WO2017162055A1 - 环二核苷酸cGAMP-脂质体在抗肿瘤中的应用 - Google Patents

环二核苷酸cGAMP-脂质体在抗肿瘤中的应用 Download PDF

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WO2017162055A1
WO2017162055A1 PCT/CN2017/076383 CN2017076383W WO2017162055A1 WO 2017162055 A1 WO2017162055 A1 WO 2017162055A1 CN 2017076383 W CN2017076383 W CN 2017076383W WO 2017162055 A1 WO2017162055 A1 WO 2017162055A1
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cgamp
liposome
cancer
tumor
cyclic dinucleotide
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PCT/CN2017/076383
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谭瀛轩
向道凤
袁红
张跃茹
谭相石
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聊城市奥润生物医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy

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  • the invention belongs to the field of biomedical technology, and particularly relates to the application of a cyclic dinucleotide cGAMP-liposome in antitumor and in preparing antitumor drugs.
  • Tumor is one of the major diseases that seriously endanger human health. It is characterized by excessive cell proliferation and differentiation. WHO experts predict that the global population of cancer will reach 20 million in 2020, and the death toll will reach 12 million. The tumor will become the first human killer in this century and pose the most serious threat to human survival.
  • the incidence and mortality of lung cancer, colorectal cancer, gastric cancer, liver cancer, etc. are among the highest in all kinds of malignant tumors. According to the National Cancer Registry (2012 China Cancer Registration Annual Report), there are about 3.12 million new cases of cancer every year, an average of 8,550 people per day, and 6 people per minute are diagnosed with cancer in the country. Lung cancer, gastric cancer, colorectal cancer, liver cancer and esophageal cancer are among the top five cancers in the country. As the incidence and mortality of malignant tumors increase year by year, the demand for treatment of malignant tumors is increasing.
  • Chemotherapy is one of the effective ways to treat tumors.
  • the mechanism of action of traditional chemotherapeutic drugs is mainly to prevent the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) or protein, or directly affect these macromolecules, thereby inhibiting the proliferation and death of tumor cells.
  • Some drugs are also Tumor growth can be inhibited by altering the hormone balance in the body.
  • anti-tumor drugs have been developed into 6 categories: 1 antimetabolites; 2 alkylating agents; 3 cytotoxic antibiotics; 4 plant alkaloids and other natural drugs; 5 anti-tumor hormones; 6 platinum and other anti-tumor drugs .
  • TKI small molecule tyrosine kinase inhibitors
  • other hot-acting mechanisms include immunostimulants, angiogenesis inhibitors, cell cycle inhibitors, immunosuppressants and stimulators, protein kinase inhibitors, and the like.
  • Microbial and viral DNA can induce an endogenous potent immune response by stimulating interferon secretion in infected mammalian cells.
  • the immune response of the endoplasmic reticulum (ER) receptor protein (STING) to cytoplasmic DNA is an essential factor.
  • ER endoplasmic reticulum
  • STING endoplasmic reticulum receptor protein
  • cGAMP cyclized cGMP-AMP dinucleotide synthetase
  • cGAMP is a cytoplasmic DNA sensor that acts as a second messenger to stimulate INF- ⁇ induction by STING, mediates the activation of TBK1 and IRF-3, and then initiates transcription of the INF- ⁇ gene.
  • cGAMP binds to STING, activates the transcription factor IRF3 and produces beta interferon.
  • Liposomes Liposomal sustained-release drug delivery has evolved over the decades and has made great strides in the field of anti-tumor.
  • the membrane materials for preparing liposomes are mainly phospholipids and cholesterol, etc. At present, a plurality of liposome preparations have been marketed, and have been widely used in clinical practice.
  • As a drug carrier liposomes have broad application prospects in prolonging drug half-life, enhancing drug efficacy, and targeting fixed-point administration.
  • the object of the present invention is also to propose a liposome-encapsulated cyclic dinucleotide cGAMP sustained-release drug for preparing an antitumor drug, so as to prepare an antitumor drug with low toxicity and good effect.
  • the experimental study of the present invention shows that the liposome-encapsulated cyclic dinucleotide cGAMP can inhibit the growth of a variety of tumor cells, has obvious anti-tumor effect, and can be used for preparing anti-tumor drugs.
  • the invention also relates to antineoplastic agents prepared using liposome-encapsulated cyclic dinucleotide cGAMP.
  • the tumor is selected from the group consisting of lung cancer, gastric cancer, liver cancer, colorectal cancer, melanoma, renal tumor, ovarian cancer, prostate cancer, bladder cancer, breast cancer, esophageal cancer, colon cancer, nasopharyngeal cancer, brain tumor, cervical Cancer, blood cancer, bone cancer, lymphoma, pancreatic cancer, etc.
