of interventional embolization using F-FDG.

[0110] A method for assessing tumor apoptosis and proliferation: Through tumor sections stained with fluorescently labeled TUNEL or Ki67 proteins, the proportion of TUNEL-positive cells or Ki67-positive cells relative to tumor cells within the field of view is observed and counted as the apoptosis rate or value-added of tumor cells.

[0111] The tumor cell line in this embodiment is the H22 tumor cell line.

[0112] The present invention provides a composite embolic agent comprising an active metal microsphere or nanohydride material and an iodine oil dispersion protectant.

[0113] The active metal microspheres are one or more of potassium, calcium, sodium, magnesium, aluminum, zinc, gallium, iron, manganese, and tin. The active metal microspheres are micron-sized, with a particle size of 0.1 to 20 microns. The active metal microspheres are prepared from active metal ingots by an aerosol powder method. The hydride is one or more of cationic metal hydrides, such as calcium hydride, magnesium hydride, lithium hydride, sodium hydride, potassium hydride, strontium hydride, and cerium hydride.

[0114] The above hydrides are all nano-sized, with particle sizes ranging from 5 to 200 nm. The nano-hydride raw materials are obtained by exfoliating the hydride raw materials using a liquid-phase exfoliation solvent method. The specific reaction conditions are as follows: the metal hydride raw materials are dispersed in the exfoliation solvent N-methylpyrrolidone, and then subjected to ultrasonic exfoliation for 20 minutes, followed by ultracentrifugation to obtain the nano-hydride products.

[0115] The active metal microspheres or nano-hydride particles are then mixed with iodine oil and uniformly dispersed using ultrasound to obtain a composite embolic agent, with the mass percentage of active metal microspheres or nano-hydride in the composite embolic agent being 0.1-10%. The resulting composite embolic agent is then delivered locally to liver cancer tissue via interventional procedures. The iodine oil deposits in the liver cancer tissue, triggering embolization therapy. The active metal microspheres or hydride release hydrogen in situ, inducing hydrogen therapy. The release of the active metal microspheres or hydride further modulates the tumor microenvironment, further amplifying the effects of embolization therapy. The composite embolic agent described in this invention uses the active metal or metal hydride to modulate the tumor microenvironment by in situ releasing hydrogen and hydroxide, demonstrating superior effects in composite embolization therapy compared to embolization therapy using iodine oil alone.

[0116] Example 1: Preparation of magnesium microsphere-iodine oil composite embolic agent A magnesium metal ingot was placed in an aerosol powder production device and heated to 700°C to form a stable, fluid liquid. The liquid magnesium was then atomized and cooled with an inert argon gas at a speed of 2-2.5 Mach to obtain magnesium powder. The powder was then passed through a 1000-mesh sieve to obtain 10-micron magnesium microspheres. The structural analysis of the resulting magnesium microspheres was performed, and the results are shown in Figures 1 and 2.

[0117] The magnesium microspheres prepared above were dispersed in a commercially available iodine oil composite embolic agent at a mass fraction of 1% magnesium microspheres, followed by ultrasonic dispersion or shaking to obtain a magnesium microsphere-iodine oil composite embolic agent. If desired, the composite embolic agent can be customized so that the mass ratio of magnesium microspheres falls within the 1% range. The commercially available iodine oil used as the dispersant was a clear, pale yellow liquid, while the prepared magnesium microsphere-iodine oil composite embolic agent was a dark yellow liquid, an optical photograph of which is shown in Figure 5.

[0118] Figure 1 shows a micrograph of the prepared magnesium microspheres, which shows that the particle size is about 10 microns and the morphology is uniform.

[0119] Figure 2 shows the rate of hydrogen release from magnesium microspheres in buffer solutions with different pH values ​​(7.4, 6.4, 5.5). It can be seen that the higher the acidity of the solution, the greater the amount of bubbles generated and the faster the rate of hydrogen release.

[0120] Example 2: Preparation of calcium hydride-iodine oil composite embolic agent Calcium hydride powder and organic solvent N-methylpyrrolidone were placed in a reactor, and the ratio of calcium hydride powder to N-methylpyrrolidone (M 質量(mg) :V 体積(mL) ) was set to 10:1. The calcium hydride powder was uniformly dispersed in N-methylpyrrolidone by vigorously shaking. The mixed dispersion was placed in an ultrasonic cleaner and subjected to ultrasonic treatment for 0.3 hours. The ultrasonic cleaner output was 100 W and the operating temperature was 15°C. The treated reaction system was subjected to ultracentrifugation to remove the precipitate, which was then washed several times with ethanol to obtain calcium hydride nanoparticles. The structure of the obtained calcium hydride nanoparticles was analyzed, and the results are shown in Figures 3 and 4.

[0121] Among these, Figure 3 is a transmission electron micrograph of the prepared calcium hydride nanoparticles, which shows that the particle size of the preparation is approximately 7.9 nm and the morphology is uniform in size.

[0122] Figure 4 shows the X-ray diffraction spectrum of the synthesized nano-calcium hydride, where the abscissa represents the 2θ angle and the ordinate represents the intensity. The 2θ angles of the characteristic diffraction peaks of calcium hydride nanoparticles are 28.18, 30.38, 32.04, 41.72, and 47.56, corresponding to the (011), (102), (111), (211), and (013) diffraction crystal planes, respectively. These diffraction peak data are consistent with the standard X-ray diffraction data for calcium hydride (JCPDS no. 31-0266). This demonstrates that calcium hydride nanoparticles can be prepared using the synthesis method described in this invention.

[0123] The nano-calcium hydride powder prepared as described above was dispersed in a commercially available iodine oil composite embolic agent at a concentration of 0.4% by mass, followed by ultrasonication or shaking to obtain a calcium hydride-iodine oil composite embolic agent. The composite embolic agent can be customized to suit individual needs, with the mass ratio of nano-calcium hydride powder ranging from 0.4%. The commercially available iodine oil used as the dispersant is a clear, pale yellow liquid, as shown in the optical photograph in Figure 6 (left). The prepared nano-calcium hydride-iodine oil composite embolic agent is a milky white liquid, as shown in the optical photograph in Figure 6 (right).

[0124] Test Example: The hydrogen release properties of the nano-calcium hydride-iodine oil composite embolic agent obtained in Example 2 were tested. Fifty microliters of the composite embolic agent was added dropwise to an EP tube containing 3 ml of water, and the generation of hydrogen gas was monitored in real time. As shown in the optical photograph in Figure 7, numerous bubbles were generated within the EP tube, demonstrating the excellent in-situ hydrogen release performance of the nano-calcium hydride-iodine oil composite embolic agent, confirming the stability and practicality of the composite embolic agent.

