CN106659708B - 胶球奈米复合物 - Google Patents
胶球奈米复合物 Download PDFInfo
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- CN106659708B CN106659708B CN201580035396.6A CN201580035396A CN106659708B CN 106659708 B CN106659708 B CN 106659708B CN 201580035396 A CN201580035396 A CN 201580035396A CN 106659708 B CN106659708 B CN 106659708B
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- flavonoid
- cancer
- micellar nanocomplex
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Abstract
本发明涉及胶球奈米复合物及其制备方法。胶球纳米复合物包括胶球和包覆在所述胶球内的试剂,其中所述胶球包含聚合物‑类黄酮接合物,其中所述聚合物与所述类黄酮的B环键结。胶球奈米复合物可以作为药物传送系统,具有益的应用。
Description
技术领域
本发明通常指用于药物传送的胶球奈米复合物,及其制备方法。本发明也跟聚合物与类黄酮B环组成的类黄酮多聚体接合物有关,及其制备方法。
背景技术
化疗,最常见的一种癌症治疗手段,通过口服或注射给予细胞毒杀药物。传统抗癌药物投药的挑战在于体内非特异性的分布,导致严重副作用的毒性。此外,口服药物的治疗效果受限于其生物体可用率低,因为这些药物一定要通过消化道。这几十年来,研究人员聚焦于发展药物运输系统,克服传统药物的投药限制,藉此改进药物的药动和生体分布。
近几年,绿茶儿茶素已被广泛研究,因为他们有多种健康益处,包括预防心血管疾病和癌症。在儿茶素中,表没食子儿茶素-3-没食子酸酯(EGCG)是含量最多,且被认为是绿茶好处的重要角成分。多项研究指出EGCG有抗氧化、抗糖尿病、抗菌、抗发炎和降胆固醇效果。再者,研究指出它可透过瞄准癌细胞生存所必须的多种讯息传导路径,有效抑制癌症生长和转移。
虽然有这些有效活性,EGCG的临床应用受限于其安定性差,以及口服生体可用率低。举例,EGCG不稳定,在生理环境下很容易被分解。报告指出,EGCG在37℃,pH7.4的0.05M磷酸盐缓冲生理食盐水(PBS)下,半衰期小于30分钟。此外,摄入的EGCG会很容易被胃酸水解,并在肠胃道被代谢分解。导致口服EGCG后的血浆浓度,无法达到治疗效果所要的浓度。
因此需要提供一个药物传送系统,克服或至少改善一个或多个上述缺点。也有需要提供一个制备该药物传送系统的方法。
发明内容
根据本发明第一点,提供一个胶球奈米复合物,包括一胶球和一试剂包覆于胶球,所述胶球包含一聚合物-类黄酮接合体,其所述聚合物会与所述类黄酮的B环键结。
有利的是本发明提供一种胶球奈米复合物,可用作药物传送系统。胶球奈米复合物拥有小尺寸和高药物承载量,有利癌症标靶的药物传送。另外有利的是包括可在生理条件利用胶球奈米复合物达到试剂的缓释效果。更有利的是还包括此奈米结构可作为各种非水溶性抗癌试剂的有效运送载体。另外有利的是胶球奈米复合物可有效抑制癌症生长,并降低投与试剂的相关毒性。另外有利的是胶球奈米复合物可作为一独特且有效的药物传送系统,拥有加成治疗效果,来自药物传送系统或胶球载体和试剂。
