CN110974840A - 一种类固醇硫酸酯酶抑制剂及其药物用途 - Google Patents
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Abstract
本发明公开了一种类固醇硫酸酯酶抑制剂并可用于制备防治该酶异常活化导致疾病的药物。上述抑制剂的体外酶活性抑制实验表明:虎杖苷可抑制类固醇硫酸酯酶的活性,且抑制效果较好。与此同时,体外细胞模型杀伤实验表明虎杖苷对于存在类固醇硫酸酯酶高表达的乳腺癌细胞的治疗效果明显优于其野生型组及空白对照组。此外,体内动物药效学实验结果表明虎杖苷可明显抑制类固醇硫酸酯酶高表达的乳腺癌细胞生长活性。因此,可以将虎杖苷药物作为有效成分制备类固醇硫酸酯酶抑制剂,并作为用来制备防治该酶的异常活化导致疾病(包括并不限于乳腺癌)的药物。
Description
技术领域
本发明属于医药应用技术领域,涉及虎杖苷作为有效成分制备类固醇硫酸酯酶抑制剂,并可用于制备防治该酶的异常活化导致的乳腺癌疾病。
背景技术
类固醇硫酸酯酶(Steroid Sulfatase,STS)是一种抗原,其能够刺激机体产生特异性免疫应答,并能与免疫应答产物抗体和致敏淋巴细胞在体内外发生结合,从而产生免疫效应(特异性反应)的物质。抗原的基本特性有两种,一是诱导免疫应答的能力,也就是免疫原性;二是与免疫应答的产物发生反应,也就是抗原性。
近年来相关研究表明类固醇硫酸酯酶与乳腺癌关系密切。绝经后乳腺癌患者外周循环中的***水平明显降低,而乳腺癌组织内的***仍处于较高水平,因此,对于绝经后乳腺癌患者,肿瘤细胞自身合成的***较外周血中的***在肿瘤细胞生长上的促进作用可能更为重要。乳腺癌组织可以通过类固醇硫酸酯酶(STS)途径合成雌酮,进而生成***。部分研究发现乳腺癌组织中STS的表达率及活性均明显升高。因此,STS在乳腺癌组织合成***的过程中可能发挥了主要作用[1]。因此,继续深入探寻STS抑制剂,并发掘制备防治STS异常活化导致的乳腺癌的新型药物迫在眉睫。
中药在我国一直有着举足轻重的地位。近年来,相关专家学者不断从中草药中分离提取出了一系列抗肿瘤活性成分,这些都为今后的研究提供了广阔的应用前景。虎杖苷(Polydatin,PD)是从蓼科蓼属植物虎杖(Polygonum Cuspidatum)的干燥根茎中提取的第四种单体,故又名虎杖结晶4号,在葡萄和葡萄酒中大量存在。近年来,国内外相关学者对虎杖苷的一些研究表明:虎杖苷在抗血小板凝集/抗血栓形成、加强心肌细胞收缩和舒张功能、改善休克后重要组织器官的微循环等方面具有显著作用[2-8];与此同时,虎杖苷还具有减轻子宫内膜异位症所引起的慢性疼痛及改善结肠炎等作用[9,10]。但虎杖苷作为STS抑制剂,并在防治乳腺癌的作用目前还未见报道。
发明内容
本发明的目的是克服现有技术的不足,提供其特征主要是由虎杖苷作为一种类固醇硫酸酯酶抑制剂。
本发明的第二个目的是提供虎杖苷在制备防治类固醇硫酸酯酶的异常活化导致的乳腺癌疾病,且应为包含luminal A型、 luminal B型 、HER-2型和三阴型的乳腺癌全部分子病理类型。
本发明的技术方案概述如下:
一种类固醇硫酸酯酶抑制剂在用于制备防治该酶的异常活化导致的疾病药物中的应用;所述的类固醇硫酸酯酶抑制剂指的是虎杖苷,所述的疾病包括并不限于乳腺癌。包含luminal A型、 luminal B型 、HER-2型和三阴型的全部分子病理类型。
本发明进一步公开了类固醇硫酸酯酶抑制剂虎杖苷的组合物,它包含虎杖苷以及一种或多种药学上可接受的载体、赋形剂或稀释剂。该组合物主要固体口服制剂、液体口服制剂、注射剂剂型,其中虎杖苷药物浓度小于等于12.1μg/ml。
本发明更加详细的描述如下:
一种类固醇硫酸酯酶抑制剂,主要是由虎杖苷组成。抑制剂中,虎杖苷药物浓度在小于等于12.1μg/ml对类固醇硫酸酯酶具有较好的抑制作用,最好是12.1μg/ml。
虎杖苷的分子式为C20H22O8;结构式如式(I)所示:
(I)。
虎杖苷作为一种类固醇硫酸酯酶抑制剂在用于制备防治类固醇硫酸酯酶的异常活化导致的乳腺癌疾病,包括luminal A型、 luminal B型 、HER-2型和三阴型的全部乳腺癌分子病理类型。