[0125] Application Example 1: Interventional embolization therapy for rabbit hepatocellular carcinoma using the magnesium microsphere-iodine oil composite embolic agent obtained in Example 1 Using CT imaging guidance, VX2 hepatocellular carcinoma tissue was directly implanted into the left lobe of the liver, and tumor formation was allowed after two weeks to obtain an in situ rabbit hepatocellular carcinoma tumor model. The hormone-treated rabbits were randomly divided into three groups: (1) control group, (2) iodine oil group, and (3) magnesium microsphere-iodine oil composite embolic agent group. The detailed treatment plan is shown in Figure 8. Under DSA fluoroscopic guidance, a 2.0-F microcatheter and a coaxial guidewire trocar were used to access the left hepatic artery containing the tumor lesion via the femoral artery. Then, 0.3 mL of iodine oil or magnesium microsphere-iodine oil composite embolic agent was slowly injected into the left hepatic artery through the microcatheter, avoiding reflux. Postoperative treatment efficacy was monitored using CT imaging and weighted CT. While iodine oil was deposited in the liver cancer lesion, magnesium microspheres were delivered locally to the lesion. The magnesium microspheres slowly reacted with water to release hydrogen and magnesium hydroxide into the liver tumor, neutralizing the slightly acidic tumor microenvironment. The hydrogen then acted as a trigger for hydrogen therapy, and the combination of these two compounds enhanced the effectiveness of iodine oil embolization therapy.

[0126] Specific experimental results are shown in Figures 9 and 10. First, as shown in Figure 9, the size of the hepatocellular carcinoma lesions in the left lobe of the liver of the hormone-treated rabbits was 1.0-1.5 cm, indicating successful establishment of a hepatocellular carcinoma model. After femoral artery intervention, large amounts of iodine oil were observed deposited in the liver tumors of the rabbits in the iodine oil group and the magnesium microsphere-iodine oil composite embolic agent group, indicating that the interventional embolization procedure was highly successful. One week after the intervention, the therapeutic effect of this invention was evaluated using CT images combined with Optiray contrast agent. As shown in Figure 10, the tumor in the control group rapidly increased in volume by 3.3 times, and the CT signal intensity of the lesion in the CT subtraction image was 26.68, indicating progressive disease according to the Metropolitan Response Evaluation Criteria for Oncology (mRECIST). In the iodine oil embolization group, tumor growth was inhibited and no increase in volume was observed. However, some tissues in the lesions still enhanced on enhanced CT images (CT subtraction images showed partial white enhancement of the lesions, with a CT signal intensity of 3.63). This indicated that complete tumor eradication was not achieved with iodine oil embolization alone at this dose, and the mRECIST evaluation indicated a partial response. However, in the group administered with the magnesium microsphere-iodine oil composite embolic agent, no enhancement of the tumor site was observed (CT subtraction images showed no white enhancement of the lesions, with a CT signal intensity of 0.86). This indicated that the composite embolic agent had a good therapeutic effect, and the mRECIST evaluation indicated a complete response.

[0127] Application Example 2: The calcium hydride-iodine oil composite embolic agent obtained in Example 2 in interventional embolization therapy for rabbit hepatocellular carcinoma Using a similar modeling scheme as described above, VX2 hepatocellular carcinoma tissue was directly implanted into the left lobe of the liver with CT imaging guidance. Tumors were allowed to form after two weeks, resulting in rabbit in situ hepatocellular carcinoma tumor models. Tumor-bearing rabbits were randomly divided into three groups: (1) control, (2) iodine oil, and (3) nano-calcium hydride-iodine oil composite embolic agent. Under DSA fluoroscopy, a 2.0-F microcatheter and a trocar with a coaxial guidewire were used to access the left hepatic artery containing the tumor lesion via the femoral artery. Then, 0.3 mL of iodine oil or nano-calcium hydride-iodine oil composite embolic agent was slowly injected into the left hepatic artery through the microcatheter, avoiding reflux. Postoperative treatment efficacy was monitored using CT imaging.

[0128] The hepatocellular carcinoma lesions in the left lobe of the liver of the rabbits with tumor embolization measured 1.0-1.5 cm. After the interventional procedure, large amounts of iodine oil were observed deposited in the tumor-containing areas of the livers of the rabbits in the iodine oil-treated and nano-calcium hydride-iodine oil composite embolic agent-treated groups, demonstrating the success of the interventional embolization procedure. One week after the interventional procedure, the therapeutic effect of the present invention was evaluated using CT images combined with Optiray contrast agent. The results are shown in Figure 11. The tumors in the control group rapidly grew, increasing tenfold in volume. CT subtraction images showed a CT signal intensity of 21.46 in the lesion area, indicating disease progression according to mRECIST. In the iodine oil embolization group, tumor growth was inhibited and no increase in volume was observed, but some tissue in the lesion still enhanced on enhanced CT images (CT subtraction showed partial white enhancement in the lesion, with a CT signal intensity of 3.86). This indicated that complete tumor eradication could not be achieved with iodine oil embolization alone at this dose, and the mRECIST evaluation indicated a partial response. However, in the group administered the nanosized calcium hydrogen carbonate-iodine oil composite embolic agent of the present invention, no enhancement was observed in the tumor site (CT subtraction showed no white enhancement in the lesion, with a CT signal intensity of 1.35). This indicates that the composite embolic agent demonstrated a good therapeutic effect, and the mRECIST evaluation indicated a complete response.

[0129] Since glucose transporter protein-3 is overexpressed on the surface of tumor cells, fluorinated glucose significantly accumulates in tumor tissues, making it a powerful clinical diagnostic tool for tumors. 18 F-FDG was used as a radionuclide probe to evaluate the efficacy of interventional embolization therapy using positron emission tomography (PET) / CT imaging. As shown in Figures 12 and 13, PET / CT imaging revealed that the preoperative hepatocellular carcinoma lesions were 0.2 mm in diameter, 0.2 mm in length, and 0.3 mm in width. 18 Strong F strength of 6.95 18 On the 7th day after surgery, the tumor volume and hypermetabolic area in the untreated control group increased, and the mean 18 The F intensity increased to 9.64. 18 F-FDG signal was significantly reduced, with an average 18 The F intensity decreased to 5.26, but was still at an intermediate level. It is noteworthy that the nano-calcium hydride-iodine oil composite embolic agent group showed a significant improvement in the hepatocellular carcinoma site. 18 F-FDG signal completely disappeared, and the average 18 The F intensity was 2.40, which was not different from that of normal tissue (average of normal tissue). 18 The F intensity was 2.20, confirming that the nano-calcium hydride-iodized oil composite embolic agent had optimal combined therapeutic effects. The deposition of iodized oil enabled in situ delivery of nano-calcium hydride to the tumor site, and the in situ sustained release of hydrogen and calcium hydroxide enhanced the interventional embolization therapy effect, suggesting that the nano-calcium hydride-iodized oil composite embolic agent is an embolic agent with translational potential.

