CN115612902B - Magnesium-based alloy microparticles with synergistic TACE (tar-based) liver cancer resisting effect and preparation method thereof - Google Patents
Magnesium-based alloy microparticles with synergistic TACE (tar-based) liver cancer resisting effect and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a magnesium-based alloy micron particle with synergistic TACE liver cancer resisting effect and a preparation and application method thereof, wherein metal magnesium is used as a carrier, other zinc, selenium and molybdenum metal particles with anticancer effect are smelted, and micron-sized alloy particles with controllable degradation and mild effect are prepared by adopting a high-temperature spraying method and can be stored in distilled water for a long time for standby. Tumor tissue is locally implanted before TACE treatment, the negative effects of TACE are reversed in various modes such as degradation product alkalization microenvironment, antioxidation and the like in the early stage, and the nano-level particles can directly play an anticancer role in cells after endocytosis in the final stage. The invention provides a novel anti-tumor biodegradable material which has the negative effects of reversing TACE and enhancing the anti-liver cancer curative effect of TACE for clinic, so that the survival of patients with clinic malignant tumor is benefited.
Description
Technical Field
The invention belongs to medical functional alloy materials and preparation, and relates to magnesium-based alloy microparticles with synergistic TACE liver cancer resistance, and a preparation method and an application method thereof. The magnesium metal is used as a carrier, other beneficial metal particles such as zinc, selenium, molybdenum and the like with an anticancer effect are smelted, and the degradation rate of the magnesium-based alloy in tumor tissues is finally controlled by optimizing the smelting ratio of the magnesium to other metals and the particle size of the magnesium-based alloy. The chemical characteristics and degradation products of the magnesium degradation process are utilized to play the roles of directly/indirectly resisting cancers such as alkalization tumor microenvironment, antioxidation and the like to inhibit proliferation, invasion and metastasis of liver cancer, reduce the dry property of the liver cancer, further play the roles of coordinating TACE to resist the liver cancer and reversing the negative effects of TACE treatment, and have stronger pertinence to the treatment of the liver cancer.
Background
According to the Bazerana Clinical Liver Cancer (BCLC) staging system, TACE is the first method to treat mid-stage liver cancer, including polyanodulized liver cancer that is unresectable and free of extrahepatic diffusion. BCLC systems also suggest that TACE should be used when other recommended treatments are not feasible or successful in the early stages of liver cancer. TACE is often more widely recommended for various clinical situations in asian countries. TACE shows slightly different clinical conditions according to different staging systems, but TACE is still a well established method for treating intermediate and late HCC, see literature: young Chang, sound Won Jeong, jae Young Jang, et al Recent Updates of Transarterial Chemoembolilzation in Hepatocellular Carcinoma.int.J.mol.Sci.2020,21,8165.TACE mainly plays an anti-liver cancer role by blocking liver cancer blood supply and simultaneously combining local injection of chemotherapy drugs (such as oxaliplatin), and although imaging equipment and super-selection technology related to TACE treatment are continuously improved in the last 10 years, survival benefit of liver cancer patients is still limited. Several studies have shown that TACE, while being resistant to liver cancer, accelerates invasive metastasis of cancer, ultimately leading to treatment failure, see literature: raoul JL, gilabert M, adhoute X: to TACE or not to TACELessons from a negative three.Lancet Gastroenterol Hepatol 2017,2 (8): 541-543. The main reasons for TACE failure are: (1) anaerobic glycolysis and microenvironment acidification of cancer cells are aggravated by the anoxic environment caused by the arterial embolism of the blood supply of the tumor, so that invasion and metastasis of the cancer cells are promoted; (2) repeated chemotherapy can exacerbate liver cancer cell drug resistance; (3) TACE causes cancer tissue infiltration of inflammatory interstitial cells while necrosis of cancer tissue, and the process plays an important role in liver cancer metastasis, recurrence and drug resistance.
In order to enhance the clinical effect, TACE combined treatment schemes are proposed, and the curative effect and safety of the TACE combined treatment schemes are verified through a large number of clinical researches. However, the study shows that TACE combined with radiofrequency ablation, radiotherapy, systemic treatment and other schemes do not bring significant benefit to patients, see literature: strobel O, buchler MW Treatment effect of liver resection vs RFA or TACE in hepatocellular Carcinoma. Proliferation, recurrence and metastasis of liver cancer remain clinical challenges. At present, no biodegradable material which has the functions of reversing the negative effect of TACE and enhancing the curative effect of TACE on liver cancer at the same time exists clinically. By searching journals, literature data, patents and the like at home and abroad, related reports and related patent authorizations are not found. Therefore, a new strategy capable of effectively improving the acidification of liver cancer microenvironment and reversing chemotherapy resistance is sought for the anti-liver cancer treatment of the synergistic TACE, which is a key for improving survival benefit of liver cancer patients.
