CN107205963B - 含有醛抑制剂和双胍类化合物的抑制癌症干细胞生长的药物组合物 - Google Patents
含有醛抑制剂和双胍类化合物的抑制癌症干细胞生长的药物组合物 Download PDFInfo
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Abstract
本发明涉及一种抑制癌症干细胞生长的药物组合物，含有醛抑制剂和双胍类化合物。本发明的药物组合物含有醛抑制剂和双胍类化合物组合，可以有效抑制癌症干细胞如神经球的生长，并且还可以抑制癌细胞的增殖、侵袭和转移，从而预防和/或治疗癌症如脑癌。
Description
技术领域
本发明涉及到一种抑制癌症干细胞生长的药物组合物，含有醛抑制剂和双胍类化合物。
背景技术
癌症是世界上最常见的死因之一。每年约有1000万新发癌症病例，癌症占总死因的12％左右，使癌症成为第三大死因。。
在各种癌症中，特别是脑癌，其特征在于无论年龄如何，都会发生，婴儿的发生频率高于其他癌症。脑癌整体上是指发生在脑组织和脑周围脑膜的原发性脑癌，以及发生在从颅骨或身体其他部位癌症转移的继发性脑癌。这种脑癌在许多方面与其他器官发生的癌症不同。具体地，在胃，肺，乳房等器官中出现的癌症在每个器官中限于一种或两种，并且通常具有相同或相似的特征。然而，在大脑中，出现了各种各样的癌症，包括例如多形性胶质母细胞瘤，恶性胶质瘤，淋巴瘤，生殖细胞瘤，转移性肿瘤等。
在这些脑癌中，神经胶质瘤，特别是多形性胶质细胞瘤(GBM)是最恶性和侵袭性的脑癌，因此是一种预后很差的非常致命的疾病，诊断后其平均存活期约为1年或更短。由于脑细胞和肿瘤细胞之间的界限不清楚，手术几乎不可能完全去除GBM。
尽管在癌症治疗领域取得了进展，但目前主要的治疗方法包括手术，放射和化疗。化疗方法主要用于治疗转移性，或特别是侵袭性癌症。目前用于临床实践的大多数癌症治疗剂是细胞毒素。细胞毒剂通过破坏或杀伤表现出快速生长的细胞而起作用。
理想的细胞毒性剂对癌症和肿瘤细胞具有特异性，而不影响正常细胞。不幸的是，还没有发现这种理想的细胞毒性剂，而是使用尤其靶向快速分裂的细胞(肿瘤和正常细胞)的药剂。因此，非常需要对癌细胞具有细胞毒性但对正常细胞仅具有温和作用的材料。事实上，近来许多研究集中在开发可以特别抑制肿瘤细胞生长的替代抗癌剂。
因此，迫切需要开发除手术治疗以外的化学治疗剂，但是还没有开发出有效的治疗方法，因此需要研究和开发。
技术问题
本发明的目的在于提供一种可有效抑制癌症干细胞生长的药物组合物，以抑制癌细胞的增殖，侵袭和转移，从而预防和/或治疗癌症。
技术方案
本发明人进行了广泛的研究，结果发现醛抑制剂和双胍类化合物的共同给药可以抑制癌症干细胞的生长以抑制癌细胞的增殖，侵袭和转移，从而预防和/或治疗癌症。基于这一发现，完成本发明。
如本文所用，术语“癌症干细胞”通常是指具有自我更新或分化潜能的癌细胞，这是干细胞特征的特征潜力。例如，癌症干细胞可以包括在脑中枢神经系统中的干细胞的神经球。与一般癌细胞不同，在正常肿瘤生长条件下(“正常肿瘤生长条件”是指细胞生长所需的营养物(葡萄糖)充足，肿瘤微环境生长条件丰富的状态，因此不存在细胞应激)，癌症干细胞可以以较慢的速率增殖，或者可以维持在休眠状态，因此对抗癌剂可能具有抗性。例如，与正常肿瘤细胞不同，癌症干细胞可以控制转录调节因子如PGC-1a的表达，因此其中主要代谢调节物质的功能可能与通常的癌细胞不同。因此，术语“癌症干细胞”通常是指通过这种不同代谢调节能力和与其机制连接的细胞信号传导系统的调节而获得在营养缺乏条件下对细胞凋亡具有抗性的细胞，并具有侵袭性和/或转移潜能。然而，癌症干细胞不限于此，并且可以包括可以分化成一般癌细胞的任何细胞。
如本文所用，表达“抑制癌症干细胞的生长”意在包括抑制癌症干细胞维持，抑制癌症干细胞恶化和抑制癌症干细胞侵袭。
具体而言，本发明涉及一种抑制癌症干细胞生长的药物组合物，含有醛抑制剂和双胍类化合物。优选地，醛抑制剂可以是棉酚，双胍类化合物可以是苯乙双胍。