[0130] To further confirm the efficacy of embolization therapy, liver cancer tissue was isolated, and tissue sections were stained with H&E, TUNEL, and Ki67. Histopathological analysis was performed to evaluate tumor tissue damage, apoptosis, and cell proliferation. As shown in Figure 14, the group treated with the nano-calcium hydride-iodine oil composite embolic agent had the highest tumor cell apoptosis rate (control: 2.1%, iodine oil alone: ​​62.7%, nano-calcium hydride-iodine oil composite embolic agent: 87.6%) and the lowest cell proliferation rate (control: 87.5%, iodine oil alone: ​​26.1%); nano-calcium hydride-iodine oil composite suppository: 2.9%) compared with the control group and the iodine oil alone group (Figures 15 and 16). These results confirm that this composite embolic agent has excellent therapeutic effects as a novel embolic agent and is a promising drug for clinical applications.

[0131] Example 3: Magnesium-Platinum Metal Composite Structure (Mg@Pt Composite Structure) The magnesium-platinum metal composite structure is composed of a magnesium core structure and platinum particles bonded to the surface of the magnesium core structure. Figure 17 shows the particle size distribution of the magnesium-platinum metal composite structure. The particle size distribution of the magnesium-platinum metal composite microspheres is about 25 μm. The magnesium-platinum metal composite structure is prepared as follows:

[0132] A 0.1% ethanol solution of chloroplatinic acid was prepared, and 100 mg of magnesium microspheres (24 microns in diameter) were added to the ethanol solution. After ultrasonic treatment, the original gray-white magnesium microspheres were observed to turn black-brown. Once the ethanol had completely evaporated, a magnesium-platinum metal composite (Mg@Pt composite) was obtained.

[0133] The number, shape, and size of the magnesium core particles were matched to the corresponding chloroplatinic acid concentration.

[0134] Example 4: Testing the rate of hydrogen generation from the magnesium-platinum metal composite structure of Example 3 To facilitate a comparison of the hydrogen generation efficiencies of magnesium microspheres and the magnesium-platinum metal composite structure, 20 mg of each of the magnesium microspheres and the magnesium-platinum metal composite structure obtained in Example 3 was weighed and placed in a 96% ethanol solution. Hydrogen generation in both samples was observed, and hydrogen bubbles were observed during the reaction for approximately 10 seconds. As shown in Figure 18, numerous bubbles of the magnesium-platinum metal composite structure appeared in the ethanol solution. Counting the number of bubbles generated over the same period revealed that the gas generation efficiency of the magnesium-platinum metal composite structure in the ethanol solution was approximately 200 times that of simple Mg microspheres. The hydrogen generation efficiency of the magnesium-platinum metal composite structure was significantly higher than that of Mg microspheres and was therefore higher than that of the active metal monomer. This is due to the formation of a protocell composite structure between the inert metal platinum and the active metal magnesium in the magnesium-platinum metal composite structure, which enhanced the hydrogen generation efficiency of the active metal magnesium.

[0135] Hydrogen is a highly cytotoxic oxygen radical [hydroxyl radical (-OH) and peroxynitrite anion (ONOO)]. - )], disrupting the intracellular redox balance and inducing apoptosis in tumor cells, while preserving reactive oxygen species physiologically necessary for normal cell signaling with low toxicity and side effects. Therefore, the magnesium-platinum metal composite structure has high hydrogen generation efficiency and contributes to increasing the hydrogen content in the tumor microenvironment, thereby more effectively regulating the tumor microenvironment. It is believed that composite embolic agents prepared using this magnesium-platinum metal composite structure will have a superior therapeutic effect on tumors.

[0136] Example 5: Composite embolic agent This is a composite embolic agent composed of the magnesium-platinum metal composite structure of Example 3 and iodine oil. Iodine oil alone has the appearance of a clear, pale yellow liquid, while the composite embolic agent is a milky white liquid. The composite embolic agent was prepared in the following manner. The magnesium-platinum metal composite structure prepared in Example 3 was dispersed in iodine oil (commercially available), and the dispersion was homogeneous by ultrasonic treatment or shaking to obtain a magnesium-platinum metal composite structure-iodine oil composite embolic agent. The mass fraction of the magnesium-platinum metal composite structure in the iodine oil was 6.0%.

[0137] Example 6: Composite embolic agent for treating mouse tumors The magnesium-platinum metal composite structure-iodine oil composite embolic agent prepared in Example 5 was used to treat tumors in mice. First, H22 tumor cells were inoculated into the right hindquarters of the mouse to establish a subcutaneous liver cancer model. The tumors in the mice were approximately 80 mm 3 At the time of tumor growth, the mice were randomly divided into two groups and received either iodine oil embolization therapy or magnesium-platinum metal composite structure-iodine oil composite embolization therapy. The tumor growth of the mice was measured and recorded, and a tumor growth curve was created.

[0138] Comparative Example 1: Iodine oil embolic agent for treating mouse tumors Comparative Example 1 differs from Example 6 in that the mice were treated with iodine oil embolization therapy, and the tumor growth in the mice was measured and recorded, while the treatment and testing methods were the same as those in Example 6.

[0139] The results are shown in Figure 19. In Example 6, mice were treated with a Mg@Pt metal composite structure-iodine oil composite embolic agent, and the average tumor volume of the mice on day 10 after treatment was approximately 50 cubic millimeters. In Comparative Example 1, mice were treated with an iodine oil embolic agent, and the average tumor volume of the mice on day 10 was nearly 400 cubic millimeters.

[0140] Thus, the therapeutic effect of the Mg@Pt metal composite structure-iodine oil composite embolic agent of Example 6 on tumors was significantly increased compared to Comparative Example 1. The *** in Figure 19 indicates a statistically significant p-value of <0.001, where the p-value indicates a significant difference, with smaller p-values ​​indicating a more significant difference between groups. The p-value calculated herein shows a significant difference between Example 6 and Comparative Example 1 compared to Example 6, indicating that the Mg@Pt metal composite structure-iodine oil composite embolic agent has a significantly improved tumor embolization therapeutic effect compared to conventional iodine oil embolic agents.

[0141] Example 7: Magnesium-platinum metal composite structure and its preparation method A magnesium-platinum metal composite structure comprising a magnesium core structure and platinum particles bonded to the surface of the magnesium core structure, wherein the core structure is spherical and the magnesium-platinum metal composite microspheres have a particle size distribution of about 350 microns. The magnesium-platinum metal composite structure was prepared as follows. A 0.1% ethanol solution of chloroplatinic acid was prepared, and 100 mg of magnesium microspheres (particle size approximately 350 microns) were added to the ethanol solution of chloroplatinic acid. Ultrasonic treatment confirmed that the originally grayish-white magnesium microspheres had turned black-brown. After the reaction was completed, the liquid was removed and the remaining ethanol was completely evaporated, yielding a magnesium-platinum metal composite structure.