Disclosure of Invention
Technical problem to be solved
In order to improve the defects of the prior art, the invention provides magnesium-based alloy micron particles with the synergistic effect on resisting liver cancer by taking metal magnesium as a carrier, smelting other zinc, selenium and molybdenum metal particles with an anticancer effect, improving the defect of high degradation speed of the micron magnesium metal particles by smelting a certain proportion of other metals with the anticancer effect, simultaneously utilizing the product of slow degradation of the micron magnesium metal particles in tumor tissues to play a role in improving the acidic microenvironment of the tumor, reducing the dry property of the tumor and reversing the negative effect of TACE treatment, and finally playing the synergistic effect on resisting liver cancer by the TACE. The novel anti-liver cancer biodegradable material with the effects of reversing the negative effects of TACE and enhancing the anti-liver cancer curative effect of TACE is provided for clinic, so that clinic liver cancer patients benefit survival.
Technical proposal
A magnesium-based alloy micron particle with synergistic TACE liver cancer resistance is characterized in that metal magnesium is used as a carrier, and is smelted with other metal particles with anticancer effect to prepare novel magnesium-based alloy micron particles; the mass ratio of the magnesium metal to other metal particles with anticancer effect is 85-99:1-15.
The metal particles having an anticancer effect include, but are not limited to, zinc, selenium or molybdenum metal particles.
The method for preparing the magnesium-based alloy microparticles with the synergistic TACE anti-liver cancer effect is characterized by comprising the following steps:
step 1: respectively placing magnesium ingots and other metal ingots with anticancer effect into two premelting furnaces, vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas argon to remove oxidizing atmosphere gas adsorbed on the surfaces;
step 2: heating the furnace body, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing other metal ingots with anticancer effects to the melting temperature of the metal, and adopting argon for protection to completely melt the metal to obtain liquid magnesium and other liquid metals with anticancer effects;
step 3: introducing liquid magnesium and other liquid metals with anticancer effect onto a disc atomizer in an atomizing furnace, uniformly mixing the two liquid metals on the disc atomizer, and spraying the mixed liquid metals into magnesium-based alloy droplets;
step 4: rapidly condensing the magnesium-based alloy small liquid drops to form low-oxidation solid spherical magnesium-based alloy powder;
step 5: sieving magnesium-based alloy powder, grading the granularity, sieving spherical magnesium-based alloy micrometer particles with the granularity of 10-200 μm, and storing in distilled water and/or absolute alcohol for a long time.
And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen.
And step 2, heating the furnace body by using an intermediate frequency heating ring.
And 3, controlling the flow rates of the two metal liquid states on the disc atomizer which is introduced into the atomizing furnace to realize the mass ratio of the magnesium-based alloy micron particles.
And in the step 3, controlling the frequency of the atomizer and the rotating speed of the centrifugal machine to control the size of the metal liquid drops.
The atomizer frequency was 55Hz.
The application method of the magnesium-based alloy micron particle with the synergistic TACE anti-liver cancer effect is characterized by comprising the following steps of: the composition is injected into hepatic artery via femoral artery and guide wire catheter, or super selected into hepatic artery, or liver cancer focus, and implanted into tumor tissue part, and stays in capillary vessel of cancer tissue according to particle size of magnesium-based alloy, and plays an anti-liver cancer role in cooperation with TACE treatment.
When in use, after the magnesium-based alloy microparticles are dissolved in normal saline, the magnesium-based alloy microparticles are locally implanted at the tumor position by means of the aspect in the TACE treatment process before the TACE treatment is carried out for 10 min.
Advantageous effects
The medical functional alloy material exerts the advantages that magnesium metal has natural corrosion degradation characteristics and degradation products thereof have anticancer potential, combines the anticancer characteristics of zinc, molybdenum, selenium and other ions, optimizes the optimal smelting proportion of metal elements, adopts a high-temperature spraying method to prepare micron-sized alloy particles with degradation rate which accords with the TACE treatment period, controllable degradation rate and mild action, and can be stored in distilled water or absolute alcohol for a long time for standby. The magnesium-based alloy microparticles are implanted into tumor tissues during TACE treatment, play a synergistic anticancer role in various modes of alkalizing microenvironment, resisting oxidation and the like through degradation products of the magnesium-based alloy microparticles, reverse the negative effects of TACE, degrade into nano-scale particles in the cancer tissues along with the final stage of the magnesium-based alloy microparticles, and further play a direct liver cancer resisting role in cells through endocytosis.
