WO2014139456A1 - Application de l'hydroxyde d'aluminium dans la préparation d'un médicament pour le traitement du cancer du foie - Google Patents

Application de l'hydroxyde d'aluminium dans la préparation d'un médicament pour le traitement du cancer du foie Download PDF

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Publication number
WO2014139456A1
WO2014139456A1 PCT/CN2014/073411 CN2014073411W WO2014139456A1 WO 2014139456 A1 WO2014139456 A1 WO 2014139456A1 CN 2014073411 W CN2014073411 W CN 2014073411W WO 2014139456 A1 WO2014139456 A1 WO 2014139456A1
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WIPO (PCT)
Prior art keywords
liver cancer
group
tumor
aluminum hydroxide
mice
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PCT/CN2014/073411
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English (en)
Chinese (zh)
Inventor
王红阳
闻玉梅
王宾
付静
王波
任一彬
朱俊杰
汪萱怡
Original Assignee
复旦大学
中国人民解放军第二军医大学
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Application filed by 复旦大学, 中国人民解放军第二军医大学 filed Critical 复旦大学
Publication of WO2014139456A1 publication Critical patent/WO2014139456A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the field of chemical medicines, and relates to a novel use of aluminum hydroxide [ ⁇ 1( ⁇ ) 3 ] compound in pharmacy, in particular to the application of aluminum hydroxide [ ⁇ 1( ⁇ ) 3 ] compound in the preparation of a medicament for treating liver cancer.
  • liver cancer primary liver cancer
  • liver cancer is the sixth most common malignant tumor in the world, with more than 700,000 new cases per year, of which hepatocellular carcinoma accounts for about 80%.
  • the annual incidence of new liver cancer in China accounts for about 55% of the total number of global diseases.
  • Liver cancer has become the second leading cause of death in China. So far, surgical resection is still the best treatment for liver cancer, and it is the first choice for early liver cancer.
  • due to the concealed incidence of primary liver cancer rapid development has resulted in only about 10% of surgical resections at the time of diagnosis.
  • liver cancer Even if surgery is performed, there are still many cases that cannot be completely removed or the tumor is difficult to avoid postoperative recurrence. In addition, because the surgery has a great trauma to the human body, it often reduces the immunity of the patient and causes a series of complications. Therefore, in clinical practice, patients with advanced liver cancer are often unable to undergo surgery due to liver dysfunction. In this part of the patient, it is necessary to treat them by various non-surgical methods, or to perform non-surgical treatment to reduce the size of the mass, and then to perform surgical resection, that is, the second stage of removal, so that patients can obtain better benefits. Therefore, finding effective non-surgical treatment of liver cancer is crucial for improving the survival rate of patients with liver cancer, especially those with advanced liver cancer.
  • Non-specific immunotherapy refers to the use of some immunomodulators to non-specifically enhance the body's immune function and activate the body's anti-tumor immune response to achieve tumor treatment.
  • cytokines L-2, IFN, TNF, etc.
  • microorganisms and their products vitamin K, heat shock protein (HSP) and so on.
  • Active immunotherapy refers to a method for inducing specific immunity by using tumor cells or tumor antigen substances to induce specific immunity, thereby actively killing tumor cells, preventing tumor growth and recurrence and treating tumors; currently used DC vaccines and tumors are commonly used. Cell vaccines and heterologous recombinant alpha-fetoprotein vaccines.
  • Adoptive immunotherapy pointing to liver cancer patients to input immune cells with anti-tumor activity, directly killing tumors or stimulating the body's anti-tumor immune effect, thereby achieving the purpose of treating liver cancer.
  • Aluminum hydroxide [ ⁇ 1( ⁇ )3] is the only human vaccine adjuvant approved by the US FDA and the China Food and Drug Administration. The use of the vaccine not only improves the body's immune response but also has better safety. After more than 80 years of use, aluminum hydroxide adjuvant has been proven and proven in practice and has been approved for commercial use in vaccines such as DTP. Influenza Blood bacillus vaccine, hepatitis B vaccine (HBV), etc.