[0142] The morphologies of the raw magnesium microspheres and magnesium-platinum metal composite structure of Example 4 were characterized using optical microscopy, and the results are shown in Figure 20, where Figure 20a is a scanning electron microscope image of the raw magnesium microspheres and Figure 20b is a scanning electron microscope image of the magnesium-platinum metal composite structure.

[0143] Comparing Figure 20a with Figure 20b, it can be seen that the surfaces of the microspheres in the magnesium-platinum metal composite structure are rough, and the rough surface is platinum that has adhered to the surface of the magnesium microspheres. Platinum has adhered to the surface of the magnesium microspheres through a reduction reaction, forming a magnesium-platinum metal composite structure.

[0144] Example 8: Magnesium-platinum metal composite structure The difference between Example 8 and Example 7 is that the particle size of the raw material magnesium microspheres was about 500 μm, and the magnesium-platinum metal composite structure was prepared by the preparation method of Example 7.

[0145] Example 9: Magnesium-Platinum Metal Composite Structure A magnesium-platinum metal composite structure comprising a magnesium core structure and platinum particles bonded to the surface of the magnesium core structure, the core structure being rod-shaped. The rod-shaped magnesium-platinum metal composite structure was prepared as follows. A magnesium rod (diameter: 0.5 mm, length: 2 mm, commercially available) was placed in a 0.3% concentration of chloroplatinic acid ion (PtCl6 2- After 1 minute of reaction, the rod-shaped magnesium-platinum metal composite structure was taken out and washed three times with absolute ethanol to remove unreacted ions from the surface. The prepared rod-shaped magnesium-platinum metal composite structure was then placed in absolute ethanol, sealed, and stored. Based on the principle of in situ exchange reduction, a magnesium-platinum metal composite structure was formed on the magnesium surface, and PtCl6 2- reduces the platinum nanoparticles on the surface of the magnesium rod, resulting in a rod-shaped magnesium-platinum metal composite structure.

[0146] Figure 21 is an XRD diffractogram of the rod-shaped magnesium-platinum metal composite structure prepared in Example 9. The vertical lines on the abscissa axis of Figure 21 represent the positions and relative intensities of the standard XRD signal peaks of magnesium monomers, the curve graph is the XRD signal spectrum of the rod-shaped magnesium-platinum metal composite structure, and the diamond labels represent the positions of the XRD signal peaks of platinum monomers. As can be seen from Figure 21, the XRD spectrum of the magnesium-platinum metal composite rod-shaped structure shows that the magnesium monomer signals are consistent with the standard signal peak positions of magnesium monomers, and the platinum signal peak appears in addition to the strong magnesium signal, which further proves that platinum nanoparticles have successfully grown on the surface of the magnesium rod and a rod-shaped magnesium-platinum metal composite structure has been obtained.

[0147] Example 10: Test of hydrogen generation rate from rod-shaped magnesium-platinum metal composite structure obtained in Example 9 To investigate the hydrogen generation ability of the rod-shaped magnesium-platinum metal composite structure, the rod-shaped magnesium-platinum metal composite structure obtained in Example 9 and a magnesium rod alone, both prepared to the same size, were placed in 50 mL of phosphate buffer, and the amount of hydrogen generated by the rod-shaped magnesium-platinum metal composite structure and the magnesium rod alone was quantitatively measured by gas chromatography at different time intervals.

[0148] A graph of the total amount of hydrogen generated is shown in Figure 22. As can be seen from the results in Figure 22, when a magnesium rod is immersed in a buffer solution, only a small amount of hydrogen is generated in the very early stages, but the rod-shaped magnesium-platinum metal composite structure can continue to generate large amounts of hydrogen for a longer period of time, and its hydrogen generation rate and total amount are much greater than those of a simple magnesium rod. This experimental result directly demonstrates that the magnesium-platinum metal composite structure described in this invention has excellent hydrogen generation ability and has the potential for further use in tumor treatment.

[0149] Example 11: Composite embolic agent This is a composite embolic agent consisting of the magnesium-platinum metal composite structure of Example 9 and iodine oil. By adjusting the length-to-diameter ratio of the rod-shaped metal composite structure, better fixation of the metal composite structure at the site of action can be achieved, and when using the composite embolic agent of magnesium-platinum metal composite rod-shaped structure and iodine oil, occlusion of blood vessels in other normal tissues caused by the metal composite structure entering the blood circulation can be avoided.

[0150] Example 12: Aluminum-Gallium Metal Composite Structure An aluminum-gallium metal composite structure consisting of an aluminum core structure and gallium particles bonded to the surface of the aluminum core structure was prepared as follows. At room temperature, 200 mg of aluminum powder (300 mesh, approximately 48 microns) was placed in a 4 mL centrifuge tube, 200 mg of liquid metallic gallium was added dropwise, and magnetic stirring was performed for 10 minutes. Taking advantage of the strong adhesiveness of gallium to aluminum, an aluminum-gallium metal composite structure was prepared. After stirring, the tube was washed several times with absolute ethanol, sealed, and stored in absolute ethanol for standby.

[0151] Example 13: Composite embolic agent This composite embolic agent is composed of the aluminum-gallium metal composite structure of Example 12 and iodine oil. It is obtained by mixing the aluminum-gallium metal composite structure with iodine oil and then dispersing the aluminum-gallium metal composite structure more uniformly in the iodine oil using an ultrasonic method. Aluminum metal reacts with water to form aluminum hydroxide, which can be used as an immune adjuvant to regulate the immune microenvironment at tumor sites and enhance the effectiveness of immunotherapy.

[0152] Example 14: Alloy metal particle composite embolic agent The composite embolic agent is composed of platinum-gold alloy particles and iodine oil. The platinum-gold alloy particles are commercially available. The alloy particles may be further doped with other ions that provide trace elements.

[0153] For example, to obtain a composite embolic agent of alloy metal particles and iodine oil, the surface of platinum-gold alloy metal particles is exposed to metallic zinc, metallic iron, or metallic manganese.

[0154] Example 15: Large-sized metal microspheres, specifically magnesium microspheres, with a particle size of about 350±45 microns and a particle size distribution as shown in FIG. 23 are used as an example.

[0155] Example 16: The effect of hydrogen gas generation from the large-sized microspheres described in Example 15 in buffer solutions with different pH conditions was investigated. 20 mg of magnesium microspheres were placed in 4 mL of phosphate buffer solutions with different pH values, and the cumulative amount of hydrogen generated by the reaction of the magnesium microspheres in the buffer solutions with different concentrations was quantitatively measured in real time using a gas chromatograph.

[0156] Figure 24 shows the results of measuring the pH-dependent hydrogen generation of magnesium microspheres with a particle size of approximately 350±45 μm. At pH=7.4, almost no hydrogen was generated in the buffer solution. At pH=6.4, hydrogen was generated, but the yield and rate of hydrogen generation were lower than at pH=7.4. At pH=5.5, the cumulative amount of hydrogen generated by the magnesium microspheres reached approximately 3.5 times that of pH=6.4 after 350 seconds of reaction, indicating that magnesium microspheres can generate hydrogen in a weakly acidic environment and that the rate of hydrogen generation increased as the pH decreased. This indicates that larger-sized magnesium microspheres can generate hydrogen in the slightly acidic physiological environment of tumors, potentially leading to further applications in tumor hydrogen therapy.