Compared with the prior art, the invention has the following effects:
1. the partial implantation of metal magnesium realizes the slow release and controllable degradation of the partial liver cancer and the synergistic liver cancer resistance
Magnesium is used as medical implantable alkaline metal, has abundant resources, low price, good biocompatibility and degradability, and is a novel medical functional material with great clinical application prospect. Magnesium hydroxide, hydrogen and magnesium ions, which are magnesium metal degradation products, can directly/indirectly inhibit malignant progress of liver cancer through modes of alkalization microenvironment, antioxidation and the like, but have relatively high and uneven self degradation speed, and especially have extremely high degradation speed after being prepared into micron particles, so that clinical application of the magnesium metal degradation products is limited. The micron-sized magnesium-based alloy particles which can be locally implanted into liver cancer tissues and are mild and controllable in degradation are prepared, and the synergistic liver cancer resisting effect of the locally implanted magnesium-based alloy particles is difficult to realize through inhalation, oral administration or intravenous injection of metal magnesium particles and degradation products thereof. The anti-tumor effect of the magnesium metal in the invention comprises: firstly, the magnesium metal is implanted into liver cancer tissues to degrade and release alkaline substance magnesium hydroxide, so that the local PH value of the cancer tissues can be accurately improved, the dedifferentiation of tumor cells, the enhancement of 'dryness', the induction of Epithelial Mesenchymal Transition (EMT) and other cancer promotion effects caused by acidic microenvironment are reversed, and an effective anticancer effect is exerted. Second, when the oxidation reaction is enhanced and/or the antioxidative ability is impaired, the redox reaction is destroyed to generate oxidative stress, resulting in oxidative damage of lipid, protein, DNA, thereby causing/promoting the occurrence and development of tumor. The magnesium metal is directly implanted into liver cancer tissues to degrade and slowly release hydrogen, so that the local hydrogen concentration of the liver cancer can be accurately improved, and the progress of tumors is inhibited through antioxidation. The traditional hydrogen treatment strategy has very little hydrogen content reaching tumor tissues, and has difficult to exert effective anti-tumor effect. Thirdly, the local release of magnesium ions can accurately improve the local magnesium ion concentration of cancer tissues and inhibit the metastasis and invasion of tumor cells. Radiotherapy, chemotherapy, or molecular targeted therapy patients are accompanied by serum magnesium reduction, and the anticancer effect of DNA damaging therapy can be enhanced by appropriately supplementing magnesium ions, serving as an anticancer therapy sensitizer.
2. Accurately improves the safe concentration of zinc ions in the local part of liver cancer tissues, and plays a role in resisting liver cancer by directly acting on the liver cancer and/or improving the liver cancer microenvironment in a dual mode
Zinc participates in the constitution of various proteins, can be used as a signal molecule in cells in the form of free ions to participate in regulating and controlling cell metabolism, protein kinase, phosphatase activation and the like, and plays an important role in tumor cell proliferation, apoptosis, differentiation and immunoregulation. Zinc ions exert the function of double sword on tumor patients, and overload of zinc ions can cause cachexia to occur and even accelerate death of patients, and insufficient concentration can not exert an effective anti-tumor function, so that the safety window of the whole body medicine for improving the concentration of zinc ions on tumor patients is smaller. Therefore, only if the zinc ion concentration of the local liver cancer tissue is accurately increased, the anti-tumor effect can be effectively exerted. The local implantation of the invention can lead the metal zinc to exert the killing effect on liver cancer tissues to the greatest extent and enhance the utilization rate of zinc ions in the body. The anti-liver cancer effect of the metallic zinc comprises the steps of firstly, inhibiting the release of a large number of tumor-related inflammatory factors, and increasing the expression of two zinc finger proteins, namely A20 and PPAR-a, with anti-inflammatory effect; second, by inhibiting the intracellular Ras-MAPK signaling pathway, malignant progression of tumors is directly or synergistically inhibited, including inhibition of proliferation, induction of apoptosis, or enhancement of anticancer effects of radiotherapy and chemotherapy; third, the activities of antioxidant proteins and enzymes, such as glutathione and catalase, are enhanced.
3. The selenium and molybdenum metal particles integrate diagnosis and treatment, and combine physical therapy and chemical therapy
The study combines selenium and molybdenum particles with a magnesium carrier, and integrates diagnosis and treatment. In one aspect, the molybdenum-containing compounds are useful for tumor-targeted fluorescence imaging and photothermal therapy. The tumor tissue can be gathered at the tumor part through high permeability and retention effect to reach the maximum amount, the damage to surrounding tissues is reduced, and the vascular endothelial cells of the tumor tissue can be damaged through the photo-thermal killing effect. On the other hand, the compound can be used as a drug carrier, a chemotherapeutic drug and a radiotherapy sensitization preparation, and the drug effect can be enhanced through targeting design. The invention improves the toxicity and stability of the component metals, improves the targeting property, biocompatibility and photo-thermal killing effect and reduces the immune rejection effect of organisms on particles while respectively playing the anti-tumor effect of selenium and molybdenum metals.
