WO2020238085A1 - 锰离子制剂在制备治疗肿瘤药物中的用途 - Google Patents

锰离子制剂在制备治疗肿瘤药物中的用途 Download PDF

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WO2020238085A1
WO2020238085A1 PCT/CN2019/120179 CN2019120179W WO2020238085A1 WO 2020238085 A1 WO2020238085 A1 WO 2020238085A1 CN 2019120179 W CN2019120179 W CN 2019120179W WO 2020238085 A1 WO2020238085 A1 WO 2020238085A1
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manganese
manganese ion
lymphoma
tumor
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万晓春
吴海斯
毕嘉成
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深圳先进技术研究院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • 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
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention relates to the field of medicine, in particular to the use of manganese ion preparations in the preparation and treatment of tumors.
  • Tumor is a major disease threatening human life, and the incidence and mortality of tumors are increasing every year. According to the World Health Organization, the world’s new cases of cancer will reach 20 million in 2020, and 12 million will die from cancer. Although there are many ways to treat tumors, such as surgery, radiotherapy, chemotherapy, and biological therapy, each method has different defects and produces different levels of toxic side effects. Therefore, people are eager to find one that does not produce any obvious Visible side effects, safe and effective treatment of tumors.
  • Manganese (Mn) is one of the eight trace elements necessary for the human body, and it is an essential trace element for maintaining human and animal health and even life. Excessive intake or lack of Mn can cause disease. Srisuchart et al. found that animals exposed to less than 10 mg MnCl 2 /kg did not die or showed signs related to Mn toxicity [1] . A small amount of Mn can maintain the immune system function, regulate blood sugar, cell energy, bone growth, and fight against free radicals [2] .
  • Rogers et al. found that after injection of MnCl 2 into mice, it can enhance the function of immune effector cells mediated by natural cells in the body [3-5] .
  • Rogers et al. measured the activity of natural killer (NK) cells through a 51 Cr release experiment and found that the activity of NK cells was significantly enhanced.
  • NK natural killer
  • Hepes-physiological saline used sterile, pyrogen-free, 0.9% physiological saline to prepare manganese chloride (MnCl 2 ) stock solution, and used 25mM 2-N-hydroxyethyl-piperazine-N'-2-ethanesulfonic acid (Hepes, Grand Island Biological Co., Grand Island, NY) was diluted to the desired concentration in buffered saline. Hereinafter referred to as Hepes-physiological saline.
  • mice The thigh muscles of 11-week-old and 19-week-old CBA/J mice, 9-week-old A/J/ mice, and 11-week-old C57BI/6J mice were injected with 0.1-0.15 ml of Hepes-normal saline, MnCl 2 (40 , 80 or 120ug/g); 24 hours later, take mouse spleen, lyse with red blood cell lysate, wash, and resuspend to 2 ⁇ 10 7 cells/ml; label mouse lymphoma with sodium chromate (Na 25 1CrO 4 ) Cells (YAC-1 cells) and mouse T lymphoma cells (EL-4 cells), washed, resuspended to 2 ⁇ 10 5 cells/ml; spleen cells and target cells were 25:1, 50:1, 100: 1.
  • MnCl 2 MnCl 2
