CN114072504A - 与癌干细胞特异性结合的适体及其用途 - Google Patents
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Abstract
本发明涉及与癌干细胞特异性结合的适体。根据本发明的适体与癌干细胞特异性结合,降低作为癌干细胞特征的细胞粘附、细胞增殖、抗癌剂耐药性和细胞迁移,具有优异的抗癌效果。因此,适体可以以多种方式用于癌症诊断、预后预测和治疗领域。
Description
技术领域
本发明涉及与癌干细胞特异性结合的适体。
背景技术
癌组织中也存在可以像正常器官一样维持和使癌组织再生的癌干细胞。据报道,癌干细胞在体外悬浮培养中形成球体,形成球体的癌干细胞比原始细胞系具有更强的肿瘤启动能力。此外,由于癌干细胞参与癌症的发展、癌症的发生、复发或转移以及通过使施加了常规癌症治疗后减少的癌细胞再生而产生的对抗癌药物的抗性,因而防止癌干细胞的增殖在癌症治疗中很重要。
目前,在发达国家,能够获得诸如乳腺癌、肝癌、结直肠癌、和胰腺癌领域的癌干细胞信息。因此,需要对器官和组织中的癌干细胞进行研究,这可能与这些发达国家的研究方向有所不同。
在癌症的情况下,异质性即使在单个组织内也非常强,并且在抗癌治疗期间会表达对抗癌剂具有抗性的癌组织,因此这被认为是抗癌治疗失败的主要原因。据悉,癌干细胞是最高水平的表现出这种异质性特征的细胞,并且与对抗癌剂的抗性密切相关。
虽然通过一般抗癌治疗去除癌组织相对容易,但是,由于组织中所含或抗癌剂治疗后获得的癌干细胞的特征,尽管存在各种靶向治疗技术,癌细胞的耐药性仍不断表达,成为癌症患者治疗中必须克服的新近课题。为了开发靶向癌干细胞的抗癌治疗技术,有必要开发可以与癌干细胞中表达的标记性标志物特异性结合的抗体或适体。
另一方面,CD166最早被报道为一种活化白细胞粘附分子(ALCAM),目前其表达在甲状腺癌、颈癌、肺癌和肝癌中均有所发现。特别地,据报道,CD166的表达与前列腺癌的转移潜能、胆管癌的侵袭性和乳腺癌的细胞凋亡规避有关,并且最近报道CD166有作为癌干细胞的标记性标志物的可能性。此外,据报道在作为正常干细胞的间充质干细胞中,CD166也与CD40、CD90和CD105一起表达。
另外,适体是具有稳定的三级结构的单链核酸(DNA、RNA或修饰的核酸)分子,具有能够以高亲和力和特异性与靶分子结合的特征。适体通常由40mer到120mer组成,可以以固有的高亲和力(通常为pM水平)和特异性与靶分子结合。临床癌症诊断和癌症治疗领域正在积极研究适体,原因如下。
1)不会发生体内免疫排斥反应。
2)由于其体积非常小,其体内渗透和结合是有效的。
3)由于适体是通过化学合成生产的,因此其可以在短时间内以低成本生产。
4)适体比抗体具有更高的稳定性。适体可在常温下储存或运输,温度稳定性高。因此,适体对于需要长期和重复使用的诊断特别有用。
5)适体是可以通过多种方式修饰的核酸分子,因此其可以应用于各种研究和实验。
由于适体具有上述优点,因此适体可以以多种方式应用于临床癌症诊断和癌症治疗领域。美国食品和药物管理局于2005年批准了首次开发的适体相关药物。
发明内容
技术问题
因此,本发明人开发了与癌干细胞中表达的CD166特异性结合的适体,且确认该适体降低癌干细胞的特性,以及对作为表达CD166的正常干细胞的间充质干细胞的增殖和功能没有影响。基于上述结果,本发明人完成了本发明。
因此,本发明的一个目的是提供与癌干细胞特异性结合的适体及包含其的组合物,该适体包含选自由SEQ ID NO:1至6表示的核酸序列组成的组中的至少一种核酸序列或其片段。
本发明的另一个目的是提供诊断癌症的方法,该方法包括使生物样品与特异性结合癌干细胞的适体反应。
本发明的另一个目的是提供治疗癌症的方法,该方法包括向对象施用与癌干细胞特异性结合的适体。
问题解决方案
为实现上述目的,本发明提供与癌干细胞特异性结合的适体,该适体包含选自由SEQ ID NO:1至6表示的核酸序列组成的组中的至少一种核酸序列或其片段。
此外,本发明提供用于诊断癌症的组合物,该组合物包含与癌干细胞特异性结合的适体。
此外,本发明提供用于诊断癌症的试剂盒,该试剂盒包含用于诊断癌症的组合物。
此外,本发明提供用于诊断癌症的方法,该方法包括使生物样品与特异性结合癌干细胞的适体反应。
此外,本发明提供用于预防或治疗癌症的药物组合物,该药物组合物包含与癌干细胞特异性结合的适体。
此外,本发明提供抗癌佐剂组合物,该抗癌佐剂组合物包含与癌干细胞特异性结合的适体。
此外,本发明提供用于预防或减轻癌症的食品组合物,该食品组合物包含与癌干细胞特异性结合的适体。
此外,本发明提供用于癌症特异性药物递送的组合物,该组合物包含与癌干细胞特异性结合的适体。
此外,本发明提供用于治疗癌症的方法,该方法包括向对象施用与癌干细胞特异性结合的适体。
发明效果
根据本发明的适体与癌干细胞特异性结合,降低细胞粘附能力、细胞增殖、耐药性和细胞迁移(其均为癌干细胞特征),因此具有优异的抗癌效果。因此,该适体可以以多种方式用于癌症诊断、预后预测和治疗领域。
附图说明
图1表示通过RT-PCR分析确认作为一般细胞培养方法的将A2780卵巢癌细胞贴附在细胞培养皿上而培养的A2780卵巢癌细胞(A2780-AD)中、以及通过对细胞进行三维培养以选择性扩增癌干细胞而培养的A2780-SP卵巢癌干细胞系中的CD166表达获得的结果。
图2表示通过流式细胞术确认卵巢癌干细胞系A2780-SP细胞中CD166表达而获得的结果。
图3表示通过确认从卵巢癌细胞系A2780分离的CD166表达细胞和非表达细胞中的CD166表达而获得的结果。
图4表示通过确认从卵巢癌细胞系A2780分离的CD166表达细胞和非表达细胞中的癌干细胞相关基因的表达而获得的结果。
图5表示通过确认从卵巢癌细胞系A2780分离的CD166表达细胞和非表达细胞的细胞增殖能力而获得的结果。
图6表示确认在从卵巢癌细胞系A2780分离的CD166表达细胞和非表达细胞的3D细胞培养期间通过癌细胞增殖导致的球状癌球体形成能力而获得的结果。
图7表示通过确认从卵巢癌细胞系A2780中分离的CD166表达细胞和非表达细胞的药物敏感性而获得的结果。
图8表示通过确认从卵巢癌细胞系A2780分离的CD166表达细胞和非表达细胞的细胞迁移而获得的结果。
图9表示通过确认在CD166的表达受到抑制的卵巢癌细胞系A2780中的癌干细胞相关基因的表达而获得的结果。