Therefore, the invention focuses on the research and development of biomedical advanced functional materials, synthesizes magnesium-based alloy microparticles for local implantation of liver tumor tissues, solves the clinical application problems of relatively active magnesium metal and uncontrollable degradation, and furthest plays the role of resisting liver cancer of magnesium and other metal degradation products. Meanwhile, the invention provides an advanced functional material which has the negative effects of reversing TACE and enhancing the anti-liver cancer curative effect of TACE for clinic, so that clinic liver cancer patients benefit survival.
Drawings
Fig. 1: cytotoxic effects of M-6Z, M-6S, M-6M gradient time and gradient concentration on liver cancer cell lines, hepatic stellate cell lines and normal liver cell lines
A：M-6Z；B：M-6S；C：M-6M
Fig. 2: influence of magnesium-based alloy microparticles on proliferation and invasion ability of liver cancer cell lines
M-6Z, M-6S and M-6M inhibit malignant proliferation of liver cancer cell lines;
b: inhibiting invasion ability of liver cancer cell line by M-6Z
Fig. 3: growth of liver cancer tumor in mice
Fig. 4: tumor growth after treatment of liver cancer in mice
Detailed Description
The invention will now be further described with reference to examples, figures:
magnesium-based alloy microparticles and preparation examples:
embodiment one: magnesium zinc alloy micron particle (6% zinc), high temperature spray method preparation
(1) Respectively placing magnesium ingots and zinc ingots into two premelting furnaces for vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing zinc ingots to 650 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid zinc are introduced into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: zinc=94:6) is realized by controlling the flow rates of the liquid magnesium and the liquid zinc. Uniformly mixing magnesium liquid and zinc liquid on a disc atomizer, spraying the mixed magnesium liquid and zinc liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-zinc alloy micron particles with 20 mu m below the screen are stored in distilled water.
Embodiment two: magnesium zinc alloy micron particle (3% zinc), high temperature spray method preparation
(1) Respectively placing magnesium ingots and zinc ingots into two premelting furnaces for vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing zinc ingots to 650 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid zinc are introduced into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: zinc=97:3) is realized by controlling the flow rates of the liquid magnesium and the liquid zinc. Uniformly mixing magnesium liquid and zinc liquid on a disc atomizer, spraying the mixed magnesium liquid and zinc liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-zinc alloy micron particles with 20 mu m below the screen are stored in distilled water.
Embodiment III: magnesium zinc alloy micron particle (12% zinc), high temperature spray method preparation
(1) Respectively placing magnesium ingots and zinc ingots into two premelting furnaces for vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing zinc ingots to 650 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid zinc are introduced into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: zinc=88:12) is realized by controlling the flow rates of the liquid magnesium and the liquid zinc. Uniformly mixing magnesium liquid and zinc liquid on a disc atomizer, spraying the mixed magnesium liquid and zinc liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-zinc alloy micron particles with 20 mu m below the screen are stored in distilled water.
Embodiment four: magnesium zinc alloy micron particle (15% zinc), high temperature spray method preparation
(1) Respectively placing magnesium ingots and zinc ingots into two premelting furnaces for vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing zinc ingots to 650 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid zinc are introduced into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: zinc=85:15) is realized by controlling the flow rates of the liquid magnesium and the liquid zinc. Uniformly mixing magnesium liquid and zinc liquid on a disc atomizer, spraying the mixed magnesium liquid and zinc liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-zinc alloy micron particles with 20 mu m below the screen are stored in distilled water.
Fifth embodiment: magnesium-selenium alloy micron particle (3% selenium) and high-temperature spray method for preparing same
(1) Respectively placing a magnesium ingot and a selenium ingot into two premelting furnaces, vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing selenium ingots to 650 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid selenium are fed into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: selenium=97:3) is realized by controlling the flow rates of the liquid magnesium and the liquid selenium. Uniformly mixing the magnesium liquid and the selenium liquid on a disc atomizer, spraying the mixed magnesium liquid and the mixed selenium liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-selenium alloy micron particles with 20 mu m below the screen are stored in distilled water.
Example six: magnesium-selenium alloy micron particle (6% selenium) and high-temperature spray method for preparing same
(1) Respectively placing a magnesium ingot and a selenium ingot into two premelting furnaces, vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing selenium ingots to 650 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid selenium are fed into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: selenium=94:6) is realized by controlling the flow rates of the liquid magnesium and the liquid selenium. Uniformly mixing the magnesium liquid and the selenium liquid on a disc atomizer, spraying the mixed magnesium liquid and the mixed selenium liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-selenium alloy micron particles with 20 mu m below the screen are stored in distilled water.
