Use of zein as embolic agent, zein embolization system and zein-drug composite embolization system, and use in preparation of drug for transcatheter arterial chemoembolization

Abstract

Provided in the present application are the use of zein as an embolic agent, a zein embolization system and a zein-drug composite embolization system, and the use in the preparation of a drug for transcatheter arterial chemoembolization. The present application belongs to the technical field of medicine. In the present application, zein is used as an embolic agent in the preparation of a drug for transcatheter arterial chemoembolization, which has an excellent therapeutic effect. Specifically, in the present application, zein is used as an embolic agent to facilitate the starvation therapy of TACE. In addition, zein also has high tissue adhesion, so that a zein-based embolization system has a high mechanical strength, and can resist deformation caused by the blood pressure and detachment caused by blood flow flushing. In addition, in the present application, zein is used as an embolic agent to restrict the site of drug action and facilitate the extension of the therapeutic approaches of a drug in chemotherapy. On this basis, zein is integrated with TACE-supported starvation therapy, can be used for TACE treatment of liver cancer, and is beneficial to improving the therapeutic effect.

Description

Use of corn protein as embolic agent, corn protein embolization system and corn protein complex drug embolization system and application in preparation of catheter arterial chemotherapy embolization drugs

[0001] The present application claims priority to the Chinese patent application No. CN202410752766.9, filed on June 12, 2024, and entitled "Use of corn protein as embolic agent, corn protein embolization system and corn protein complex drug embolization system and application in preparation of catheter arterial chemotherapy embolization drugs", the content of which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application relates to the technical field of medicine, in particular to the use of corn protein as embolic agent, corn protein embolization system and corn protein complex drug embolization system and application in preparation of catheter arterial chemotherapy embolization drugs. BACKGROUND

[0003] Hepatocellular carcinoma (HCC) is one of the malignant tumors worldwide. Due to hidden symptoms and delayed discovery at the early stage of onset, it has poor response to treatment. Similar to other malignant tumors, most HCC patients have obvious drug resistance to conventional chemotherapy and radiotherapy, leading to adverse outcomes. In the Barcelona Clinic Liver Cancer (BCLC) guidelines, transarterial chemoembolization (TACE) including starvation therapy and chemotherapy is the recommended treatment for progressive HCC and has been proven to obtain prolonged survival and significant benefits in clinical practice.

[0004] However, the ineffectiveness or accumulation of drugs (such as chemotherapy drugs) used in TACE treatment can reduce the efficacy of TACE. For example, the iodine oil-based TACE agent used in clinical practice is inherently unstable and can be easily washed away by rapid blood flow. Although researchers have tried to modify iodine oil to improve its applicability, the liquid properties at physiological temperature (37℃) determine that the instability and elution of iodine oil-based TACE agents cannot be solved. Studies have shown that some functional microspheres such as PLGA microspheres can be used as intravascular embolic agents for embolization therapy. However, similar to iodine oil-based TACE agents, these functional microspheres still have the risk of being washed away in rapid blood flow, and the therapeutic effect still needs to be improved.

[0005] SUMMARY

[0006] The present application aims to provide the use of corn protein as embolic agent, corn protein embolization system and corn protein complex drug embolization system and application in preparation of catheter arterial chemotherapy embolization drugs. The corn protein is used as an embolic agent to prepare catheter arterial chemotherapy embolization drugs, which has excellent therapeutic effect.

[0007] To achieve the above object, the present application provides the following technical solutions.

[0008] The present application provides an application of corn protein as an embolic agent in preparing a transcatheter arterial chemoembolization drug.

[0009] The present application provides a corn protein embolic system, comprising corn protein and a solvent for dissolving the corn protein, wherein the solvent is an ethanol aqueous solution or anhydrous ethanol.

[0010] Preferably, the volume fraction of ethanol in the ethanol aqueous solution is ≥10%.

[0011] Preferably, the volume fraction of ethanol in the ethanol aqueous solution is 70-85%.

[0012] The concentration of the corn protein in the solvent is 1 mg / mL-10 g / mL.

[0013] Preferably, the concentration of the corn protein in the solvent is 0.5-2 g / mL.

[0014] The present application provides a corn protein complex drug embolic system, comprising corn protein, a drug, and a solvent for dissolving the corn protein and the drug, wherein the solvent is an ethanol aqueous solution or anhydrous ethanol.

[0015] Preferably, the volume fraction of ethanol in the ethanol aqueous solution is ≥10%.

[0016] Preferably, the volume fraction of ethanol in the ethanol aqueous solution is 70-85%.