该试剂可以是阿霉素。有利的是胶球奈米复合物包覆阿霉素,可具药物缓释。该缓释药物可能来自EGCG和阿霉素在胶球奈米复合物内的强烈交互作用。另外有利的是在某些实施例,只会在初始阶段观察到边际爆发释放,代表阿霉素分子在胶球奈米复合物内稳定地被包覆着。如此低的药物漏出是确保达到最大治疗效果和最小副作用所必需的,因该药物分子包覆在奈米结构内不会在血液循环时提早渗漏。甚至另外有利的是,此胶球奈米复合物可应用于癌症治疗的阿霉素的全身用药。
该试剂可为舒尼替尼(SU),而类黄酮可为表没食子儿茶素-3-没食子酸酯(EGCG)。有用的是此胶球奈米复合物可使SU持续的缓释。另外有利的是,在某些实施例,几乎不会观察到爆发释放,表示SU分子在胶球奈米复合物内稳定地被包覆着。
在一实施例,类黄酮可为单体类黄酮。另一实施例,类黄酮可为双体类黄酮。有利的是,单体类黄酮组成的胶球奈米复合物,跟双体类黄酮组成的胶球奈米复合物相比,SU释放比较快比较多。另外有利的是SU跟双体类黄酮的交互作用比较强。
有利的是胶球奈米复合物可使试剂不良副作用降到最低,因SU稳定地被包覆在里面,运送到标靶处。胶球奈米复合物可进一步提供SU和EGCG间的加成效果。
另外有利的是,这个含SU的胶球结构,跟SU游离态相比,可在体内加强癌症效果。更甚者,这个含SU的胶球结构跟SU游离态相比,体内副作用比较少。再者,跟SU游离态相比,用比较少剂量含SU的胶球奈米复合物就可以达到相同效果。而且,含SU的胶球奈米复合物的抑制效果,可维持一段时间,甚至在治疗暂停时。
另外有利的是,含SU的胶球奈米复合物会使血浆中SU游离态降低,使SU的不良反应减少。再者,血浆浓度的降低可能来自于类黄酮和SU的交互作用,也可能是胶球奈米粒子所致的高渗透长滞留效应。
根据本发明第二点,提供一种制备胶球奈米复合物的方法,胶球和试剂包覆于所述胶球内,这方法包括步骤:(a)加入所述试剂于合适溶液形成聚合物-类黄酮接合物,这里所述聚合物与所述类黄酮B环键结;和(b)使胶球自组装,组成所述的聚合物-类黄酮接合物,将所述试剂包覆于所述胶球内,因而形成所述的胶球奈米复合物。
有利的是,在聚合物-类黄酮接合和试剂存在下,奈米复合物会自组装。再者,利用类黄酮和试剂的键结特性就可以形成此奈米结构。
根据本发明第三点,提供一聚合物-类黄酮接合体,由聚合物和类黄酮B环键结组成。
有利的是,类黄酮和聚合物接合。在一实施例,该聚合物可为聚乙二醇(PEG),有利的是聚合物基质的奈米粒子通过网状内皮系统(RES)避免肾脏清除和滞留,使之具EPR效应,可于癌症组织堆积。再者,PEG稳固胶球展现较未修饰胶球还长的血浆半衰期,因为PEG表面预防体内RES的辨识和清除。另外有利的是,PEG可用来修饰聚合物胶球和奈米粒子表面,产生一防污表面。
根据本发明的第四点,提供一种制备如上述定义的聚合物-类黄酮接合体的方法,包括在碱性环境下通过亲核加成作用,接合所述类黄酮和所述聚合物的步骤其中,该所述聚合物有一亲核性的自由官能基。
有利的是,聚合物-类黄酮接合体可在碱性pH通过亲核性作用合成。有利的是,此接和可通过亲核性官能基的作用达成,例如聚合物的硫醇基,如在恰当酸碱环境下,生物类黄酮B环C2’位置的PEG。
在一实施例,聚合物为聚乙二醇(PEG),而亲核性自由基为硫醇基。有用的是,像EGCG类黄酮缺电子的邻苯醌可与像硫醇基的亲核性官能基作用。硫醇基存在于多种生物分子,包括半胱氨酸、谷胱甘肽和蛋白质。EGCG可和人体红血球细胞膜的半胱氨酸和甘油醛-3-磷酸去氢酶(GAPDH)共价键结。此外,当半胱氨酸和谷胱甘肽存在的时候,EGCG的共价结合物会形成。另外有利的是,所形成的EGCG半胱氨酸接合可展现较EGCG高的前氧化活性,并保持有其抑制生长和抗发炎的活性。再者,N-乙酰半胱氨酸接合的EGCG会加强EGCG于老鼠和人类肺癌细胞的生长抑制和凋亡诱导效应。