  • the commercially available aluminum hydroxide adjuvant is essentially an incompletely dehydrated product of ⁇ 1( ⁇ )3, ie, a fibrous crystalline form of particles having a size of 4.5 nm ⁇ 2.2 nm x 10 nm and an isoelectric point of 11.4.
  • the aluminum hydroxide adjuvant is in the form of an aluminum hydroxy group whose hydroxyl group can provide or accept a proton and thus behave as an amphoteric compound.
  • the adjuvant aluminum hydroxide of commercial products is a nearly transparent sol. After adhering to the vaccine antigen, the antigen is confined to a specific lattice structure formed by colloids, and the body can be enhanced by two mechanisms: "repository effect” and "immunostimulation effect". An immune response to an antigen.
  • the reservoir effect refers to the longer the antigen-presenting cell (APC) acts on the antigen during uptake, processing, and treatment, and the longer the antigen and immune cells act, the better the subsequent immune response.
  • APC antigen-presenting cell
  • aluminum hydroxide is highly concentrated on the surface and inside, and is physically presented to the immune cells without changing its chemical structure, so that the immune cells can be fully, high-level, and long-term. Contact with the vaccine antigen, thereby enabling a meaningful immune response to be induced.
  • the immunostimulatory effect mainly refers to the activation of ⁇ cell mother cellization after aluminum hydroxide, thereby promoting antibody production.
  • aluminum hydroxide can stimulate the immune effects of the body in various ways, including 1) promoting the aggregation of inflammatory cells such as neutrophils, inflammatory monocytes and dendritic cells. (DC); 2) acting on human peripheral blood mononuclear cells, inducing monocyte differentiation into mature CD40 + , CD83 + DC; 3) inducing Th2 type immune response in animal models; 4) mediating secretion of inflammatory factors , such as through the Nlrp3 inflammatory body mediated IL- ⁇ secretion; 5) through the cell surface lipids to promote DC uptake of antigen; 6) in vitro induced T cell proliferation, enhance memory CD8 + T cells, induce killer T cells Differentiation.
  • the invention provides the use of aluminum hydroxide [ ⁇ 1( ⁇ ) 3 ] in the preparation of antitumor drugs, in particular to the application of aluminum hydroxide as a separate component in the preparation of a medicament for treating liver cancer.
  • the aluminum hydroxide [ ⁇ 1( ⁇ ) 3 ] of the present invention means an aluminum hydroxide adjuvant widely used in various vaccines.
  • the present invention provides the use of aluminum hydroxide as a separate component in the preparation of a medicament for treating liver cancer.
  • various experimental methods such as tumor inoculation experiment, immunological analysis, proliferation, apoptosis and immunohistochemical detection in the tumor-bearing experimental mice are carried out, and the results show that: the administration of aluminum hydroxide can significantly inhibit the liver cancer cells in vivo. Proliferation, inducing neutrophil infiltration of tumors, tumor cell apoptosis, thereby inhibiting the growth of subcutaneous tumors in vivo and improving the survival rate of tumor-bearing mice, indicating that the use of aluminum hydroxide as the sole component in the present invention can effectively inhibit liver cancer cells. Growth, with anti-liver cancer effect.
  • the present invention utilizes an aluminum hydroxide [ ⁇ 1( ⁇ ) 3 ] compound (obtained by a commercially available channel, which is provided by the Medical Molecular Virology Laboratory of Shanghai Medical College of Fudan University in the embodiment of the present invention) as a separate component in the mouse liver.
  • an aluminum hydroxide [ ⁇ 1( ⁇ ) 3 ] compound obtained by a commercially available channel, which is provided by the Medical Molecular Virology Laboratory of Shanghai Medical College of Fudan University in the embodiment of the present invention
  • Experiments were performed in a cancer-bearing tumor model.
  • a mouse liver cancer tumor-bearing model was established by subcutaneous injection of a mouse-derived liver cancer cell line (Hepal-6 cells, provided by the laboratory of Professor Wang Hongyang of the Second Military Medical University in the embodiment of the present invention), and the growth of the subcutaneous tumor in the mouse was observed.
