CN110575458A - 一种抗肿瘤复方药物的组成及其在抗肿瘤中的应用 - Google Patents
一种抗肿瘤复方药物的组成及其在抗肿瘤中的应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域，发明了一类多功能抗肿瘤复方药物，该抗肿瘤复方药物的组成包括天然免疫通路（STING）的激动剂和磷酸二酯酶ENPP1的抑制剂。STING和ENPP1均坐落于内质网膜上，STING的激活剂、激动剂是ENPP1的水解底物，该复方药可以起到双管齐下的药效。该类复合抗肿瘤药物比单独使用天然免疫激动剂具有更好的抗肿瘤药效。因此，这种创新复合抗肿瘤药物具有高效临床应用前景。
Description
技术领域
本发明属于生物医药技术领域具体涉及一类抗肿瘤复方药物的组成及其抗肿瘤应用。
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2000万人，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8550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。
环二核苷酸cGAMP作为二级信使分子通过激活内质网膜上的STING蛋白通路诱导干扰素IFN-β和其他细胞因子的产生，调节下游蛋白质表达，诱导细胞生长停滞和凋亡。STING通路可以调节免疫原性肿瘤的先天免疫识别，促进干扰素的抗肿瘤作用。IFN-γ在体内通过TRAIL(tumor necrosis factor-related apoptosis-inducing ligand)发挥抗肿瘤作用，促进肿瘤细胞凋亡。cGAMP是先天免疫反应的关键刺激物，是STING的内源性激活剂，因此，cGAMP具有免疫抗肿瘤作用。
STING是内质网的跨膜蛋白，内质网上具有一种ENPP1的磷酸二酯酶(水解酶)。ENPP1水解酶可以降解2’3’-cGAMP。这个酶具有相当宽的底物特异性，包括ATP和NAD+，实验显示2'3'-cGAMP是良好的重组ENPP1的底物。因此，有效抑制ENPP1的催化活性可以抑制STING激活剂被ENPP1水解酶水解，延长其代谢周期，提高药效。
基于以上原理，我们发明了一类抗肿瘤复方药物，它包括天然免疫通路 (STING)激活剂和磷酸二酯酶ENPP1的抑制剂，双管齐下，达到提高免疫抗肿瘤药效。因此，该类免疫抗肿瘤复方药具有很好的临床应用前景。
发明内容
本发明的目的在于提供一类多功能抗肿瘤复方药物，它包括天然免疫通路(STING)激活剂2’3’-cGAMP(或其衍生物激动剂)和磷酸二酯酶ENPP1的抑制剂，双管齐下，达到提高免疫抗肿瘤药效。因此，该类免疫抗肿瘤复方药具有很好的临床应用前景。
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]。
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：环二核苷酸cGAMP及其衍生物的制备
cGAMP或其衍生物(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。(Li P.W，et al.,Immunity, 2013,39(6),1019-1031.)
实施例2：ENPP1抑制剂的制备
ATP及其衍生物均为ENPP1的水解底物，经过改造的ATP类似物可选择性地抑制ENPP1的酶催化活性。本发明的ENPP1的抑制剂及其制备路线见附图1.
实施例3：抗肿瘤复方创新药靶向脂质体的制备方法
(1)脂质体原料：卵磷脂(lipoid EPCs)、胆固醇(CH)、聚乙二醇等均购买自 Sigma公司。(2)叶酸靶向脂质体按文献方法制备。(Chen X.,et al.,Int J Nanomedicine,2012,7:1139-1148；Waldrep J.C.,et al.,Int J Pharm,1998, 160(2):239-249)。
(3)叶酸靶向脂质体包裹抗肿瘤复方药物
向磷脂膜中加入120mmol/L的硫酸铵溶液，振摇(120rpm、5分钟)形成空白脂质体溶液，该空白脂质体溶液在超纯水中透析过夜。该复方药溶解于超纯水中，加入到空白脂质体溶液中，65℃孵育20分钟，水浴超声减小粒径，用超滤管 (MWCO＝3000Da)超滤除去未包封药物。
(4)抗肿瘤复方药物靶向脂质体的性质表征
(a)粒径表征
利用动态光散射(Dynamic Light Scattering，DLS)测量脂质体的粒径和粒径分布(PDI)。其基本原理为微小粒子悬浮在液体中会无规则地运动(布朗运动)，光通过胶体时，粒子会将光散射，在一定角度下可以检测到光信号。大颗粒运动缓慢，散射光斑的强度也将缓慢波动；小粒子运动快速，散射光斑的密度也将快速波动，最后通过光强波动变化和光强相关函数计算出粒径及其分布。PDI表示粒径的均一度，是方差的概念。所制备的脂质体粒径约70nm。
(b)Zeta电位
Zeta电位是连续相与附着在分散粒子上的流体稳定层之间的电势差。一般用来评价或预测微粒分散体系的物理稳定性,一般Zeta电位绝对值越高,其粒子间的静电斥力也就越大,物理稳定性也就越好。一般Zeta电位绝对值达到30mV就认为体系比较稳定。本发明制备的脂质体Zeta电位绝对值为29mV，稳定性较好。