根据本发明的第五点,提供由胶球和试剂包覆于所述胶球的胶球奈米复合物应用,作为药物传送载体,该所述胶球由聚合物-生物类黄酮接合体组成,该所述聚合物与所述类黄酮B环键结。
根据本发明的第六点,提供一治疗癌症的方法,包括给予如前所定义的奈米胶球于癌症制剂。
有利的是,胶球奈米复合物跟游离态试剂相比,有较高的抗癌效果。再者,胶球奈米复合物可使试剂,如舒尼替尼(SU)的不良副作用降到最低,透过稳定地被包覆于内部并传送到标靶处。这样的传送系统也获可提供有益的加成作用。
根据本发明的第七点,提供如前所定义的胶球奈米复合物,以治疗癌症。
根据本发明的第八点,提供如前所定义的胶球奈米复合物应用,制造医药制剂以治疗癌症。
定义
本篇所用的下列文字和名词应为所述定的意思:
生物类黄酮的“B环”指选择性替代的苯基与双环结构键结(由苯环(A)与六元环(C)缩合的双环结构)。这选择性替代的苯基与C环的位置2键结。因揭露之目的,环标示如下:[结构式1]
“表没食子儿茶素没食子酸酯”指表没食子儿茶素和没食子酸的酯类,可与“表没食子儿茶素-3-没食子酸酯”或EGCG互换
本应用目的,PEG-EGCG接合体指PEG-mEGCG(单体EGCG)和PEG-dEGCG(双体EGCG)接合,除非另有说明。
“大体上”并未排除“完全”,例一组成大体上不含Y,可能为完全不含Y。必要时,大体上这个词可从本发明定义去除。
除另有说明,“包括”这个字及其相关文法变体,意指代表“开放”或“包括性”语言,使之包含所载的元素,但也允许纳入未载元素。
本篇所用的“关于”,在配方组成浓度内文,一般指所载数值的+/-5%,更可为所载数值的+/-4%,更可为所载数值的+/-3%,更可为所载数值的+/-2%,甚至更可为所载数值的+/-1%,更可为所载数值的+/-0.5%。
这份揭露,某些实施例以范围揭露。应认知为配方范围的描述主要为了方便和简短,而不该为所揭露范围的固定限制。据此,范围的描述应被认为特别指所揭露的所有可能的次范围和该范围内的个别数值。例如:范围1-6的描述应被认为已特揭露的次范围如1-3、1-4、1-5,从2-4、2-6,从3-6等,也包含范围内的个别数字,例如1、2、3、4、5和6,这适用于各范围。
在此,某些实施例的描述广泛且一般。一般性公开内每一较窄的种类和次族群也是揭露的一部份,这包括具从属中移移除任何主题的附带条件或否定限制的实施例的一般描述。不论被删去的物质是否有无在此被记述。
实施例的详细揭露
现在将公开胶球奈米复合物的示例性,非限制性实施方案。
胶球奈米复合物可以包含胶球和包封在所述胶球内的试剂,所述胶球包含聚合物-类黄酮接合物,其中所述聚合物与所述类黄酮的B环键结。
至少一个类黄酮可以键结到所述聚合物。至少两个类黄酮可以键结到所述聚合物。
聚合物可以透过连接体与所述类黄酮键结。连接体可为可以连接聚合物和类黄酮的任何化学基团。连接体可以选自含硫醚,亚胺,胺,偶氮和1,2,3-三唑基团的官能基。连接基可以是烷基。连接体可以存在于聚合物的任一部分和类黄酮任一部分之间。连接体可存在于聚合物末端和类黄酮的任一部分之间。
类黄酮可以选自单体类黄酮或双体类黄酮的官能基。单体类黄酮可以包含一个类黄酮分子。双体类黄酮可以包含由连接体连接在一起的两个类黄酮分子。双体类黄酮的其中一个类黄酮可以连接到聚合物上。双体类黄酮的两个类黄酮分子可以独立地连接到聚合物上。当一类黄酮存在于所述接合物中时,类黄酮乃通过B环与所述聚合物键结。当一类黄酮键结到所述接合物时,类黄酮是通过D环键结到所述聚合物。