  • Liposomes according to the invention include, but are not limited to, phospholipids and the like.
  • cyclic dinucleotide cGAMP of the present invention refers to 2'3'-cGAMP or Cyclic[G(2',5')pA(3',5')p].
  • the liposome-encapsulated cyclic dinucleotide cGAMP sustained-release antitumor drug used in the invention can prolong the cGAMP metabolic cycle and enhance the anti-tumor therapeutic effect, is superior to the positive drug 5-FU, and is superior to the anti-tumor treatment effect of cGAMP alone. .
  • Example 1 Preparation of liposome-encapsulated cGAMP sustained release antitumor drug
  • cGAMP (cyclized-GMP-AMP) was synthesized by cyclized cGMP-AMP dinucleotide synthetase (cGAS) under the activation conditions of DNA binding according to literature methods. The purity is above 98%. (LiP.
  • Liposomes Prepared and encapsulated cGAMP according to published literature methods to prepare liposome-encapsulated cGAMP drugs, liposomes
  • the preparation is mainly divided into the following steps: dissolving a phospholipid or the like in an organic solvent to form a lipid solution, removing the organic solvent, forming a lipid film, and then dispersing the film in the The cGAMP aqueous solution was sonicated into a uniform liposome.
  • Example 2 The tumor-bearing mouse model was used to detect the anti-tumor effect of liposome-encapsulated cGAMP sustained-release drugs, that is, the inhibition of the growth of subcutaneous xenografts in animals.
  • BALB/c nude mice BALB/c normal mice, C57/BL6 normal mice, male, weighing 16-18g, 6-8 weeks old, SPF grade, purchased from Shanghai Slack Laboratory Animals Co., Ltd. [Experimental animal quality Certificate No.: SCXK (Shanghai) 2007-0005].
  • mice All mice were free to forage and drink and were housed at the Experimental Animal Center of a military medical university of the People's Liberation Army at room temperature (23 ⁇ 2) °C. Both the feed and the water were autoclaved, and all the experimental feeding processes were SPF grade.
  • mice Intravenous injection of mice, set a dose group: 10mg/kg
  • Positive control 1 5-fluorouracil (5-FU), dose 10 mg/kg
  • Positive control 2 cGAMP, dose 10 mg/kg
  • Route of administration administration by tail vein injection
  • Dosing volume 100 microliters / only
  • the cells SW1990, the mouse colorectal cancer cell line CT26, and the mouse lung cancer Lewis tumor strain LL/2 were purchased from the cell bank of the Chinese Academy of Sciences.
  • the cells were cultured, passaged, and the cells were collected in the log phase of the cells to prepare a cell suspension at a concentration of (1.0 ⁇ 10 7 ) per ml.
  • the right forelimb of the mouse was injected subcutaneously with 0.2 ml of cell suspension (the number of cells was 2.0 ⁇ 10 6 ).
  • the tumors grew to a diameter of about 5 mm for about 10 days, and the tumors were successful. They were randomly divided into 4 groups.
  • the four groups were A: negative control group (intravenous saline group), B: 5-FU group (intravenous 5-FU 10 mg/kg group), C: cGAMP group (intravenous cGAMP) 10 mg/kg, D: The cGAMP-liposome group (intravenous cGAMP group) was 10 mg/kg.
  • human gastric cancer cell line MNK-45 human gastric cancer cell line MNK-45, human lung adenocarcinoma cell line A549, human colon cancer cell line Lovo, human liver cancer cell line SMMC-7721, human prostate cancer cell line PC-3, human Pancreatic cancer cell line SW1990, transplanted into nude mice, mouse colorectal cancer cell line CT26, transplanted into BalB/C normal mice, mouse lung cancer Lewis tumor strain LL/2, transplanted into C57/BL6 mice, observed cGAMP-lipid The anti-tumor effect of plastid drugs.
  • Data were expressed as x ⁇ s, and were processed by SPSS10.0 software.
  • the subcutaneous xenograft model was successfully prepared by subcutaneous inoculation of tumor cells in mice.
  • cGAMP-liposome, 5-FU and cGAMP could significantly inhibit tumor growth.
  • the tumor weight after 21 days of administration was significantly lower than that of the negative control group (P ⁇ 0.05). , P ⁇ 0.01), cGAMP-liposome is superior to 5-FU and cGAMP alone, indicating that cGAMP-liposome has a better anti-tumor effect.
  • the specific results are shown in Tables 1 to 8.
  • cGAMP-liposome was prepared from Example 1 and formulated into a solution having a concentration of 200 mg/mL with physiological saline.
  • mice were given a single tail vein injection of 2 g/kg cGAMP-liposome sustained-release drug by weight, and the toxicity and death of the mice within 14 days after administration were observed. It was found that the mice were normal after a single tail vein injection. Within 14 days after the administration, the mice did not die. On the 15th day, all the mice were sacrificed, dissected, and each organ was visually inspected, and no obvious lesions were observed.