图10至图13表示通过确认CD166的表达受到抑制的卵巢癌细胞系A2780的细胞增殖能力(图10)、耐药性(图11)、癌球体形成能力(图12)和细胞迁移(图13)而获得的结果。
图14表示通过确认CD166表达受抑制的细胞中的粘着斑信号传导通路(focaladhesion signaling pathway)抑制活性而获得的结果。
图15至图17表示通过确认CD166表达对肿瘤形成的影响而获得的结果,更具体地,形成的肿瘤(图15)、肿瘤大小(图16)和肿瘤重量(图17)的观察结果。
图18和19表示通过分析CD166适体与卵巢癌细胞系A2780-AD(图18)或卵巢癌干细胞系A2780-SP(图19)之间的亲和力而获得的结果。
图20表示通过比较CD166适体和抗体对卵巢癌干细胞系A2780-SP的亲和力而获得的结果。
图21至24表示通过确认CD166适体对卵巢癌干细胞的细胞粘附能力(图21)、细胞增殖能力(图22)、耐药性(图23)和细胞迁移(图24)的影响而获得的结果。
图25表示通过确认CD166适体对卵巢癌干细胞中粘着斑信号传导通路的影响而获得的结果。
图26至28表示通过确认CD166适体对卵巢癌干细胞的肿瘤形成的影响而获得的结果,更具体地,形成的肿瘤(图26)、肿瘤大小(图27)和肿瘤重量(图28)的观察结果。
图29表示通过流式细胞术确认患者来源的卵巢癌干细胞中CD166的表达而获得的结果。
图30表示通过确认CD166表达抑制对患者来源的卵巢癌干细胞中的粘着斑信号传导通路的影响而获得的结果。
图31至35表示通过确认CD166的表达受到抑制的患者来源的卵巢癌干细胞的细胞增殖能力(图31)、耐药性(图32)、癌球体形成能力(图33)、细胞迁移(图34)和细胞粘附能力(图35)而获得的结果。
图36A表示通过确认CD166适体对患者来源的卵巢癌干细胞的亲和力而获得的结果,图36B表示通过确认CD166适体对患者来源的卵巢癌干细胞的细胞粘附能力而获得的结果。
图37表示通过确认CD166适体对患者来源的卵巢癌干细胞的耐药性的影响而获得的结果。
图38表示通过确认CD166适体对患者来源的卵巢癌干细胞中的细胞迁移的影响而获得的结果。
图39表示通过确认CD166适体对患者来源的卵巢癌干细胞的粘着斑信号传导通路的影响而获得的结果。
图40表示通过比较CD166适体和抗体对作为正常干细胞的间充质干细胞的亲和力而获得的结果。
图41至图43表示通过确认CD166适体对作为正常干细胞的间充质干细胞的细胞增殖能力(图41)、细胞迁移(图42)和细胞粘附能力(图43)的影响而获得的结果。
图44表示通过确认CD166适体和CD166表达抑制对作为正常干细胞的间充质干细胞中的粘着斑信号传导通路的影响而获得的结果。
具体实施方式
以下,将详细描述本发明。
根据本发明的一个实施例,本发明提供与癌干细胞特异性结合的适体,该适体包含选自由SEQ ID NO:1至6表示的核酸序列组成的组中的至少一种核酸序列或其片段。
在本发明中,“适体”是指能够以高亲和力特异性识别目标物质的小的单链寡核酸。就此而言,当适体是RNA时,在核苷酸序列中T可被识别为U。
本发明的与癌干细胞特异性结合的适体优选包括与SEQ ID NO:1至6具有至少80%同源性的核酸序列或其片段,最优选包括选自由SEQ ID NO:1至6表示的核酸序列组成的组中的至少一种核酸序列或其片段。“具有至少80%同源性的核酸序列”是指在其中添加、缺失或取代一到若干个核苷酸以共同具有至少80%且低于100%的序列并显示相似的CD166结合能力的核酸序列。
在本发明中,“核苷酸”是指构成核酸的单元。除非本文另有说明,否则核苷酸A、T(U)、G和C分别定义为2'-脱氧腺苷、2'-脱氧胸苷(或2'-脱氧尿苷)、2'-脱氧鸟苷和2'-脱氧胞苷。此外,'N'定义为5-(N-萘基羧酰胺)-2'-脱氧尿苷(NapdU),由下式1表示。
[式1]
在本发明的一个实施方案中,与癌干细胞特异性结合的适体优选与在癌干细胞中表达的CD166特异性结合。
在本发明的一个实施方案中,与癌干细胞特异性结合的适体的大小优选为70mer至80mer,更优选74mer至78mer,甚至更优选76mer。
在本发明中,“癌症”是由具有这样特征的细胞引起的疾病的总称:侵袭性特征,其中细胞无视正常生长极限而分裂和生长;浸润性特征,其中细胞渗透到周围组织中;以及转移性特征,其中细胞扩散到身体的其他部位。所述癌症优选选自由胃癌、乳腺癌、肺癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑色素瘤、子宫肉瘤、卵巢癌、直肠癌、肛门癌、结肠癌、输卵管癌、子宫内膜癌、宫颈癌、小肠癌、内分泌癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肿瘤、尿道癌、前列腺癌、支气管癌和骨髓瘤组成的组中的至少一种,但不限于此。
在本发明中,“癌干细胞”是指具有产生肿瘤能力的细胞。癌干细胞具有与正常干细胞相同的特征,并且具体地,具有产生在特定癌症样本中所发现的所有细胞类型的能力。也就是说,癌干细胞的致瘤性与不形成肿瘤的癌细胞不同。癌干细胞通过自我更新和分化能力(这是干细胞的特征)在各种细胞类型中产生肿瘤。此外,癌干细胞与肿瘤中的其他群体不同,并且通过产生新的肿瘤而导致复发和转移。因此,开发针对癌干细胞的特定治疗方法可能会提高癌症患者的存活率。
本发明的与癌干细胞特异性结合的适体具有降低细胞粘附能力、细胞增殖、耐药性和细胞迁移(这些是癌干细胞的特征)的作用,因此可以以多种方式用于癌症诊断、预后预测和治疗领域。
根据本发明的另一个实施方案,本发明提供用于诊断癌症的组合物和用于诊断癌症的试剂盒,其包含与癌干细胞特异性结合的适体。
在本发明中,“诊断”是指证实病理症状的存在或特征。诊断不仅包括证实疾病的发作,还包括证实预后、癌症的病程、阶段等。
通过使用本发明的用于诊断癌症的组合物和用于诊断癌症的试剂盒,检测生物样品中的癌干细胞,即过表达CD166的细胞以证实癌症的存在。此外,可以证实癌症的预后、病程、阶段等以及癌症的存在。
在本发明中,“生物样品”是指从可以检测到本发明的基因或蛋白质的表达的对象获得的任何样品。该生物样品为选自由全血、血清、血浆、细胞、痰、组织、唾液、活检、液体培养物、粪便和尿液组成的组中的任一种,但不特别限于此。另外,它可以通过本发明技术领域中常用的方法进行加工而制备。
在本发明的一个实施方案中,用于诊断癌症的试剂盒可以是各种形式的试剂盒,这取决于所使用的方法。例如,其包括PCR试剂盒、DNA芯片试剂盒、蛋白质芯片试剂盒或微阵列试剂盒等,但不限于此。