[0017] Preferably, the concentration of the corn protein in the solvent is 1 mg / mL-10 g / mL.

[0018] Preferably, the concentration of the corn protein in the solvent is 0.5-2 g / mL.

[0019] Preferably, the concentration of the drug in the solvent is 0.1-99 wt%.

[0020] Preferably, the concentration of the drug in the solvent is 30-60 wt%.

[0021] The drug comprises a small molecule targeted drug, a chemotherapeutic drug, an immunotherapeutic drug, or a plant antitumor drug.

[0022] Preferably, the small molecule targeted drug comprises sorafenib, lenvatinib, or donafenib.

[0023] Preferably, the chemotherapeutic drug comprises paclitaxel, docetaxel, cisplatin, carboplatin, lobaplatin, nedaplatin, oxaliplatin, cyclophosphamide, pemetrexed, etoposide, vincristine, gemcitabine, irinotecan, fluorouracil, tegafur, dacarbazine, mitomycin, teniposide, doxorubicin, pirarubicin, mitoxantrone, vinorelbine, vindesine, raltitrexed or methotrexate.

[0024] Preferably, the immunotherapeutic drug comprises atezolizumab, trastuzumab, rituximab, bevacizumab, cetuximab or sintilimab.

[0025] Preferably, the plant antitumor drug comprises camptothecin.

[0026] The application provides application of the zein embolization system or the zein complex drug embolization system in preparation of a transcatheter arterial chemoembolization drug.

[0027] Preferably, the transcatheter arterial chemoembolization drug is a hepatic arterial chemoembolization drug.

[0028] Preferably, the hepatic arterial chemoembolization drug is a liver cancer treatment drug.

[0029] Preferably, the liver cancer treatment drug is a hepatocellular carcinoma treatment drug.

[0030] Preferably, the transcatheter arterial chemoembolization drug is a human hepatocellular carcinoma treatment drug.

[0031] The application provides a transcatheter arterial chemoembolization drug, which comprises the zein embolization system or the zein complex drug embolization system.

[0032] The application provides application of zein as an embolic agent in preparation of a transcatheter arterial chemoembolization drug. The application uses zein as an embolic agent, which is a natural material with high safety. Moreover, the zein is a hydrophobic protein but can be dissolved in an aqueous ethanol solution or anhydrous ethanol. This characteristic determines that the injectable zein will be gelled into a solid embolic agent. Once the zein contacts water, embolization is formed, and the ultimate hunger treatment of TACE is achieved. Meanwhile, the zein also has high tissue adhesion, so that the embolization system based on the zein has high mechanical strength and can resist deformation caused by blood pressure and shedding caused by blood flow flushing, solving the problems of instability, easy leakage and flushing of the current iodized oil-based TACE agent. Moreover, the application of the zein as an embolic agent can limit the action position of the drug and facilitate the expansion of the drug for the treatment mode of chemotherapy. On this basis, the hunger treatment supported by TACE can be integrated, which can be used for TACE treatment of liver cancer and is conducive to improving the treatment effect. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 is a diagram of the phenomenon of injecting Zein solution into PBS solution;

[0034] Figure 2 is a diagram of the phenomenon of injecting PBS solution into Zein solution;

[0035] Figure 3 is a force-displacement curve of a solid Zein embolization system sample;

[0036] Figure 4 is an in-vitro drug release curve of a Zein-DOX embolization system;

[0037] Figure 5 is an in-vitro drug release curve of a Zein-Drug embolization system with drug being Regorafenib;

[0038] Figure 6 is an in-vitro drug release curve of a Zein-Drug embolization system with drug being Paclitaxel;

[0039] Figure 7 is an in-vitro drug release curve of a Zein-Drug embolization system with drug being Oxaliplatin;

[0040] Figure 8 is an in-vitro drug release curve of a Zein-Drug embolization system with drug being Atezolizumab;

[0041] Figure 9 is an image of VX2 tumor isolated from the liver of a rabbit in the Control group 14 days after TACE treatment;

[0042] Figure 10 is an image of VX2 tumor isolated from the liver of a rabbit in the Lipiodol@DOX group 14 days after TACE treatment;

[0043] Figure 11 is an image of VX2 tumor isolated from the liver of a rabbit in the Zein group 14 days after TACE treatment;

[0044] Figure 12 is an image of VX2 tumor isolated from the liver of a rabbit in the Zein@DOX group 14 days after TACE treatment;

[0045] Figure 13 is a graph of the mass test results of VX2 tumor isolated from the liver of a rabbit in each group 14 days after TACE treatment;