[0157] Example 17: A composite embolic agent containing large active metal microspheres composed of the large magnesium microspheres (approximately 350±45 microns in diameter) described in Example 15 and a commercially available iodine oil embolic agent. The large magnesium microspheres and iodine oil were mixed at a mass ratio of magnesium microspheres to iodine oil of 10:100. A uniformly dispersed emulsion was obtained by ultrasonic treatment.

[0158] The magnesium-platinum composite structure can generate hydrogen in physiological solutions under neutral pH conditions, and the activated metal microspheres can generate hydrogen in physiological solutions under weakly acidic pH conditions. These microspheres and compatible embolic agents formed with iodine oil all have the function of supplying hydrogen gas to enhance tumor embolization therapy.

[0159] Example 18: Magnesium microspheres with a particle size of approximately 175 μm were produced by ultrasonic atomization powder method. The obtained magnesium microspheres were observed under a microscope to observe their microscopic morphology and count their particle size distribution, and the results are shown in Figure 25. The particle size range of the magnesium microspheres was about 174 ± 19 μm, which indicates that the median particle size of the magnesium microspheres was about 174 μm.

[0160] The hydrogen release rate from 5 mg of magnesium microspheres from Example 18 was measured in citric acid-sodium citrate buffer at different pH values ​​(pH 5.5, 6.4, and 7.4). The statistical results are shown in Figure 26 by determining the concentration of hydrogen released at different time points. The ordinate represents the hydrogen concentration, and the unit mM is millimoles per liter. The greater the amount of hydrogen released per unit time, the stronger the response of the magnesium microspheres. These results indicate that, compared with the neutral pH buffer (pH 7.4), the amount of hydrogen released per unit time was greater in buffers at pH 6.4 and pH 5.5. This suggests that magnesium microspheres are more likely to generate hydrogen in a weakly acidic environment, contributing to an improved microenvironment (5.5-6.5) at the tumor site and enhancing the efficacy of embolization therapy.

[0161] Example 19: Use of magnesium microspheres from Example 18 for embolization therapy in a rabbit liver cancer model Using CT imaging guidance, VX2 hepatocellular carcinoma tissue was directly implanted into the left lobe of the liver, and after two weeks, an in situ rabbit hepatocellular carcinoma tumor model was obtained. Figure 27 (left) shows the image obtained after establishment of the rabbit hepatocellular carcinoma model. The establishment of the hepatocellular carcinoma model in the left lobe of the liver of the hormone-fed rabbit was confirmed, with the size of the hepatocellular carcinoma lesions measuring 1.0-1.5 cm.

[0162] The hormonal rabbits were randomly divided into two groups and treated separately.

[0163] Example 19.1: The magnesium microspheres of Example 18 were implanted into rabbit hepatocellular carcinoma lesions according to the scheme of Figure 8 for embolization therapy. Comparative Example 19.2: Control group, no treatment manipulation.

[0164] As a result of observing the blood vessels at the lesion site using the method described above, it was found that part of the blood supply to the rabbit's liver had disappeared, as shown in the right panel of Figure 27 (compared to the left panel, the original angiogram was shallower, indicating insufficient blood supply), which indicates that embolization of the hepatic artery was achieved by administering the 175 μm magnesium microspheres provided in Example 18 using the femoral artery interventional procedure.

[0165] At the same time, an ultrasound examination was performed to detect gas echoes in the liver lesions, and the results are shown in Figure 28. Comparing the preoperative (left) and postoperative (right) images, the areas embolized with magnesium microspheres displayed stronger signals, i.e., stronger gas echoes, indicating that the magnesium microspheres generated hydrogen at the embolization site, demonstrating that the magnesium microspheres generated hydrogen at the same time as embolization, thereby demonstrating the effectiveness of hydrogen therapy.

[0166] On days 4 and 7 after treatment, the therapeutic effect was evaluated by CT scans using iophorol contrast agent. The results are shown in Figure 29 for CT scan data taken at different times before and after treatment for Example 19.1 and Comparative Example 19.2. As a result, in Comparative Example 19.2, the tumor volume on day 4 of administration increased 2.5-fold compared to the tumor volume on the day before administration, and the tumor volume on day 7 of administration increased 5.8-fold compared to the tumor volume on the day before administration, resulting in a progressive disease (PD) assessment according to the modified Response Evaluation Criteria for Infectious Diseases (mRECIST). The rabbit hepatocellular carcinoma lesions in Example 19.1 showed slower tumor volume changes, with the tumor volume on day 4 increasing 2-fold compared to the tumor volume on the day before administration, and the tumor volume on day 7 increasing 1.8-fold, resulting in a significant remission assessment according to the modified Response Evaluation Criteria for Infectious Diseases (mRECIST).

[0167] Ki67 is present in the late G1, S, G2, and M phases of the cell cycle, but is not expressed in G0 cells. Therefore, Ki67 signal intensity reflects cell proliferation activity. A stronger Ki67 signal indicates higher cell proliferation activity, a higher malignancy, and a poorer patient prognosis. By observing Ki67 staining in frozen sections of tumor tissue and counting Ki67 fluorescence intensity, we found that the proliferation activity of the control 2 sample was significantly higher than that of Example 19.1. This indicates that the proliferation of rabbit hepatocellular carcinoma cells decreased after magnesium microsphere embolization, indicating that magnesium microsphere embolization can effectively inhibit hepatocellular carcinoma and potentially treat it.

[0168] Example 20: A manganese-platinum metal composite structure consisting of a first metal, manganese, and a second metal, platinum, bonded to the surface of the manganese. A manganese-platinum metal composite structure was prepared using a displacement method as follows. At room temperature, 200 mg of manganese powder (1-5 μm) was dispersed in 10 mL of absolute ethanol solution. Under magnetic stirring, an absolute ethanol solution containing 0.5% sodium chloroplatinate (PtCl6) was added dropwise. Using the principle of in-situ positional substitution reduction, the platinum nanoparticles on the surface of the μm-sized manganese particles were spontaneously reduced to obtain a manganese-platinum metal composite. After approximately 30 minutes of reaction, the manganese-platinum metal composite was recovered by centrifugation and washed several times with absolute ethanol to remove unreacted ions from the surface. The composite was then sealed and stored in absolute ethanol.

[0169] In the obtained manganese-platinum metal composite structure, due to the difference in the active metals between manganese and platinum, the platinum nanoparticles attached to the manganese metal surface act as the positive electrode of the primary cell reaction, and manganese acts as the negative electrode of the primary cell reaction. Therefore, the manganese-platinum metal primary cell composite structure can spontaneously carry out the primary cell reaction in aqueous solution and continuously generate hydrogen, thereby achieving the goal of improving the tumor microenvironment and realizing hydrogen therapy.