  • mice After washing, resuspend the cells in incomplete RPMI-1640 medium to 2 ⁇ 10 6 cells/ml; each treated mouse tail 1 ⁇ 10 7 iodine 125-5-fluoro-2'-deoxyuridine radiolabeled YAC-1 cells were injected intravenously; the mice were sacrificed by cervical dislocation after 30 minutes, 1 hour, 2 hours and 4 hours; the mice were taken out The mouse spleen and lungs were placed in a tube; the mouse lungs and spleen radioactive YAC-1 cells were detected. It was found that the radioactivity recovered from the lungs decreased from about 20% 30 minutes after injection to less than 1% after 4 hours.
  • MnCl 2 enhanced the NK activity in A/J mice with low immune response. Meanwhile MnC1 2 also enhances NK activity in vivo aging CBA / J's.
  • Surgical treatment is risky and traumatizes the human body, which reduces the patient’s immunity and resistance to disease.
  • 2 There are many complications of radiotherapy, even causing partial loss of function; for patients with advanced tumors, the effect of radiotherapy is not perfect. Not suitable for patients with poor physique and older age.
  • 3 The chemotherapeutic drugs are poor in selectivity, killing a large number of normal cells while killing tumor cells, destroying the body's own immune system function; inhibiting the function of bone marrow hematopoietic stem cells, and easy to develop drug resistance.
  • the present invention provides a safe and effective method for tumor treatment under the condition of making up for the deficiencies of surgery, radiotherapy, chemotherapy, biological treatment and traditional Chinese medicine treatment, and the most important thing is that the method does not have side effects caused by other tumor treatment methods.
  • One aspect of the present invention provides the use of manganese ion preparations in the preparation of drugs for treating tumors, wherein manganese ion is used as the sole active ingredient.
  • the manganese ion is a divalent manganese ion.
  • the divalent manganese ion is preferably one or a combination of manganese chloride or manganese sulfate, manganese dihydrogen phosphate, and manganese nitrate.
  • the manganese ion preparations are solutions, emulsions, suspensions, injections, and freeze-dried powder injections.
  • the manganese ion preparation is an injection, and its solvent is selected from water for injection, buffer solution, and physiological saline.
  • the tumor is a lymphoma selected from a tumor of non-Hodgkin's lymphoma or a tumor of Hodgkin's lymphoma.
  • non-Hodgkin's lymphoma is selected from T cell lymphoma, diffuse large B cell lymphoma (DLBCL), peripheral T cell lymphoma (PTCL), skin T cell lymphoma (CTCL) and Any combination of it.
  • DLBCL diffuse large B cell lymphoma
  • PTCL peripheral T cell lymphoma
  • CTCL skin T cell lymphoma
  • Figure 1 is a graph of tumor growth trends at different time points in the blank group and the administration group.
  • the MnCl 2 powder was dissolved in sterile phosphate buffered saline solution (PBS) to prepare an 8M stock solution, which was filtered and sterilized with a 0.25 micron filter membrane. Dilute with PBS to the desired concentration.
  • PBS sterile phosphate buffered saline solution
  • C57BL/6 mice were subcutaneously inoculated with mouse T lymphoma (RMA-S) cells to establish a tumor model, and the RMA-S cells in good growth condition were inoculated at 2 ⁇ 10 6 / ml with 0.1ml in 6 ⁇ 10 Week-old C57BL/6 mice were subcutaneously inoculated into the right armpit of C57BL/6 mice, that is, C57BL/6 mice were subcutaneously inoculated with 2 ⁇ 10 5 RMA-S cells to establish tumor models, each group of 5 mice; on the day of inoculation with RMA-S tumor cells

