CN111315400A - Antimitoscin:用于根除癌症干细胞的线粒体生物发生的靶向抑制剂 - Google Patents
Antimitoscin:用于根除癌症干细胞的线粒体生物发生的靶向抑制剂 Download PDFInfo
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Abstract
具有固有的抗线粒体特性的抗生素可被化学修饰以将抗生素靶向线粒体,并且所得的“antimitoscin”可具有增强的抗癌特性,以及其他有利的特性。还描述了鉴定antimitoscin的方法,使用antimitoscin以靶向癌症干细胞的方法,以及含有一种或多种antimitoscin作为活性成分的用于治疗癌症的药物组合物。还公开了特异性antimitoscin化合物和antimitoscin组。
Description
技术领域
本公开涉及“antimitoscin”,即具有固有的抗线粒体性质的抗生素,其被化学修饰以将抗生素靶向线粒体,并且包括合成antimitoscin的方法,使用antimitoscin以靶向癌症干细胞的方法,以及用于治疗癌症和降低癌细胞中的抗药性的药物组合物,该药物组合物含有一种或多种antimitoscin作为活性成分。
背景技术
研究人员努力开发新的抗癌治疗方法。常规的癌症疗法(例如辐射、烷化剂如环磷酰胺以及抗代谢物如5-氟尿嘧啶)已经尝试通过干扰参与细胞生长和DNA复制的细胞机制来选择性地检测和根除快速生长的癌细胞。其他癌症疗法已使用选择性结合快速生长癌细胞上的突变肿瘤抗原的免疫治疗(例如单克隆抗体)。不幸的是,在这些治疗之后肿瘤经常在相同或不同的部位复发,表明并非所有癌细胞都被根除。复发可能是由于化疗剂量不足和/或出现对治疗有抗性的癌症克隆。因此,需要新的癌症治疗策略。
突变分析的进展允许对癌症发展过程中发生的基因突变进行深入研究。尽管具有基因组景观的知识,现代肿瘤学难以鉴定跨越癌症亚型的原发性驱动突变。严酷的现实似乎是每个患者的肿瘤是独特的,并且单个肿瘤可以包含多个不同的克隆细胞。因此,需要一种强调不同癌症类型之间的共性的新方法。靶向肿瘤和正常细胞之间的代谢差异有望成为新的癌症治疗策略。对来自人乳腺癌样品的转录谱数据的分析揭示了与线粒体生物发生和/或线粒体翻译相关的超过95个升高的mRNA转录本。Sotgia等人,Cell Cycle,11(23):4390-4401(2012)。另外,95种上调的mRNA中超过35种编码线粒体核糖体蛋白(MRP)。人乳腺癌干细胞的蛋白质组学分析同样揭示了几种线粒体核糖体蛋白以及与线粒体生物发生相关的其他蛋白的显著过表达。Lamb等人,Oncotarget,5(22):11029-11037(2014)。
使用某些抑菌抗生素或OXPHOS抑制剂的脱靶效应对线粒体生物发生的功能性抑制提供了癌症干细胞增殖需要功能性线粒体的额外证据。本发明人最近表明线粒体荧光染料(MitoTracker)可有效用于富集和纯化来自异质活细胞群体的癌症干细胞样细胞(CSC)。Farnie等人,Oncotarget,6:30272-30486(2015)。具有最高线粒体质量(mass)的癌细胞具有最强的经历贴壁非依赖性生长的机能水平,这是通常与转移潜能相关的特征。“Mito-high”细胞亚群在体内也具有最高的肿瘤启动活性,如使用临床前模型所示。本发明人还证明了几类无毒抗生素可用于停止CSC繁殖。Lamb等人,Oncotarget,6:4569-4584(2015)。由于需氧细菌和线粒体之间保守的进化相似性,某些种类的抗生素或具有抗生素活性的化合物可以抑制线粒体蛋白质翻译作为脱靶副效应。
发明内容
鉴于前述背景,本公开的目的是证明具有固有的抗线粒体特性的现有抗生素可被化学修饰以靶向线粒体,并因此可用于根除CSC。本文描述了具有固有的抗线粒体性质的现有抗生素的实例,该抗生素已经被一种或多种线粒体靶向信号化学修饰,从而具有增强的抗癌性质。本文所用的术语“antimitoscin”泛指具有固有的抗线粒体特性的抗生素,其被化学修饰以将抗生素靶向线粒体。现有技术认为抗生素中固有的抗线粒体活性是不希望的副作用。实际上,由于过度的抗线粒体特性,一些潜在的抗生素已经被排除在试验之外,并且研究人员已经将抗线粒体活性视为潜在的缺点。然而,在本方法下,抗生素的固有的抗线粒体活性可以成为全新治疗的基础。本发明人已经确定可以通过化学修饰来利用和增强这些抗线粒体特性。结果,具有固有的抗线粒体活性的抗生素可被重新用作抗癌治疗以及其他潜在治疗的新治疗剂。这些化合物可以结合线粒体核糖体的大亚基或小亚基(或在某些情况下,两者都结合)并抑制线粒体生物发生。或者,这些化合物可结合到线粒体内膜以阻断OXPHOS通路并因此抑制线粒体代谢。本公开还描述了合成antimitoscin的方法,使用antimitoscin以靶向癌症干细胞的方法,以及用于治疗癌症和降低抗药性的药物组合物,该药物组合物含有一种或多种antimitoscin作为活性成分。本公开还描述了用于监测antimitoscin疗法的有效性的方法。该方法可包括从患者获得组织样品,确定样品中至少一种CSC标记物的水平,以及如果确定样品具有相对于阈值水平降低的至少一种CSC标记物水平,则将antimitoscin疗法分类为有效的。CSC标记物可以是CD44、Sox2、Nanog、Oct4、MYC和ALDH中的至少一种。
在一些实施方案中,本公开可采取antimitoscin的形式。本文公开了示例性antimitoscin。在一些实施方案中,antimitoscin包含具有固有的抗线粒体特性的抗生素和线粒体靶向化合物。在一些实施方案中,抗生素是四环素家族(tetracycline family)、红霉素家族(erythromycin family)、氯霉素、双羟萘酸扑蛲宁(pyrvinium pamoate)、阿托伐醌和贝达喹啉(bedaquiline)的成员。线粒体靶向化合物可以是对抗生素的化学修饰。在一些实施方案中,线粒体靶向化合物是选自包括膜靶向信号和线粒体核糖体靶向信号的组的至少一种化合物。在一些实施方案中,膜靶向信号是选自包括棕榈酸、硬脂酸、肉豆蔻酸和油酸的组的化合物。在一些实施方案中,线粒体靶向信号选自包括三苯基和胍盐的组。在一些实施方案中,antimitoscin具有抗癌活性。在一些实施方案中,antimitoscin与线粒体核糖体的大亚基或小亚基结合。在一些实施方案中,antimitoscin与线粒体核糖体的大亚基和线粒体核糖体的小亚基中的至少一种结合。在一些实施方案中,antimitoscin与线粒体内膜结合。在一些实施方案中,antimitoscin具有放射增敏活性、光敏化活性、使癌细胞对化疗剂敏感、使癌细胞对天然物质敏感、和/或使癌细胞对热量限制敏感。在一些实施方案中,本公开涉及治疗癌症的方法,其包括向有需要的患者施用药学有效量的antimitoscin和药学上可接受的载体。在一些实施方案中,本公开涉及用于治疗癌症的药物组合物,其含有至少一种antimitoscin作为活性成分。在一些实施方案中,药物组合物包含多种antimitoscin。本方法的实施方案可以采取合成antimitoscin的方法的形式。本方法的实施方案还可以采取改善抗生素的抗癌性质的形式。
发明人分析了可靶向多种癌症类型的CSC的表型特性,并确定了CSC对线粒体生物发生的严格依赖性,以实现CSC的克隆扩增和存活。本发明人以前的工作证明,不同种类的FDA批准的抗生素,特别是四环素类如强力霉素(doxycycline)和红霉素,具有抑制线粒体生物发生的脱靶效应。因此,这样的化合物具有根除CSC的功效。然而,这些常用抗生素没有被设计成靶向线粒体,因此它们的抗癌功效是有限的。在本方法中,具有固有的抗线粒体特性的现有抗生素可被化学修饰以形成antimitoscin,以靶向线粒体并抑制线粒体生物发生和代谢。Antimitoscin选择性地抑制CSC,因为线粒体生物发生在CSC中上调并且是增殖和存活所必需的。由于它们抑制线粒体生物发生的能力,antimitoscin具有增强的抗癌性质。
附图说明
图1示出了四环素家族的成员,包括(A)四环素、(B)强力霉素、(C)替加环素(tigecycline)和(D)米诺环素(minocycline)。
