CN116637117A - 异连翘酯苷在制备乳腺癌治疗药物中的应用 - Google Patents
异连翘酯苷在制备乳腺癌治疗药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种异连翘酯苷在制备乳腺癌治疗药物中的应用。异连翘酯苷能显著抑制乳腺癌MDA‑MB‑231细胞的转移，划痕修复实验证明了药物抑制肿瘤细胞的迁移效率，Transwell小室侵袭实验证明了药物抑制肿瘤细胞的侵袭效率。因此，能够将异连翘酯苷用于制备治疗乳腺癌转移的药物。
Description
技术领域
本发明属于医药技术领域，具体涉及一种异连翘酯苷在制备乳腺癌治疗药物中的应用。
背景技术
连翘为常用大宗药材之一，始载于《神农本草经》，2020版中国药典亦有收载，为木犀科植物连翘Forsythia suspensa(Thunb.)Vahl的干燥果实。秋季果实初熟尚带绿色时采收，除去杂质，蒸熟，晒干，习称“青翘”；果实熟透时采收，晒干，除去杂质，习称“老翘”。具有清热解毒、消肿散结、疏散风热等功效。其主要含有木脂素类、苯乙醇苷类、黄酮类、萜类及挥发油类、酚酸类等化学成分，具有抗炎、抑菌、抗病毒、抗氧化等药理活性。
连翘作为药物使用已有悠久历史，苯乙醇苷类成分为其主要活性成分，其中异连翘酯苷(Isoforsythiaside，IFA)为2012年报道的一个苯乙醇苷类成分，其结构式如下：
异连翘酯苷有显著的的抗氧化、抑菌作用，并且可用于治疗阿尔兹海默症。但其抗肿瘤活性尚未被报道。
发明内容
发明目的：本发明目的在于针对现有技术的不足，提供一种异连翘酯苷在制备乳腺癌治疗药物中的应用。本发明实验发现，异连翘酯苷能显著抑制乳腺癌MDA-MB-231细胞的转移，因此，能够将其用于制备治疗乳腺癌转移的药物。
本发明实验研究发现：异连翘酯苷能显著抑制乳腺癌的转移。划痕修复实验证明了药物抑制肿瘤细胞的迁移效率。与溶剂组相比，随着异连翘酯苷浓度增加，MDA-MB-231细胞划痕愈合能力显著下降。说明异连翘酯苷可明显抑制乳腺癌MDA-MB-231细胞迁移能力且存在剂量依赖性。Transwell小室侵袭实验证明了药物抑制肿瘤细胞的侵袭效率。随着异连翘酯苷浓度的增加，MDA-MB-231细胞穿过Transwell小室聚碳酯底膜的能力逐渐下降，减弱细胞迁移的能力；Transwell侵袭实验在小室内加入模拟细胞外基质的Matrigel，实验结果证明MDA-MB-231细胞降解Matrigel基底膜能力随异连翘酯苷剂量增加而降低，降低细胞侵袭的能力。构建balb/c裸鼠尾静脉接种MDA-MB-231细胞肺转移模型，与模型组相比，异连翘酯苷治疗组中转移灶的数量明显较少且大多数结节直径减小。可见，异连翘酯苷具有抑制乳腺癌转移的作用。
技术方案：本发明的目的通过下述技术方案实现：
本发明提供了一种异连翘酯苷在制备乳腺癌治疗药物中的应用。
所述异连翘酯苷可作为唯一活性成分制备乳腺癌治疗药物。
所述异连翘酯苷可与其它药物联合使用制备乳腺癌治疗药物。
所述乳腺癌治疗药物包括异连翘酯苷及药学上可接受的载体或辅料。
所述辅料包含润湿剂、防腐剂、抗氧剂、乳化剂、增溶剂、崩解剂、黏合剂或稀释剂中的一种或几种。
所述润湿剂选自水或乙醇中的至少一种。
所述防腐剂选自苯甲酸及其盐类、山梨酸及其盐类或尼泊金酯类中的至少一种。
所述抗氧剂选自亚硫酸盐、抗坏血酸、亚硫酸氢盐、没食子酸及其脂类中的至少一种。
所述乳化剂选自吐温类、司盘类、果胶、琼脂、甘油脂肪酸酯类、海藻酸钠或二氧化硅中的至少一种。
所述增溶剂选择吐温类、聚氧乙烯脂肪醇醚类、硫酸化物或磺酸化物中的一种。
所述崩解剂选自淀粉、羧甲基淀粉钠、交联聚维酮、低取代羟丙基纤维素或交联聚乙烯吡咯烷酮中的至少一种。
所述黏合剂选自淀粉浆、羧甲基纤维素钠、聚维酮、羟丙基纤维素、甲基纤维素或乙基纤维素中的至少一种。
所述稀释剂选自淀粉类、糖类、纤维素类或无机盐类中的至少一种。
所述乳腺癌治疗药物的剂型为片剂、胶囊剂、颗粒剂、混悬剂、口服液、注射剂或输液剂。