[0170] Elemental analysis of the prepared manganese-platinum metal composite structure was performed using an X-ray diffractometer. Figure 30 shows the X-ray diffraction spectrum of the manganese-platinum metal composite structure. In addition to the signal peaks of metallic manganese, a platinum signal appears, proving that metallic platinum had adhered to the surface of the metallic manganese core through an oxidation-reduction reaction, forming a metal composite structure.

[0171] Example 21: In vitro hydrogen generation efficiency experiment The manganese-platinum metal composite structure prepared in Example 20 was placed in a phosphate buffer solution, and the amount of hydrogen generated at different time points was quantitatively detected using gas chromatography. Figure 31 shows a statistical graph of the amount of hydrogen generated by metallic manganese and the manganese-platinum metal composite structure in phosphate buffer solution at different time points. The results indicate that manganese is unable to generate hydrogen stably and sustainably in phosphate buffer solution. In contrast, the manganese-platinum metal composite structure was able to generate hydrogen more stably and sustainably, and also generated a higher total amount of hydrogen. After 72 hours of reaction, the cumulative amount of hydrogen generated was 10 times that of manganese. Therefore, manganese-platinum metal composite structures with an active metal as their core structure are expected to be more suitable for hydrogen therapy than inactive metals.

[0172] Example 22: Validation of manganese-platinum metal composite structures for tumor treatment in mice Using the manganese-platinum metal composite structure prepared in Example 20, the tumor microenvironment control ability and hydrogen generation ability were examined in a mouse subcutaneous colon cancer tumor model. First, a mouse subcutaneous colon cancer tumor model was established, and 3 × 10 6 CT26 mouse colon cancer cells were inoculated into the right hindquarters of the mouse, and the subcutaneous colon cancer tumor volume of the mouse was approximately 150 mm. 3 At maturity, the mice were randomly divided into three groups.

[0173] Example 22.1: Control group, no treatment. Example 22.2: A suspension of metallic micron-sized manganese particles was injected intratumorally at 1.5 mg / particle. Example 22.3: A manganese-platinum metal composite structure suspension was injected into the tumor at a dose of 1.5 mg / unit. The manganese-platinum metal composite structure prepared by the method described in Example 20 was injected into the tumor of the mice, and after treatment with different means, the tumor volume was measured every two days until the volume reached 1500 mm, which was regarded as the end point of monitoring. 3The tumor growth was monitored until it reached a larger size. As shown in Figure 32, in Example 22.2, tumor growth in the mice was only slightly inhibited, with only a small difference from the control group. On the other hand, in Example 22.3, tumor growth in the mice was significantly inhibited. This indicates that the manganese-platinum metal composite structure described in the present invention can be used for hydrogen therapy of tumors, and that the effect is significantly improved compared to hydrogen therapy using micron-sized manganese particles.

[0174] Example 23: Retention at the lesion site Tumors were subcutaneously inoculated into mice, and tumor volumes were 60–80 mm 3 At the time of tumor mass reaching 1000 mg / mL, 50 microliters of the magnesium microsphere-iodine oil composite embolic agent obtained in Example 1 was injected into the tumor of each mouse. The mice were sacrificed at different time points and tumors were harvested. The tumors were then excised using an aquaregia microscope, and the Mg content in the tissue was measured using ICP-OES. The intratumoral magnesium retention rate was calculated as follows: magnesium retention rate = mass of magnesium in the tumor / total dose used. Figure 33 shows the statistics of residual magnesium at the tumor site of mice at different times after intratumoral injection of the magnesium microsphere-iodine oil composite embolic agent.

[0175] As shown in Figure 33, the magnesium microspheres remained at the tumor site for a certain period of time (approximately 4 days), demonstrating that the composite embolic agent remained at the tumor site for a long period of time, providing long-term embolization and microenvironment regulation effects. As time continued, the magnesium microsphere content gradually decreased, demonstrating that the magnesium microspheres could be effectively metabolized, indicating that they could be slowly decomposed, i.e., they could be decomposed and metabolized in the body, posing little risk to the human body.

[0176] Example 24: Tumor site pH regulation Mice were inoculated with tumors subcutaneously until tumor volumes reached 100–150 mm 3At this point, a pH electrode was inserted into the tumor to detect intratumoral pH. Then, 50 microliters of the magnesium microsphere-iodine oil composite embolic agent prepared in Example 1 (40 mg / mL) was injected into the tumor, and the changes in intratumoral pH were monitored with the pH electrode.

[0177] Figure 34 shows the time course of intratumoral pH in mice from Example 24. Before injection of the magnesium microsphere-iodine oil composite embolic agent prepared in Example 1, the tumor site had a weakly acidic pH environment, maintained at approximately 6.7. After intratumoral injection of the magnesium microsphere-iodine oil composite embolic agent, the intratumoral pH rose to approximately 7.6 and remained stable. This indicates that the magnesium microsphere composite embolic agent prepared in Example 1 has the ability to adjust the acidic microenvironment within the tumor and improve the acidic environment at the tumor site. A low pH at the tumor site promotes tumor progression, impacts the efficacy of tumor treatment, creates a suppressive immune microenvironment, and promotes immune escape. The magnesium microsphere-iodine oil composite embolic agent prepared in Example 1 can improve the acidic microenvironment at the tumor site, thereby better inhibiting tumor growth. Improving the acidic microenvironment at the tumor site helps reduce tumor drug resistance, thereby improving the efficacy of tumor treatment when combined with other therapies such as chemotherapy, radiotherapy, and immunotherapy.

[0178] Example 25: Hydrogen generation efficiency of magnesium-platinum metal composite structures with different metal ratios A magnesium-platinum metal composite structure was obtained by subjecting a commercially available magnesium rod to a substitution reaction in an ethanol solution of sodium chloroplatinate at room temperature for approximately 1 minute. Varying the concentration of the sodium chloroplatinate solution allowed the substitution reaction to occur more efficiently and quickly, and by varying the supply ratio, magnesium-platinum metal composite structures with different ratios could be obtained. The magnesium rod had a minor axis of approximately 0.5 mm and a major axis of approximately 2 mm. The resulting magnesium-platinum metal composite structure was roughly the same size as the magnesium rod, with only a small amount of metallic platinum adhering to the surface of the magnesium rod.