图2示出了红霉素家族的成员,包括(A)红霉素、(B)克拉霉素(clarithromycin)和(C)阿奇霉素(azithromycin)。
图3示出了已知通过脱靶副效应抑制线粒体核糖体或线粒体蛋白质翻译的其他抗生素,包括(A)氯霉素、(B)放线酰胺素(actinonin)和(C)左氧氟沙星。
图4示出了已知通过直接影响线粒体氧消耗来抑制线粒体核糖体或线粒体蛋白质翻译的其他抗生素,包括(A)双羟萘酸扑蛲宁、(B)阿托伐醌和(C)贝达喹啉。
图5显示了膜靶向信号的结构,包括脂肪酸类(A)硬脂酸、(B)肉豆蔻酸、(C)棕榈酸和(D)油酸。
图7显示了通过膜或线粒体靶向信号与抗生素的附着(共价或非共价)将抗生素转化成antimitoscin的方法的图。
图8显示了两种antimitoscin的结构。
具体实施方式
以下描述充分详细地示出了本方法的实施方案以实现本方法的实践。尽管参考这些特定实施方案描述了本方法,但是应当理解,本方法可以以不同的形式实施,并且本描述不应当被解释为将任何所附权利要求限制于本文所阐述的特定实施方案。相反,提供这些实施方案使得本公开将是透彻和完整的,并且向本领域技术人员充分传达本方法的范围。
线粒体是用于治疗从癌症到细菌和真菌感染到衰老的许多疾病的未开发的途径。功能性线粒体是癌症干细胞增殖所必需的。抑制癌细胞中的线粒体生物发生和代谢阻碍了这些细胞的增殖。因此,线粒体抑制剂代表了一类新的抗癌治疗剂。
如本文公开的,具有固有的抗线粒体特性的现有抗生素可以用至少一种线粒体靶向化合物进行化学修饰。线粒体靶向化合物可以是对抗生素的化学修饰,并且化学修饰可以根据本领域已知的化学合成方法进行。线粒体靶向化合物可以是膜靶向信号和线粒体-核糖体靶向信号之一。在一些实施方案中,具有固有的抗线粒体特性的抗生素可以用至少一种膜靶向信号和至少一种线粒体靶向信号进行化学修饰。所得antimitoscin可用作抗癌治疗剂,以及靶向细菌和致病酵母,提供抗衰老益处,用作放射增敏剂和/或光敏化剂,和/或使大量癌细胞和癌症干细胞对化疗剂、药物和/或其他天然物质敏感。
经化学修饰以将抗生素靶向线粒体的新抗生素(本文称为“antimitoscin”)具有固有的抗线粒体特性,该新抗生素可通过向具有固有的抗线粒体特性的抗生素添加至少一种膜靶向信号和/或至少一种线粒体靶向信号来形成。这种化学修饰提高了这些化合物特异性靶向线粒体、特别是线粒体核糖体的效率。所得化合物,一种antimitoscin,具有显著增强的治疗性能,包括抗癌性能。
图1-4提供了具有固有的抗线粒体特性的已知抗生素的实例,在本方法中,该抗生素被化学修饰以将抗生素靶向线粒体以形成antimitoscin。四环素家族中的抗生素是具有固有的抗线粒体性质的抗生素的实例,其被化学修饰以将抗生素靶向线粒体以形成具有抗癌治疗功效的antimitoscin。图1示出了四环素家族的成员,包括(A)四环素、(B)强力霉素、(C)替加环素和(D)米诺环素。这些广谱抗生素中的每一种可以用至少一种线粒体核糖体靶向化合物进行化学修饰以形成antimitoscin。应当理解,所示的特定抗生素是说明性的,并且本方法的范围不仅限于所示的那些结构。例如,本文未具体鉴定的四环素家族的其他成员可用作形成antimitoscin的起始化合物。仅作为实例的非穷举列表,这可以包括金霉素、土霉素、地美环素、赖甲环素、甲氯环素、甲烯土霉素、罗利环素、金霉素、omadacycline和sarecycline。
红霉素家族中的抗生素是具有固有的抗线粒体特性的抗生素的另外实例,其被化学修饰以将抗生素靶向线粒体以形成具有抗癌治疗功效的antimitoscin。图2显示了红霉素家族成员样品的化学结构,包括(A)红霉素、(B)阿奇霉素和(C)克拉霉素。这些抗生素中的每一种可以用至少一种线粒体靶向化合物进行化学修饰以形成antimitoscin。应当理解,所示的特定抗生素是说明性的,并且本方法的范围不仅限于所示的那些结构。例如,本文未具体鉴定的四环素家族的其他成员可用作形成antimitoscin的起始化合物。仅举几个另外的实例,这可以包括,例如金霉素、土霉素、地美环素、赖甲环素、甲氯环素、甲烯土霉素、米诺环素、罗利环素、替加环素、omadacycline和sarecycline。
经过化学修饰以将抗生素靶向线粒体的具有固有抗线粒体特性的其他已知抗生素,可以是antimitoscin。图3显示已知抑制线粒体核糖体或线粒体蛋白质翻译作为脱靶副效应的其他抗生素。这些实例包括氯霉素、放线酰胺素和左氧氟沙星。这些化合物中的每一种可以用至少一种线粒体靶向化合物进行化学修饰以形成antimitoscin。图4显示了已知通过干扰线粒体复合物I、II、III、IV和/或V影响线粒体氧消耗的其他抗生素。这些实例包括双羟萘酸扑蛲宁、阿托伐醌和贝达喹啉。这些化合物中的每一种可以用至少一种线粒体靶向化合物进行化学修饰以形成antimitoscin。
与抗生素不同,antimitoscin被特别设计成通过附着至少一种膜靶向信号和/或至少一种线粒体靶向信号来靶向线粒体。图5提供了膜靶向信号的实例,包括脂肪酸如棕榈酸、硬脂酸、肉豆蔻酸和油酸。应当理解,这不是膜靶向信号的完整列表,并且可以使用未列出的膜靶向信号而不背离本方法。图6提供了线粒体靶向信号的实例,包括基于三苯基(TPP)和胍盐的部分。应当理解,这不是线粒体靶向信号的完整列表,并且可以使用未列出的线粒体靶向信号而不背离本方法。
图7显示了通过膜或线粒体靶向信号701与抗生素703、营养制品705、本领域已知的常规化学疗法707和其他化合物或疗法709中的一种或多种的附着(共价或非共价)将抗生素转化成antimitoscin的方法的图。
如本文所述,antimitoscin可以通过用至少一种膜靶向信号和/或至少一种线粒体靶向信号化学修饰具有固有的抗线粒体特性的抗生素来形成。图8显示了antimitoscin的两个实例。在这些实例中,四环素家族成员的侧链已被(A)棕榈酸和(B)碳间隔臂(carbon-spacer-arm)和TPP替代。应当理解,线粒体靶向化合物可以在其他位置与抗生素连接而不背离本发明的方法。
图8所示的特定antimitoscin制剂是由图1-4中鉴定的示例性抗生素形成的antimitoscin的实例。应当理解,可以选择antimitoscin单独用于治疗用途,或者与一种或多种antimitoscin和/或与其他物质组合以增强其他治疗剂的功效。例如,由不同抗生素形成的antimitoscin可以一起用于治疗制剂中。此外,由抗生素形成但具有不同线粒体靶向化合物(例如图8所示的结构)的antimitoscin可以一起用于治疗制剂中。该治疗剂可以常规药物组合物的形式使用,该药物组合物可以使用一种或多种已知方法制备。例如,药物组合物可以通过使用稀释剂或赋形剂制备,例如本领域已知的一种或多种填充剂、疏松剂(bulking agent)、粘合剂、润湿剂、崩解剂、表面活性剂、润滑剂等。可以根据治疗目的选择各种类型的施用单位形式。药物组合物形式的实例包括但不限于片剂、丸剂、粉剂、液体、混悬剂、乳剂、颗粒剂、胶囊剂、栓剂、注射制剂(溶液和混悬剂)、局部乳膏和本领域已知的其他形式。为了形成片剂形式的药物组合物,可以使用任何已知的赋形剂,例如载体如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、环糊精、结晶纤维素、硅酸等;粘合剂如水、乙醇、丙醇、简易糖浆、葡萄糖溶液、淀粉溶液、明胶溶液、羧甲基纤维素、shelac、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等。另外,可以使用崩解剂,例如干燥淀粉、藻酸钠、琼脂粉末、层状粉末、碳酸氢钠、碳酸钙、聚氧乙烯脱水山梨糖醇的脂肪酸酯、月桂醇硫酸钠、硬脂酸的单甘油酯、淀粉、乳糖等。崩解抑制剂,例如白糖、硬脂精(stearin)、椰子油、氢化油;可以使用吸收促进剂如季铵碱、月桂醇硫酸钠等。可以使用润湿剂如甘油、淀粉和本领域已知的其他润湿剂。可以使用吸附剂,例如淀粉、乳糖、高岭土、膨润土、胶状硅酸等。可以使用润滑剂,例如纯化的滑石、硬脂酸盐、硼酸粉末、聚乙二醇等。如果需要片剂,它们可以进一步用常规包衣材料进行包衣,以将片剂制成糖包衣片剂、明胶薄膜包衣片剂、肠包衣片剂、薄膜包衣片剂、双层片剂和多层片剂。适于局部施用的药物组合物可以配制成软膏剂、乳膏剂、混悬剂、洗剂、粉剂、溶液剂、糊剂、凝胶剂、泡沫剂、喷雾剂、气雾剂或油剂。这种药物组合物可包括常规添加剂,其包括但不限于防腐剂、有助于药物渗透的溶剂、助溶剂、润肤剂、推进剂、粘度调节剂(胶凝剂)、表面活性剂和载体。