这里，“棉酚”是在棉花植物中大量含有的苯酚衍生物。在中国，发现这种棉酚抑制男性精子功能。因此，棉酚已被研究用作男性口服避孕药。此外，“苯乙双胍”通常被称为糖尿病治疗剂，生理上调节碳水化合物代谢和脂质代谢。
在本发明中，棉酚和苯乙双胍的组合优选表现出对抑制癌症干细胞生长具有非常高的协同效应。这里，棉酚优选为下述式1表示的化合物或其衍生物，但不限于此，苯乙双胍优选为下述式2表示的化合物或其衍生物，但不限于此：
式1
式2
在本发明的药物组合物中，醛类抑制剂和双胍类化合物的重量比可以为1:1～100，优选为1:2～20。
此外，在本发明的药物组合物中，醛抑制剂的含量可以为0.5～50μM。
此外，在本发明的药物组合物中，双胍类化合物的含量可以为10～1000μM。
如上所述，本发明的组合物可抑制癌症干细胞的生长，从而预防和/或治疗选自下组的癌症：子宫癌，乳腺癌，胃癌，脑癌，直肠癌，结肠直肠癌，皮肤癌，血癌和肝癌。优选地，本发明的组合物可以抑制神经球的增殖，维持，恶性和侵袭能力，从而有效地预防和/或治疗脑癌，特别是胶质母细胞瘤。
然而，本发明的药物组合物可以与其它另外的抗癌剂共同使用，不仅有效治疗癌症干细胞，而且有效地治疗一般的癌细胞。
可用于本发明的抗癌剂可以是选自下组的一种或多种：氮芥、伊马替尼、奥沙利铂、利妥昔单抗、埃罗替尼，来那替尼，拉帕替尼、吉非替尼、凡德他尼、尼罗替尼、司马沙尼、博舒替尼、阿西替尼、西地尼布、来他替尼、曲妥珠单抗、吉非替尼、硼替佐米、舒尼替尼、卡铂、索拉非尼、贝伐单抗、顺铂、西妥昔单抗、槲寄生、天冬酰胺酶、维甲酸、羟考脲、达沙替尼、雌莫司汀、单抗奥佐米星、替伊莫单抗、依铂、甲氨基乙酰丙酸、安吖啶、阿仑单抗、甲基苄肼、前列地尔、硝酸钬壳聚糖、吉西他滨、脱氧氟尿苷、培美曲塞、替加氟、卡培他滨、吉美嘧啶、奥替拉西、阿扎胞苷、甲氨蝶呤、尿嘧啶、阿糖胞苷、氟尿嘧啶、氟达拉滨、依诺他滨、氟他胺、地西他滨、巯嘌呤、硫鸟嘌呤、克拉屈滨、卡莫氟、雷替曲塞、多西他赛、紫杉醇、伊立替康、贝洛替康、拓扑替康、长春瑞滨、依托泊苷、长春新碱、长春碱、替尼泊苷、阿霉素、表柔比星、米托蒽醌、丝裂霉素、博来霉素、柔红霉素、放线菌素D、吡柔比星、阿柔比星，培洛霉素、西罗莫司、替莫唑胺、白消安、异环磷酰胺、环磷酰胺、美法仑、六甲蜜胺、达卡巴嗪、噻替派、尼莫司汀、苯丁酸氮芥、卫矛醇、甲酰四氢叶酸、特莱托奈(tretonine)、依西美坦、氨鲁米特、阿那格雷、长春瑞滨、法倔唑、他莫昔芬、托瑞米芬、睾内酯、阿那曲唑、来曲唑、伏罗唑、比卡鲁胺、洛莫司汀和卡莫司汀，但不限于此。
在本发明中，药物组合物可以是胶囊，片剂，颗粒剂，可注射溶液，软膏，粉剂或饮料的形式。药物组合物可以用于人类给药。
为了使用，根据常规方法，本发明的药物组合物可以配制成口服制剂，包括粉末，颗粒剂，胶囊，片剂，水性混悬液等，皮肤外用制剂，栓剂和无菌注射溶液，但是不限于此。本发明的药物组合物可以含有药学上可接受的载体。本发明的药学上可接受的载体包括可用于口服给药的粘合剂，润滑剂、崩解剂，赋形剂、增溶剂，分散剂、稳定剂、悬浮剂、颜料和芳香剂等，和可用于注射的缓冲剂、防腐剂、止痛剂、增溶剂、等渗剂和稳定剂等，和可用于局部给药的碱，赋形剂，润滑剂，防腐剂等。本发明的药物组合物可以通过与如上所述的药学上可接受的载体以各种方式混合配制。例如，对于口服给药，本发明的药物组合物可以配制成片剂、锭剂、胶囊剂、酏剂，混悬剂、糖浆剂和晶片等，对于注射剂，可以配制成单剂量安瓿或多剂量小瓶。此外，本发明的药物组合物可以配制成溶液、混悬液、片剂、胶囊和缓释制剂等。
同时，适用于制剂的载体、赋形剂和稀释剂的实例中包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、甲基羟基苯甲酸酯、丙基羟基苯甲酸酯、滑石粉、硬脂酸镁和矿物油。此外，本发明的药物组合物还可以含有填充剂、抗凝剂、润滑剂、润湿剂、香料、乳化剂和防腐剂等。
据本发明的药物组合物的给药途径包括但不限于口服、静脉内、肌内、动脉内、髓内、硬膜内、心内、经皮、皮下、腹膜内、鼻内、胃肠、局部、舌下和直肠内途径。优选口服或肠胃外给药。如本文所用，术语“肠胃外”指包括皮下、经皮、静脉内、肌内、关节内、滑膜内、胸骨内、硬膜内，病灶内和颅内注射或输液技术。本发明的药物组合物也可以配制成栓剂直肠内给药。