[0046] Figure 14 is a graph of the volume test results of VX2 tumor isolated from the liver of a rabbit in each group 14 days after TACE treatment;

[0047] Figure 15 is a DSA image of a Control group rabbit VX2 model before injection;

[0048] Figure 16 is a DSA image of a Control group rabbit VX2 model after injection;

[0049] Figure 17 is a DSA image of a Lipiodol@DOX group of a rabbit VX2 model before injection;

[0050] Figure 18 is a DSA image of a Lipiodol@DOX group of a rabbit VX2 model after injection;

[0051] Figure 19 is a DSA image of a Zein group of a rabbit VX2 model before injection;

[0052] Figure 20 is a DSA image of a Zein group of a rabbit VX2 model after injection;

[0053] Figure 21 is a DSA image of a Zein@DOX group of a rabbit VX2 model before injection;

[0054] Figure 22 is a DSA image of a Zein@DOX group of a rabbit VX2 model after injection. DETAILED DESCRIPTION

[0055] The application provides an application of corn protein as an embolic agent in preparation of a transcatheter arterial chemoembolization drug.

[0056] The application uses corn protein as an embolic agent in preparation of a transcatheter arterial chemoembolization drug, and has excellent therapeutic effect. In the application, the CAS number of the corn protein is 9010-66-6; in the examples of the application, the corn protein is specifically purchased from Aladdin Reagent Company, and the item number is Z304904.

[0057] In the application, the transcatheter arterial chemoembolization drug can be specifically used as a hepatic arterial chemoembolization drug for treating liver cancer, preferably hepatocellular carcinoma, and specifically human hepatocellular carcinoma. The transcatheter arterial chemoembolization drug preferably comprises a corn protein embolization system or a corn protein complex drug embolization system; in the test examples of the application, the corn protein complex drug embolization system is specifically verified for the performance of inhibiting tumor growth and metastasis and the performance of reducing intratumoral vascular density by taking a rabbit VX2 tumor model as an example. Details are described below.

[0058] The present application provides a zein embolization system, which comprises zein and a solvent for dissolving the zein, and the solvent is aqueous ethanol or anhydrous ethanol. In the present application, the volume fraction of ethanol in the aqueous ethanol is preferably ≥10%, more preferably 10-99.9%, further preferably 30-95%, more further preferably 50-90%, again further preferably 70-85%, still further preferably 80%; and the concentration of the zein in the solvent is preferably 1 mg / mL-10 g / mL, more preferably 10 mg / mL-5 g / mL, further preferably 0.1-3 g / mL, more further preferably 0.5-2 g / mL, again further preferably 1 g / mL.

[0059] In the present application, the zein is preferably dissolved in the aqueous ethanol to obtain the zein embolization system. In the present application, the dissolving is preferably carried out under stirring; the stirring speed is preferably ≤1000 rpm, more preferably 100-500 rpm, further preferably 300 rpm; and the stirring time is preferably 3-5 h, more preferably 4 h.

[0060] The present application provides a zein complex drug embolization system, which comprises zein, a drug and a solvent for dissolving the zein and the drug, and the solvent is aqueous ethanol or anhydrous ethanol. In the present application, the volume fraction of ethanol in the aqueous ethanol is preferably ≥10%, more preferably 10-99.9%, further preferably 30-95%, more further preferably 50-90%, again further preferably 70-85%, still further preferably 80%; and the concentration of the zein in the solvent is preferably 1 mg / mL-10 g / mL, more preferably 10 mg / mL-5 g / mL, further preferably 0.1-3 g / mL, more further preferably 0.5-2 g / mL, again further preferably 1 g / mL. In the present application, the concentration of the drug in the solvent is preferably 0.1-99 wt%, more preferably 1-90 wt%, further preferably 10-80 wt%, more further preferably 20-70 wt%, again further preferably 30-60 wt%, still further preferably 40-50 wt%.

[0061] In the present application, the drug preferably includes a small molecule targeted drug, a chemotherapeutic drug, an immunotherapeutic drug, or a plant antitumor drug. In the present application, the small molecule targeted drug preferably includes sorafenib, lenvatinib, or donafenib; the chemotherapeutic drug preferably includes paclitaxel, docetaxel, cisplatin, carboplatin, lobaplatin, nedaplatin, oxaliplatin, cyclophosphamide, pemetrexed, etoposide, vincristine, gemcitabine, irinotecan, fluorouracil, tegafur, dacarbazine, mitomycin, teniposide, doxorubicin, pirarubicin, mitoxantrone, vinorelbine, vindesine, raltitrexed, or methotrexate; the immunotherapeutic drug preferably includes atezolizumab, trastuzumab, rituximab, bevacizumab, cetuximab, or sintilimab; and the plant antitumor drug preferably includes camptothecin. In the examples of the present application, the drug release effect of the zein complex drug embolization system is verified by taking doxorubicin, lenvatinib, paclitaxel, oxaliplatin, and atezolizumab as examples.