用于诊断癌症的试剂盒可以包括用于测量基因表达或其蛋白质表达水平的试剂,以及用于免疫学分析的本领域常用的工具、反应剂等。该工具或反应剂的实例包括但不限于合适的载体、能够产生可检测信号的标记性物质、生色团、增溶剂、去污剂、缓冲剂、稳定剂等。当标记性物质是酶时,它可以包括能够测量酶活性的底物和反应终止剂。载体包括可溶性载体和不溶性载体,可溶性载体的实例包括本领域已知的生理学上可接受的缓冲剂,例如PBS,不溶性载体的实例包括聚苯乙烯、聚乙烯、聚丙烯、聚酯、聚丙烯腈、氟树脂、交联葡聚糖、多糖、诸如在乳胶上镀有金属的磁性微粒的聚合物、其他纸、玻璃、金属、琼脂糖及其组合。
由于本发明的试剂盒包括上述组合物作为组分,因此省略多余的描述以免本说明书过度复杂。
根据本发明的另一个实施方案,本发明提供用于诊断癌症的方法,该方法包括使生物样品与特异性结合癌干细胞的适体反应。
在本发明的一个实施方案中,该方法可以通过使生物样品与特异性结合癌干细胞的适体反应并测量反应程度(即表达程度)来提供关于癌症诊断的信息。
根据本发明的另一个实施方案,本发明提供用于预防或治疗癌症的药物组合物,该药物组合物包含与癌干细胞特异性结合的适体。
此外,本发明提供用于治疗癌症的方法,该方法包括向对象施用与癌干细胞特异性结合的适体。
当本发明的组合物用作药物组合物时,本发明的药物组合物可以根据常规方法以各种形式配制和使用。例如,可以配制成口服制剂如粉末、颗粒、片剂、胶囊、混悬剂、乳剂和糖浆,并且可以配制成外用剂、栓剂、无菌注射液的形式。
本发明的组合物可以包含一种或多种已知的对癌症具有预防或治疗作用的活性成分以及与癌干细胞特异性结合的适体。
本发明的组合物还可包括药学上可接受的添加剂,其中可以使用淀粉、糊化淀粉、微晶纤维素、乳糖、聚维酮、胶态二氧化硅、磷酸氢钙、乳糖、甘露醇、太妃糖、阿拉伯树胶、预胶化淀粉、玉米淀粉、粉状纤维素、羟丙基纤维素、欧巴代、羟基乙酸淀粉钠、巴西棕榈蜡、合成硅酸铝、硬脂酸、硬脂酸镁、硬脂酸铝、硬脂酸钙、白糖等作为药学上可接受的添加剂。基于组合物,根据本发明的药学上可接受的添加剂的含量优选为0.1至90重量份,但不限于此。
在实际临床施用期间,本发明的组合物可以以各种口服或肠胃外制剂施用。在配制组合物时,其可以使用通常使用的稀释剂或赋形剂例如填充剂、增量剂、粘合剂、润湿剂、崩解剂、表面活性剂等来制备,优选使用本领域已知的合适的试剂。
用于口服的固体制剂包括片剂、丸剂、粉末、颗粒、胶囊等,固体制剂通过混合至少一种或多种赋形剂如淀粉、碳酸钙、蔗糖或乳糖、明胶等来制备。除了简单的赋形剂外,还使用润滑剂如硬脂酸镁和滑石。此外,用于口服的液体制剂包括混悬剂、内服剂、乳剂、糖浆等。除了水和液体石蜡(其为常用的简单稀释剂)之外,还可以包括各种赋形剂,例如润湿剂、甜味剂、香料、防腐剂等。
用于肠胃外施用的制剂包括无菌水溶液、非水溶剂、混悬剂、乳剂、冻干制剂和栓剂。可以使用丙二醇、聚乙二醇、植物油(比如橄榄油)、可注射酯(比如油酸乙酯)等作为非水溶剂和悬浮剂。可以使用witepsol、聚乙二醇(macrogol)、吐温61、可可脂、月桂脂、甘油明胶等作为栓剂的基质。
本发明的药物组合物的剂量可以根据药物组合物的配制方法、施用方式、施用时间和/或施用途径等而变化。此外,它可以根据各种因素而变化,包括:通过施用该药物组合物达到的反应类型和程度,施用对象的类型、年龄、体重和一般健康状况,疾病的症状或严重程度,性别,饮食,排泄,在同时或在不同时间对对象一起使用的药物或组合物的其他组分,和医学领域中众所周知的类似因素,并且本领域技术人员可以容易地确定和规定用于所需治疗的有效剂量。
本发明的药物组合物的施用途径和方式可以各自独立,对其方式没有特别限制,并且可以选择任何施用途径和施用方式,只要药物组合物能够到达所需的部位即可。
本发明的药物组合物可单独使用或与使用手术、放射疗法、激素疗法、化学疗法和生物反应调节剂的方法组合用于预防或治疗癌症。
根据本发明的另一个实施方案,本发明提供抗癌佐剂组合物,该抗癌佐剂组合物包含与癌干细胞特异性结合的适体。
本发明的抗癌佐剂组合物可以是药物组合物或食品组合物的形式,更具体地,可以是抗癌药物佐剂或抗癌食品佐剂。
在本发明中,“抗癌佐剂”是指可以作为佐剂来增强本领域通常使用的癌症治疗剂的效果的试剂,通过使用根据本发明的佐剂可以增强癌症治疗剂或抗癌疗法的效果。
根据本发明的另一个实施方案,本发明提供一种用于预防或减轻癌症的食品组合物,该食品组合物包含与癌干细胞特异性结合的适体。
当本发明的组合物用作食品组合物时,本发明的食品组合物是指具有预防或减轻癌症和由癌症引起的疾病的效果的食品,并且在长时间服用时对人体应无害。
食品的种类没有特别限制。可以添加上述物质的食品的实例包括肉、香肠、面包、巧克力、糖果、小吃、糖果糕点、比萨、拉面、其他面条、口香糖、乳制品(包括冰淇淋)、各种汤、饮料、茶、饮品、酒精饮料、复合维生素等,并且包括所有普通意义上的健康食品。
在本发明的一个实施方案中,本发明的食品组合物可以是食品添加剂。该食品添加剂可以通过添加与癌干细胞特异性结合的适体那样使用或与其他食品或食品成分一起使用,并且可以根据常规方法适当使用。活性成分的混合量可以根据使用目的(预防性、保健性或治病性治疗)适当确定。
在本发明的一个实施方案中,本发明的食物组合物可以是保健饮料组合物。除了与癌干细胞特异性结合的适体之外,保健饮料组合物还可像常规饮料那样包含各种调味剂或天然碳水化合物作为附加组分。可以使用单糖(如葡萄糖和果糖)、二糖(如麦芽糖和蔗糖)、天然甜味剂(如糊精和环糊精)、合成甜味剂(如糖精和阿斯巴甜)等作为上述天然碳水化合物。天然碳水化合物的比例通常为每100ml本发明组合物约0.01g至10g,优选约0.01g至0.1g。
除上述之外,本发明的组合物可包括各种营养物、维生素、电解质、调味剂、着色剂、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇、碳酸饮料中使用的碳酸化剂等。此外,本发明的组合物可以包括用于生产天然果汁、果汁饮料和蔬菜饮料的果肉。这些组分可以单独使用或组合使用。这些添加剂的比例并不关键,但通常在每100重量份本发明组合物的0.01至0.1重量份的范围内选择。
根据本发明的另一个实施方案,本发明提供用于癌症特异性药物递送的组合物,该组合物包含与癌干细胞特异性结合的适体。
与癌干细胞特异性结合的适体特异性结合癌干细胞中过度表达的CD166。通过使用它,可以将药物如抗癌剂递送到已经出现癌症的部位。
本发明的实施方式