Embodiment seven: magnesium-selenium alloy micron particle (12% selenium) and high-temperature spray method for preparing same
(1) Respectively placing a magnesium ingot and a selenium ingot into two premelting furnaces, vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing selenium ingots to 650 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid selenium are fed into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: selenium=88:12) is realized by controlling the flow rates of the liquid magnesium and the liquid selenium. Uniformly mixing the magnesium liquid and the selenium liquid on a disc atomizer, spraying the mixed magnesium liquid and the mixed selenium liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-selenium alloy micron particles with 20 mu m below the screen are stored in distilled water.
Example eight: magnesium-selenium alloy micron particle (15% selenium) and high-temperature spray method for preparing same
(1) Respectively placing a magnesium ingot and a selenium ingot into two premelting furnaces, vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing selenium ingots to 650 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid selenium are fed into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: selenium=85:15) is realized by controlling the flow rates of the liquid magnesium and the liquid selenium. Uniformly mixing the magnesium liquid and the selenium liquid on a disc atomizer, spraying the mixed magnesium liquid and the mixed selenium liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-selenium alloy micron particles with 20 mu m below the screen are stored in distilled water.
Example nine: magnesium-molybdenum alloy micron particles (3% molybdenum) and high-temperature spray method for preparing same
(1) Respectively placing a magnesium ingot and a molybdenum ingot into two premelting furnaces, vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing molybdenum ingots to 2700 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid molybdenum are introduced into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: molybdenum=97:3) is realized by controlling the flow rates of the liquid magnesium and the liquid molybdenum. Uniformly mixing magnesium liquid and molybdenum liquid on a disc atomizer, spraying the mixed magnesium liquid and molybdenum liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-molybdenum alloy micron particles with 20 mu m below the screen are stored in distilled water.
Example ten: magnesium-molybdenum alloy micron particles (6% molybdenum) and high-temperature spray method for preparing same
(1) Respectively placing a magnesium ingot and a molybdenum ingot into two premelting furnaces, vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing molybdenum ingots to 2700 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid molybdenum are introduced into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: molybdenum=94:6) is realized by controlling the flow rates of the liquid magnesium and the liquid molybdenum. Uniformly mixing magnesium liquid and molybdenum liquid on a disc atomizer, spraying the mixed magnesium liquid and molybdenum liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-molybdenum alloy micron particles with 20 mu m below the screen are stored in distilled water.
Example eleven: magnesium-molybdenum alloy micron particles (12% molybdenum), high-temperature spray method preparation
(1) Respectively placing a magnesium ingot and a molybdenum ingot into two premelting furnaces, vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing molybdenum ingots to 2700 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid molybdenum are introduced into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: molybdenum=88:12) is realized by controlling the flow rates of the liquid magnesium and the liquid molybdenum. Uniformly mixing magnesium liquid and molybdenum liquid on a disc atomizer, spraying the mixed magnesium liquid and molybdenum liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-molybdenum alloy micron particles with 20 mu m below the screen are stored in distilled water.
Embodiment twelve: magnesium-molybdenum alloy micron particles (15% molybdenum) and high-temperature spray method for preparing same
(1) Respectively placing a magnesium ingot and a molybdenum ingot into two premelting furnaces, vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing molybdenum ingots to 2700 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid molybdenum are introduced into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: molybdenum=85:15) is realized by controlling the flow rates of the liquid magnesium and the liquid molybdenum. Uniformly mixing magnesium liquid and molybdenum liquid on a disc atomizer, spraying the mixed magnesium liquid and molybdenum liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-molybdenum alloy micron particles with 20 mu m below the screen are stored in distilled water.
Comparative example one: magnesium aluminum alloy micron particle (6% aluminum), high temperature spray method preparation
(1) Respectively placing a magnesium ingot and an aluminum ingot into two premelting furnaces, vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing the magnesium ingot to 680 ℃, heating the furnace body containing the aluminum ingot to 680 ℃, and adopting argon for protection to completely melt the metal;
(3) The liquid magnesium and the liquid aluminum are introduced into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: aluminum=94:6) is realized by controlling the flow rates of the liquid magnesium and the liquid aluminum. Uniformly mixing magnesium liquid and aluminum liquid on a disc atomizer, spraying the mixed magnesium liquid and aluminum liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is sieved and then passes through a 600-800-mesh sieve, spherical magnesium-aluminum alloy micrometer particles with 20 mu m below the sieve are stored in distilled water.