本发明首先运用体外酶活性抑制实验,其结果表明:虎杖苷可抑制类固醇硫酸酯酶的活性,且抑制效果较好。
其次,通过体外细胞模型杀伤实验表明虎杖苷对于存在类固醇硫酸酯酶高表达的乳腺癌细胞的治疗效果明显优于其野生型组及空白对照组。与此同时,体内动物药效学实验结果表明:虎杖苷可明显抑制类固醇硫酸酯酶高表达的乳腺癌细胞生长活性。
本发明公开的类固醇硫酸酯酶抑制剂包含虎杖苷以及一种或多种药学上可接受的载体、赋形剂或稀释剂组成的药物组合物。该药物组合物可以制成固体口服制剂、液体口服制剂、注射剂等剂型。
本发明的类固醇硫酸酯酶抑制剂还可以通过非肠道形式给药。优选的非肠道给药形式为注射剂给药。所述固体及液体口服制剂包括:片剂、肠溶片、胶囊、糖浆剂、口服溶液剂、注射剂等等。
本发明的类固醇硫酸酯酶抑制剂药物组合物制备如下:使用标准和常规的技术,使本发明化合物与制剂学上可接受的固体或液体载体结合,以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备成微粒或微球。固体剂型包括片剂、胶囊、缓释片、缓释微丸等等。固体载体可以是至少一种物质,其可以充当稀释剂、香味剂、增溶剂、润滑剂、悬浮剂、粘合剂、崩解剂以及包裹剂。惰性固体载体包括磷酸镁、硬脂酸镁、滑粉糖、乳糖、果胶、丙二醇、聚山梨酯80、糊精、淀粉、明胶、纤维素类物质例如甲基纤维素、微晶纤维素、低熔点石蜡、聚乙二醇、甘露醇、可可脂等。液体剂型包括溶剂、悬浮液例如注射剂、粉剂等等。
附图说明
图1 虎杖苷在体外对STS活性的抑制影响;
图2 虎杖苷针对人源性乳腺癌细胞MDA-MB-231(野生型)、MDA-MB-231(空白对照质粒过表达处理)、MDA-MB-231(STS质粒过表达处理)进行24h作用处理后,观察各组细胞存活情况;
图3虎杖苷针对人源性乳腺癌细胞MCF-7(野生型)、MCF-7(空白对照质粒过表达处理)、MCF-7(STS质粒过表达处理)进行24h作用处理后,观察各组细胞存活情况;
图4虎杖苷针对人源性乳腺癌细胞MDA-MB-231(野生型)、MDA-MB-231(空白对照质粒过表达处理)、MDA-MB-231(STS质粒过表达处理)的荷瘤小鼠进行15天给药处理后,第15天肿瘤大小情况;
图5虎杖苷针对人源性乳腺癌细胞MDA-MB-231(野生型)、MDA-MB-231(空白对照质粒过表达处理)、MDA-MB-231(STS质粒过表达处理)的荷瘤小鼠进行15天给药处理后,第15天各组肿瘤平均重量情况。
具体实施方式
下面通过具体的实施方案叙述本发明。除非特别说明,本发明中所用的技术手段均为本领域技术人员所公知的方法。另外,实施方案应理解为说明性的,而非限制本发明的范围,本发明的实质和范围仅由权利要求书所限定。对于本领域技术人员而言,在不背离本发明实质和范围的前提下,对这些实施方案中的物料成分和用量进行的各种改变或改动也属于本发明的保护范围。本发明所用原料及试剂均有市售。其中虎杖苷有市售:
实验用人源性STS重组蛋白酶购买于abcam公司(商业化产品);
人源性乳腺癌细胞MDA-MB-231(ATCC® HTB-26™)购买于美国ATCC细胞中心;
人源性乳腺癌细胞MCF-7购自于中国医学科学院基础医学研究所细胞资源中心。
下面结合具体实例对本发明作进一步的说明。
实施例1
虎杖苷的分子式为C20H22O8;结构式如式(I)所示:
(I)。
以虎杖苷作为活性成分,加入药学可接收的辅料按常规方法可制成各种规格的液体注射剂。
虎杖苷的给药途径包括多种,如注射给药,腔内给药等。
(1)注射剂的制备:
虎杖苷200 mg,甘露醇700 mg,PEG3000 10mg,蒸馏水100 ml,使pH值为7.0-7.5过滤滤液浓度为3mg/ml,按每安瓶2毫升分装,冷冻干燥后即得注射剂。
(2)片剂的制备:
虎杖苷10 mg ,微晶纤维素 35 mg,淀粉 45 mg,聚乙烯吡咯烷酮 4 mg,羧甲基淀粉钠盐4.5 mg,硬脂酸镁0.5 mg,滑石粉1 mg;将虎杖苷活性成分,淀粉和纤维素过筛,并充分混合,将聚乙烯吡咯烷酮溶液与上述的粉混合,过筛,制得湿颗粒于50℃干燥,将羧甲基淀粉钠盐,硬脂酸镁和滑石粉预先过筛,然后加入到上述的颗粒中压片。