antimitoscin也可用于逆转癌细胞中的抗药性。抗药性被认为至少部分基于癌细胞中增强的线粒体功能。特别地,对如他莫昔芬等内分泌疗法表现出抗性的癌细胞预期具有增强的线粒体功能。antimitoscin抑制线粒体功能,因此可用于降低和在一些情况下逆转癌细胞中的抗药性。另外,先前产生的数据提示靶向线粒体核糖体的线粒体功能抑制剂(称为“mitoriboscin”)可用于靶向细菌和致病性酵母,提供抗衰老益处,用作放射增敏剂和/或光敏化剂,使大量癌细胞和癌症干细胞对化疗剂、药物和/或其他天然物质(例如膳食补充剂和热量限制)敏感。考虑到它们的线粒体抑制特性,antimitoscin可类似地用于靶向细菌和致病性酵母,提供抗衰老益处,用作放射增敏剂和/或光敏化剂,使大量癌细胞和癌症干细胞对化疗剂、药物和/或其他天然物质敏感。
除了抗生素之外,具有抗生素活性的其他化合物可以用膜或线粒体靶向信号修饰以具有增强的抗癌活性。例如,可以用至少一种线粒体靶向的化合物修饰营养制品和常规化学治疗以特异性靶向线粒体。当特异性靶向线粒体时,可以提高这些化合物的功效。可被修饰以靶向线粒体的具有抗生素活性的营养制品的实例包括咖啡酸苯乙酯(发现于蜂胶中)、抗坏血酸(维生素C)和其他维生素和痕量矿物质、多酚、表没食子儿茶素-3-没食子酸酯、白藜芦醇和槲皮素。应当理解,这不是具有抗生素活性的营养制品的完整列表,并且可以使用未列出的营养制品而不背离本方法。
下表总结了可以连接以产生antimitoscin的说明性抗生素和化学靶向信号。
表1用于产生antimitoscin的说明性成分
本公开还涉及监测antimitoscin疗法的有效性的方法。在一些实施方案中,可以监测一种或多种CSC标记物以确定用一种或多种antimitoscin治疗的有效性。与未处理的对照相比,CSC标记物的相对水平可响应antimitoscin的治疗而降低。在一些实施方案中,CSC标记物是CD44、Sox2、Nanog、Oct4、MYC和ALDH中的至少一种。可以在肿瘤组织样品中测量一种或多种CSC标记物的相对水平。一种或多种CSC标记物的相对水平可通过本领域已知的用于测量标记物的RNA、DNA和/或蛋白质水平的多种方法来测量,包括但不限于定量PCR和/或RT-PCR试剂盒、微阵列、Northern印迹和Western印迹。
这里在本发明的描述中使用的术语仅用于描述特定实施方案的目的,而不旨在限制本发明。如在本发明的说明书和所附权利要求书中所使用的,单数形式“一(a、an)”和“所述/该(the))”也旨在包括复数形式,除非上下文另外清楚地指示。考虑到下面的详细描述,本发明包括将变得显而易见的许多替换、修改和等同物。
应当理解,尽管术语“第一(first)”、“第二(second)”、“第三(third)”、“a”、“b”和“c”等可在本文中用于描述本发明的各种要素,但不应被这些术语限制。这些术语仅用于将本发明的一个要素与另一个要素区分开。因此,下面讨论的第一要素可以被称为要素方面,不脱离本发明的教导,第三要素也是类似的情况。因此,术语“第一”、“第二”、“第三”、“a”、“b”和“c”等不旨在必然地将顺序或其他层次结构传递给相关联的要素,而是仅用于标识目的。操作(或步骤)的顺序不限于权利要求中给出的排序。
除非另外定义,否则本文使用的所有术语(包括技术和科学术语)具有与本发明所属领域的普通技术人员通常理解的相同含义。还应当理解,诸如在常用词典中定义的那些术语应当被解释为具有与它们在本申请和相关领域的上下文中的含义一致的含义,并且不应当被解释为理想化或过于正式的含义,除非在此明确地如此定义。这里在本发明的描述中使用的术语仅用于描述特定实施方案的目的,而不旨在限制本发明。本文提及的所有出版物、专利申请、专利和其他参考文献均全文引入作为参考。在术语冲突的情况下,以本说明书为准。
此外,如本文所用,“和/或”是指并涵盖一个或多个相关所列项目的任何和所有可能的组合,以及当以备选方式(“或”)解释时缺少组合。
除非上下文另有说明,本文所述的本发明的各种特征可以任何组合使用。此外,本发明还意图,在本发明的一些实施方案中,可以排除或省略在此阐述的任何特征或特征的组合。为了说明,如果说明书陈述复合体包括组分A、B和C,则特别意图可以省略和放弃A、B或C中的任何一个或其组合。
如本文所用,过渡短语“基本上由……组成”(和语法变体)应解释为涵盖所列举的材料或步骤“和不会实质上影响所要求保护的发明的基本和新颖特征的那些材料或步骤”。因此,本文所用的术语“基本上由……组成(consisting essentially of)”不应被解释为等同于“包含(comprising)”。
本文所用的术语“约”当涉及可测量值时,例如量或浓度等,意指包括特定量的±20%、±10%、±5%、±1%、±0.5%或甚至±0.1%的变化。本文提供的用于可测量值的范围可包括其中的任何其他范围和/或单个值。
已经如此描述了本发明的某些实施方案,应当理解,由所附权利要求限定的本发明不限于在以上描述中阐述的特定细节,因为在不脱离所附权利要求的精神或范围的情况下,其许多明显的变化是可能的。
Claims (31)
1.一种antimitoscin。
2.根据权利要求1所述的antimitoscin,其中,所述antimitoscin包含具有固有的抗线粒体特性的抗生素和线粒体靶向化合物。
3.根据权利要求2所述的antimitoscin,其中,所述抗生素选自包括四环素家族的至少一个成员、红霉素家族的至少一个成员、氯霉素、双羟萘酸扑蛲宁、阿托伐醌和贝达喹啉的组。
4.根据权利要求2所述的antimitoscin,其中,所述线粒体靶向化合物是至少一种选自包括膜靶向信号和线粒体核糖体靶向信号的组的化合物。
5.根据权利要求4所述的antimitoscin,其中,所述膜靶向信号是选自包括棕榈酸、硬脂酸、肉豆蔻酸和油酸的组的化合物。
7.根据权利要求1所述的antimitoscin,其中,所述antimitoscin具有抗癌活性。
8.根据权利要求1所述的antimitoscin,其中,所述antimitoscin结合线粒体核糖体的大亚基。
9.根据权利要求1所述的antimitoscin,其中,所述antimitoscin结合线粒体核糖体的小亚基。
10.根据权利要求1所述的antimitoscin,其中,所述antimitoscin结合线粒体核糖体的大亚基或线粒体核糖体的小亚基中的至少一种。
11.根据权利要求1所述的antimitoscin,其中,所述antimitoscin结合线粒体膜。
12.根据权利要求1所述的antimitoscin,其中,所述antimitoscin具有放射增敏活性。
13.根据权利要求1所述的antimitoscin,其中,所述antimitoscin具有光敏化活性。
14.根据权利要求1所述的antimitoscin,其中,所述antimitoscin使癌细胞对化疗剂敏感。
15.根据权利要求1所述的antimitoscin,其中,所述antimitoscin使癌细胞对天然物质敏感。
16.根据权利要求1所述的antimitoscin,其中,所述antimitoscin使癌细胞对热量限制敏感。
17.一种治疗癌症的方法,所述方法包括向有此需要的患者施用药学有效量的antimitoscin和药学上可接受的载体。
18.一种用于治疗癌症的药物组合物,其含有至少一种antimitoscin作为活性成分。
19.根据权利要求18所述的药物组合物,其包含多种antimitoscin。
20.一种antimitoscin合成方法,所述方法包括:
用线粒体靶向化合物化学修饰具有抗癌性质的抗生素。
21.根据权利要求20所述的方法,其中,所述抗生素选自包括四环素家族的至少一个成员、红霉素家族的至少一个成员、氯霉素、双羟萘酸扑蛲宁、阿托伐醌和贝达喹啉的组。
22.根据权利要求20所述的方法,其中,所述线粒体靶向化合物是至少一种选自包括膜靶向信号和线粒体核糖体靶向信号的组的化合物。