[0179] 4 mg of this magnesium-platinum metal composite structure was placed in 50 mL of pH 6.5 phosphate buffer solution, and the reaction was allowed to stand for 24 hours. The amount of hydrogen generated from the metal composite structures with different metal ratios was then detected by gas chromatography. Figure 35 is a statistical graph showing the amount of hydrogen generated in the solution of magnesium-platinum metal composite structures with different ratios for 24 hours (the mass fraction of metallic platinum relative to metallic magnesium in Example 25 is 0.2%, 0.5%, 2%, 5%, and 10%). The vertical axis represents the total amount of hydrogen generated in the system in approximately 24 hours, and the horizontal axis represents the mass fraction of platinum relative to the magnesium rod in the magnesium-platinum metal composite structure.

[0180] As can be seen from Figure 35, as the mass fraction of platinum in the magnesium rod increases, the total amount of hydrogen generated in 24 hours gradually increases. When the mass fraction of platinum reaches 5%, the total amount of hydrogen generated in 24 hours tends to stabilize. When the mass fraction of platinum in the magnesium exceeds 5%, the total amount of hydrogen generated in 24 hours no longer changes significantly. This indicates that the ratio of the two metals in the magnesium-platinum metal composite structure affects the hydrogen generation efficiency of the magnesium-platinum metal composite structure. The mass fraction of platinum relative to magnesium can be in the range of 0.2% to 10%, preferably 0.2% to 5%. A platinum content that is too high will not significantly improve hydrogen generation efficiency; rather, it will increase the content of metal elements in the body, increasing metabolic burden and production costs. Therefore, within the appropriate ratio range, hydrogen generation efficiency can be ensured, production costs can be reduced, and safety to the human body can be further improved.

[0181] Example 26: Hydrogen generation efficiency of manganese-platinum metal composite structures with different metal ratios Commercially available manganese powder (particle size approximately 2.5 μm) was placed in an ethanol solution of sodium chloroplatinate and subjected to a substitution reaction at room temperature for approximately 10 minutes to obtain a manganese-platinum metal composite structure. Manganese-platinum metal composite structures with different ratios were obtained by varying the concentration of the sodium chloroplatinate solution depending on the supply ratio. Of these, the particle size of the manganese powder was approximately 2.5 μm, and the particle size of the manganese powder after the attachment of metallic platinum ranged from 2.5 to 5.5 μm.

[0182] 40 mg of this manganese-platinum metal composite structure was placed in 50 mL of phosphate buffer solution with a pH of 6.5, and the reaction was allowed to stand for 24 hours. The amount of hydrogen generated from the metal composite structures with different metal ratios was then detected by gas chromatography. Figure 36 is a statistical graph of the amount of hydrogen generated from the manganese-platinum metal composite structures with different ratios in the solution for 24 hours in Example 25.2 (the mass fraction of platinum relative to manganese was 0, 1%, 2%, 5%, 10%, and 20%, respectively).

[0183] The vertical axis represents the total amount of hydrogen generated in the system in about 24 hours, and the horizontal axis represents the mass ratio of platinum powder to manganese powder in the manganese-platinum metal composite structure.

[0184] As can be seen from FIG. 36, the amount of hydrogen generated increases as the mass ratio of platinum to micron-sized manganese particles increases.

[0185] The total amount of hydrogen generated over 24 hours gradually increases, and when the platinum mass fraction reaches 10%, the total amount of hydrogen generated over 24 hours tends to stabilize. When the platinum mass fraction on manganese exceeds 10%, the total amount of hydrogen generated over 24 hours no longer changes significantly. This indicates that the ratio of the two metals in the manganese-platinum metal composite structure affects the hydrogen generation efficiency of the manganese-platinum metal composite structure. The platinum mass fraction relative to manganese can be in the range of 1% to 20%, preferably 1% to 10%. A platinum content that is too high will not significantly improve hydrogen generation efficiency; instead, it will increase the content of metal elements in the body, increasing metabolic burden and production costs. Therefore, within the appropriate ratio range, hydrogen generation efficiency can be ensured, production costs can be reduced, and safety to the human body can be further improved.

[0186] Example 27: Hydrogen generation efficiency of other alloy metal microspheres When preparing magnesium-platinum alloy microspheres, the hydrogen generation efficiency gradually decreased as the particle size increased and the platinum content decreased. This is thought to be due to the reduced platinum content, which makes it more difficult for platinum to disperse on the surface of the alloy microspheres. Compared to metal composite structures, the efficiency of the primary cell reaction occurring on the surface decreased, resulting in a slower hydrogen generation rate. However, the alloy microspheres still had the ability to generate hydrogen, suggesting potential for further applications in tumor embolization therapy.

[0187] To achieve better results, it is desirable to generate more hydrogen at the lesion site. However, because the amount of hydrogen that can dissolve in tissues and physiological environments is limited, the actual treatment needs can be met by changing the dosage and frequency of administration. Therefore, by using different sizes of metal microspheres, alloy metal microspheres, and metal composite structures as components of hydrogen therapy in composite embolic agents, tumor therapy can be achieved.

[0188] Apparently, the above embodiments are merely examples for clarity, not for limiting the embodiments.

[0189] While several embodiments of the present invention that are presently believed to be useful have been discussed in the foregoing disclosure by way of various examples, it should be understood that such details serve for illustrative purposes only, and that the scope of the appended claims is not limited to the disclosed embodiments, but rather is intended to cover all modifications and equivalent combinations consistent with the substance and scope of the embodiments of the present application.

[0190] Similarly, it should be noted that the foregoing description of the embodiments of the present application sometimes groups various features together in a single embodiment, accompanying drawing, or description thereof to simplify the presentation of the disclosure and, therefore, to facilitate understanding of one or more embodiments of the present invention. However, this method of disclosure does not imply that more features than are recited in the claims are required for the subject matter of the present application. In fact, an embodiment may have fewer than all features of a single embodiment disclosed above.

[0191] In some embodiments, numbers describing the number of components or attributes are used, and it should be understood that such numbers used in describing the embodiments are, in some instances, modified by the modifiers "about," "approximately," or "generally." Unless otherwise specified, "about," "approximately," or "generally" indicates that a degree of variation in the stated numerical value is permitted. Accordingly, in some embodiments, the numerical parameters used in the specification and claims are approximations and may vary depending on the desired properties of particular embodiments.

[0192] Finally, it should be understood that the embodiments described herein are merely used to illustrate the principles of the present embodiments. Other variations may fall within the scope of the present application. Thus, by way of example, and not of limitation, alternative configurations of the present embodiments may be contemplated consistent with the teachings of the present application. Thus, the present embodiments are not limited to the embodiments explicitly shown and described herein.

Claims

1. A tumor preparation comprising active metal microspheres, the active metal microspheres being prepared from an active metal, the metal activity of the active metal being stronger than that of hydrogen, and the active metal being selected from at least one of magnesium, zinc, gallium, manganese, and tin.

2. 2. The antitumor preparation of claim 1, wherein the particle size of the active metal microspheres is 0.1 to 500 microns, preferably 0.1 micron or more, or 0.1 micron or more, or 0.5 micron or more, or 1 micron or more, or 5 microns or more, or 10 microns or more, or 20 microns or more, or 50 microns or more, or 100 microns or more, or 150 microns or more, or 200 microns or more, or 250 microns or more, or 300 microns or more, or 350 microns or more, or 400 microns or more, or 450 microns or more, and preferably 500 microns or less.