本发明的药物组合物可以根据各种因素而变化，包括使用的具体化合物的活性，患者的年龄，体重，一般健康状况，性别，饮食，给药时间，给药途径，排泄率，药物含量以及要预防或治疗的特定疾病的严重程度。药物组合物的剂量可以由本领域技术人员根据患者的状况，体重，疾病的严重程度，药物的形式以及给药途径和给药时间适当地选择，可以为0.0001-50mg/kg/天或0.001-50mg/kg/天。药物组合物可以每天给药一次或数次。剂量并不是以任何方式限制本发明的范围。根据本发明的药物组合物可以配制成丸剂、糖衣片、胶囊、液体、凝胶、糖浆、浆液或悬浮液。
有利效果
本发明的药物组合物含有醛抑制剂和双胍类化合物的组合，可有效抑制肿瘤干细胞如神经球细胞的生长，还可以抑制癌细胞的增殖、侵袭和转移，从而预防和/或治疗癌症如脑癌。
附图说明
图1显示参考实施例1中在不同浓度棉酚下进行的MTT测定的结果。
图2显示在实验实施例1中的实施例和比较实施例的各组合物处理后U87细胞活力的变化。
图3显示以实验实施例2中各种处理后的U87神经球细胞的照片。
图4显示以实验实施例2中各种处理后U87神经球细胞半径的变化。
图5显示以实验实施例2中各种处理后U87神经球细胞的形成程度。
图6显示以实验实施例3中各种处理后U87神经球细胞的照片。
图7显示在实验实施例4中的各种处理之后的原位异种移植模型小鼠中脑癌的发生程度。
图8显示在实验实施例4中各种处理后原位异种移植模型小鼠的存活率。
最佳实施例
本发明提供含有醛抑制剂和双胍类化合物组合的药物组合物，其可以有效地抑制癌症干细胞如神经球的生长，以抑制癌细胞的增殖，侵袭和转移，从而防止和/或治疗癌症如脑癌。
发明模式
以下，参照实施例对本发明进行更详细的说明。对于本领域技术人员来说显而易见的是，这些实施例仅用于说明性目的，并不意图限制本发明的范围。
实施例
参考实施例1：用棉酚处理后细胞活力的分析
用0.5、1、5、10和50μM棉酚处理U87细胞(GBM细胞)72小时(图1)。
如图1所示，当细胞用各种浓度的棉酚处理72小时，细胞的生长被抑制。
实验实施例1：用棉酚和苯乙双胍组合处理后细胞活力的分析
将U87细胞接种到96孔板上并在37℃下培养24小时。然后，用如下表1所示的实施例和比较实施例的各药物组合物处理细胞，然后用浓度为20μL/孔的MTS试剂处理细胞，并在37℃下孵育4小时。接下来，测定490nm处的吸光度，然后相对于未处理对照组计算吸光度的变化，以确定细胞活力。结果如图2所示。
表1
| 组合物 | |
| 比较实施例1 | - |
| 比较实施例2 | 0.5μM棉酚 |
| 比较实施例3 | 1μM棉酚 |
| 比较实施例4 | 10μM苯乙双胍 |
| 实施例1 | 10μM苯乙双胍+0.5μM棉酚 |
| 实施例2 | 10μM苯乙双胍+1μM棉酚 |
如图2所示，与用棉酚或苯乙双胍单独处理细胞相比，当细胞用棉酚和苯乙双胍组合进行处理时，细胞的活力显著降低。
实验实施例2：神经球形成分析
U87细胞在含有2wt％1xB27，0.02wt％bFGF(20ng/ml)，0.02wt％EGF(20ng/ml)和50U/ml青霉素-50mg/ml链霉素(100x，Gibco，英杰(韩国)公司，首尔，韩国)的DMEM/F-12培养基中培养以形成肿瘤球。接下来，将细胞以10个细胞/孔的密度接种到96孔板上，并用1μM棉酚、10μM棉酚、10μM苯乙双胍、1μM棉酚和10μM苯乙双胍的组合物、或10μM棉酚和10μM苯乙双胍的组合物处理。然后，将细胞在37℃下培养3周。为了观察U87细胞的形态和大小，用倒置相差显微镜(1x71倒置显微镜；奥林巴斯,东京,日本)观察获得的细胞培养物，并用数码相机(DP70数字显微镜相机；奥林巴斯)照相。照片如图3所示。另外，各种处理的神经球的半径变化如图4所示，神经球的形成程度如图5所示。