[0062] In the present application, the zein and the drug are dissolved in an aqueous ethanol solution to obtain the zein complex drug embolization system. In the present application, the zein and the drug are respectively dissolved in an aqueous ethanol solution to obtain a zein solution and a drug solution; and then the zein solution and the drug solution are mixed. In the present application, the concentration of the zein solution is preferably 1 mg / mL to 10 g / mL, more preferably 10 mg / mL to 5 g / mL, further preferably 0.1 to 3 g / mL, more further preferably 0.5 to 2 g / mL, and still further preferably 1 g / mL; and the concentration of the drug solution is preferably 1 mg / mL to 10 g / mL, more preferably 10 mg / mL to 5 g / mL, further preferably 0.1 to 3 g / mL, more further preferably 0.5 to 2 g / mL, and still further preferably 1 g / mL. In the present application, the drug solution is added to the zein solution under ultrasonic conditions, and after the addition is completed, the mixing is performed under stirring. The stirring time is preferably 1.5 to 2.5 h, and more preferably 2 h.

[0063] The present application provides an application of the zein embolization system or the zein complex drug embolization system in the preparation of a transcatheter arterial chemoembolization drug. In the present application, the transcatheter arterial chemoembolization drug is preferably a hepatic arterial chemoembolization drug, the hepatic arterial chemoembolization drug is preferably a liver cancer treatment drug, the liver cancer treatment drug is preferably a hepatocellular carcinoma treatment drug, and the hepatocellular carcinoma treatment drug is preferably a human hepatocellular carcinoma treatment drug.

[0064] The present application provides a transcatheter arterial chemoembolization drug, which includes the zein embolization system or the zein complex drug embolization system.

[0065] The application uses Zein as an embolic agent, and its high tissue adhesion makes the Zein-based embolic system have high mechanical strength, which can resist deformation caused by blood pressure and shedding caused by blood flow flushing. In particular, the hydrophilic components of Zein (such as polysaccharides) are also designed to enhance the storage stability of the Zein-based embolic agent in water, which exceeds the currently clinically commonly used liquid hydrophobic iodine oil in terms of avoiding drug leakage. At the same time, it is superior to iodine oil-based TACE agents in inducing TAE unlocking starvation therapy and TACE treatment, and delaying the progression of HCC by reducing intratumoral vascular density. Moreover, the application complex Zein with drugs to form a Zein complex drug embolic system, which can combine starvation therapy with chemotherapy, and is beneficial to improve the therapeutic effect. The results of the test example show that the Zein complex drug embolic system provided by the application has a strong inhibitory effect on the progression of HCC in the in situ rabbit VX2 tumor model, and the lung metastasis foci are significantly reduced, which not only provides a new TACE drug for HCC, but also establishes a new strategy for improving postoperative metastasis and resisting common HCC metastasis in clinic.

[0066] The technical solutions in the application will be described clearly and completely in combination with the embodiments in the application. Obviously, the described embodiments are only some of the embodiments of the application, not all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the application.

[0067] Embodiment 1

[0068] The Zein embolic system is prepared as follows:

[0069] The Zein is mixed with an 80% volume fraction ethanol aqueous solution at a solid-liquid ratio of 1 g / mL, and stirred at room temperature and a stirring rate of 300 rpm for 4 h to form a uniform Zein ethanol dispersion, which is the Zein embolic system.

[0070] Embodiment 2

[0071] The Zein complex DOX embolic system is prepared as follows:

[0072] The corn protein was mixed with 80% ethanol aqueous solution at a ratio of 1 g / mL, and stirred at room temperature and a stirring rate of 300 rpm for 4 h to form a uniform corn protein ethanol dispersion; doxorubicin hydrochloride (DOX) was mixed with 80% ethanol aqueous solution at a ratio of 1 g / mL to obtain a DOX ethanol dispersion solution; the DOX ethanol dispersion solution was added to the corn protein ethanol dispersion under ultrasonic conditions (the volume ratio of the DOX ethanol dispersion solution to the corn protein ethanol dispersion was 3:1), and after the addition was completed, the mixture was stirred at room temperature and a stirring rate of 300 rpm for 2 h to obtain a corn protein-DOX embolization system (denoted as Zein-DOX embolization system).