Comparative example two: magnesium-manganese alloy micron particle (6% manganese), high-temperature spray method preparation
(1) Respectively placing a magnesium ingot and a manganese ingot into two premelting furnaces, vacuumizing, setting the temperature to 300 ℃, and purging by adopting high-temperature inert gas (argon) to remove the gas which is adsorbed on the surface and contains oxidizing atmosphere;
(2) Heating the furnace body by using an intermediate frequency heating ring, heating the furnace body containing magnesium ingots to 680 ℃, heating the furnace body containing manganese ingots to 1300 ℃, and adopting argon for protection to completely melt metals;
(3) The liquid magnesium and the liquid manganese are fed into a disc atomizer in an atomizing furnace, and the mass ratio of magnesium-based alloy micron particles (magnesium: manganese=94:6) is realized by controlling the flow rates of the liquid magnesium and the liquid manganese. Uniformly mixing magnesium liquid and manganese liquid on a disc atomizer, spraying the mixed magnesium liquid and manganese liquid into small liquid drops, controlling the frequency of the atomizer to be 55Hz, and controlling the size of the metal liquid drops by controlling parameters such as the rotating speed of a centrifugal machine;
(4) Rapidly condensing the alloy droplets to form low-oxidation solid spherical magnesium-based alloy powder;
(5) And (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 600-800-mesh screen, spherical magnesium-manganese alloy micron particles with 20 mu m below the screen are stored in distilled water.
Table 1 treatment group nutritional treatment regimen
1.1 magnesium-based alloy microparticles have no direct cytotoxicity to liver cancer cells, hepatic stellate cells and normal liver cells
The liver cancer cell line, hepatic stellate cell line and normal liver cell line are treated by adopting the gradient time and gradient concentration of M-6Z, M-6S and M-6M, and the LDH expression of the cell supernatant is detected, so that the LDH expression in the supernatant becomes an increasing trend with the increase of time and concentration, but the overall increase is not obvious. And M-6Z reached plateau at 24h and 4 mg. (see FIG. 1)
The gradient time and gradient concentration of M-6Z, M-6S and M-6M can be used for treating hepatoma cell strain, hepatic stellate cell strain and normal liver cell strain. 1-A M-6Z;1-B M-6S;1-C M-6M.
1.2 detection of two human hepatoma cell lines MHCC97H and Hep3B, CCK8 showed a significant enhancement of inhibition with increasing M-6Z, M-6S and M-6M concentrations (see FIG. 2).
Transwell cells were added to matrigel construct in vitro invasion cells, and the lower cell was constructed with M-6Z 4mg/ml system, and the invasion ability of hepatoma cell lines MHCC97H (58.33+ -7.51 vs.24.31+ -6.87p=0.0044) and Hep3B (65.00+ -6.51 vs.40.17+ -8.7p=0.0095) was significantly inhibited (see FIG. 2).
Experimental design II (animal experiment)
1.1 Experimental purposes and objects
The anticancer effect and safety of the combined treatment scheme of the invention and TACE are discussed.
75C 57BL/6 healthy mice with age of 8 weeks
1.2 method
75 mice were randomized into 15 groups of 5 cases each, each with 14 treatment groups and 1 control group given different treatment regimens (see table 2).
Mouse in situ liver cancer model construction
The H22 cell line was cultured in 1640 medium containing 10% fetal bovine serum, and cells in exponential growth phase were collected. The mice were fixed in supine position after anesthesia, and H22 hepatoma cell suspension (5X 105/25. Mu.L) was injected under She Baomo outside the liver, and a small bubble was formed at the injection site, which proved that the injection was successful
Magnesium-based alloy microparticle injection for in-situ cancer mice
Mice were treated for TACE on day 30 after H22 cell inoculation. The skin was conventionally sterilized and 5ml of 2% lidocaine hydrochloride injection was locally anesthetized. Determining the focus position and the puncture needle direction by first radiography, and probing the focus in detail; the second radiography guides the puncture injection puncture needle to enter through the guiding device and the skin, the puncture needle passes through the abdomen and the intercostals, the focus shows clear magnesium-based alloy microparticles (1 mg is dissolved in 5ml of physiological saline for uniform mixing and slow injection) are injected, and after the injection is completed, the needle is quickly pulled out, and the puncture point is pressurized to avoid bleeding.
Mouse tumor ischemia operation 24h after local injection
Grouping: treatment group, control group
Mice were fasted for 12h preoperatively and were free to drink water.
Mice were anesthetized: pentobarbital sodium (100 ul/20 g) was injected intraperitoneally, the limbs were fixed with tape after anesthesia in the supine position, the abdominal hair was removed with an electric shaver, 1% iodophor was sterilized, and sterile towel was laid.
Taking a median wale incision in the abdomen, cutting off a skin layer and a muscle layer respectively, going up to the xiphoid process and down to the bladder, pulling open and fixing the bilateral muscle layers by using an alic forceps to expose the liver, wetting a cotton swab, separating the hepatic portal, and exposing a left lobe and a middle lobe Glisson system of the liver.
5) The main blood supply vessel of the tumor is peeled off by using a microscopic forceps under a body microscope, and the blood supply of the tumor is blocked by using a noninvasive vascular clamp.