在图4中，神经球半径的百分比变化表示为各种处理后神经球的平均半径相对于接种到96孔板上的神经球的平均半径的百分比，在图5中，神经球形成的程度表示为每次处理后的神经球细胞数相对于接种到96孔板上的神经球细胞数的百分数。
从图3的细胞照片可以看出，即使用棉酚或苯乙双胍单独处理神经球细胞时，神经球细胞的大小减小，但是当用棉酚和苯乙双胍的组合处理神经球细胞时，没有观察到神经球细胞。
此外，如图4和图5所示，与用棉酚或苯乙双胍单独处理细胞相比，当用棉酚和苯乙双胍的组合处理细胞时，神经球细胞的半径显着降低，并且当用棉酚和苯乙双胍组合物处理时，神经球细胞的数量也显着降低。
实验实施例3：Transwell侵袭实验
将U87细胞(2×105个细胞/孔)悬浮于0.1ml生长培养基中，然后用1μM棉酚、10μM棉酚、10μM苯乙双胍、1μM棉酚和10μM苯乙双胍的组合物、或10μM棉酚和10μM苯乙双胍的组合物处理，并加到transwell室的上部孔(8mm孔径；康宁玻璃)。这里，transwell室的上部注入0.5ml生长培养基，上部用8.4mg/ml具有降低的生长因子的Matrigel(康宁Matrigel基质)预包被。室中细胞在37℃下培养48小时，然后用棉签去除过滤器上表面的非侵入细胞，将迁移到过滤器下表面的细胞固定并用Diff-Quick试剂盒(Fisher)染色，然后用相差显微镜(奥林巴斯)观察获得的细胞培养物。细胞培养物的照片如6所示。为测定细胞侵袭，对每孔10个微观场的细胞数进行计数。
如图6所示，与单独用棉酚或苯乙双胍处理细胞相比，当用棉酚和苯乙双胍的组合处理细胞时，神经球细胞的半径显着降低，并且当用棉酚和苯乙双胍组合物处理时，神经球细胞的数量也显着降低。
这表明与单独使用棉酚或苯乙双胍治疗相比，本发明的棉酚和苯乙双胍组合治疗可以有效抑制脑癌症干细胞的增殖和转移，从而显著的增加脑癌的治疗效果。
实验实施例4：原位异种移植模型中棉酚作用的评估
在动物研究中使用的棉酚和苯乙双胍分别溶解于DMSO和PBS中。共同给药的棉酚和苯乙双胍的组合物溶解在含有10wt％DMSO和1wt％氢化蓖麻油的PBS中。
对于原位异种移植模型的构建，使用4-8周龄雄性无胸腺裸鼠(中央实验室，韩国)。为了稳定化，在实验使用前，将小鼠保持在灭菌环境中至少一周，同时给予足够的饮食。动物研究中的所有方案均由延世大学机构动物护理和使用委员会批准。首先，通过腹膜内注射30mg/kg的舒泰和10mg/kg的赛拉嗪麻醉小鼠，通过使用汉密尔顿注射器将2×105U87-luc细胞移植到大脑的右额叶至4.5mm的深度。通过微注射注射泵将U87-luci细胞以0.5μl/分钟的速率同时注射到同一组的5只小鼠中。此后，每天口服给予棉酚(40mg/kg)和/或苯乙双胍(100mg/kg)。根据给药的种类，小鼠组在下表2中所示。
表2
| 给药的种类 | |
| 比较实施例6 | U87-leu细胞移植后给予蒸馏水 |
| 实施例4 | U87-leu细胞移植后单独给予棉酚 |
| 实施例5 | U87-leu细胞移植后单独给予苯乙双胍 |
| 实施例6 | U87-leu细胞移植后棉酚和苯乙双胍共同给药 |
每天检查体重的增加或减少，并且当体重与实验开始前相比减少15wt％时，根据批准的方案将小鼠安乐死。
使用IVIS成像系统和图像分析程序(实时成像V4.2软件)进行生物发光的收集和分析。为此，在信号测量前15分钟，在用2.5％异氟烷麻醉下，将100μl的d-萤光素(30mg/mLPBS)腹膜内注射到每只小鼠中。U87-luc细胞移植后的1，3和5周进行信号测定，每次5秒。结果如图7所示。
使用原位异种移植模型获得的实验结果如图7所示。可以看出，细胞移植5周后，在比较实施例6，实施例4(棉酚单独给药)和实施例5(单独给药苯乙双胍)中观察到荧光，结果表明U87-leu细胞引起脑癌，但与比较实施例6、实施例4和实施例5相比，实施例6(棉酚和苯乙双胍的共同给药)显示非常低的脑癌水平。此外，小鼠存活率的测定结果(图8)表明实施例6的小鼠组的存活率高于比较例6和实施例4和5的小鼠组的存活率。