[0073] Test Example 1

[0074] 1. Phase transition test of Zein, the steps were as follows: Zein was mixed with 80% ethanol aqueous solution to obtain a Zein solution (Zein concentration was 30 wt%), and the Zein solution was injected into PBS solution (pH value was 7.4) and the PBS solution was injected into the Zein solution, respectively.

[0075] FIG. 1 is a phenomenon diagram of injecting the Zein solution into the PBS solution, and FIG. 2 is a phenomenon diagram of injecting the PBS solution into the Zein solution; the results showed that Zein formed a solid after phase transition when it encountered the PBS solution, and had the potential to form an embolization system.

[0076] 2. Mechanical property test, the steps were as follows: 1 mL of Zein embolization system was taken by a syringe and injected into PBS solution to make it phase transition into a solid state, the Zein embolization system that phase transitioned in the PBS solution was taken out by tweezers, and a model (diameter 10 mm, height 10 mm) was used to prepare a solid Zein embolization system sample, and then rheological analysis and mechanical property detection were performed. FIG. 3 is a force-displacement curve of the solid Zein embolization system sample, and the results showed that the solid Zein embolization system sample had a large elastic modulus and a small degree of deformation under the action of pressure. The degree of deformation of the solid Zein embolization system sample was less than 4 mm under the action of 75 N pressure.

[0077] The above experiments showed that the cross-linked structure formed after the phase transition of Zein could provide sufficient mechanical strength to maintain the continuous embolization state in the blood vessel.

[0078] Test Example 2

[0079] The drug release experiment of the Zein-DOX embolization system was performed as follows: a simulated blood vessel model was used to simulate the normal diameter (2-5 mm) of the hepatic artery, and the length of the blood vessel was 20 mm. One end of the simulated blood vessel was adhered with AB adhesive, and then saline was injected into the simulated blood vessel, and 1 mL of the Zein-DOX embolization system was injected into the other end of the simulated blood vessel. At different time points, the concentration of doxorubicin permeating through the outer wall of the simulated blood vessel was measured by ultraviolet spectroscopy, so as to calculate the in vitro drug release efficiency of the Zein-DOX embolization system.

[0080] Figure 4 is the in vitro drug release curve of the Zein-DOX embolization system. The results show that the drug has a sustained release in the embolization system, and the release efficiency reaches 30% at 24 h and tends to be stable, which achieves the therapeutic effect while avoiding the generation of drug dose-related toxicity. This indicates that the solid Zein-DOX embolization system obtained by the wrapping effect of Zein determines the sustained chemotherapy mediated by DOX release.

[0081] Test Example 3

[0082] According to the method of Example 1, the only difference is that "doxorubicin hydrochloride" is replaced with "lenvatinib", and finally a corn protein complex drug embolization system loaded with lenvatinib is prepared, and then the drug release experiment is performed according to the method of Test Example 2.

[0083] Figure 5 is the in vitro drug release curve of the Zein-DOX embolization system loaded with lenvatinib. The results show that the drug has a sustained release in the embolization system, and the release efficiency exceeds 30% at 24 h and tends to be stable, which achieves the therapeutic effect while avoiding the generation of drug dose-related toxicity. This indicates that the solid Zein-DOX embolization system obtained by the wrapping effect of Zein determines the sustained chemotherapy mediated by DOX release.

[0084] Test Example 4

[0085] According to the method of Example 1, the only difference is that "doxorubicin hydrochloride" is replaced with "paclitaxel", and finally a corn protein complex drug embolization system loaded with paclitaxel is prepared, and then the drug release experiment is performed according to the method of Test Example 2.

[0086] Figure 6 is the in vitro drug release curve of the Zein-DOX drug-loaded embolization system, which shows that the drug has a slow-release effect in the embolization system, and continues to release after embolization, with a release efficiency of about 30% at 24 h and approaching a plateau, achieving a therapeutic effect while avoiding the generation of drug dose-related toxicity. This shows that the Zein-DOX drug-loaded embolization system determines the release-mediated sustained chemotherapy of the chemotherapeutic drug paclitaxel.

[0087] Test Example 5

[0088] The procedure of Example 1 was followed, except that "doxorubicin hydrochloride" was replaced by "oxaliplatin", and a Zein-oxaliplatin drug-loaded embolization system was finally prepared, and then a drug release experiment was performed according to the procedure of Test Example 2.