  • mice the results showed that the subcutaneous tumor volume of the blank group and the saline group was significantly increased and many experimental mice died, while the experimental group administered only aluminum hydroxide [ ⁇ 1( ⁇ ) 3 ] When the mice died, the growth rate of the subcutaneous tumors in the mice was significantly slowed down, and the subcutaneous tumors of several mice were significantly reduced, which was invisible.
  • H&E staining of the mouse organs it was shown that after administration of ⁇ 1( ⁇ ) 3 , as in the blank group and the saline-administered group, no significant damage was observed in the main organs of the mouse.
  • immunohistochemical staining of subcutaneous tumors in mice it was shown that after administration of ⁇ 1( ⁇ ) 3 , the proliferation of tumor cells was significantly slowed down and apoptosis was significantly increased.
  • the present invention has been experimentally shown that the administration of ⁇ 1( ⁇ ) 3 can significantly inhibit the proliferation of liver cancer cells, induce apoptosis, thereby inhibiting the growth of subcutaneous tumors in vivo and improving the survival rate of tumor-bearing mice, indicating that ⁇ 1 of the present invention ( ⁇ ) 3 As a sole and unique component, it can safely and effectively inhibit the growth of liver cancer cells, and has an anti-liver cancer effect.
  • ⁇ 1( ⁇ ) 3 of the present invention can be used as a single active ingredient for preparing a medicament for treating liver cancer, and can also be used as a separate component and other effective liver cancer intervention methods or anti-hepatocarcinoma drugs for comprehensive intervention of liver cancer.
  • ⁇ 1( ⁇ ) 3 is used as a separate active ingredient in combination with surgical or radiological interventions or other anti-hepatocarcinoma drugs for the comprehensive intervention of liver cancer.
  • the invention provides a new idea for the selection of interventional measures for liver cancer and the clinical application of ⁇ 1( ⁇ ) 3 .
  • the present invention will be described in detail below through the specific drawings and embodiments. It is to be understood that the specific embodiments and the drawings are intended for the purpose of illustration Variations are also included within the scope of the invention.
  • Figure 1 is a model of a mouse liver cancer bearing tumor.
  • FIG 2 is a control group, saline group and ⁇ 1 ( ⁇ ) tumor growth graph 3 groups of mice,
  • Fig. 2-1 is a growth curve of tumors of each group of mice
  • Fig. 2-2 is a representative picture of subcutaneous tumors of each group of mice after 6 weeks of treatment.
  • Figure 3 is a survival curve of the blank group, the saline group, and the ⁇ 1 ( ⁇ ) group 3 mice.
  • FIG 4 is a control group, saline group and ⁇ 1 ( ⁇ ) 3 mice organs
  • Fig. 4-1 is a representative picture of the organs of each group after 6 weeks of treatment
  • Fig. 4-2 is a H&E staining diagram of the organs of each group of mice.
  • Figure 5 is a Ki67 immunohistochemical staining of subcutaneous tumors of blank group, saline group and ⁇ 1 ( ⁇ ) group 3 mice.
  • Figure 6 shows the apoptosis of TUNEL cells in subcutaneous tumors of blank group, saline group and ⁇ 1( ⁇ ) group 3 mice.
  • FIG H & E staining is a saline group, the subcutaneous tumor growth curves of FIG Al (OH) 3 7 days beginning 11 days of treatment group, and detection of immune cells in tumor sections and subcutaneous chart of FIG H & E staining,
  • Figure 7-1 is a graph showing the subcutaneous tumor growth of mice in the saline group, ⁇ 1 ( ⁇ ) 3 7 days, and 11 days starting treatment group;
  • Fig. 7-2 is a flow chart showing the flow cytometry and data of neutrophils in the spleen and tumor of the mice in the saline group, ⁇ 1 ( ⁇ ) 3 7 days and 11 days;
  • Figure 7-3 is a H&E staining of subcutaneous tumor sections of mice in the saline group, ⁇ 1 ( ⁇ ) 3 7 days, and 11 days starting treatment group.
  • Example 1 Establishment of a tumor-bearing model of mouse liver cancer
  • Example 2 Tumor growth in mice of blank group, saline group and ⁇ 1 ( ⁇ ) group 3
  • mice in the blank group were not treated, and the mice in the experimental group were given ⁇ 1( ⁇ )3 solution (dissolved in physiological saline), 0.25 mg/mouse, once every 3 days, intraperitoneally.
  • the control group was given an equal amount of normal saline (0.9% NaCl liquid), once every 3 days, intraperitoneally.