当所述接合物中存在不只一个类黄酮时,至少一个类黄酮会通过B环与所述聚合物键结。另一个所述至少一个类黄酮通过A环与所述聚合物键结。当所述接合物中存在不只一个类黄酮时,至少一个类黄酮通过B环与所述聚合物键结。另一个所述至少一个类黄酮通过B环与所述聚合物键结。当所述接合物中存在不只一个类黄酮时,至少一个类黄酮通过B环与所述聚合物键结。另一个所述至少一个类黄酮通过D环与所述聚合物键合。
当所述接合物中存在不只一个类黄酮时,至少一个类黄酮会通过D环与所述聚合物键结,另一个所述至少一个类黄酮通过A环与所述聚合物键结。当所述接合物中存在不只一个类黄酮时,至少一个类黄酮通过D环与所述聚合物键结。另一个所述至少一个类黄酮通过B环与所述聚合物键结。当所述接合物中存在不只一个类黄酮时,至少一个类黄酮通过D环与所述聚合物键结。另一个所述至少一个类黄酮通过D环与所述聚合物键合。
聚合物可以是亲水性聚合物。亲水性聚合物可以包含选自丙烯酰胺,烷基,恶唑啉,烯基,亚胺,丙烯酸,甲基丙烯酸酯,二醇,环氧乙烷,醇,胺,酸酐,酯,内酯,碳酸酯,羧酸,丙烯酸酯,羟基,磷酸盐,对苯二甲酸,酰胺和醚的组中的单体。
亲水性聚合物可以选自含聚丙烯酰胺,聚(N-异丙基丙烯酰胺),聚(恶唑啉),聚乙烯亚胺,聚(丙烯酸),聚甲基丙烯酸酯,聚(乙二醇),聚(环氧乙烷),聚(乙烯醇),聚(乙烯基吡咯烷酮),聚醚,聚(烯丙基胺),聚酐,聚(β-氨基酯),聚(丁二酸丁二醇酯),聚己内酯,聚碳酸酯,聚二氧杂环己酮,聚(丙三醇),聚乙醇酸,聚(3-羟基丙酸),聚(甲基丙烯酸乙酯),聚(N-(2-羟丙基)甲基丙烯酰胺聚合物),聚乳酸,聚(乳酸-共-乙醇酸),聚(原酸酯),聚(2-恶唑啉),聚(癸二酸),聚(对苯二甲酸酯-共-磷酸酯)中的基团及其共聚物。
亲水性聚合物可以是多糖体。聚合物可以是选自透明质酸,葡聚醣,支链淀粉,壳聚醣,纤维素,直链淀粉,淀粉,明胶,角叉菜胶,环糊精,硫酸葡聚醣,蔗糖多聚体(Ficoll),胶凝糖,瓜尔胶,果胶,聚蔗糖,支链淀粉,硬葡聚糖,黄原胶,木葡聚糖和藻酸盐的多糖体。
亲水性聚合物可以是聚乙二醇(PEG)。PEG是已经用于生物医学应用的合成聚合物,因其具亲水性,柔性和生物相容性。具体地,PEG已被用于修饰聚合物胶球和奈米粒子表面以产生防污表面。
有利地,选择聚乙二醇(PEG)作为待与类黄酮接合的聚合物。在控制的pH条件下,在类黄酮B环C2'位置的亲核作用,加上PEG的硫醇基团,完成接合。
类黄酮可以选自黄酮,异黄酮,黄烷,原花色素和花青素组成的基团。
所述黄酮可以选自芹菜素,木犀草素,桔皮晶,白杨素,6-羟基黄酮,黄芩苷,灯盏花乙素,汉黄芩素,地奥司明,黄酮哌酯和7,8-二羟基黄酮组成的基团。
异黄酮可以选自包含金雀异黄酮,大豆素,黄豆黄素,染料木苷,豆苷,黄豆黄苷,乙酰基染料木苷,乙酰基豆苷,乙酰基黄豆黄苷,丙二酰基染料木苷,丙二酰基豆苷和丙二酰基黄豆黄苷组成的组中。
所述黄烷可以选自包含(-)-表儿茶素,(+)-表儿茶素,(-)-儿茶素,(+)-儿茶素,表儿茶素没食子酸酯,表没食子儿茶素,表没食子儿茶素没食子酸酯,非瑟酮醇,没食子儿茶素,没食子儿茶素没食子酸酯,牧豆树醇和双洋槐儿茶素,鞣花鞣剂,没食子单宁,乌龙茶酮,根皮单宁,单宁,茶柠檬素,茶二苯骈卓酚酮,茶黄素,茶多醌,茶红素,聚酯型儿茶素和其混合物的组。
花青素可以选自橙花色素,辣椒素,矢车菊素,花翠素,欧林甙,多菌素,锦葵花素,天竺葵色素,甲基花青素,矮牵牛,美丽夫人色素和蔷薇素组成的组。