3. The tumor formulation described in Claim 1 or 2, characterized in that the tumor formulation further contains a dispersant, preferably the dispersant is an organic phase.

4. The antitumor preparation according to claim 3, characterized in that the mass ratio of the active metal microspheres to the dispersant is 0.1:100 to 50:

100.

5. The tumor preparation of claim 1, wherein the active metal microspheres are decomposable.

6. Use of a tumor preparation described in any one of claims 1 to 5 in the preparation of a tumor embolism treatment preparation.

7. A composite embolic agent, characterized in that it contains activated metal microspheres.

8. The composite embolic agent described in claim 7, characterized in that the metal activity of the active metal is stronger than the activity of hydrogen, and preferably the active metal microspheres are prepared from an active metal, and the active metal is selected from at least one of magnesium, zinc, gallium, manganese, and tin.

9. The composite embolic agent according to claim 7 or 8, wherein the particle size of the active metal microspheres is 0.1 to 500 microns, preferably 0.1 micron or more, or 0.1 micron or more, or 0.5 micron or more, or 1 micron or more, or 5 microns or more, or 10 microns or more, or 20 microns or more, or 50 microns or more, or 100 microns or more, or 150 microns or more, or 200 microns or more, or 250 microns or more, or 300 microns or more, or 350 microns or more, or 400 microns or more, or 450 microns or more, and preferably 500 microns or less.

10. 9. The composite embolic agent according to claim 7 or 8, further comprising a dispersing agent, preferably an organic phase.

11. 11. The composite embolic agent according to claim 10, wherein the mass ratio of the active metal microspheres to the dispersing agent is 0.1:100 to 50:

100.

12. the dispersant is an oil phase; 11. The composite embolic agent according to claim 10, wherein the dispersing agent is preferably selected from one or more of iodine oil, poppy seed oil, soybean oil and olive oil.

13. A tumor preparation comprising the composite embolic agent according to any one of claims 7 to 12.

14. A metal composite structure comprising a core structure and a bonding layer bonded to a surface of the core structure, wherein the core structure is a first metal and the bonding layer is a second metal.

15. The metal composite structure according to claim 14, characterized in that the metal activity of the first metal is stronger than the hydrogen activity, preferably the first metal is selected from one or more of magnesium, zinc, gallium, manganese and tin, or the metal activity of the second metal is weaker than the hydrogen activity, preferably the second metal is selected from one or more of copper, silver, platinum and gold.

16. The metal composite structure according to claim 15, characterized in that the first metal is magnesium, the second metal is platinum, and the platinum has a mass fraction of magnesium of 0.2% to 10%, preferably, the platinum has a mass fraction of magnesium of 0.2% to 5%.

17. The metal composite structure of claim 15, wherein the particle size of the metal composite structure is 0.1 to 500 microns, preferably the particle size of the metal composite structure is 0.1 micron or more, or 0.1 micron or more, or 0.5 micron or more, or 1 micron or more, or 5 microns or more, or 10 microns or more, or 20 microns or more, or 50 microns or more, or 100 microns or more, or 150 microns or more, or 200 microns or more, or 250 microns or more, or 300 microns or more, or 350 microns or more, or 400 microns or more, or 450 microns or more, and preferably the particle size of the metal composite structure is 500 microns or less, and the particle size of the metal composite structure is uniformly distributed.

18. A metal composite structure described in any one of claims 14 to 17, characterized in that the metal composite structure is disassembled.

19. Application of the metal composite structure described in any one of claims 14 to 18 in the preparation of a tumor embolism treatment formulation.

20. A composite embolic agent comprising the metal composite structure according to any one of claims 14 to 19 and a dispersant, wherein the metal composite structure is dispersed in the dispersant.

21. 21. The composite embolic agent according to claim 20, wherein the mass ratio of the metal composite structure to the dispersant is 0.1:100 to 50:

100.

22. The composite embolic agent described in claim 20, characterized in that the mass fraction of the metal composite structure in the dispersing agent is 0.1% to 50%, and preferably the mass fraction of the metal composite structure in the organic phase is 0.1% or more, or 5% or more, or 10% or more, or 15% or more, or 20% or more, or 25% or more, or 30% or more, or 50% or less.

23. The composite embolic agent according to any one of claims 20 to 22, characterized in that the dispersing agent is an organic phase.

24. 24. The composite embolic agent according to claim 23, wherein the organic phase is an oil phase, and preferably the oil phase is selected from one or more of iodine oil, poppy seed oil, soybean oil and olive oil.

25. 20. The method for preparing a metal composite structure according to any one of claims 14 to 19, characterized in that it comprises a step of bonding the second metal to the surface of the first metal, preferably using a physical or chemical method to bond the second metal to the surface of the first metal.

26. the chemical method is selected from substitution methods; 26. The method of claim 25, wherein the substitution process comprises subjecting the first metal to a solution containing high valent ions of the second metal, the solution of high valent ions of the second metal comprising at least one of chloroaurate ions, chloroplatinate ions, copper ions, and silver ions.

27. the physical method is a mechanical stirring method or a vapor deposition method; 26. The method for preparing a metal composite structure according to claim 25, wherein said mechanical stirring method comprises mixing and stirring said second metal in a solid state and said first metal in a liquid state.

28. An alloy metal particle, characterized in that the alloy metal particle comprises at least two metals having different activities, and the two metals having different activities are present in an alloy mixture.

29. 30. The alloy metal particle of claim 28, wherein the alloy metal particle comprises at least one active metal monomer and at least one inert metal monomer, the active metal monomer being alloyed with the inert metal monomer.

30. the active metal monomer has a metal activity greater than its hydrogen activity; 30. The alloy metal particle of claim 28, wherein the active metal monomer is preferably selected from one or more of magnesium, zinc, gallium, manganese and tin.

31. the inert metal monomer has a metal activity less than the activity of hydrogen; 30. The alloy metal particle of claim 28, wherein the inert metal monomer is preferably selected from one or more of copper, silver, platinum and gold.

32. 32. The alloy metal particle of any one of claims 28 to 31, wherein the alloy metal particle size is between 0.1 and 500 microns.

33. 33. A composite embolic agent comprising the alloy metal particles according to any one of claims 28 to 32 and a dispersant, wherein the alloy metal particles are dispersed in the dispersant, and the mass fraction of the alloy metal particles in the dispersant is 0.1% to 50%.

34. 34. The composite embolic agent of claim 33, wherein the dispersing agent is an organic phase.

35. 35. The composite embolic agent according to claim 33 or 34, wherein the organic phase is an oil phase, preferably the oil phase is selected from one or more of iodine oil, poppy seed oil, soybean oil and olive oil.

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