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Abstract

锰离子制剂在制备治疗肿瘤的药物中的用途，其中，锰离子作为唯一活性成分，所述的锰离子为二价锰离子，具体为氯化锰或硫酸锰、磷酸二氢锰、硝酸锰中的一种或多种的组合；所述肿瘤为淋巴瘤。

Description

锰离子制剂在制备治疗肿瘤药物中的用途 技术领域
本发明涉及药物领域，具体涉及锰离子制剂在制备治疗肿瘤中的用途。
背景技术
肿瘤是威胁人类生命的主要疾病，并且肿瘤发病率和死亡率每年都在上升，据世界卫生组织预测，2020年全球癌症新发病例将达到2000万，因癌症死亡1200万人。虽然目前治疗肿瘤手段有很多种，比如手术、放疗、化疗以及生物治疗等，但是每种手段都存在不同方面的缺陷，产生不同程度的毒副作用，因此人们迫切希望找到一种不会产生任何明显可见副作用、安全有效的治疗肿瘤的方法。
锰(Mn)是人体必需的8种微量元素之一，是维持人和动物健康乃至生命必不可少微量元素。过多摄入或者缺乏Mn都会导致疾病发生。Srisuchart等发现动物暴露于小于10mg MnCl 2/kg没有死亡或表现出与Mn毒性相关的迹象 [1]。微量的Mn可以维持免疫系统功能，调节血糖、细胞能量、骨骼生长、对抗自由基等 [2]。
1983年，Rogers等发现给小鼠注射MnCl 2后，可以增强其体内天然细胞介导的免疫效应细胞功能 [3-5]。例如，给小鼠单次肌肉注射MnCl 2后，Rogers等通过 51Cr释放实验测定自然杀伤(NK)细胞活性，发现NK细胞活性显著增强。Rogers等用无菌、无热原，0.9％的生理盐水制备氯化锰(MnCl 2)储液，用25mM 2-N-羟乙基-哌嗪-N'-2-乙磺酸(Hepes，Grand Island Biological Co.，Grand Island，NY)缓冲的盐水中稀释至所需浓度。以下称为Hepes-生理盐水。给11周龄和19周龄的CBA/J小鼠、9周龄A/J/小鼠、11周龄C57BI/6J小鼠大腿肌肉注射0.1-0.15毫升的Hepes-生理盐水、MnCl 2(40，80或120ug/g)；24小时后取小鼠脾脏，用红细胞裂解液裂解，洗涤，重悬至2×10 7个/毫升；用铬酸钠(Na 251CrO 4)标记小鼠淋巴瘤细胞(YAC-1细胞)和小鼠T淋巴瘤细胞(EL-4细胞)，洗涤，重悬至2×10 5个/毫升；脾脏细胞和靶细胞按25:1、50:1、100:1共孵育4小时候；检测细胞培养液上清 51Cr，计算NK细胞活性。结果发现，NK细胞活性呈现出剂量相关的增加；80ug/g MnCl 2处理的小鼠NK细胞活性最高，可持续3天；提高了低免疫应答的C57BI/6J和A/J/小鼠的脾脏细胞杀伤YAC-1肿瘤细胞；提高了CBA/J小鼠脾脏细胞杀伤EL-4肿瘤细胞；提高了老龄CBA/J小鼠脾脏细胞杀伤YAC-1肿瘤细胞。Rogers等还做了体内实验验证。给10周龄和22-24周龄的CBA/J和10周龄A/J小鼠大腿肌肉注射0.1-0.15毫升的Hepes-生理盐水、MnCl 2(80ug/g)；24小时后， 用碘125-5-氟-2'-脱氧尿苷标记YAC-1肿瘤细胞，洗涤后，用不完全RPMI-1640培养基重悬细胞至2×10 6个/毫升；每只处理过的小鼠尾静脉注射1×10 7个碘125-5-氟-2'-脱氧尿苷放射物标记的YAC-1细胞；30分钟、1小时、2小时和4小时后颈部脱位处死小鼠；取出小鼠脾脏和肺部并置于管中；检测小鼠肺部和脾脏放射性YAC-1细胞。发现从肺部回收的放射性从注射后30分钟的约20％降低至4小时后的不到1％。在1，2和4小时时，在Mn处理的小鼠的肺中观察到增强的肿瘤细胞清除率；通过回收的放射性百分比降低显示，在4小时时在Mn处理的小鼠的脾脏中观察到增强的肿瘤细胞清除率。结果也显示了MnCl 2增强了低免疫应答的A/J小鼠体内的NK活性。同时MnC1 2还增强了老龄CBA/J的体内NK活性。
目前肿瘤治疗手段包括：手术治疗；放射治疗；化学治疗；生物治疗；中医疗法；中西医结合疗法等。这些治疗方法都存在不同方面的缺陷：①手术治疗风险大，对人体创伤大，使患者免疫力降低，对疾病抵抗力下降。②放射治疗并发症较多，甚至引起部分功能丧失；对于晚期肿瘤患者，放射治疗效果并不完好。不适合体质较差，年龄偏大的患者。③化疗药物的选择性差，在杀死肿瘤细胞的同时杀死了大量的正常细胞，破坏了人体自身的免疫系统功能；抑制骨髓造血干细胞的功能，并易产生耐药性。④生物治疗，成本高，对于晚期带有较多癌组织、特别是带有实体瘤的病人，相对显得无能为力。⑤中医治疗，治疗效果不如化疗，对肿瘤局部的控制作用不好。而本发明在弥补手术、放疗、化疗、生物治疗和中药治疗的不足条件下，为肿瘤治疗提供了一种安全有效方法，且最主要的是该方法没有其它肿瘤治疗方法带来的副作用。