[0089] Figure 7 is the in vitro drug release curve of the Zein-oxaliplatin drug-loaded embolization system, which shows that the drug has a slow-release effect in the embolization system, and continues to release after embolization, with a release efficiency of more than 40% at 24 h and approaching a plateau, achieving a therapeutic effect while avoiding the generation of drug dose-related toxicity. This shows that the Zein-oxaliplatin drug-loaded embolization system determines the release-mediated sustained chemotherapy of the chemotherapeutic drug oxaliplatin.

[0090] Test Example 6

[0091] The procedure of Example 1 was followed, except that "doxorubicin hydrochloride" was replaced by "atrilizumab", and a Zein-atrilizumab drug-loaded embolization system was finally prepared, and then a drug release experiment was performed according to the procedure of Test Example 2.

[0092] Figure 8 is the in vitro drug release curve of the Zein-atrilizumab drug-loaded embolization system, which shows that the drug has a slow-release effect in the embolization system, and continues to release after embolization, with a release efficiency of about 40% at 24 h and approaching a plateau, achieving a therapeutic effect while avoiding the generation of drug dose-related toxicity. This shows that the Zein-atrilizumab drug-loaded embolization system determines the release-mediated sustained treatment of the immunotherapeutic drug atrilizumab.

[0093] Test Example 7

[0094] Regarding the experiment of the Zein-DOX embolization system inhibiting tumor growth and metastasis, the procedure was as follows:

[0095] New Zealand white rabbits (2.5-3.0 kg) were used to construct the VX2 tumor model. Specifically, the experimental rabbits were dissected on the abdomen, and a VX2 tumor mass was implanted in the left lobe of the liver. After layering and suturing, the abdominal incision was disinfected. The general condition, diet, and surgical incision of the experimental rabbits were observed after the operation. Ten to 14 days after the VX2 mass was implanted, the size and shape of the liver tumor were observed by enhanced CT (designated as day 0). Enhanced CT confirmed that the left lobe of the rabbit liver had a uniform density, clear boundary tumor nodule, which was confined to the liver parenchyma, and the rest of the liver was uniform in texture, and no metastatic lesions were found. Eighteen male VX2 tumor rabbits (2.5-3.0 kg) were randomly divided into 6 groups (n=3).

[0096] Group A: control group (normal saline); Group B: conventional TACE, i.e. Lipiodol-DOX (20 mg DOX mixed with 10 mL liquid iodized oil, under CT fluoroscopy, according to the iodine oil deposition in the tumor area, whether the small branches of the portal vein appeared around the tumor as the boundary, the iodine oil was retained in the blood vessels or there was reflux to stop injection), selective access to the tumor feeding artery, then use gelatin sponge to block the artery to prevent embolization of the artery leakage; Group C: Zein; Group D: Zein-DOX (or Zein@DOX). TACE was performed under digital subtraction angiography (DSA), and microcatheter was used to position the tumor tissue and its vascular system by superselective catheterization. Intraoperative TACE angiography showed that the common hepatic artery flowed into the proper hepatic artery, which entered the liver and was divided into left and right branches, supplying the left and right lobes. All VX2 tumors were located in the left lobe of the liver, which was supplied by the left hepatic artery. After the left hepatic artery was determined, different groups were injected into the left hepatic artery according to the above administration scheme. The end point of embolization was set as no tumor staining or iodine oil deposition in the small branches of the portal vein after injection of the above drugs. In the iodine oil-free group, 0.5 mL iodine Holol was added as a DSA contrast agent and injected (for imaging), until the contrast agent reflux was observed. Fourteen days after treatment, the rabbits were dissected.

[0097] Figure 9 is an image of VX2 tumor isolated from the liver of a rabbit in the Control group 14 days after TACE treatment, Figure 10 is an image of VX2 tumor isolated from the liver of a rabbit in the Lipiodol® DOX group 14 days after TACE treatment, Figure 11 is an image of VX2 tumor isolated from the liver of a rabbit in the Zein group 14 days after TACE treatment, Figure 12 is an image of VX2 tumor isolated from the liver of a rabbit in the Zein@DOX group 14 days after TACE treatment, Figure 13 is a graph of the results of the mass test of VX2 tumor isolated from the liver of rabbits in each group 14 days after TACE treatment, and Figure 14 is a graph of the results of the volume test of VX2 tumor isolated from the liver of rabbits in each group 14 days after TACE treatment. The results show that the tumor tissues in each group were homogeneously soft and produced large areas of liquefaction and necrosis. The tumor weight and volume of the other three groups were significantly lower than that of the control group. The zein-based TACE drug (i.e., Zein@DOX) was superior to the iodine oil-based TACE drug (i.e., Lipiodol® DOX) in inhibiting tumor progression, which can be attributed to its enhanced stability, drug leakage inhibition, and continuous drug release. The sustained release of DOX mediated Zein-DOX had the strongest ability to inhibit HCC progression, with the lowest tumor weight.