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Abstract

本发明提供了脂质体包裹的环二核苷酸cGAMP在抗肿瘤中的应用。

Description

环二核苷酸cGAMP-脂质体在抗肿瘤中的应用 技术领域
本发明属于生物医药技术领域具体涉及一种环二核苷酸cGAMP-脂质体在抗肿瘤中以及在制备抗肿瘤药物中的应用。
背景技术
肿瘤是一类严重危害人类生命健康的重大疾病之一，表现为细胞过度增殖和分化异常。WHO专家预测，2020年全球人口肿瘤发病将达到2 000万人，死亡人数将达到1 200万人，肿瘤将成为本世纪人类第一杀手，对人类生存构成最严重的威胁。肺癌、结/直肠癌、胃癌、肝癌等的发病率和死亡率均居各类恶性肿瘤的前列。据全国肿瘤登记中心发布的(2012中国肿瘤登记年报》统计，每年新发生肿瘤病例约为312万例，平均每天8 550人，全国每分钟有6人被诊断为癌症。从病种来看，肺癌、胃癌、结/直肠癌、肝癌和食管癌，居全国恶性肿瘤发病的前五位。随着恶性肿瘤发病率和死亡率的逐年增加，恶性肿瘤治疗需求越来越大。
化疗是治疗肿瘤的有效方法之一。传统化疗药物的作用机制主要是阻止脱氧核糖核酸(DNA)、核糖核酸(RNA)或蛋白质的合成，或直接对这些大分子发生作用，从而抑制肿瘤细胞的分裂增殖，使之死亡。有些药物也 可以通过改变体内激素平衡而抑制肿瘤生长。目前抗肿瘤药物已发展到6大类：①抗代谢药；②烷化剂；③细胞毒素类抗生素；④植物生物碱和其他天然药；⑤抗肿瘤激素类；⑥铂类及其他抗肿瘤药。随着临床治疗模式的转变和一些新的抗肿瘤药物靶点的发现，抗肿瘤药物领域的研发发生了巨大变化：就药物的作用机制而言，从传统的非特异性的细胞毒类药物转向了非细胞毒类的靶向药物开发。2012年FDA批准的抗肿瘤药物中，小分子酪氨酸激酶抑制剂(TKI)成为研发最热门的一类抗肿瘤药物，尤其是作用于多个靶点的TKI(约占3/4)，截至2013年6月美国FDA批准的TKI已达18种。此外，其他热点作用机制药物包括免疫刺激剂、血管生成抑制剂、细胞周期抑制剂、免疫抑制剂和刺激剂、蛋白激酶抑制剂等。
在感染的哺乳动物细胞中微生物和病毒DNA能通过刺激干扰素分泌诱导內源强有力的免疫应答。内质网(ER)受体蛋白(STING)对胞质DNA的免疫应答是必需的因素。最近的研究表明，环化cGMP-AMP二核苷酸合成酶(cGAS)在结合DNA后的活化条件下，内源性地催化cGAMP的合成。cGAMP是一种胞质DNA传感器，它作为第二信使通过STING刺激INF-β的感应，介导TBK1和IRF-3的活化，进而启动INF-β基因的转录。最近报道，重组cGAS在DNA结合条件下催化环化cGMP-AMP二核苷酸GAMP。cGAS结合18bp dsDNA的复合物的晶体结构也已被报道，cGAMP在抗病毒免疫方面的研究已被证实。cGAMP结合STING，使转录因子IRF3激活并产生β干扰素。
脂质体缓释药物递送已经发展历经几十年时间，在抗肿瘤领域取得了长足的进步。制备脂质体的膜材料主要是磷脂和胆固醇等，目前已有多个脂质体制剂上市，并在临床上取得了广泛的应用。作为一种药物载体，脂质体在延长药物半衰期，增强药效，靶向定点给药等方面具有广阔的应用前景。
发明内容
本发明的目的在于提供脂质体包裹的环二核苷酸cGAMP在抗肿瘤中的应用。
本发明的目的还在于提出脂质体包裹的环二核苷酸cGAMP缓释药物在制备抗肿瘤药物中的应用，以制备毒性低、效果好的抗肿瘤药物。
本发明实验研究表明，脂质体包裹的环二核苷酸cGAMP可以抑制多种肿瘤细胞的生长，具有明显的抗肿瘤作用，可用于制备抗肿瘤药物。
本发明还涉及利用脂质体包裹的环二核苷酸cGAMP所制备的抗肿瘤药。
具体地，所述肿瘤选自肺癌、胃癌、肝癌、结肠直肠癌、黑色素瘤、肾瘤、卵巢癌、前列腺癌、膀胱癌、乳腺癌、食管癌、大肠癌、鼻咽癌、脑肿瘤、宫颈癌、血癌、骨癌、淋巴癌、胰脏癌等。
本发明所述的脂质体包括但不限于磷脂等。
本发明所述的环二核苷酸cGAMP，如不加说明，指的是2’3’-cGAMP或Cyclic[G(2’,5’)pA(3’,5’)p]。
本发明获得的有益效果如下：