1.Srisuchart,B.,M.J.Taylor,and R.P.Sharma,Alteration of Humoral and Cellular-Immunity in Manganese Chloride-Treated Mice.Journal of Toxicology and Environmental Health,1987.22(1):p.91-99.
2.Erikson,K.M.,et al.,Interactions between excessive manganese exposures and dietary iron-deficiency in neurodegeneration.Environmental Toxicology and Pharmacology,2005.19(3):p.415-421.
3.Smialowicz,R.J.,et al.,Manganese Chloride Enhances Murine Cell-Mediated Cytotoxicity:Effects on Natural Killer Cells.Journal of Immunopharmacology,1984.6(1-2):p.1-23.
4.Smialowicz,R.J.,et al.,Manganese Chloride Enhances Natural Cell-Mediated Immune Effector Cell-Function-Effects on Macrophages.Immunopharmacology,1985.9(1):p.1-11.
5.Rogers,R.R.,et al.,Augmentation of Murine Natural-Killer Cell-Activity by Manganese Chloride.Toxicology and Applied Pharmacology,1983.70(1):p.7-17.
发明内容
本发明一个方面提供了锰离子制剂在制备治疗肿瘤的药物中的用途，其中，锰离子作为唯一活性成分。
在本发明的技术方案中，所述的锰离子为二价锰离子。
在本发明的技术方案中，二价锰离子优选为氯化锰或硫酸锰、磷酸二氢锰、硝酸锰中的一种或多种的组合。
在本发明的技术方案中，锰离子制剂为溶液剂、乳剂、混悬剂、注射剂、冻干粉针剂。
在本发明的技术方案中，锰离子制剂为注射剂，其溶剂选自注射用水、缓冲溶液、生理盐水。
在本发明的技术方案中，所述肿瘤为淋巴瘤选自非霍奇金淋巴瘤的肿瘤或霍奇金淋巴瘤的肿瘤。
在本发明的技术方案中，非霍奇金淋巴瘤选自t细胞淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、外周T细胞淋巴瘤(PTCL)、皮肤T细胞淋巴瘤(CTCL)和其任何组合。
有益效果
①锰离子制剂成本低廉；
②MnCl 2注射液制作简单；
③无任何明显可见的副作用；
④可激活机体免疫细胞活性，增强免疫细胞抗肿瘤应答功能。
附图说明
图1为空白组和给药组不同时间点肿瘤生长趋势图。
具体实施方式
实施例1 配置MnCl 2注射液
将MnCl 2粉末溶解于无菌磷酸缓冲盐溶液(PBS)，制备成8M储液，并用孔径为0.25微米滤膜过滤灭菌。用PBS稀释至所需浓度。
实施例2 MnCl 2对淋巴瘤小鼠的体内疗效实验
对C57BL/6小鼠皮下接种小鼠T淋巴癌(RMA-S)细胞建立肿瘤模型，取生长状态良好的RMA-S细胞，按细胞数2×10 6/ml，0.1ml接种于6～10周龄C57BL/6小鼠右侧腋下皮下，即给C57BL/6小鼠皮下接种2×10 5RMA-S细胞,建立肿瘤模型，每组5只小鼠；以接种RMA-S肿瘤细胞当日为试验第1天，每天给小鼠腹腔注射400uL无菌PBS、或由无菌PBS溶解的 MnCl 2(2mg/kg)1次，连续注射6天；MnCl 2处理小鼠后的第6天、9天、12天测量肿瘤大小，记录数据，并用下列公式计算肿瘤结节大小：瘤径r(mm)＝(长径+短径)/2，使用下列公式计算肿瘤球体积：肿瘤球体积V(mm 3)＝(4/3)πr 3；采用Graph Pad Prism软件处理数据，多重t检验(Multiple t tests)统计学方法分析。通过图1的趋势可以看出在12天时肿瘤体积的明显不同，具有统计学差异，给药组肿瘤体积约为空白组的二分之一。