23.根据权利要求22所述的方法,其中,所述膜靶向信号是至少一种选自包括棕榈酸、硬脂酸、肉豆蔻酸和油酸的组的化合物。
25.一种用于改善抗生素的抗癌性质的方法,所述方法包括:
用线粒体靶向化合物化学修饰具有抗癌性质的抗生素。
26.根据权利要求25所述的方法,其中,所述抗生素选自包括四环素家族的至少一个成员、红霉素家族的至少一个成员、氯霉素、双羟萘酸扑蛲宁、阿托伐醌和贝达喹啉的组。
27.根据权利要求25所述的方法,其中,所述线粒体靶向化合物是至少一种选自包括膜靶向信号和线粒体核糖体靶向信号的组的化合物。
28.根据权利要求27所述的方法,其中,所述膜靶向信号是至少一种选自包括棕榈酸、硬脂酸、肉豆蔻酸和油酸的组的化合物。
30.一种用于监测antimitoscin疗法的有效性的方法,所述方法包括:
从专利中获得组织样品;
确定所述样品中至少一种CSC标记物的水平;
以及如果确定所述样品具有相对于阈值水平降低的至少一种CSC标记物水平,则将所述antimitoscin疗法分类为有效的。
31.根据权利要求30所述的方法,其中,所述CSC标记物是CD44、Sox2、Nanog、Oct4、MYC和ALDH中的至少一种。
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Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3060510A1 (en) | 2017-04-21 | 2018-10-25 | Lunella Biotech, Inc. | Vitamin c and doxycycline: a synthetic lethal combination therapy for eradicating cancer stem cells (cscs) |
CA3060509A1 (en) | 2017-04-21 | 2018-10-25 | Federica Sotgia | Targeting hypoxic cancer stem cells (cscs) with doxycycline: implications for improving anti-angiogenic therapy |
EP3624840A4 (en) | 2017-05-19 | 2021-03-10 | Lunella Biotech, Inc. | ANTIMITOSCINE: TARGETED INHIBITORS OF MITOCHONDRIAL BIOGENESIS TO DESCRIBE CANCER STEM CELLS |
MX2019014806A (es) | 2017-06-26 | 2020-02-10 | Lunella Biotech Inc | Mitocetoscinas: agentes terapeuticos basados en mitocondrias que fijan como objetivo el metabolismo de cetonas en celulas cancerosas. |
WO2019075226A1 (en) | 2017-10-11 | 2019-04-18 | Lunella Biotech, Inc. | ANTI-MITOCHONDRIAL INHIBITORS FOR ONCOGENIC RAS AND MYC |
WO2019108729A1 (en) * | 2017-12-01 | 2019-06-06 | Lunella Biotech, Inc. | Repurposcins: targeted inhibitors of mitochondrial biogenesis for eradicating cancer stem cells |
BR112021006423A2 (pt) | 2018-10-02 | 2021-07-06 | Lunella Biotech Inc | derivados de azitromicina e roxitromicina como fármacos senolíticos |
PE20220499A1 (es) * | 2018-12-17 | 2022-04-07 | Lunella Biotech Inc | Terapias de combinacion triple para anti-envejecimiento |
BR112021011963A2 (pt) * | 2018-12-17 | 2021-09-08 | Lunella Biotech, Inc. | Terapias de combinação tripla para alvejamento de mitocôndria e exterminação de células-tronco de câncer |
WO2020242857A1 (en) | 2019-05-24 | 2020-12-03 | Lunella Biotech, Inc. | Therapeutics and methods for predicting and overcoming endocrine resistance in breast cancer |
CA3144666A1 (en) * | 2019-06-26 | 2020-12-30 | Lunella Biotech, Inc. | Carbocyanine compounds for targeting mitochondria and eradicating cancer stem cells |
WO2021081500A1 (en) | 2019-10-24 | 2021-04-29 | The Medical College Of Wisconsin, Inc. | Mitochondria-targeted atovaquone: a more potent and more effective antitumor, antimicrobial, and antimalarial drug |
IL302095A (en) * | 2020-10-22 | 2023-06-01 | Lunella Biotech Inc | Mitochondrial ATP inhibitors targeting the gamma subunit prevent metastasis |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040161405A9 (en) * | 2001-12-11 | 2004-08-19 | Rothbard Jonathan B. | Guanidinium transport reagents and conjugates |
US20090099080A1 (en) * | 2007-09-10 | 2009-04-16 | Altieri Dario C | Mitochondria-targeted anti-tumor agents |
CN101810570A (zh) * | 2010-04-16 | 2010-08-25 | 成都师创生物医药科技有限公司 | 蒽环类抗肿瘤抗生素脂肪酸复合物脂质纳米粒制剂及其制备方法 |
US20110268722A1 (en) * | 2010-04-22 | 2011-11-03 | Siegelin Markus D | Combination therapies with mitochondrial-targeted anti-tumor agents |
CN102753142A (zh) * | 2009-12-02 | 2012-10-24 | 贝蒂纳·海尔 | 含益生菌、抗生素和不饱和非酯化脂肪酸的直肠、阴道或尿道给药的栓剂 |
CN102911226A (zh) * | 2011-08-03 | 2013-02-06 | 胡梨芳 | 红霉素衍生物及其制备方法和用途 |
CN105884633A (zh) * | 2016-05-07 | 2016-08-24 | 浙江大学 | 一种四环素硬脂酸嫁接物及其制备和应用 |