在下文中,将通过实施例更详细地描述本发明。这些实施例仅用于说明本发明,对于本领域技术人员来说显而易见的是,本发明的范围不应被解释为受这些实施例的限制。
实施例1.确认卵巢癌细胞和卵巢癌干细胞中的CD166表达
进行RT-PCR以检测CD166在卵巢癌细胞系A2780细胞和通过A2780细胞三维培养分离并建立的卵巢癌干细胞系A2780-SP细胞中的表达。从A2780和A2780-SP细胞中提取mRNA后,通过RT-PCR确定CD166的表达。具体地,从卵巢癌细胞系A2780和卵巢癌干细胞系A2780-SP细胞中分离出总RNA。对于RT-PCR,使用2μg总RNA和逆转录cDNA合成试剂盒(NanoHelixCo.)根据制造商的说明合成第一链cDNA。此后,将含有Ready 2×Go预混合PCR试剂盒(Ready 2×Go pre-mix PCR kit;NanoHelix Co.)和10pM CD166特异性引物(CD166:5'-CAGAACACGATGAGGCAGAC-3',5'-AGCAAGGAGGAGACCAACAA-3')的反应溶液20μl用于扩增等量的cDNA,然后确认CD166的表达。RT-PCR结果如图1所示。
如图1所示,确认A2780细胞不表达CD166,而A2780-SP细胞表达CD166。
此外,进行流式细胞术(FACS)以确认CD166在卵巢癌细胞系A2780细胞和通过A2780细胞三维培养分离并建立的卵巢癌干细胞系A2780-SP细胞中的表达。具体地,使用CD166 FACS抗体(PE Mouse Anti-Human CD166,货号:559263,BD Pharminggen),对卵巢癌细胞系A2780细胞和卵巢癌干细胞系A2780-SP细胞进行染色,并使用FACS Canto II(BDBioscience)进行流式细胞术。通过流式细胞术确认CD166在A2780和A2780-SP细胞中的表达结果如图2所示。
如图2所示,确认了在A2780-SP细胞(其为卵巢癌干细胞系)中CD166的表达水平高。
实施例2.使用卵巢癌细胞系中的CD166进行流式细胞术并确认癌干细胞主要基因的表达
使用流式细胞仪(ARIA3)从卵巢癌细胞系A2780中分离CD166表达细胞和非表达细胞,并通过RT-PCR确认在分离的CD166表达细胞中各种癌干细胞相关基因的表达。具体地,从卵巢癌细胞系A2780和卵巢癌干细胞系A2780-SP细胞中分离出RNA,并且通过RT-PCR确认作为耐药基因的ABC转运蛋白(ABCB1、ABCG2、ABCC6)、被称为癌干细胞的标志物的ALDH和干细胞能力相关基因(OCT4、SOX2)的表达水平。对于RT-PCR,使用2μg总RNA和逆转录cDNA合成试剂盒(NanoHelix Co.)根据制造商的说明合成第一链cDNA。使用含有Ready 2×Go预混合PCR试剂盒(Ready 2×Go pre-mix PCR kit;NanoHelix Co.)和各10pM引物(GAPDH:5'-TCCATGACAACTTTGGTATCG-3',5'-TGTAGCCAAATTCGTTGTCA-3';OCT4A:5'-GATCGGATCCATGGCGGGACACCTGGCT-3',5'-CCTTCCCAAATAGAACCC-3';SOX2:5'-CAACATGATGGAGACGGAGC-3',5'-GTGCATCTTGGGGTTCTCCT-3';ALDH1:5'-CTCGAAATTAAGTACACCAA-3',5'-TCAGTAGA CCCTGTGAATGC-3';ABCB1:5'-CCATCAGTCCTGTTCTTG-3',5'-CTGCTCCTCTTGCATTT-3';ABCG2:5'-TTCAGCCGTGGAACTCTTTG-3',5'-CCACACTCTGACCTGCTGCT-3';ABCC6:5'-AGACAGACGCTGGGACCC-3',5'-ACCATCTTGGCTTTGAAGAGTG-3')的20μl反应溶液来扩增等量cDNA,接着确认CD166的表达。CD166表达的确认结果如图3所示,癌干细胞相关基因表达的确认结果如图4所示。
如图3所示,确认了从卵巢癌细胞系A2780分离的CD166表达细胞(CD166+)表达CD166,非CD166表达细胞(CD116-)不表达CD166。
如图4所示,确认了癌干细胞的耐药性相关基因ABC转运蛋白(ABCB1、ABCG2、ABCC6)、被称为癌干细胞的标志物的ALDH和干细胞能力相关基因(OCT4、SOX2)的表达增加。
实施例3.确认CD166表达对细胞增殖、耐药性、球体形成能力和细胞迁移的影响
3-1.确认CD166对细胞增殖的影响
为了确认CD166表达对细胞增殖率的影响,将CD166表达细胞和非表达细胞各1×104个细胞贴附于24孔板,然后每1天在一定时间用0.25%胰蛋白酶EDTA分离细胞,连续2天,在血细胞计数器上测定细胞数量,结果如图5所示。
如图5所示,确认了CD166表达细胞比非表达细胞具有更快的增殖速度。
3-2.确认CD166对球体形成能力的影响
通过球体形成实验确认从卵巢癌细胞系中分离的CD166表达细胞的自我更新能力。为了确认根据CD166表达变化的球体形成能力,使用CD166 FACS抗体(PE小鼠抗人CD166,货号:559263,BDPharminggen)从A2780细胞中分离CD166表达细胞和非表达细胞。此后,将各100至10,000个细胞接种在24孔超低贴附培养板(24well-Ultra-Low Attachmentculture plate)中并培养7天。球体形成实验的结果如图6所示。
如图6所示,观察到CD166表达细胞比非表达细胞形成更多的球体。结果表明CD166表达细胞具有高度的自我更新和非贴壁增殖能力,这是干细胞最重要的特征。
3-3.确认CD166对抗癌剂敏感性的影响
为了测量药物敏感性,使CD166表达细胞和非表达细胞各1×104个细胞贴附在96孔板上。用浓度为0、0.01μM、0.1μM和1μM的抗癌剂紫杉醇处理贴壁细胞并培养48小时。将MTT溶液(Sigma-Aldrich,Inc.St.Louis,MO)加入到培养的细胞中并反应4小时。反应完成后,用DMSO(sigma-Aldrich)处理细胞,测量570nm吸光度以分析药物敏感性。药物敏感性分析结果如图7所示。
如图7所示,确认了CD166表达细胞对抗癌剂紫杉醇具有抗性。结果表明CD166表达细胞是癌干细胞。
3-4.确认CD166对迁移的影响