本发明所用的脂质体包裹的环二核苷酸cGAMP缓释抗肿瘤药物能够延长cGAMP代谢周期，增强抗肿瘤治疗效果，优于阳性药物5-FU，且优于单独使用cGAMP抗肿瘤治疗效果。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中，以下所述的实施例是为了更好地阐述本发明，并不是用来限制本发明的范围。
实施例1：脂质体包裹的cGAMP缓释抗肿瘤药物的制备
cGAMP(环化-GMP-AMP)按文献方法在结合DNA后的活化条件下，由环化cGMP-AMP二核苷酸合成酶(cGAS)催化合成。纯度在98％以上。(LiP.W，et al.,Immunity,2013,39(6),1019-1031.)脂质体按照已经公开的文献方法制备并包裹cGAMP，制备成脂质体包裹的cGAMP药物，脂质体制备主要分为以下步骤:将磷脂等溶于有机溶剂，形成脂质溶液，去除有机溶剂，形成脂质薄膜，接着将薄膜分散在 cGAMP水溶液中经超声处理成均一的脂质体。(Chen X.,et al.,Int J Nanomedicine,2012,7:1139-1148；Waldrep J.C.,et al.,Int J Pharm,1998,160(2):239-249)
实施例2：采用荷瘤鼠模型进行检测脂质体包裹的cGAMP缓释药物的抗肿瘤作用即对动物皮下移植瘤生长的抑制作用。
动物
种属、品系、性别、体重、来源、合格证
BALB/c裸鼠、BALB/c普通小鼠、C57/BL6普通小鼠，雄性，体重16-18g，6-8周龄，SPF级，购于上海斯莱克实验动物有限责任公司[实验动物质量合格证号：SCXK(沪)2007-0005]。
饲养条件
所有小鼠均自由觅食和饮水，在室温(23±2)℃下饲养于中国人民解放军某军医大学实验动物中心。饲料及水均经高压灭菌处理，全部实验饲养过程为SPF级。
剂量设置
静脉注射小鼠，设置1个剂量组：10mg/kg
试验对照
阴性对照：生理盐水溶液
阳性对照1：5-氟尿嘧啶(5-FU)，剂量10mg/kg
阳性对照2：cGAMP，剂量10mg/kg
给药方法
给药途径：尾静脉注射给药
给药体积：100微升/只
给药次数：每天1次，连续21天
每组动物数：10只
肿瘤细胞株
人胃癌细胞株MNK-45，人肺腺癌细胞株A549，人结肠癌细胞株Lovo，人肝癌细胞株SMMC-7721，人前列腺癌细胞株PC-3，人胰腺癌 细胞SW1990，小鼠结直肠癌细胞株CT26，小鼠肺癌Lewis瘤株LL/2，均购自中国科学院细胞库。
试验主要步骤
1.肿瘤模型鼠的建立与干预
细胞培养，传代，在细胞对数期收集细胞，做成浓度为(1.0×107)每毫升的细胞悬液，小鼠右前肢腋下注射0.2ml细胞悬液(细胞数目为2.0×106个/只)，10d左右肿瘤长至直径约5mm，致瘤成功，随机均分为4组。四组分别为A：阴性对照组(静脉注射生理盐水组)、B：5-FU组(静脉注射5-FU 10mg/kg组)、C：cGAMP组(静脉注射cGAMP)10mg/kg、D：cGAMP-脂质体组(静脉注射cGAMP组)10mg/kg。每天给药1次，连续给药21天。21天后，处死小鼠并称瘤体重量，抑瘤率＝[1-实验组平均瘤重(B、C、D组为实验组)/A组平均瘤重)]×100％。
分别制备8种皮下移植瘤模型：人胃癌细胞株MNK-45，人肺腺癌细胞株A549，人结肠癌细胞株Lovo，人肝癌细胞株SMMC-7721，人前列腺癌细胞株PC-3，人胰腺癌细胞SW1990，移植到裸鼠，小鼠结直肠癌细胞株CT26，移植到BalB/C普通小鼠，小鼠肺癌Lewis瘤株LL/2，移植到C57/BL6小鼠，观察cGAMP-脂质体药物抗肿瘤效果。
2.统计分析
数据用x±s表示，利用SPSS10.0软件进行处理，采用单因素方差分析(one-way ANOVA)检验比较各组瘤重差异的显著性，显著性水平a＝0.05。
结果
小鼠皮下接种肿瘤细胞后制备成功皮下移植瘤模型，cGAMP-脂质体、5-FU和cGAMP均可明显抑制肿瘤生长，给药21天后的瘤重均显著低于阴性对照组(P<0.05，P<0.01)，cGAMP-脂质体优于5-FU和cGAMP单独用药，表明cGAMP-脂质体具有更优的抗肿瘤作用。具体结果见表1-表8。
表1 cGAMP-脂质体对裸鼠人胃癌细胞株MNK-45皮下移植瘤的作用