Family Cites Families (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2862921A (en) * | 1953-08-13 | 1958-12-02 | Upjohn Co | Erythromycin esters |
US3517067A (en) | 1964-02-11 | 1970-06-23 | Eastman Kodak Co | Syntheses of quaternary phosphonium salts |
DK149776C (da) | 1984-01-06 | 1987-04-21 | Orion Yhtymae Oy | Antibiotisk virksom erytromycinforbindelse og praeparat indeholdende forbindelsen |
EP0310361A3 (en) | 1987-09-30 | 1989-05-24 | Beckman Instruments, Inc. | Tridentate conjugate and method of use thereof |
SI9011409A (en) | 1990-07-18 | 1995-10-31 | Pliva Pharm & Chem Works | O-methyl azitromycin derivates, methods and intermediates for their preparation and methods for preparation of pharmaceuticals products which comprise them |
EP0656422B1 (en) | 1993-11-05 | 2000-04-26 | Amersham Pharmacia Biotech UK Limited | Chloramphenicol acetyl transferase (CAT) assay |
WO1995015770A1 (en) | 1993-12-09 | 1995-06-15 | Neorx Corporation | Pretargeting methods and compounds |
US5441939A (en) | 1994-03-04 | 1995-08-15 | Pfizer Inc. | 3"-desmethoxy derivatives of erythromycin and azithromycin |
CA2189001A1 (en) | 1994-04-26 | 1995-11-02 | Nobuhiro Narita | Medicinal composition as a remedy for nonsmall cell lung cancer |
NZ304095A (en) | 1995-05-03 | 1998-10-28 | Pfizer | 9-(substituted acylamino) tetracyclic derivatives and medicaments |
US6576636B2 (en) | 1996-05-22 | 2003-06-10 | Protarga, Inc. | Method of treating a liver disorder with fatty acid-antiviral agent conjugates |
US5837696A (en) | 1997-01-15 | 1998-11-17 | The Research Foundation Of State University Of New York | Method of inhibiting cancer growth |
WO1999026582A2 (en) | 1997-11-25 | 1999-06-03 | University Of Otago | Mitochondrially targeted compounds |
PT941998E (pt) | 1998-03-03 | 2004-12-31 | Pfizer Prod Inc | Antibioticos macrolidos do tipo 3,6-cetal |
AUPP437698A0 (en) | 1998-06-30 | 1998-07-23 | Baumgart, Karl | Methods for treatment of coronary, carotid and other vascular disease |
US6858598B1 (en) | 1998-12-23 | 2005-02-22 | G. D. Searle & Co. | Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
US7485298B2 (en) | 2002-05-23 | 2009-02-03 | Michael Powell | Diagnosis and treatment of human dormancy-related sequellae |
RU2223103C1 (ru) * | 2002-07-17 | 2004-02-10 | Открытое акционерное общество "Биосинтез" | Фармацевтическая композиция, обладающая антибактериальным действием |
EP2517729A3 (en) | 2003-01-27 | 2013-01-02 | Endocyte, Inc. | Vitamin receptor binding drug delivery conjugates |
WO2005062851A2 (en) | 2003-12-22 | 2005-07-14 | Pappolla Miguel A | Indole-3-propionamide and derivatives thereof |
JP2005200419A (ja) | 2004-01-16 | 2005-07-28 | National Health Research Inst | 癌治療法 |
CA2557216A1 (en) | 2004-02-26 | 2005-09-09 | Advanced Ocular Systems Limited | Heparin for the treatment of ocular pathologies |
US20060083727A1 (en) | 2004-07-15 | 2006-04-20 | Nanobac Pharmaceuticals, Inc. | Methods and compositions for the treatment of diseases characterized by calcification and/or plaque formation |
TW200616604A (en) | 2004-08-26 | 2006-06-01 | Nicholas Piramal India Ltd | Nitric oxide releasing prodrugs containing bio-cleavable linker |
ATE523519T1 (de) | 2005-01-14 | 2011-09-15 | Glaxo Group Ltd | Makrolidverbindungen mit biotin und fotoaffinitätsgruppe zur identifizierung eines makrolid-targets |
CN1706391A (zh) * | 2005-05-09 | 2005-12-14 | 史同瑞 | 土霉素混悬乳剂 |
RU2447889C2 (ru) | 2005-07-18 | 2012-04-20 | Бипар Сайенсиз, Инк. | Способ лечения рака (варианты) |