虽然已经详细描述了本发明的实施例，但是对于本领域技术人员来说显而易见的是，本发明的范围不限于这些实施例，并且在不脱离技术精神的情况下可以进行各种改变和修改如所附权利要求中所限定的。
工业使用性
如上所述，本发明的药物组合物含有醛抑制剂和双胍类化合物的组合，其可以有效抑制癌症干细胞如神经球的生长，并且还可以抑制癌细胞的增殖，侵袭和转移，从而预防和/或治疗癌症如脑癌。
Claims (3)
1.一种棉酚和苯乙双胍在制备用于抑制胶质母细胞瘤生长的药物组合物中的用途。
2.如权利要求1所述的用途，其特征在于，所述的棉酚和苯乙双胍的重量比为1:1-10。
3.如权利要求1所述的用途，其特征在于，所述抑制脑胶质母细胞瘤生长是抑制胶质母细胞瘤维持，抑制胶质母细胞瘤恶化，或抑制脑胶质母细胞瘤侵袭。
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| KR10-2016-0010118 | 2016-01-27 | ||
| PCT/KR2016/001111 WO2016126073A2 (ko) | 2015-02-02 | 2016-02-02 | 알데히드 억제제 및 비구아나이드 계열 화합물을 포함하는 암 줄기세포의 성장 억제용 약학적 조성물 |
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| KR101904893B1 (ko) * | 2016-02-18 | 2018-10-10 | 연세대학교 산학협력단 | 폴리페놀 화합물을 유효성분으로 포함하는 암 치료용 약학조성물 |
| WO2018155921A1 (ko) * | 2017-02-22 | 2018-08-30 | 국립암센터 | 고시폴 및 펜포르민을 유효성분으로 포함하는 췌장암 예방 및 치료용 약학적 조성물 |
| WO2019147089A1 (ko) | 2018-01-26 | 2019-08-01 | 재단법인 대구경북첨단의료산업진흥재단 | 칼슘 채널 억제제 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 |
| KR102428313B1 (ko) * | 2018-07-09 | 2022-08-03 | 연세대학교 산학협력단 | 알데히드 억제제, 및 항암제를 포함하는 뇌암 치료용 약학조성물 |
| KR102260846B1 (ko) * | 2018-07-09 | 2021-06-07 | 국립암센터 | 고시폴, 펜포르민 및 항암제를 포함하는 암 예방 또는 치료용 약학적 조성물 |
| US20220193020A1 (en) | 2019-04-04 | 2022-06-23 | Daegu-Gyeongbuk Medical Innovation Foundation | Pharmaceutical Composition Comprising Trimebutine or Pharmaceutically Acceptable Salt Thereof as an Active Ingredient For Prevention or Treatment of Cancer |
| KR102339439B1 (ko) | 2019-04-04 | 2021-12-16 | 재단법인 대구경북첨단의료산업진흥재단 | 트리메부틴 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물 |
| WO2020213938A1 (ko) * | 2019-04-15 | 2020-10-22 | 주식회사 진센 | 사포닌을 유효성분으로 포함하는 암 치료용 약학조성물 |
| WO2020213939A1 (ko) * | 2019-04-15 | 2020-10-22 | 주식회사 진센 | 항암제의 병용투여용 약학조성물 |