[0098] Test Example 8

[0099] For the experiment on the Zein-DOX embolization system reducing intratumoral vascular density (reducing blood vessels), the steps are as follows:

[0100] New Zealand white rabbits (2.5-3.0 kg) were used to construct a rabbit VX2 tumor model, which was specifically to dissect the abdomen of the rabbit, implant a VX2 tumor mass in the left lobe of the liver, and disinfect the abdominal incision after layered suture. The general condition, diet, and surgical incision of the experimental rabbits were observed after the operation. Ten to fourteen days after the VX2 mass was implanted, the size and morphology of the liver tumor were observed by enhanced CT (designated as day 0). Enhanced CT confirmed that the left lobe of the rabbit liver had a tumor nodule with uniform density and clear boundaries, which was confined to the liver parenchyma, and the rest of the liver was uniform in texture, with no metastatic lesions. Eighteen male VX2 tumor rabbits (2.5-3.0 kg) were randomly divided into 6 groups (n=3).

[0101] Group A: control group (normal saline); Group B: conventional TACE, i.e. Lipiodol® DOX, selectively entering the tumor feeding artery, then blocking the artery with a gelatin sponge to prevent embolization artery leakage; Group C: Zein; Group D: Zein-DOX (or denoted as Zein® DOX). TACE was performed under digital subtraction angiography (DSA), using a microcatheter to position the tumor tissue and its vascular system by superselective catheterization. Intraoperative TACE angiography showed that the common hepatic artery flowed into the proper hepatic artery, which was divided into left and right branches after entering the liver, supplying the left and right lobes. All VX2 tumors were located in the left lobe of the liver, fed by the left hepatic artery. After the left hepatic artery was determined, different groups were injected into the left hepatic artery according to the above drug administration regimen. The end point of embolization was set as no tumor staining or iodine oil deposition in the small branches of the portal vein after injection of the above drugs. In the no-iodine oil group, 0.5 mL iodine Holol was added as a DSA contrast agent and injected (for easy imaging), until the contrast agent reflux was observed. Fourteen days after treatment, the rabbits were imaged by DSA.

[0102] Fig. 15 is a DSA image of a Control group rabbit VX2 model before injection, Fig. 16 is a DSA image of a Control group rabbit VX2 model after injection, Fig. 17 is a DSA image of a Lipiodol® DOX group rabbit VX2 model before injection, Fig. 18 is a DSA image of a Lipiodol® DOX group rabbit VX2 model after injection, Fig. 19 is a DSA image of a Zein group rabbit VX2 model before injection, Fig. 20 is a DSA image of a Zein group rabbit VX2 model after injection, Fig. 21 is a DSA image of a Zein® DOX group rabbit VX2 model before injection, and Fig. 22 is a DSA image of a Zein® DOX group rabbit VX2 model after injection; wherein the circled part represents the blood vessels supplying the tumor. The results show that the Zein-based TACE drug (i.e. Zein® DOX) is superior to the iodine oil-based TACE drug (i.e. Lipiodol® DOX) in inducing TAE unlocking starvation therapy and TACE therapy, and delaying the progression of HCC by reducing intratumoral vascular density.

[0103] From the above examples and test examples, it can be seen that the corn protein used as an embolic agent has at least the following beneficial effects:

[0104] 1. High mechanical strength and high vascular adhesion: the Zein-based embolic system has high mechanical strength and high vascular adhesion, which can resist deformation caused by blood pressure and resist shedding caused by blood flow flushing, significantly improving the stability and retention of the embolic agent.

[0105] 2. Improve the local maintenance and slow release of drugs: Compared with traditional TACE treatment, the application realizes the efficient maintenance and slow release of drugs at the tumor site through the gelation characteristics of Zein, thereby improving the treatment effect and reducing side effects.

[0106] 3. Significantly inhibit tumor growth and metastasis: Using the synergistic effect of drug release, the progression of hepatocellular carcinoma is significantly delayed, and lung metastatic lesions are significantly reduced in animal models.

[0107] 4. Safety and biocompatibility: Zein as a natural material has high safety and biocompatibility, providing a good foundation for clinical application.