CN1837229A (zh) * | 2005-08-05 | 2006-09-27 | 济南思创生物技术有限公司 | 克拉霉素衍生物及其制备方法和药物应用 |
DE102005039579B4 (de) | 2005-08-19 | 2022-06-30 | Magforce Ag | Verfahren zur Einschleusung von therapeutischen Substanzen in Zellen |
CN1837225A (zh) * | 2005-08-23 | 2006-09-27 | 济南思创生物技术有限公司 | 阿奇霉素衍生物及其制法和药物应用 |
WO2007139930A2 (en) | 2006-05-26 | 2007-12-06 | Bayer Healthcare Llc | Drug combinations with substituted diaryl ureas for the treatment of cancer |
US20090311249A1 (en) | 2006-06-02 | 2009-12-17 | Luca Gianni | Capecitabine Combination Therapy |
US20080118432A1 (en) * | 2006-09-07 | 2008-05-22 | Ivan Bergstein | Monitoring cancer stem cells |
WO2008054726A2 (en) | 2006-10-30 | 2008-05-08 | Southern Research Institute | Targeting nbs1-atm interaction to sensitize cancer cells to radiotherapy and chemotherapy |
LT2117520T (lt) | 2006-12-14 | 2018-12-10 | Abraxis Bioscience, Llc | Krūties vėžio terapija hormonų receptoriaus statuso pagrindu su nanodalelėmis, apimančiomis taksaną |
US8075902B2 (en) | 2007-01-03 | 2011-12-13 | Michael Powell | Diagnosis and treatment of cancer related to human dormancy |
DE102007025423A1 (de) | 2007-05-30 | 2008-12-04 | Friedrich-Schiller-Universität Jena | Triphenylphosphonium-Derivate zum gezielten Transport und Freisetzen von Substanzen in Mitochondrien sowie Verfahren zu deren Verwendung |
US20090099062A1 (en) | 2007-05-31 | 2009-04-16 | Ethan Lee | Pyrvinium For The Treatment of Cancer |
US8647673B2 (en) | 2007-07-24 | 2014-02-11 | Wayne State University | Nanoparticles for imaging and treating chlamydial infection |
WO2009038656A1 (en) | 2007-09-17 | 2009-03-26 | Kosta Steliou | Mitochondria-targeting antioxidant therapeutics |
WO2009045443A2 (en) | 2007-10-02 | 2009-04-09 | The University Of Rochester | Methods and compositions related to synergistic responses to oncogenic mutations |
BRPI1014978A2 (pt) | 2009-04-17 | 2019-07-02 | Colby Pharmaceutical Company | método de tratamento do câncer e composição farmacêutica. |
GB0912584D0 (en) | 2009-07-20 | 2009-08-26 | Ucl Business Plc | Cyclosporin conjugates |
EP2470170A4 (en) | 2009-08-25 | 2013-01-02 | Harvard College | USE OF METFORMIN IN THE TREATMENT AND PREVENTION OF CANCER |
EP2506840B1 (en) | 2009-12-04 | 2021-01-06 | Oncoimmune Inc. | Uses of hypoxia-inducible factor inhibitors |
CA2790240A1 (en) | 2010-03-10 | 2011-09-15 | University Health Network | Use of tigecycline for treatment of cancer |
US20120141467A1 (en) | 2010-12-03 | 2012-06-07 | Schneider Daniel J | Ascorbic acid to treat chronic obstructive lung diseases and non-Hodgkin's lymphoma |
US10513539B2 (en) | 2011-02-10 | 2019-12-24 | Ruprecht-Karls-Universitat Heidelberg | Hydrophobic modified peptides and their use for liver specific targeting |
EA032840B8 (ru) | 2011-06-22 | 2020-06-18 | Вайоми Терапеутикс Лимитед | Пролекарства на основе конъюгатов противогрибковых агентов и их применение |
ES2627120T3 (es) | 2011-07-08 | 2017-07-26 | Helmholtz-Zentrum für Infektionsforschung GmbH | Medicamento para el tratamiento del cáncer de hígado |
US9801922B2 (en) | 2011-08-03 | 2017-10-31 | University Of Iowa Research Foundation | Compositions and methods of treating cancer |
US9180134B2 (en) | 2011-08-18 | 2015-11-10 | Ecole Polytechnique Federale De Lausanne (Epel) | Mitochondrial ribosomal proteins as aging regulators |
WO2013040206A1 (en) | 2011-09-14 | 2013-03-21 | Lewis Thomas J | Novel formulations comprising macrolide and tetracycline and their uses |
CA2866080C (en) | 2012-03-01 | 2021-01-19 | University Of Cincinnati | Ros-activated compounds as selective anti-cancer therapeutics |