Claims (23)

  1. 锰离子制剂在制备治疗肿瘤的药物中的用途，其中，锰离子作为唯一活性成分。
  2. 根据权利要求1所述的用途，所述的锰离子为二价锰离子。
  3. 根据权利要求2所述的用途，二价锰离子优选为氯化锰或硫酸锰、磷酸二氢锰、硝酸锰中的一种或多种的组合。
  4. 根据权利要求1-3任一项所述的用途，锰离子制剂为溶液剂、乳剂、混悬剂、注射剂、冻干粉针剂。
  5. 根据权利要求4所述的用途，锰离子制剂为注射剂，其溶剂选自注射用水、缓冲溶液、生理盐水。
  6. 根据权利要求1-5任一项所述的用途，所述肿瘤为淋巴瘤。
  7. 根据权利要求6所述的用途，淋巴瘤选自非霍奇金淋巴瘤的肿瘤或霍奇金淋巴瘤的肿瘤。
  8. 根据权利要求7所述的用途，非霍奇金淋巴瘤选自t细胞淋巴瘤、弥漫性大B细胞淋巴瘤、外周T细胞淋巴瘤或皮肤T细胞淋巴瘤。
  9. 锰离子制剂在治疗肿瘤中的用途，其中锰离子制剂中锰离子作为唯一活性成分。
  10. 根据权利要求9所述的用途，所述的锰离子为二价锰离子。
  11. 根据权利要求10所述的用途，二价锰离子优选为氯化锰或硫酸锰、磷酸二氢锰、硝酸锰中的一种或多种的组合。
  12. 根据权利要求9-11任一项所述的用途，锰离子制剂为溶液剂、乳剂、混悬剂、注射剂、冻干粉针剂。
  13. 根据权利要求12所述的用途，锰离子制剂为注射剂，其溶剂选自注射用水、缓冲溶液、生理盐水。
  14. 根据权利要求9-12任一项所述的用途，所述肿瘤为淋巴瘤。
  15. 根据权利要求9所述的用途，淋巴瘤选自非霍奇金淋巴瘤的肿瘤或霍奇金淋巴瘤的肿瘤。
  16. 根据权利要求15所述的用途，非霍奇金淋巴瘤选自t细胞淋巴瘤、弥漫性大B细胞淋巴瘤、外周T细胞淋巴瘤或皮肤T细胞淋巴瘤。
  17. 一种治疗肿瘤的锰离子制剂，其中，锰离子作为唯一活性成分。
  18. 根据权利要求17所述的锰离子制剂，所述的锰离子为二价锰离子。
  19. 根据权利要求18所述的锰离子制剂，二价锰离子优选为氯化锰或硫酸锰、磷酸二氢锰、硝酸锰中的一种或多种的组合。
  20. 根据权利要求17-19任一项所述的锰离子制剂，锰离子制剂为溶液剂、乳剂、混悬剂、注射剂、冻干粉针剂。
  21. 根据权利要求20所述的锰离子制剂，锰离子制剂为注射剂，其溶剂选自注射用水、缓冲溶液、生理盐水。
  22. 根据权利要求17-21任一项所述的锰离子制剂，所述肿瘤为淋巴瘤。
  23. 根据权利要求22所述的锰离子制剂，淋巴瘤选自非霍奇金淋巴瘤的肿瘤或霍奇金淋巴瘤的肿瘤。
PCT/CN2019/120179 2019-05-24 2019-11-22 锰离子制剂在制备治疗肿瘤药物中的用途 WO2020238085A1 (zh)

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JPH04103532A (ja) * 1990-08-24 1992-04-06 Tatsuo Miyoshi 制癌剤

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JPH04103532A (ja) * 1990-08-24 1992-04-06 Tatsuo Miyoshi 制癌剤

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