[0108] 5. Comprehensive multi-modal treatment strategy: The application effectively combines starvation therapy with chemotherapy, which can achieve multi-modal synergistic treatment of hepatocellular carcinoma to overcome the shortcomings of single treatment method.

[0109] In summary, the application uses corn protein as an embolic agent, which has significant advantages in stability, drug release control, and inhibition of tumor growth and metastasis, providing a new effective means for the treatment of hepatocellular carcinoma.

[0110] The above is only the preferred embodiment of the application, it should be pointed out that for the person skilled in the art, without departing from the principle of the application, a number of improvements and refinements can be made, these improvements and refinements should also be considered as the protection scope of the application.

Claims

1. Use of zein as an embolic agent in the preparation of a transcatheter arterial chemoembolization drug.

2. A zein embolic system comprising zein and a solvent for dissolving the zein, the solvent being an aqueous ethanol solution or anhydrous ethanol.

3. The zein embolization system of claim 2, wherein, The volume fraction of ethanol in the aqueous ethanol solution is ≥10%.

4. The zein embolization system of claim 3, wherein, The volume fraction of ethanol in the aqueous ethanol solution is 70-85%.

5. The zein embolization system according to any one of claims 2 to 4, wherein, The concentration of the zein in the solvent is 1 mg / mL-10 g / mL.

6. The zein embolization system of claim 5, wherein, The concentration of the zein in the solvent is 0.5-2 g / mL.

7. A zein complex drug embolic system comprising zein, a drug, and a solvent for dissolving the zein and the drug, the solvent being an aqueous ethanol solution or anhydrous ethanol.

8. The zein complex drug embolization system according to claim 7, characterized in that, The volume fraction of ethanol in the aqueous ethanol solution is ≥10%.

9. The zein complex drug embolization system according to claim 8, characterized in that, The volume fraction of ethanol in the aqueous ethanol solution is 70-85%.

10. The zein complex drug embolization system according to any one of claims 7 to 9, characterized in that, The concentration of the zein in the solvent is 1 mg / mL-10 g / mL.

11. The zein complex drug embolization system according to claim 10, characterized in that, The concentration of the zein in the solvent is 0.5-2 g / mL.

12. The zein complex drug embolization system according to claim 7, wherein, The concentration of the drug in the solvent is 0.1-99 wt%.

13. The zein complex drug embolization system according to claim 12, wherein, The concentration of the drug in the solvent is 30-60 wt%.

14. The zein complex drug embolization system according to claim 7, 12 or 13, characterized in that, The drug comprises a small molecule targeted drug, a chemotherapeutic drug, an immunotherapeutic drug, or a plant antitumor drug.

15. The zein complex drug embolization system according to claim 14, wherein, The small molecule targeted drug comprises sorafenib, lenvatinib, or donafenib.

16. The zein complex drug embolization system of claim 14, wherein, The chemotherapeutic drug comprises paclitaxel, docetaxel, cisplatin, carboplatin, lobaplatin, nedaplatin, oxaliplatin, cyclophosphamide, pemetrexed, etoposide, vincristine, gemcitabine, irinotecan, fluorouracil, tegafur, dacarbazine, mitomycin, teniposide, doxorubicin, pirarubicin, mitoxantrone, vinorelbine, vindesine, raltitrexed, or methotrexate.

17. The zein complex drug embolization system of claim 14, wherein, The immunotherapeutic drug comprises atezolizumab, trastuzumab, rituximab, bevacizumab, cetuximab, or sintilimab.

18. The zein complex drug embolization system of claim 14, wherein, The plant antitumor drug comprises camptothecin.

19. Use of the zein embolic system of any one of claims 2-6 or the zein complex drug embolic system of any one of claims 7-18 in the preparation of a transcatheter arterial chemoembolization drug.

20. The use according to claim 19, characterized in that, The transcatheter arterial chemoembolization drug is a hepatic arterial chemoembolization drug.

21. The use according to claim 20, characterized in that, The hepatic arterial chemoembolization drug is a liver cancer treatment drug.

22. The use according to claim 21, characterized in that, The liver cancer treatment drug is a hepatocellular carcinoma treatment drug.

23. Use according to any one of claims 19 to 22, characterized in that, The transcatheter arterial chemoembolization drug is a human hepatocellular carcinoma treatment drug.

24. A transcatheter arterial chemoembolization medicament, comprising: a compound of Formula (I) ###00006### (I) or a pharmaceutically acceptable salt thereof. The transcatheter arterial chemoembolization drug comprises the zein embolic system of any one of claims 2-6 or the zein complex drug embolic system of any one of claims 7-18.

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