  • Example 3 Survival curves of mice in the blank group, saline group, and ⁇ 1 ( ⁇ ) group 3
  • mice The blank group, the saline group, and the ⁇ 1 ( ⁇ ) group 3 mice were treated as described in Example 2, and the survival of the mice was observed daily and the survival curve was drawn. As shown in the results in Fig. 3, as of the end of the experiment, 4 mice died in the empty group, 5 mice died in the saline group, and only one mouse died in the ⁇ 1 ( ⁇ ) group. The results showed that injection of ⁇ 1( ⁇ )3 significantly improved the survival rate of tumor-bearing mice.
  • Example 4 Organs in the blank group, saline group, and ⁇ 1 ( ⁇ ) group 3
  • mice The blank group, the saline group and the ⁇ 1 ( ⁇ ) group 3 mice were treated as described in Example 2, and the mice were sacrificed 6 weeks later, and the organs of each group (heart, liver, spleen, lung and kidney) were collected. , fixed in formalin, embedded in paraffin, sectioned and H&E stained.
  • H&E staining method 1) Organ tissue paraffin section Wax to water; 2) Sumu semen staining for 5 min, water washing; 3) 1% hydrochloric acid ethanol 1-3 s, water washing; 4) 0.5% eosin staining lmin, water washing; 5) dehydration sealing.
  • Ki67 is a proliferating cell-associated nuclear antigen whose function is closely related to mitosis and is indispensable in cell proliferation. Ki67 is an antigen that marks the proliferative state of cells, and its positive staining indicates that cell proliferation is active.
  • Ki67 staining method 1) Deparaffinization of paraffin sections of tumor tissue to water; 2) 3% H202 room temperature lOmin, water washing; 3) antigen retrieval; 4) goat serum blocking for 30 min; 5) addition of Ki67 antibody (1:100, purchased from Cell Signaling Technology), overnight at 4 °C; 6) Adding horseradish peroxidase-labeled secondary antibody (purchased from Shanghai Changdao Biotechnology Co., Ltd.) at 37 ° C for 30 min; 7) DAB color development (purchased from DAKO); 8) Hematoxylin counterstaining, hydrochloric acid alcohol differentiation; 9) Dehydration sealing.
  • mice were treated as described in Example 2. After 6 weeks, the mice were sacrificed, and the subcutaneous tumor tissues were removed, fixed in formalin, embedded in paraffin, and produced. The sections were subjected to TUNEL apoptosis detection (TUNEL FITC staining kit was purchased from Shanghai Rui'an Biotechnology, and the experimental procedure is described in the kit manual).
  • the TUNEL method uses the action of terminal deoxyribonucleotidyl transferase to catalyze the incorporation of fluorescein FITC-labeled deoxyuridine triphosphate at the end of apoptotic cell cleavage DNA, and then directly observe FITC-labeled cells under a fluorescence microscope. Dead cells.
  • mice Twenty-one male C57BL/6J mice, 5-6 weeks old, were randomly divided into 3 groups, 7 rats in each group. Each mouse was inoculated with 1 ⁇ 10 7 Hepal-6 cells by subcutaneous injection.
  • ⁇ 1( ⁇ )3 solution dissolved in physiological saline
  • 0.25 mg/0.25 mL/only once every 3 days, was intraperitoneally injected at 7, 11 days after inoculation.
  • the control group was given an equal amount of normal saline (0.9% NaCl) 7 days after inoculation. Liquid), once every 3 days, intraperitoneal injection.
  • tumor volume tumor long diameter X tumor short diameter 2 / 2
  • spleen was treated with grinding, red cleavage, etc. to obtain single cell suspense, neutrophils, macrophages, NK, CD 4 , CD 8 T , T reg, etc.
  • Cell flow detection The tumor tissue was subjected to shearing, collagenase and DNase digestion treatment to obtain a single cell suspension, and flow cytometry of neutrophils and macrophages was performed. A part of the tumor tissue was taken for pathological sectioning, and HE staining was performed with reference to Example 2.
  • the results of microscopic observation of the tumor were as follows: 1) 100 times of the injection of aluminum adjuvant was found to cause necrosis of cells in the tumor, and the necrosis of the ⁇ 1( ⁇ )3 7 day treatment group was severer than that of the 11-day treatment group. No necrosis was observed in the group; 2) 4001( ⁇ )3 was observed at 400 times. There was a large amount of neutrophil infiltration in the tumor in the 7-day treatment group, but in the saline group and ⁇ 1( ⁇ )3 11-day treatment group.