US9526795B2 (en) | 2012-08-28 | 2016-12-27 | Annam Biosciences, Llc | N-BOC-dendrimers and their conjugates |
WO2014036654A1 (en) | 2012-09-06 | 2014-03-13 | Mcmaster University | Compounds and methods for selectively targeting cancer stem cells |
US20140106004A1 (en) | 2012-10-12 | 2014-04-17 | Bing Lou Wong | Hemoglobin-based oxygen carrier-containing pharmaceutical composition for cancer targeting treatment and prevention of cancer recurrence |
US9636329B2 (en) | 2012-11-06 | 2017-05-02 | Northwestern University | Methods of treating cancer with glut inhibitors and oxidative phosphorylation inhibitors |
US9622982B2 (en) | 2013-01-14 | 2017-04-18 | Health Clinics Limited | Cancer drug and uses |
US9937161B2 (en) | 2013-03-06 | 2018-04-10 | The General Hospital Corporation | Combinatorial compositions and methods for treatment of melanoma |
PT2989110T (pt) | 2013-04-24 | 2018-11-15 | Jira Neuzil | Derivados de tamoxifeno para o tratamento de doenças neoplásicas, especialmente com nível elevado de proteína her2 |
EP3016715A4 (en) | 2013-07-01 | 2017-02-08 | University Of Georgia Research Foundation, Inc. | Precise delivery of therapeutic agents to cell mitochondria for anti-cancer therapy |
WO2015050844A1 (en) | 2013-10-01 | 2015-04-09 | Dana-Farber Cancer Institute, Inc. | Methods of treating cancer with atovaquone-related compounds |
CN103536530A (zh) * | 2013-10-30 | 2014-01-29 | 王玉万 | 盐酸多西环素长效注射剂及制备方法 |
US20150231069A1 (en) | 2014-02-20 | 2015-08-20 | Pankaj Modi | Oral formulations of chemotherapeutic agents |
US10398663B2 (en) | 2014-03-14 | 2019-09-03 | University Of Georgia Research Foundation, Inc. | Mitochondrial delivery of 3-bromopyruvate |
US20170224730A1 (en) | 2014-06-10 | 2017-08-10 | Institute For Myeloma & Bone Cancer Research | Anti-cancer effects of proteasome inhibitors in combination with glucocorticoids, arsenic containing compounds, and ascorbic acid |
GB201414806D0 (en) | 2014-08-20 | 2014-10-01 | Ucl Business Plc | Cyclosporin conjugates |
US10413558B2 (en) | 2014-10-17 | 2019-09-17 | Targeted Therapies Research And Consulting Center Sprl | Multi-ingredient pharmaceutical composition for use in cancer therapy |
CN104352566A (zh) * | 2014-10-21 | 2015-02-18 | 河南牧翔动物药业有限公司 | 一种水包油型复方金霉素纳米乳 |
JP6439931B2 (ja) | 2015-02-26 | 2018-12-19 | 大日本印刷株式会社 | 吸着搬送装置および吸着搬送方法 |
RU2727474C2 (ru) | 2015-10-06 | 2020-07-21 | Редхилл Байофарма Лтд. | Виды комбинированной терапии для лечения рака |
US11725041B2 (en) | 2016-08-11 | 2023-08-15 | The Council Of The Queensland Institute Of Medical Research | Immune-modulating compounds |
CN106511317A (zh) * | 2016-12-13 | 2017-03-22 | 浙江中同科技有限公司 | 一种掩味克拉霉素颗粒的制备方法 |
US20200121739A1 (en) | 2017-01-18 | 2020-04-23 | Evelo Biosciences, Inc. | Bacteria for treating cancer |
WO2018136598A1 (en) | 2017-01-18 | 2018-07-26 | Evelo Biosciences, Inc. | Methods of treating cancer |
CA3060510A1 (en) | 2017-04-21 | 2018-10-25 | Lunella Biotech, Inc. | Vitamin c and doxycycline: a synthetic lethal combination therapy for eradicating cancer stem cells (cscs) |
CA3060509A1 (en) | 2017-04-21 | 2018-10-25 | Federica Sotgia | Targeting hypoxic cancer stem cells (cscs) with doxycycline: implications for improving anti-angiogenic therapy |
WO2018202910A1 (en) | 2017-05-05 | 2018-11-08 | Fondazione Istituto Italiano Di Tecnologia | Combination of antibiotic and bcl-2 inhibitor and uses thereof |
EP3624897A4 (en) | 2017-05-19 | 2021-07-14 | Lunella Biotech, Inc. | COMPANION DIAGNOSIS FOR MITOCHONDRIAL INHIBITORS |