为了确认CD166的表达是否促进细胞迁移,而对细胞迁移的程度进行了体外确认。具体地,为了确认细胞迁移,使用CD166 FACS抗体(PE小鼠抗人CD166,货号:559263,BDPharminggen)从A2780细胞中分离CD166表达细胞和非表达细胞。此后,根据制造商的说明,使用96孔趋化室(Neuro Probe,Gaithersburg,MD)测量细胞迁移。确认细胞迁移的结果如图8所示。
如图8所示,观察到CD166表达细胞比非表达细胞具有更高的迁移能力。
实施例4.确认CD166表达抑制对卵巢癌干细胞的干细胞相关基因表达、细胞增殖、耐药性、球体形成能力和细胞迁移的影响
使用siRNA抑制卵巢癌干细胞系A2780-SP中的CD166表达,通过实施例1和2的RT-PCR方法确认CD166表达受抑制的细胞中各种癌干细胞相关基因的表达。具体地,为了抑制CD166的表达,构建对照(si对照)(5'-UUC UCC GAA CGU GUC ACG UTT-3';5'-ACG UGA CACGUU CGG AGA ATT-3')和si CD166(5'-AAG CCC GAU GGC UCC CCA GUA UU-3';5'-AAU ACUGGG GAG CCA UCG GGC UU-3')。通过构建的siRNA与卵巢癌干细胞系A2780-SP细胞反应抑制CD166的表达。癌干细胞相关基因表达的确认结果如图9所示。
如图9所示,确认通过使用siRNA抑制CD166的表达降低了癌干细胞的耐药基因ABC转运蛋白(ABCB1、ABCG2、ABCC6)、被称为癌干细胞标志物(ALDH)的ALDH的活性和干细胞能力相关基因(OCT4,SOX2)的表达。
接着,按与上述实施例2同样的方式,测量CD166表达受抑制的细胞的增殖、耐药性、球体形成能力和细胞迁移,结果分别如图10至13所示。
如图10至13所示,确认了CD166表达受抑制的细胞的细胞增殖能力降低、药物敏感性增加,并且球体形成能力和迁移减少。结果表明CD166的表达在卵巢癌干细胞的干细胞功能中起重要作用。
实施例5.确认在对卵巢癌干细胞CD166表达的抑制使癌干细胞特征受到抑制的过程中粘着斑信号传导通路的抑制
使用siRNA抑制卵巢癌干细胞系A2780-SP中的CD166表达,并且通过蛋白质印迹确认CD166表达受抑制的细胞的粘着斑信号传导通路。具体地,为了抑制CD166的表达,构建对照(si对照)(5'-UUC UCC GAACGU GUC ACG UTT-3';5'-ACG UGA CAC GUU CGG AGA ATT-3')和si CD166(5'-AAG CCC GAU GGC UCC CCA GUA UU-3';5'-AAU ACU GGG GAG CCA UCGGGC UU-3')。通过构建的siRNA与卵巢癌干细胞系A2780-SP细胞反应来抑制CD166的表达,并且在抑制表达后培养细胞。培养48小时后,收集细胞,通过蛋白质印迹来确认被称为粘着斑信号传导通路主要基因的FAK、SRC、Paxillin和CD44的蛋白表达。将针对CD166(ab109215,Abcam)、CD44(5640S,Cell Signaling Technology)、p-PAXILLIN(2541S,CellSignaling Technology)、p-SRC(2101S,Cell Signaling Technology)、p-FAK(3284S,CellSignaling Technology)、FAK(3285S,Cell Signaling Technology)和GAPDH(MAB374,EMDMilliore Corp,Billerica,MA)的抗体用作一抗。CD166表达受抑制的细胞中粘着斑信号传导通路抑制活性的确认结果如图14所示。
如图14所示,确认了在CD166的表达受到抑制的A2780-SP细胞中,参与细胞粘附的p-PAXILLIN和p-SRC的表达受到抑制。特别地,确认了FAX磷酸化位点中已知参与粘附的p-FAK Y925位点在细胞内的表达降低。
实施例6.确认CD166表达对肿瘤形成的影响
确认CD166表达对肿瘤形成的影响。使用流式细胞仪(ARIA3)从卵巢癌细胞系A2780中分离CD166表达细胞和非表达细胞。将分离出的细胞各1×105个细胞皮下接种到裸鼠中。此时,分别地,裸鼠左侧接种CD166表达细胞,裸鼠右侧接种非CD166表达细胞。接种后,从第18天开始测量肿瘤形成大小。在接种后第38天对裸鼠实施安乐死。从裸鼠中分离肿瘤,最后测量肿瘤的重量和大小。分别地,分离出的肿瘤的观察结果如图15所示,测量肿瘤大小的结果如图16所示,测量肿瘤重量的结果如图17所示。
如图15至17所示,确认了在CD166表达细胞中肿瘤更快形成。同样,确认了CD166表达细胞中的肿瘤比非CD166表达细胞中的肿瘤重,并且其大小也更大。
实施例7.与癌干细胞中表达的CD166特异性结合的适体的构建
构建与癌干细胞中表达的CD166特异性结合的适体。CD166适体(CD166 AT)由Aptamer Sciences Inc.(Pohang,Korea)合成。构建的与CD166特异性结合的适体的序列如表1所示。
[表1]
其中,A、T(U)、G和C分别定义为2'-脱氧腺苷、2'-脱氧胸苷(或2'-脱氧尿苷)、2'-脱氧鸟苷和2'-脱氧胞苷。'N'定义为5-(N-萘基羧酰胺)-2'-脱氧尿苷(NapdU),其由以下式1表示。
[式1]
将构建的适体溶解在无菌三级蒸馏水中,然后加热至95℃保持5分钟。将加热后的适体冷却至25℃,用于后述实验。
实施例8.确认卵巢癌细胞和卵巢癌干细胞中CD166适体的亲和力
8-1.确认CD166适体对卵巢癌细胞和卵巢癌干细胞的亲和力
确认实施例7中构建的CD166适体是否识别卵巢癌细胞和卵巢癌干细胞。进行以下实验以分析CD166适体与卵巢癌细胞系A2780细胞之间的相互作用。首先,将每种CD166适体(AT-1、AT-2、AT-3、AT-4、AT-5和AT-6)溶解在无菌三级水中,然后在95℃加热5分钟。加热后冷却至25℃。将适体以500nM的浓度加入到卵巢癌细胞系A2780细胞中,然后在室温培养细胞并染色。此后,使用流式细胞仪(荧光激活细胞分选仪,FACS)分析与CD166适体反应的细胞,结果如图18所示。
如图18所示,确认了CD166适体显示出与A2780细胞的相互作用,但信号强度低。这是因为CD166在卵巢癌细胞系A2780中的表达低。
此外,以与上述相同的方式,将卵巢癌干细胞系A2780-SP细胞与CD166适体反应,然后进行FACS,结果如图19所示。