6) When the tumor tissue turns from reddish brown to pale, it indicates successful blockage of blood supply. After successful blocking of the blood vessels, the disinfection cuts are sewn layer by layer in sequence, placed on an electric blanket or a thermostatic plate for continuous heat preservation until awake, placed in a squirrel cage paved with fine soft shavings, placed with fine soft food in the cage, and each mouse is individually fed, and the living state of the mouse is observed.
1.1 results
1.3.1 mouse growth conditions
Mice in the treatment group and the control group are normal in activity, have a bright hair, have normal drinking water, have no abnormal changes in urination and urination, and die during the experiment. Tumor tissues can be detected by each group of mice in the liver cancer in-situ model, and the tumor formation rate reaches 100%.
1.3.2 Effect of magnesium-based alloy microparticles on tumor growth in Experimental mice
The in-situ model of the liver cancer of the nude mouse is built, the local multipoint injection of magnesium-zinc alloy microparticles into the liver cancer focus is carried out after 4 weeks of liver cell injection and the tumor ischemia intervention of the mouse is carried out after 24 hours of injection, the mouse is killed and the tumor focus is detected after 1 week and 2 weeks, and the tumor volume is obviously reduced. The tumor inhibiting effect of magnesium-based alloy microparticles was better after 2 weeks of treatment, with treatment group 1 being the best, treatment groups 5 and 9 times, and treatment groups 13 and 14 being the worst. (see FIG. 4).
1.3.3 influence of magnesium-based alloy microparticles on viscera coefficients of experimental mice
The organ coefficients of the organs of the treatment group are compared with those of the control group, the organ coefficients of the treatment group 13 and the treatment group 14 are obviously reduced (P is smaller than 0.001), and the difference of the other groups is not statistically significant (P is larger than 0.05) compared with the control group. The results are shown in Table 2.
Discussion of beneficial effects:
the magnesium-based alloy microparticles which are locally implanted and cooperate with TACE to treat liver cancer, which are designed by the invention, exert the advantages that magnesium metal has natural corrosion degradation characteristics and degradation products thereof have anticancer potential, and combine the anticancer characteristics of zinc, molybdenum, selenium and other ions to ensure that the synergistic anti-tumor effect with TACE is optimal. Compared with the single TACE treatment, the total effective rate, the disease control rate, the tumor volume and the survival condition are all obviously improved, and 6% of the magnesium-zinc alloy has the best effect and has no statistical difference in the occurrence rate of each group of complications.
Zinc is an important trace element of human body, participates in the constitution of various proteins, can be used as a signal molecule in cells in the form of free ions to participate in regulating and controlling cell metabolism, protein kinase, phosphatase activation and the like, and plays an important role in tumor cell proliferation, apoptosis, differentiation and immunoregulation. Patients with tumors often suffer from a lack of zinc ions, and increasing the uptake of zinc ions can reduce the incidence of tumors. The low zinc can induce the activation of NFkB signal, thereby promoting the release of a large number of tumor-related inflammatory factors, such as TNF-a and IL-1B, and the zinc ion supplementation can increase zinc finger proteins of A20 and PPAR-a with anti-inflammatory effect. In addition, zinc ions can inhibit malignant progression of tumors directly or synergistically by inhibiting the intracellular Ras-MAPK signaling pathway, such as: inhibit proliferation, induce apoptosis, or enhance anticancer effects of radiotherapy and chemotherapy. In the invention, magnesium-6% zinc alloy microparticles (Mg-6 Zn) have the best anti-tumor effect in combination with TACE.
Selenium compounds can inhibit metastasis of murine melanoma cells by inducing cell cycle arrest and cell death. In addition, selenium compounds can sensitize various cancer cells to a variety of widely used drugs. Selenium induces apoptosis or blocks cell cycle, inhibits cell proliferation, regulates redox status, detoxifies carcinogens, stimulates the immune system and inhibits angiogenesis, etc. mechanisms have been considered as important mechanisms for selenium anti-tumor effects, and as a medicament, use for tumor therapy has been increasingly studied. However, selenium compounds are highly toxic and poorly targeted as an organic selenium formulation. Therefore, the invention adopts nano selenium material, which has higher bioavailability, stronger biological activity and lower toxicity compared with organic selenium and inorganic selenium. In addition, the nano selenium is used as a drug carrier, and has the advantages of good biocompatibility, high loading rate, low toxicity, easy synthesis, easy storage and the like. Although nano-selenium particles can inhibit cancer cell growth for a long time, solid tumors cannot be effectively eliminated in a short time. Therefore, 3% magnesium-selenium alloy microparticles (Mg-3 Se) are used as the optimal proportion, and can be combined with TACE to quickly eliminate tumors and improve the curative effect of treatment.