Figure PCTCN2017076383-appb-000001
Figure PCTCN2017076383-appb-000002
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组。
表2 cGAMP-脂质体对裸鼠人肺腺癌细胞株A549皮下移植瘤的作用
Figure PCTCN2017076383-appb-000003
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组。
表3 cGAMP-脂质体对裸鼠人结肠癌细胞株Lovo皮下移植瘤的作用
Figure PCTCN2017076383-appb-000004
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组。
表4 cGAMP-脂质体对裸鼠人肝癌细胞株SMMC-7721皮下移植瘤的作用
Figure PCTCN2017076383-appb-000005
Figure PCTCN2017076383-appb-000006
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表5 cGAMP-脂质体对裸鼠人前列腺癌细胞株PC-3皮下移植瘤的作用
Figure PCTCN2017076383-appb-000007
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组。
表6 cGAMP-脂质体对裸鼠人胰腺癌细胞SW1990皮下移植瘤的作用
Figure PCTCN2017076383-appb-000008
Figure PCTCN2017076383-appb-000009
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表7 cGAMP-脂质体对BalB/C鼠结直肠癌细胞CT26皮下移植瘤的作用
Figure PCTCN2017076383-appb-000010
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表8 cGAMP-脂质体对C57鼠肺癌Lewis瘤株LL-2皮下移植瘤的作用
Figure PCTCN2017076383-appb-000011
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
实施例3 cGAMP-脂质体的急性毒性研究
实验材料
ICR小鼠20只(购于上海斯莱克实验动物有限责任公司[实验动物质量合格证号：SCXK(沪)2007-0005])，雌雄各半，体重18～22g，动物以颗粒饲料喂养，自由摄食和饮水。
cGAMP-脂质体由实施例1制备，用生理盐水配制成浓度为200mg/mL的溶液。
实验方法
ICR小鼠按体重单次尾静脉注射2g/kg的cGAMP-脂质体缓释药物，观察给药后小鼠14天内的毒性反应及死亡情况。结果发现，小鼠单次尾静脉注射给药后，小鼠活动正常。给药后14天内，小鼠未出现死亡，第15天，全部小鼠处死，解剖，肉眼检查各脏器，均未见明显病变。
实验结果
上述急性毒性实验结果表明，静脉注射给药最大耐受量MTD不低于2g/Kg，说明cGAMP-脂质体药物的急性毒性低。

Claims (5)

  1. cGAMP-脂质体在抗肿瘤中的应用。
  2. cGAMP-脂质体在制备抗肿瘤药物中的应用。
  3. 根据权利要求2所述的cGAMP-脂质体在制备抗肿瘤药物中的应用，其特征在于，所述肿瘤包括但不限于胃癌、肺癌、结肠癌、肝癌、前列腺癌或胰腺癌等。
  4. 使用cGAMP等环二核苷酸-脂质体制备缓释抗肿瘤药物。
  5. 使用脂质体包裹环二核苷酸，制备缓释药物，增强环二核苷酸抗病的药效。
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CN112957475B (zh) * 2021-02-04 2022-07-22 李文峰 一种预防和或治疗肿瘤的组合物及应用
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