本发明的药物可以采用各种已知的方式施用，例如口服、注射等施用方式。本发明的药物可单独给药也可与其他药物联合用药。口服组合物可以是任何口服可接受的剂型，包含但不限于片剂、胶囊剂、颗粒剂、混悬剂和口服液。
无菌可注射组合物可按照本领域已知的技术，使用适合的分散剂或润湿剂和助悬剂来配制。可以使用的药学上可接受的载体和溶剂包括水、氯化钠溶液等。
本发明药物可以制成普通制剂，也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
可以改变本发明的药物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可以有效实现所需治疗响应、对患者无毒的活性成分的量。所选择的剂量水平取决于多种因素，包括施用途径、施用时间、排泄速率、治疗的持续时间、与异连翘酯苷组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、一般健康状况和既往病史以及医学领域中公知的类似因素。
所述异连翘酯苷显著抑制乳腺癌MDA-MB-231细胞的转移能力。
所述异连翘酯苷显著抑制乳腺癌细胞MDA-MB-231细胞迁移侵袭能力。
有益效果：
本发明所述的异连翘酯苷可作为活性成分，应用于抑制乳腺癌细胞转移的药物中，为制备抑制乳腺癌转移的药物提供了新选择。本发明所述的异连翘酯苷能显著抑制乳腺癌MDA-MB-231细胞的转移。因此，异连翘酯苷可用于制备乳腺癌治疗药物。
附图说明
图1为异连翘酯苷(IFA)在MDA-MB-231细胞上的划痕抑制实验结果；其中，图1A为IFA在MDA-MB-231细胞上的划痕实验，比例尺＝100μm；图1B为划痕实验定量结果；n＝3,x±SD。与溶剂组相比，**p<0.01为有较大显著差异，***p<0.001为有极大显著性差异。
图2为异连翘酯苷(IFA)在MDA-MB-231细胞上的转移侵袭抑制实验结果；其中，图2A为IFA在MDA-MB-231细胞上Transwell实验，比例尺＝100μm；图2B为迁移实验定量结果；图2C为侵袭实验定量结果；n＝3,x±SD。与溶剂组相比，**p<0.01为有较大显著差异，***p<0.001为有极大显著性差异。
图3为异连翘酯苷(IFA)在小鼠体内抑制MDA-MB-231细胞肺转移实验结果；其中，各组别小鼠肺部结节定量图；图3C为治疗期间，各组别小鼠体重变化图；图3D为各组别小鼠肺部H&E染色图，比例尺＝100μm；n＝6,x±SD；与Model相比，*p<0.5为有显著差异，**p<0.01为有较大显著差异。
具体实施方式
下面通过具体实施例对本发明技术方案进行详细说明，但是本发明的保护范围不局限于所述实施例。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。
实施例1划痕修复实验
取对数生长期的乳腺癌细胞MDA-MB-231细胞(中国科学院细胞库，上海)接种于6孔板中，次日待细胞贴壁且密度达90％，使用200μL无菌枪头在单细胞表面层进行细胞划线。
划痕后，无菌PBS洗细胞3次，给药4，16，32μM的异连翘酯苷(上海源叶生物科技有限公司)和等量PBS于MDA-MB-231细胞中，且该实验采用无血清培养基(格来赛生命科技有限公司，上海)。放入37℃和5％ CO2的培养箱培养24h。
于倒置显微镜下观察并拍照细胞0h、24h的划痕愈合情况。使用Image J软件计算细胞划痕之间的距离面积，计算划痕愈合率。划痕愈合率＝(0h划痕宽度-24h划痕宽度)/0h划痕宽度×100％。
实验结果如图1所示，与溶剂组相比，随着异连翘酯苷浓度的增加，MDA-MB-231细胞划痕愈合能力显著下降。这说明异连翘酯苷可明显抑制乳腺癌细胞MDA-MB-231细胞迁移能力且存在剂量依赖性。
实施例2Transwell小室侵袭实验