| KR102552913B1 (ko) * | 2019-12-02 | 2023-07-07 | 주식회사 하임바이오 | 알데히드 억제제 및 비구아나이드 계열 화합물을 포함하는 속발성 암의 예방 및 치료용 약학조성물 |
| KR20210084919A (ko) * | 2019-12-30 | 2021-07-08 | 주식회사 하임바이오 | Sglt-2 억제제 및 고시폴을 유효성분으로 포함하는 암의 예방 또는 치료용 약학 조성물 |
| KR102569443B1 (ko) * | 2020-01-08 | 2023-08-22 | 주식회사 하임바이오 | 비구아나이드계 화합물을 유효성분으로 포함하는 혈액암의 예방 및 치료용 약학조성물 |
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| US20120302629A1 (en) * | 2009-08-07 | 2012-11-29 | The Regents Of The University Of Michigan | Biomarkers for gossypol chemotherapy and methods of treating disease |
| JP6206939B2 (ja) * | 2011-10-11 | 2017-10-04 | 国立大学法人 千葉大学 | 肝がん幹細胞阻害剤 |
| KR101579371B1 (ko) * | 2014-02-27 | 2015-12-22 | 국립암센터 | 고시폴 및 펜포르민을 유효성분으로 함유하는 암 치료용 약제학적 조성물 |
| US20180015056A1 (en) | 2015-02-02 | 2018-01-18 | Industry-Academic Cooperation Foundation, Yonsei University | Pharmaceutical composition for inhibiting growth of cancer stem cells, containing aldehyde inhibitor and biguanide-based compound |
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| WO2013019058A2 (en) * | 2011-08-04 | 2013-02-07 | Hanall Biopharma Co., Ltd. | Pharmaceutical composition for inhibiting cancer recurrence or metastasis |
| KR101242726B1 (ko) * | 2012-01-26 | 2013-03-13 | 한국과학기술원 | 종양줄기세포 특성 암의 진단 및 치료제 |
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| DK3254680T3 (da) | 2021-10-11 |
| KR101765575B1 (ko) | 2017-08-07 |
| EP3254680A4 (en) | 2018-08-22 |
| JP2018507196A (ja) | 2018-03-15 |
| CN107205963A (zh) | 2017-09-26 |
| KR20160094861A (ko) | 2016-08-10 |
| ES2893155T3 (es) | 2022-02-08 |
| US20190254995A1 (en) | 2019-08-22 |
| US10646460B2 (en) | 2020-05-12 |
| JP6469877B2 (ja) | 2019-02-13 |
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