EP3624840A4 (en) | 2017-05-19 | 2021-03-10 | Lunella Biotech, Inc. | ANTIMITOSCINE: TARGETED INHIBITORS OF MITOCHONDRIAL BIOGENESIS TO DESCRIBE CANCER STEM CELLS |
WO2018218242A1 (en) | 2017-05-26 | 2018-11-29 | Epicentrx, Inc. | Methods and compositions for combination therapy |
WO2019104115A1 (en) | 2017-11-24 | 2019-05-31 | Lunella Biotech, Inc. | Triphenylphosphonium-derivative compounds for eradicating cancer stem cells |
WO2019126179A1 (en) | 2017-12-20 | 2019-06-27 | Lunella Biotech, Inc. | Targeting mitochondrial fission through mdivi-1 derivatives |
-
2018
- 2018-05-18 EP EP18803298.1A patent/EP3624840A4/en active Pending
- 2018-05-18 CU CU2019000092A patent/CU20190092A7/es unknown
- 2018-05-18 RU RU2019142102A patent/RU2019142102A/ru not_active Application Discontinuation
- 2018-05-18 CA CA3063717A patent/CA3063717C/en active Active
- 2018-05-18 CR CR20190524A patent/CR20190524A/es unknown
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- 2018-05-18 JP JP2019563871A patent/JP6938682B2/ja active Active
- 2018-05-18 WO PCT/US2018/033466 patent/WO2018213751A1/en active Search and Examination
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-
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- 2019-11-12 IL IL270598A patent/IL270598B/en unknown
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- 2019-11-18 CO CONC2019/0012888A patent/CO2019012888A2/es unknown
- 2019-11-19 EC ECSENADI201982194A patent/ECSP19082194A/es unknown
- 2019-11-19 DO DO2019000294A patent/DOP2019000294A/es unknown
- 2019-11-19 ZA ZA2019/07654A patent/ZA201907654B/en unknown
-
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- 2021-04-16 ZA ZA2021/02509A patent/ZA202102509B/en unknown
- 2021-10-01 US US17/491,672 patent/US11865130B2/en active Active
-
2022
- 2022-03-07 ZA ZA2022/02712A patent/ZA202202712B/en unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040161405A9 (en) * | 2001-12-11 | 2004-08-19 | Rothbard Jonathan B. | Guanidinium transport reagents and conjugates |
US20090099080A1 (en) * | 2007-09-10 | 2009-04-16 | Altieri Dario C | Mitochondria-targeted anti-tumor agents |
CN102753142A (zh) * | 2009-12-02 | 2012-10-24 | 贝蒂纳·海尔 | 含益生菌、抗生素和不饱和非酯化脂肪酸的直肠、阴道或尿道给药的栓剂 |
CN101810570A (zh) * | 2010-04-16 | 2010-08-25 | 成都师创生物医药科技有限公司 | 蒽环类抗肿瘤抗生素脂肪酸复合物脂质纳米粒制剂及其制备方法 |
US20110268722A1 (en) * | 2010-04-22 | 2011-11-03 | Siegelin Markus D | Combination therapies with mitochondrial-targeted anti-tumor agents |
CN102911226A (zh) * | 2011-08-03 | 2013-02-06 | 胡梨芳 | 红霉素衍生物及其制备方法和用途 |
CN105884633A (zh) * | 2016-05-07 | 2016-08-24 | 浙江大学 | 一种四环素硬脂酸嫁接物及其制备和应用 |
Non-Patent Citations (4)
Title |
---|
LAMB R.等: "Antibiotics that targe mitochondria effectively eradicate cancer stem cells,across multiple tumor types :Treating cancer like an infectious disease", 《ONCOTARGET》 * |
刘珂等: "HPLC测定硬脂酸红霉素颗粒中的红霉素A", 《华西药学杂志》 * |
朱毅等: "微生物来源的肿瘤血管生成抑制剂", 《中国新药杂志》 * |
韩韬等: "四环素类化合物抗肿瘤转移及其治疗其他疾病作用研究进展", 《国外医药抗生素分册》 * |
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AU2018270129B2 (en) | 2021-01-07 |
CR20190524A (es) | 2020-01-10 |
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EP3624840A1 (en) | 2020-03-25 |
US11865130B2 (en) | 2024-01-09 |
KR20200010343A (ko) | 2020-01-30 |
RU2019142102A (ru) | 2021-06-21 |
DOP2019000294A (es) | 2020-02-16 |
NZ760422A (en) | 2023-11-24 |
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US20200179424A1 (en) | 2020-06-11 |
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PE20200605A1 (es) | 2020-03-10 |
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