将Matrigel基质胶(上海诺娃医药科技有限公司，上海)铺在Transwell小室(赛默飞世尔科技公司，上海)内微孔滤膜上，放至培养箱37℃活化1h。取对数生长期的MDA-MB-231细胞用无血清培养基稀释成浓度为5×106个/mL的细胞悬液。将活化的小室置于24孔板中，取400μL含有异连翘酯苷(4，16和32μM)的细胞悬液，缓慢均匀滴加入Transwell小室上室内。下室加入600μL含有30％血清的培养基(格来赛生命科技有限公司，上海)，放入培养箱37℃培养24h。24h后取出小室，用棉签轻轻擦去上室未迁移的细胞，4％多聚甲醛固定20min，0.5％结晶紫染色30min，用PBS冲去浮色，置于显微镜下观察。随机选取上、下、左、右、中五个视野，计算迁移细胞平均数。
如图2所示，随着异连翘酯苷浓度的增加，MDA-MB-231细胞穿过Transwell小室聚碳酯底膜的能力逐渐下降，减弱细胞迁移的能力；Transwell侵袭实验在小室内加入模拟细胞外基质的Matrigel，实验结果证明MDA-MB-231细胞降解Matrigel基底膜能力随异连翘酯苷A剂量增加而降低，降低细胞侵袭的能力。以上结果表明，异连翘酯苷抑制乳腺癌MDA-MB-231细胞迁移侵袭能力，且药效具有剂量依赖性。
实施例3构建Balb/c裸鼠静脉接种MDA-MB-231细胞肺转移模型
取对数生长期的MDA-MB-231细胞用消化酶消化后，用PBS洗涤细胞两次以去除残留血清。细胞计数板进行细胞计数，用预冷的PBS稀释至细胞浓度1×107个/mL。将细胞悬液置于冰上，乳腺癌肺转移模型采用尾静脉注射乳腺癌细胞的接种方法。将雌性Balb/c裸鼠(南京青龙山动物繁育场、5-6周龄、18g)使用尾静脉固定器固定。每只鼠尾静脉接种100μL的MDA-MB-231细胞悬液。将接种的实验鼠随机分为6组，每组6只：空白对照组；模型组；模型+阳性药组(Taxol，上海源叶生物科技有限公司，10mg/kg)；模型+异连翘酯苷(12mg/kg)组；模型+异连翘酯苷(25mg/kg)组；模型+异连翘酯苷(50mg/kg)组。空白对照组和模型组注射等量PBS缓冲液。尾静脉接种后，每三天腹腔注射给药一次。并测量记录小鼠体重变化，期间共计33天。观察乳腺癌细胞体内转移情况，并取出肺转移灶进行进一步病理检测。
如图3A和3B所示，统计拍照小鼠肺中乳腺癌转移性结节，与模型组相比，各异连翘酯苷治疗组中转移灶的数量明显较少且大多数结节直径减小。治疗期间，观测小鼠体重变化。与正常组相比，异连翘酯苷干预后对小鼠体重影响没有显著变化(图3C)。取小鼠肺组织，进行病理指标检测H&E染色。结果(图3D)显示，空白组小鼠送检肺组织肺泡结构清晰，支气管上皮细胞未见变性、脱落，未见明确肿瘤组织。模型组小鼠肿瘤细胞在肺组织内弥漫片状分布，肿瘤细胞间界限不清。各异连翘酯苷治疗组，小鼠肺组织中细胞核呈异型，染色质略呈空泡状，可见肿瘤结节，较模型组更少。以上结果表明异连翘酯苷能显著抑制MDA-MB-231乳腺癌细胞的体内肺转移。
如上所述，尽管参照特定的优选实施例已经表示和表述了本发明，但其不得解释为对本发明自身的限制。在不脱离所附权利要求定义的本发明的精神和范围前提下，可对其在形式上和细节上作出各种变化。
Claims (8)
1.异连翘酯苷在制备乳腺癌治疗药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述异连翘酯苷作为唯一活性成分制备乳腺癌治疗药物。
3.根据权利要求1所述的应用，其特征在于，所述异连翘酯苷与其它药物联合使用制备乳腺癌治疗药物。
4.根据权利要求1-3任一项所述的应用，其特征在于，所述乳腺癌治疗药物包括异连翘酯苷及药学上可接受的载体或辅料。
5.根据权利要求4所述的应用，其特征在于，所述辅料包含润湿剂、防腐剂、抗氧剂、乳化剂、增溶剂、崩解剂、黏合剂或稀释剂中的一种或几种。
6.根据权利要求4所述的用途，其特征在于，所述乳腺癌治疗药物的剂型为片剂、胶囊剂、颗粒剂、混悬剂、口服液、注射剂或输液剂。
7.根据权利要求1所述的用途，其特征在于，所述异连翘酯苷显著抑制乳腺癌MDA-MB-231细胞的转移能力。
8.根据权利要求1所述的用途，其特征在于，所述异连翘酯苷显著抑制乳腺癌细胞MDA-MB-231细胞迁移侵袭能力。
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