Molybdenum-containing compounds are useful for fluorescence imaging and photothermal therapy targeting tumors. The high permeability and retention effect can gather at the tumor part and reach the maximum amount, the damage to surrounding tissues is small, and the photo-thermal killing effect can kill the vascular endothelial cells of the tumor tissues.
In conclusion, the special invention pertinently enhances the effectiveness of TACE treatment and relieves the drug resistance of TACE. Wherein, the magnesium-zinc alloy microparticles (Mg-6 Zn), the magnesium-selenium alloy microparticles (Mg-3 Se) and the magnesium-molybdenum alloy microparticles (Mg-3 Mo) have good synergistic anti-tumor effect, and the Mg-6Zn effect is optimal. The patient is benefited in great clinic, and serious adverse events are not caused, so that the safety and the effectiveness meet the requirements.
Claims (8)
1. The magnesium-based alloy microparticles with synergistic TACE liver cancer resisting effect are characterized in that metal magnesium is used as a carrier and is smelted with other metal particles with anticancer effect to form magnesium-based alloy microparticles; the mass ratio of the magnesium metal to other metal particles with anticancer effect is 85-97:1-15;
the metal particles with anticancer effect comprise zinc, selenium or molybdenum metal particles;
the magnesium-based alloy micron particles with the synergistic TACE liver cancer resistance are prepared according to the following steps:
step 1: respectively placing magnesium ingots and other metal ingots with anticancer effect into two premelting furnaces, vacuumizing, setting the temperature to 333 ℃, and purging by adopting high-temperature inert gas argon to remove oxidizing atmosphere gas adsorbed on the surfaces;
step 2: heating the furnace body, heating the furnace body containing magnesium ingots to 683 ℃, heating the furnace body of other metal ingots with anticancer effect to the melting temperature of the metal, and adopting argon for protection to completely melt the metal to obtain liquid magnesium and other liquid metals with anticancer effect;
step 3: introducing liquid magnesium and other liquid metals with anticancer effect onto a disc atomizer in an atomizing furnace, uniformly mixing the two liquid metals on the disc atomizer, and spraying the mixed liquid metals into magnesium-based alloy droplets;
step 4: rapidly condensing the magnesium-based alloy small liquid drops to form low-oxidation solid spherical magnesium-based alloy powder;
step 5: sieving magnesium-based alloy powder, grading the granularity, and storing spherical magnesium-based alloy micron particles with 13-233um under the sieve in distilled water and/or absolute alcohol;
and (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 633-833 mesh screen.
2. A method for preparing magnesium-based alloy microparticles with synergistic TACE liver cancer resistance according to claim 1, which is characterized by comprising the following steps:
step 1: respectively placing magnesium ingots and other metal ingots with anticancer effect into two premelting furnaces, vacuumizing, setting the temperature to 333 ℃, and purging by adopting high-temperature inert gas argon to remove oxidizing atmosphere gas adsorbed on the surfaces;
step 2: heating the furnace body, heating the furnace body containing magnesium ingots to 683 ℃, heating the furnace body of other metal ingots with anticancer effect to the melting temperature of the metal, and adopting argon for protection to completely melt the metal to obtain liquid magnesium and other liquid metals with anticancer effect;
step 3: introducing liquid magnesium and other liquid metals with anticancer effect onto a disc atomizer in an atomizing furnace, uniformly mixing the two liquid metals on the disc atomizer, and spraying the mixed liquid metals into magnesium-based alloy droplets;
step 4: rapidly condensing the magnesium-based alloy small liquid drops to form low-oxidation solid spherical magnesium-based alloy powder;
step 5: sieving magnesium-based alloy powder, grading the granularity, and storing spherical magnesium-based alloy micron particles with 13-233um under the sieve in distilled water and/or absolute alcohol;
and (3) carrying out granularity classification on the alloy powder by adopting a vibrating screen, wherein the alloy powder is screened and then passes through a 633-833 mesh screen.
3. The method according to claim 2, characterized in that: and step 2, heating the furnace body by using an intermediate frequency heating ring.
4. The method according to claim 2, characterized in that: and 3, controlling the flow rates of the two metal liquid states on the disc atomizer which is introduced into the atomizing furnace to realize the mass ratio of the magnesium-based alloy micron particles.
5. The method according to claim 2, characterized in that: and in the step 3, controlling the frequency of the atomizer and the rotating speed of the centrifugal machine to control the size of the metal liquid drops.
6. The method according to claim 2, characterized in that: the atomizer frequency was 55Hz.
7. A method for using magnesium-based alloy microparticles with synergistic TACE anti-liver cancer effect as claimed in claim 1, which is characterized in that: is used for synergistic TACE anti-tumor treatment.
8. The method according to claim 7, wherein: when in use, after the magnesium-based alloy microparticles are dissolved in normal saline, the magnesium-based alloy microparticles are locally implanted at the tumor position before TACE treatment for 24 hours.
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