如图19所示,确认了CD166适体与卵巢癌干细胞系A2780-SP细胞相互作用,信号强度高。特别地,确认了CD166适体中的AT-5与卵巢癌干细胞的结合最具特异性。
8-2.CD166适体和CD166抗体在癌干细胞中的亲和力比较
比较CD166适体AT-5和作为对照的CD166 FACS抗体(PE小鼠抗人CD166,货号:559263,BD Pharminggen)对卵巢癌干细胞系A2780-SP细胞的亲和力。亲和力的比较以与实施例8-1相同的方式进行,结果如图20所示。
如图20所示,确认了CD166适体和CD166抗体与A2780-SP细胞的结合表现出相似的结合特异性和亲和力。结果表明,CD166适体与CD166表达细胞特异性结合,并且该适体与CD166抗体具有相似的结合亲和力。
实施例9.确认CD166适体对卵巢癌干细胞的细胞粘附能力、细胞增殖、耐药性和细胞迁移的影响
使用CD166适体AT3、AT4和AT5来确认CD166适体对细胞粘附能力的影响。具体地,使用CD166FACS抗体从卵巢癌干细胞中分离CD166表达细胞。使用分离的细胞进行CD166适体的细胞粘附实验。首先,将1x105个细胞接种在96孔板中,然后用20μg/ml胶原蛋白封闭1小时。封闭后,加入0.1%牛血清白蛋白(BSA)并孵育1小时以限制非特异性结合。将分离的细胞各自暴露于CD166适体(500nM)1小时,然后用4%甲醛固定。固定细胞用hoest33342染色。使用显微镜对染色细胞进行观察和计数,结果如图21所示。
如图21所示,确认了在用具有高亲和力的CD166适体AT4和AT5处理的实验组中细胞粘附减少。
使用CD166适体AT5来确认CD166适体对细胞增殖的影响。具体地,将CD166表达细胞中1×104个细胞各贴附于24孔板,然后分别分为CD166适体AT-5处理组和未处理组,并处理。在适体处理0、24、48和72小时后,将MTT溶液(Sigma-Aldrich,Inc.St.Louis,MO)加入细胞并反应4小时。将与MTT溶液反应的细胞用DMSO(sigma-Aldrich)处理,然后测量570nm吸光度。CD166适体对细胞增殖的影响的确认结果如图22所示。
如图22所示,确认了用CD166适体处理的癌干细胞的细胞增殖受到抑制。
使用CD166适体AT5来确认CD166适体对药物敏感性的影响。具体地,将CD166表达细胞中1×104个细胞各接种到24孔板中,然后用0.1μM抗癌剂紫杉醇和CD166适体AT-5处理。对照仅用0.1μM紫杉醇处理。适体处理0、24、48、72小时后,加入MTT溶液至细胞中并反应4小时。将与MTT溶液反应的细胞用DMSO处理,然后测量570nm吸光度。CD166适体对药物敏感性的影响的确认结果如图23所示。
如图23所示,确认了用CD166适体处理的细胞的耐药性(这是癌干细胞的特征)降低。
使用CD166适体AT5来确认CD166适体对细胞迁移的影响。具体地,将CD166表达细胞中1×104个细胞各接种到24孔板中,然后分别分为CD166适体AT-5处理组和未处理组,并处理。体外确认用适体处理的细胞的迁移程度,结果如图24所示。
如图24所示,确认了用CD166适体处理的癌干细胞的细胞迁移减少。
上述结果表明,当CD166表达细胞用与CD166特异性结合的适体处理时,作为卵巢癌干细胞的主要特征的细胞粘附、细胞增殖、耐药性和细胞迁移均减少,从而抑制了卵巢癌干细胞。
实施例10.确认在CD166适体抑制卵巢癌干细胞粘附能力过程中对粘着斑信号传导通路的抑制
从卵巢癌干细胞系A2780-SP中分离CD166高癌细胞。分离的细胞分别与CD166适体AT-5反应1小时,然后通过蛋白质印迹确认CD166表达受抑制的细胞中的粘着斑信号传导通路。以与实施例5相同的方式进行蛋白质印迹。CD166表达受抑制的细胞中粘着斑信号传导通路的确认结果如图25所示。
如图25所示,在CD166的表达受到抑制的A2780-SP细胞中,确认了参与细胞粘附的p-PAXILLIN和p-SRC的表达受到抑制。特别地,确认了FAX磷酸化位点中已知参与粘附的p-FAK Y925位点在细胞内的表达降低。
实施例11.确认CD166适体对肿瘤形成的影响
确认CD166适体AT-5对肿瘤形成的影响。具体地,使用流式细胞仪(ARIA3)从卵巢癌干细胞系A2780-SP中分离CD166高表达的细胞。分离的细胞分别与CD166适体AT-5反应1小时。将与适体反应的细胞(1×105个细胞)皮下接种到裸鼠中。此时,裸鼠左侧接种未经适体处理的细胞,裸鼠右侧接种经CD166适体AT-5处理的细胞。接种后,从第18天开始测量肿瘤形成大小。在接种的第38天对裸鼠实施安乐死。从裸鼠中分离肿瘤,最后测量肿瘤的重量和大小。分别将分离出的肿瘤的观察结果示于图26,测量肿瘤大小的结果示于图27,测量肿瘤重量的结果示于图28。
如图26至28所示,确认了在接种经CD166适体AT-5处理的细胞的部位,肿瘤形成受到抑制,且肿瘤大小小于适体未处理组的肿瘤大小。此外,确认了在接种经CD166适体AT-5处理的细胞的部位,肿瘤重量比对照显著降低。
实施例12.确认患者来源的卵巢癌干细胞中CD166的表达
进行流式细胞术(FACS)以确认CD166在从卵巢癌患者分离的癌干细胞中的表达。患者来源的卵巢癌细胞的分离通过先前描述的方法(STEM CELLS 2016;34:551-564)进行。更具体地,对于流式细胞术,使用CD166 FACS抗体(PE小鼠抗人CD166,货号:559263,BDPharminggen),并对患者来源的卵巢癌干细胞进行染色。此后,使用FACS Canto II(BDBioscience)进行流式细胞术。
通过流式细胞术确认CD166在患者来源的卵巢癌干细胞中的表达的结果如图29所示。
如图29所示,确认了患者来源的卵巢癌干细胞中CD166的表达水平高。
实施例13.确认CD166表达抑制对患者来源的卵巢癌干细胞的粘着斑信号传导通路、细胞增殖、耐药性、球体形成能力和细胞迁移的影响
使用siRNA来抑制患者来源的卵巢癌干细胞中的CD166表达,并且通过蛋白质印迹来确认CD166表达受抑制的细胞中的粘着斑信号传导通路。CD166表达的抑制和蛋白质印迹按照与实施例4和5相同的方式进行。CD166表达受抑制的细胞中粘着斑信号传导通路的确认结果如图30所示。
如图30所示,确认了在CD166的表达受到抑制的患者来源的卵巢癌干细胞中,参与细胞粘附的p-PAXILLIN和p-SRC的表达受到抑制。特别地,确认了FAX磷酸化位点中已知参与粘附的p-FAK Y925位点在细胞内的表达降低。确认了癌干细胞相关基因的表达。