实施例4：采用荷瘤鼠模型进行检测该抗肿瘤复方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普通小鼠、C57/BL6普通小鼠，雄性，体重18-20g，7-8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。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：cGAMP,10mg/kg；复方抗肿瘤药,10mg/kg
试验对照
阴性对照：生理盐水溶液
阳性对照：cGAMP，剂量10mg/kg；
给药方法
给药途径：腹腔注射给药
给药体积：100微升/只
给药次数：连续21天给药，每天1次
每组动物数：10只
肿瘤细胞株
小鼠结直肠癌细胞株CT26，小鼠肺癌Lewis瘤株LL/2，人卵巢癌细胞株SK-OV-3，人黑色素瘤细胞株A375，人胃癌细胞株MNK-45，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)， 10天左右肿瘤长至直径约5mm，致瘤成功，随机均分为4组。分别为A：阴性对照组；B：cGAMP组；C：抗肿瘤复方药组；D：抗肿瘤复方药靶向脂质体组。连续给药21天。21天后，处死小鼠并称瘤体重量，计算抑瘤率＝[1-实验组平均瘤重/A组平均瘤重)]×100％。
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-wayANOVA)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，抗肿瘤复方创新药及其靶向脂质体和单独天然免疫通路激活剂(cGAMP)均可明显增强抑制肿瘤生长，给药 21天后的瘤重均显著低于阴性对照组(P<0.05，P<0.01)，抗肿瘤复方药具有更优的抗肿瘤作用。具体结果表1-5：
表1、抗肿瘤复方药对BalB/C小鼠结直肠癌细胞CT26皮下移植瘤的作用
(n＝10，mean±SD)
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表2、抗肿瘤复方药对C57小鼠肺癌Lewis瘤株LL-2皮下移植瘤的作用 (n＝10，mean±SD)
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表3、抗肿瘤复方药对人黑色素瘤细胞株A375鼠皮下移植瘤的作用 (n＝10，mean±SD)
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表4、抗肿瘤复方药对人胃癌细胞株MNK-45鼠皮下移植瘤的作用 (n＝10，mean±SD)
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表5、抗肿瘤复方药对人卵巢癌细胞株SK-OV-3鼠皮下移植瘤的作用 (n＝10，mean±SD)
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
实施例4抗肿瘤复方药的急性毒性研究
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20～25g，动物以颗粒饲料喂养，自由摄食和饮水。
抗肿瘤复方药由实施例2制备，用生理盐水配制成浓度为200mg/mL的溶液。
实验方法
ICR小鼠按体重单次腹腔注射2g/kg的复合免疫抗肿瘤药缓释药物，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，说明复合免疫抗肿瘤药的急性毒性低。
附图说明
附图1.
8-氮杂-ATP-α-亚甲基-γ-巯基
附图2.
磷酸二酯酶ENPP1抑制剂化合物
Claims (6)
1.抗肿瘤复方药物的组成，包括天然免疫通路（STING通路）激动（活）剂和磷酸二酯酶ENPP1的抑制剂，天然免疫通路（STING通路）激动（活）剂包括但不限于环二核苷酸cGAMP及其各种各样的衍生物和类似物（环二核苷酸的组成包括两个ATP、两个GTP、或混合ATP/GTP及其ATP/GTP的取代衍生物或改造形成的类似物），磷酸二酯酶ENPP1的抑制剂包括但不限于ATP及其各种ATP的衍生物、类似物，或通过高通量筛选得到的ENPP1小分子抑制剂等）。
2.新发明的磷酸二酯酶ENPP1抑制剂包括但不限于附图1-2列出的化合物（化学结构及其制备方法）。
3.该复方抗肿瘤物化合物在抗肿瘤中的应用及其在制备抗肿瘤药物中的应用。
4.根据权利要求1-3所述的抗肿瘤复方药物可制备成的脂质体和靶向脂质体（包括但不限于叶酸靶向脂质体和免疫靶向脂质体）。
5.根据权利要求1-4所述的此类抗肿瘤复方药物，应用于治疗各种肿瘤，包括但不限于结直肠癌、卵巢癌、前列腺癌、睾丸癌、肺癌、鼻咽癌、食道癌、恶性淋巴瘤、头颈部癌、甲状腺癌及成骨肉瘤等多种实体肿瘤。
6.根据权利要求1-4，该抗肿瘤复方药物，包括但不限于抗肿瘤药物，该类复方药物可应用于基于STING天然免疫通路激活／加强治疗的其它适应症，包括但不限于：神经退行性疾病（AD、PD）、心脑血管疾病、糖尿病、类风湿关节炎、多发性硬化症等相关的疾病。