(3)胶囊的制备
虎杖苷晶型10 mg,活性成分辅料分别过100目筛,称取处方量的主药和辅料充分混合,加入羟丙甲纤维素溶液适量制软材,过24目筛,制得湿颗粒于50-60℃烘箱中干燥约2-3小时,将硬脂酸镁和滑石粉与颗粒混合均匀,整粒,测定中间体含量,用2号胶囊灌装。
实施例2
虎杖苷对类固醇硫酸酯酶体外抑制作用的影响。
我们通过使用虎杖苷药物溶液在体外作用人源性类固醇硫酸酯酶,发现虎杖苷对该酶的活性存在明显的抑制作用,特别是虎杖苷药物浓度小于等于12.1μg/ml时对类固醇硫酸酯酶具有十分好的抑制作用,因此提示可以将虎杖苷作为有效成分制备类固醇硫酸酯酶抑制剂。具体结果详见图1。
注:目前类固醇硫酸酯酶的异常活化表达,这一现象在引发乳腺癌疾病中广泛存在。因为目前针对抑制类固醇硫酸酯酶异常活化的抑制剂药物较少,且大都为化学合成类药物,毒副作用较大,且价格成本昂贵。因此有望将低毒且廉价的中药成分代表虎杖苷作为活性成分开发针对治疗类固醇硫酸酯酶的异常活化导致的乳腺癌疾病。
实施例3
虎杖苷对人源性乳腺癌细胞模型MDA-MB-231及MCF-7各组细胞活性的抑制影响比较。
我们将本实验室构建并筛选好的MDA-MB-231(空白对照质粒过表达处理)、MDA-MB-231(STS质粒过表达处理)、MDA-MB-231(野生型)、MCF-7(空白对照质粒过表达处理)、MCF-7(STS质粒过表达处理)及MCF-7(野生型)共六种人源性乳腺癌细胞系按照每孔5000个细胞数量,分别使用96孔细胞培养板进行铺板,待细胞贴壁后,分别加入不同浓度的虎杖苷(10μg/ml、20μg/ml)药液,继续培养24后,吸掉原先废液,每孔再加入一定量的含有CCK-8试剂的培养基,继续37℃环境孵育1h,而后使用酶标仪在波长450nm处进行吸光度值读取。实验结果显示:不同浓度的虎杖苷对两种人源性乳腺癌细胞模型MDA-MB-231(STS质粒过表达处理)及MCF-7(STS质粒过表达处理)的抑制效果好于各自的野生型及空白对照组,从而明显体现出虎杖苷在针对治疗STS高表达异常类型的乳腺癌肿瘤疾病的良好特效专属性。具体结果详见图2与图3。
实施例4
比较虎杖苷对人源性乳腺癌细胞MDA-MB-231(野生型)、MDA-MB-231(空白对照质粒过表达处理)、MDA-MB-231(STS质粒过表达处理)的肿瘤细胞荷瘤小鼠的治疗效果的影响。
我们将本实验室构建并筛选好的MDA-MB-231(空白对照质粒过表达处理)、MDA-MB-231(STS质粒过表达处理)及MDA-MB-231(野生型)共三种人源性乳腺癌细胞系按照接种每点二百万个细胞数量接种在免疫缺陷鼠Balb/c皮下,小鼠共分为三个实验组。大约两周待小鼠皮下出现肉眼可见瘤块时,三组小鼠皆行虎杖苷(100mg/kg)腹腔注射给药,每日一次。第15天实验结束,处死全部小鼠,取瘤拍照并称重。
通过小鼠体内药效实验我们再一次发现:虎杖苷对存在STS过表达的乳腺癌肿瘤细胞的抑制效果远好于其对应的野生型组及空白质粒表达对照组,这与我们在前面的体外实验结果是相一致的。具体结果详见图4与图5。
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Claims (4)
1.一种类固醇硫酸酯酶抑制剂在用于制备防治该酶的异常活化导致的疾病药物中的应用;所述的类固醇硫酸酯酶抑制剂指的是虎杖苷,所述的疾病包括并不限于乳腺癌。
2.权利要求1所述的乳腺癌指的是:包含luminal A型、 luminal B型 、HER-2型和三阴型的全部分子病理类型。
3.一种含有权利要求1所述的类固醇硫酸酯酶抑制剂虎杖苷的组合物,其特征在于它包含虎杖苷以及一种或多种药学上可接受的载体、赋形剂或稀释剂。
4.权利要求3所述的药物组合物,其中为固体口服制剂、液体口服制剂、注射剂剂型;所述虎杖苷药物浓度小于等于12.1μg/ml。
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