接着,以与上述实施例2相同的方式测量CD166表达受抑制的细胞的增殖、耐药性、球体形成能力、细胞迁移和细胞粘附,结果分别如图31至35所示。
如图31至35所示,确认了CD166表达被抑制的患者来源的卵巢癌干细胞的细胞增殖能力降低,药物敏感性增加,球体形成能力、细胞迁移和细胞粘附减少。结果表明在患者来源的卵巢癌干细胞中,CD166的表达对干细胞功能起重要作用。
实施例14.确认CD166适体对患者来源的卵巢癌干细胞的亲和力
确认了实施例8中表现出高亲和力的CD166适体AT5是否识别患者来源的卵巢癌干细胞。亲和力的确认以与实施例8相同的方式进行,结果如图36A所示。
如图36A所示,确认了CD166适体AT5与患者来源的卵巢癌干细胞相互作用,信号强度高。
实施例15.确认CD166适体对患者来源的卵巢癌干细胞的细胞粘附能力、耐药性和细胞迁移的影响
使用CD166适体AT3和AT5来确认CD166适体对细胞粘附能力、耐药性和细胞迁移的影响。具体地,以与实施例9相同的方式进行细胞粘附能力、耐药性和细胞迁移,结果分别如图36B、37和38所示。
如图36B、37和38所示,结果表明,当患者来源的卵巢癌干细胞用与CD166特异性结合的适体处理时,作为癌干细胞主要特征的细胞粘附、耐药性和细胞迁移都会减少,从而抑制患者来源的卵巢癌干细胞的特征。
实施例16.确认在CD166适体抑制患者来源的卵巢癌干细胞的细胞粘附能力过程中对粘着斑信号传导通路的抑制
患者来源的卵巢癌干细胞分别与CD166适体AT-3和AT-5反应1小时,然后通过蛋白质印迹确认CD166表达受抑制的细胞中的粘着斑信号传导通路。以与实施例5相同的方式进行蛋白质印迹。CD166表达受抑制的细胞中粘着斑信号传导通路的确认结果如图39所示。
如图39所示,确认了参与细胞粘附的p-PAXILLIN和p-SRC的表达被CD166适体AT-5抑制。特别地,确认了FAX磷酸化位点中已知参与粘附的p-FAK Y925位点在细胞内的表达降低。
实施例17.CD166适体和CD166抗体对间充质干细胞的亲和力的比较
比较CD166适体AT-5和作为对照的CD166 FACS抗体(PE小鼠抗人CD166,货号:559263,BD Pharminggen)对间充质干细胞(正常干细胞)的亲和力。亲和力的比较以与实施例8-1相同的方式进行,结果如图40所示。
如图40所示,确认了CD166适体和CD166抗体与间充质干细胞的结合表现出相似的结合特异性和亲和力。结果表明,CD166适体与CD166表达细胞特异性结合,并且该适体与CD166抗体具有相似的结合亲和力。
实施例18.确认CD166适体对间充质干细胞的细胞增殖能力、细胞迁移和细胞粘附的影响
使用CD166适体AT5来确认CD166适体对细胞增殖能力、细胞迁移和细胞粘附的影响。具体地,按照与实施例9相同的方式进行细胞增殖能力、细胞迁移和粘附。
如图41至43所示,确认了当作为正常干细胞的间充质干细胞用与CD166特异性结合的适体处理时,细胞增殖能力、细胞迁移和细胞粘附没有变化。结果表明它不影响正常干细胞的特征。
实施例19.确认在间充质干细胞中通过CD166适体和CD166表达抑制产生的粘着斑信号传导通路
间充质干细胞分别与CD166适体AT-5反应1小时,然后通过蛋白质印迹确认CD166表达受抑制的细胞中的粘着斑信号传导通路。以与实施例5相同的方式进行蛋白质印迹。另外,通过实施例4的方法确认间充质干细胞中CD166表达抑制引起的粘着斑信号传导通路,结果如图44所示。
如图44所示,确认了参与细胞粘附的p-PAXILLIN和p-SRC在正常干细胞中的表达不受CD166适体AT-5处理和CD166表达抑制的影响。另外,确认了FAX的磷酸化位点中已知参与粘附的p-FAK Y925位点在细胞内的表达没有受到影响。
总体而言,本发明人开发了与癌干细胞中表达的CD166特异性结合的适体,并确认该适体使作为癌干细胞特征的细胞粘附能力、细胞增殖、耐药性和细胞迁移降低,从而表现出抗癌效果。因此,本发明的适体可以以多种方式用于癌症诊断、预后预测和治疗领域。
在下文中,将通过制备例更详细地描述本发明。制备例仅用于说明本发明,并且不应将本发明的范围解释为受制备例的限制。
制备例1.用于预防或治疗癌症的药物组合物的制备
1-1.粉末的制备
1mg与癌干细胞特异性结合的适体
100mg乳糖
10mg滑石
将上述成分混合并填充在密封袋中制成粉末。
1-2.片剂的制备
1mg与癌干细胞特异性结合的适体
100mg玉米淀粉
100mg乳糖
2mg硬脂酸镁
将上述成分混合然后根据常规的片剂制造方法压片以制备片剂。
1-3.胶囊的制备
1mg与癌干细胞特异性结合的适体
3mg结晶纤维素
14.8mg乳糖
0.2mg硬脂酸镁
根据常规的胶囊制造方法,将上述成分混合并填充在明胶胶囊中以制备胶囊。
1-4.注射剂的制备
1mg与癌干细胞特异性结合的适体
180mg甘露醇
2974mg注射用无菌蒸馏水
26mgNa2HPO4·2H2O
按照常规的注射剂制造方法,以每1安瓿(2ml)中含有上述成分的含量来制备注射剂。
1-5.液体的制备
1mg与癌干细胞特异性结合的适体
10g异构糖
5g甘露醇
适量纯净水
按照常规的制液方法,将各成分加入纯净水中溶解,加入适量柠檬香精,然后将上述成分混合,再加入纯净水调至总量为100毫升,接着装入棕色瓶中并消毒以制备液体。
以上,对本发明的具体部分进行了详细说明。本领域技术人员清楚,这些具体描述仅为优选实施方案,本发明的保护范围并不因此而受到限制。因此,本发明的实质范围旨在由所附权利要求及其等同物来限定。
序列表
<110> 株式会社海赛尔科技
<120> 与癌干细胞特异性结合的适体及其用途
<130> 1-385P
<160> 6
<170> KoPatentIn 3.0
<210> 1
<211> 76
<212> DNA
<213> Artificial Sequence
<220>
<223> AT1, clone 1
<400> 1
tcagccgcca gccagttccn ncagccnngn agagncanga ncgnnancgg ancngaggga 60
ccagagcacc acagag 76
<210> 2
<211> 76
<212> DNA
<213> Artificial Sequence
<220>
<223> AT2, clone 2
<400> 2