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| KR20240105346A (ko) | 2020-05-08 | 2024-07-05 | 주식회사 티씨노바이오사이언스 | 엑토뉴클레오티드 피로포스파타아제-포스포디에스터라아제의 저해 활성을 갖는 신규한 프탈라진 유도체 및 이들의 용도 |
| KR20210136874A (ko) | 2020-05-08 | 2021-11-17 | 주식회사 티씨노바이오사이언스 | 엑토뉴클레오티드 피로포스파타아제-포스포디에스터라아제의 저해 활성을 갖는 신규한 프탈라진 유도체 및 이들의 용도 |
| WO2021225407A1 (ko) | 2020-05-08 | 2021-11-11 | 주식회사 티씨노바이오사이언스 | 엑토뉴클레오티드 피로포스파타아제-포스포디에스터라아제의 저해 활성을 갖는 신규한 프탈라진 유도체 및 이들의 용도 |
| WO2022011992A1 (zh) * | 2020-07-11 | 2022-01-20 | 杭州星鳌生物科技有限公司 | 一种用于治疗阿尔茨海默症的免疫激动剂复合物 |
| KR20220095154A (ko) | 2020-12-29 | 2022-07-06 | 주식회사 티씨노바이오사이언스 | 엑토뉴클레오티드 피로포스파타아제-포스포디에스터라아제의 저해 활성을 갖는 신규한 나프티리딘온 유도체 및 이들의 용도 |
| WO2022146022A1 (ko) | 2020-12-29 | 2022-07-07 | 주식회사 티씨노바이오사이언스 | 엑토뉴클레오티드 피로포스파타아제-포스포디에스터라아제의 저해 활성을 갖는 신규한 나프티리딘온 유도체 및 이들의 용도 |
| KR20240152794A (ko) | 2020-12-29 | 2024-10-22 | 주식회사 티씨노바이오사이언스 | 엑토뉴클레오티드 피로포스파타아제-포스포디에스터라아제의 저해 활성을 갖는 신규한 나프티리딘온 유도체 및 이들의 용도 |
| KR20220110118A (ko) | 2021-01-29 | 2022-08-05 | 주식회사 티씨노바이오사이언스 | 엑토뉴클레오티드 피로포스파타아제-포스포디에스터라아제의 저해 활성을 갖는 신규한 벤조트리아졸 유도체 및 이들의 용도 |
| KR20240113429A (ko) | 2021-01-29 | 2024-07-22 | 주식회사 티씨노바이오사이언스 | 엑토뉴클레오티드 피로포스파타아제-포스포디에스터라아제의 저해 활성을 갖는 신규한 벤조트리아졸 유도체 및 이들의 용도 |
| WO2022164249A1 (ko) | 2021-01-29 | 2022-08-04 | 주식회사 티씨노바이오사이언스 | 엑토뉴클레오티드 피로포스파타아제-포스포디에스터라아제의 저해 활성을 갖는 신규한 벤조트리아졸 유도체 및 이들의 용도 |
| KR20220160378A (ko) | 2021-05-27 | 2022-12-06 | 한국과학기술연구원 | 엑토뉴클레오티드 피로포스파타아제-포스포디에스터라아제의 저해 활성을 갖는 신규한 피롤로피리미딘 유도체 및 이들의 용도 |
| US12060352B2 (en) | 2021-05-27 | 2024-08-13 | Korea Institute Of Science And Technology | Substituted pyrrolo[2,3-d]pyrimidines having ectonucleotide pyrophosphatase-phosphodiesterase inhibitory activity |
| WO2023011076A1 (zh) * | 2021-08-05 | 2023-02-09 | 杭州星鳌生物科技有限公司 | 载物脂质体的多靶点复合体及含其的载药平台与应用 |
| CN115702939A (zh) * | 2021-08-05 | 2023-02-17 | 杭州星鳌生物科技有限公司 | 载物脂质体的多靶点复合体及含其的载药平台与应用 |
| KR20230090463A (ko) | 2021-12-15 | 2023-06-22 | 한국과학기술연구원 | 엑토뉴클레오티드 피로포스파타아제-포스포디에스터라아제의 저해 활성을 갖는 신규한 피리도피리미딘 유도체 및 이들의 용도 |
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| Publication number | Publication date |
|---|---|
| WO2019233300A1 (zh) | 2019-12-12 |
| US20210023115A1 (en) | 2021-01-28 |
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