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
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Abstract

La présente invention concerne une application de l'hydroxyde d'aluminium, Al(OH)3, en tant que composant individuel dans la préparation d'un médicament pour le traitement du cancer du foie. L'inhibition de la croissance de cellules de cancer du foie est possible, et l'utilisation conjointement avec d'autres procédés de prévention du cancer du foie ou médicaments contre le cancer du foie est possible.
PCT/CN2014/073411 2013-03-15 2014-03-13 Application de l'hydroxyde d'aluminium dans la préparation d'un médicament pour le traitement du cancer du foie WO2014139456A1 (fr)

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CN201310084217.0 2013-03-15
CN201310084217.0A CN104042628B (zh) 2013-03-15 2013-03-15 氢氧化铝在制备治疗肝癌药物中的应用

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9682103B1 (en) * 2016-03-30 2017-06-20 Baylor University Administration of a poly-oxygenated metal hydroxide to reduce the proliferation of carcinoma cells

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107174589B (zh) * 2016-03-11 2020-11-03 中国人民解放军第二军医大学东方肝胆外科医院 氢氧化铝在制备防治肝纤维化药物中的应用
CN115192707B (zh) * 2022-06-30 2023-05-30 重庆医科大学附属第二医院 一种肿瘤抗原诱捕纳米粒及其制备方法与应用

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WO2006038606A1 (fr) * 2004-10-05 2006-04-13 Shionogi & Co., Ltd. Dérivé de biaryle
CN101513526A (zh) * 2008-12-15 2009-08-26 张积仁 联合疫苗在肿瘤治疗中的应用
WO2010038691A1 (fr) * 2008-09-30 2010-04-08 アステラス製薬株式会社 Composition pharmaceutique particulaire destinée à être administrée oralement
WO2010051820A1 (fr) * 2008-11-10 2010-05-14 Aarhus Universitet Vaccination contre multiplexée par la cytokine
CN101991850A (zh) * 2010-11-05 2011-03-30 东南大学 纳米氢氧化铝佐剂的制备工艺

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CN102526724B (zh) * 2011-01-14 2015-07-22 四川大学 氢氧化铝凝胶-多糖复合免疫佐剂及其制备方法和用途

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Publication number Priority date Publication date Assignee Title
WO2006038606A1 (fr) * 2004-10-05 2006-04-13 Shionogi & Co., Ltd. Dérivé de biaryle
WO2010038691A1 (fr) * 2008-09-30 2010-04-08 アステラス製薬株式会社 Composition pharmaceutique particulaire destinée à être administrée oralement
WO2010051820A1 (fr) * 2008-11-10 2010-05-14 Aarhus Universitet Vaccination contre multiplexée par la cytokine
CN101513526A (zh) * 2008-12-15 2009-08-26 张积仁 联合疫苗在肿瘤治疗中的应用
CN101991850A (zh) * 2010-11-05 2011-03-30 东南大学 纳米氢氧化铝佐剂的制备工艺

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9682103B1 (en) * 2016-03-30 2017-06-20 Baylor University Administration of a poly-oxygenated metal hydroxide to reduce the proliferation of carcinoma cells

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CN104042628A (zh) 2014-09-17

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