tcagccgcca gccagttcan nganaaggnn aggacncnnn cngnnggnan ccncacngga 60
ccagagcacc acagag 76
<210> 3
<211> 76
<212> DNA
<213> Artificial Sequence
<220>
<223> AT3, clone 3
<400> 3
tcagccgcca gccagttcgc gcncgnnncg gaggggangc agaccccncn cgcnnngcga 60
ccagagcacc acagag 76
<210> 4
<211> 76
<212> DNA
<213> Artificial Sequence
<220>
<223> AT4, clone 4
<400> 4
tcagccgcca gccagttccn ncnagagnca ngcacgnnan cggaccngnc ggcgaangga 60
ccanancacc acagag 76
<210> 5
<211> 76
<212> DNA
<213> Artificial Sequence
<220>
<223> AT5, clone 5
<400> 5
tcagccgcca gccagttcan nnganaaagc nccgnnancg ggccccnngn agagncanga 60
ccagagcacc acagag 76
<210> 6
<211> 76
<212> DNA
<213> Artificial Sequence
<220>
<223> AT6, clone 6
<400> 6
tcagccgcca gccagttcnc gcnnncggnc ancangaacg gcncgnnncg gaacngncga 60
ccagagcacc acagag 76
Claims (13)
1.与癌干细胞特异性结合的适体,所述适体包含选自由SEQ ID NO:1至6表示的核酸序列组成的组中的至少一种核酸序列或其片段。
2.根据权利要求1所述的与癌干细胞特异性结合的适体,其中所述适体与CD166特异性结合。
3.根据权利要求1所述的与癌干细胞特异性结合的适体,其中所述适体的大小为70mer至80mer。
4.根据权利要求1所述的与癌干细胞特异性结合的适体,其中所述癌症为选自由胃癌、乳腺癌、肺癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内黑色素瘤、子宫肉瘤、卵巢癌、直肠癌、肛门癌、结肠癌、输卵管癌、子宫内膜癌、宫颈癌、小肠癌、内分泌癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肿瘤、尿道癌、前列腺癌、支气管癌和骨髓瘤组成的组中的至少一种。
5.用于诊断癌症的组合物,所述组合物包含根据权利要求1所述的与癌干细胞特异性结合的适体。
6.用于诊断癌症的试剂盒,所述试剂盒包含根据权利要求5所述的用于诊断癌症的组合物。
7.根据权利要求6所述的用于诊断癌症的试剂盒,其中所述用于诊断癌症的试剂盒是PCR试剂盒、DNA芯片试剂盒、蛋白质芯片试剂盒或微阵列试剂盒。
8.用于诊断癌症的方法,所述方法包括:
使生物样品与根据权利要求1所述的与癌干细胞特异性结合的适体反应。
9.用于预防或治疗癌症的药物组合物,所述药物组合物包含根据权利要求1所述的与癌干细胞特异性结合的适体。
10.抗癌佐剂组合物,所述抗癌佐剂组合物包含根据权利要求1所述的与癌干细胞特异性结合的适体。
11.用于预防或减轻癌症的食品组合物,所述食品组合物包含根据权利要求1所述的与癌干细胞特异性结合的适体。
12.用于癌症特异性药物递送的组合物,所述组合物包含根据权利要求1所述的与癌干细胞特异性结合的适体。
13.用于治疗癌症的方法,所述方法包括:
将根据权利要求1所述的与癌干细胞特异性结合的适体施用于对象。
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US20180207269A1 (en) * | 2015-07-17 | 2018-07-26 | The Trustees Of Columbia University In The City Of New York | Methods of Treating CD166-Expressing Cancer |
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WO2014025234A2 (ko) * | 2012-08-09 | 2014-02-13 | 연세대학교 산학협력단 | 암 줄기세포에 특이적으로 결합하는 핵산 앱타머 및 이의 용도 |
KR101641920B1 (ko) * | 2014-09-05 | 2016-07-22 | 한국생명공학연구원 | EpCAM에 특이적으로 결합하는 핵산 앱타머 및 이의 용도 |
MX2017014136A (es) * | 2015-05-04 | 2018-07-06 | Cytomx Therapeutics Inc | Anticuerpos anti-cd166, anticuerpos anti-cd166 activables, y metodos de uso de los mismos. |
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WO2014019025A1 (en) * | 2012-08-02 | 2014-02-06 | Deakin University | Epcam aptamer for detection of cancer stem cells |
US20150299708A1 (en) * | 2012-08-02 | 2015-10-22 | Deakin University | Cd133 aptamers for detection of cancer stem cells |
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KR20200115885A (ko) | 2020-10-08 |
EP3950946A4 (en) | 2023-10-25 |
EP3950946A1 (en) | 2022-02-09 |
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