试剂可以是治疗试剂。治疗试剂可以是选自烷化剂,蒽环霉素,细胞骨架破坏剂,埃博霉素,组蛋白脱乙酰酶抑制剂,拓扑异构酶I抑制剂,拓扑异构酶II抑制剂,激酶抑制剂,单株抗体,抗体-药物接合物,核苷酸类似物,前驱物类似物,胜肽抗生素,铂基剂,类视黄醇,长春花生物碱,细胞激素,抗代谢物和长春花生物碱衍生物,以及其它细胞毒素组成的化疗试剂。
化疗试剂可以选自放线菌素,阿法替尼,全反式视黄酸,阿西替尼,阿扎胞苷,硫唑嘌呤,贝伐单抗,博来霉素,博素替尼,硼替佐米,卡铂,卡培他滨,西妥昔单抗,顺铂,苯丁酸氮芥,克里唑蒂尼,环磷酰胺,阿糖胞苷,达沙替尼,柔红霉素,多西他赛,去氧氟尿苷,阿霉素,表柔比星,埃博霉素A(C26H39NO6S),埃博霉素B(C27H41NO6S),埃博霉素C(C26H39NO5S),埃博霉素D(C27H41NO5S),埃博霉素E(C26H39NO7S),埃博霉素F(C27H41NO7S),埃罗替尼,依托泊苷,氟尿嘧啶,福莫替尼,吉非替尼,吉西他滨,羟基脲,伊达比星,伊马替尼,伊立替康,拉帕替尼,乐伐替尼,氮芥,巯嘌呤,氨甲蝶呤,米托蒽醌,尼罗替尼,奥沙利铂,太平洋紫杉醇,帕尼单抗,帕唑帕尼,哌加他尼,培美曲塞,雷珠单抗,瑞格菲尼,鲁索替尼,索拉非尼,舒尼替尼,曲妥珠单抗,替尼泊苷,硫鸟嘌呤,托法替尼,托泊替康,戊柔比星,威罗菲尼,长春质碱,长春新碱,硫酸长春地辛,长春瑞滨组成的组。
化疗试剂可以是阿霉素。
化疗试剂可以是舒尼替尼(SU)。SU是多靶点酪氨酸激酶抑制剂和用于透明细胞性肾细胞癌(ccRCC)的一线治疗。具体来说,SU瞄准血管内皮生长因子(VEGF)和血小板衍生生长因子(PDGF)受体,其在肿瘤血管生成和增殖中扮演重要角色,导致肿瘤血管形成减少以及癌细胞死亡。它已被核准用于晚期RCC,胃肠道间质瘤(GIST)和胰腺神经内分泌肿瘤(pNET)。它还显示具有治愈转移性乳癌,晚期非小细胞肺癌,晚期肝细胞癌,神经内分泌肿瘤和白血病的潜力。然而,它可引起严重的副作用,例如肝脏,心脏和胃肠道毒性,高血压,皮肤问题和手足综合征。
胶球奈米复合物可以有30至300nm,50至300nm,100至300nm,30至50nm,30至100nm,30至150nm,150至300nm,200至300nm,250至300nm,100至150nm,100至200nm,100至250nm,130至180nm或130至250nm范围内的尺寸。
胶球奈米复合物于所述胶球内,其所述试剂的负载效率可为大于30%,大于35%,大于40%,大于45%,大于50%,大于55%,大于60%,大于65%,大于70%,大于75%或80%。
所述胶球奈米复合物,所述试剂于所述胶球内的加载量,其范围可为1至10w/w%,5至25w/w%,20至45w/w%,30至50w/w%,35至50w/w%,40至50w/w%,45至50w/w%,30至35w/w%,30至40w/w%或30至45w/w%。
制备胶球奈米复合物的方法可以包括胶球和包覆于所述胶球内的试剂,该方法包括以下步骤:
a.将在合适的溶剂中的所述试剂加入聚合物-类黄酮接合物中,其中所述聚合物与所述类黄酮的B环键结;和
b.使包含所述聚合物-类黄酮接合物的胶球自行组装,并将所述试剂包覆在所述胶球内,从而形成所述胶球奈米复合物。
步骤(a)可进一步包括以下步骤:
a.除去所述溶剂以形成所述试剂和所述聚合物-类黄酮接合物的干膜;和
b.用水性溶剂水合所述干膜。
该方法还可进一步包括在合适的溶剂中通过过滤或透析分离所形成的胶球奈米复合物的步骤。
聚合物-类黄酮接合物可以包含结合到类黄酮B环的聚合物。
聚合物-类黄酮接合物的聚合物可以选自多糖,聚丙烯酰胺,聚(N-异丙基丙烯酰胺),聚(恶唑啉),聚乙烯亚胺,聚(丙烯酸),聚甲基丙烯酸酯,聚(乙二醇)聚(环氧乙烷),聚(乙烯醇),聚(乙烯吡咯烷酮),聚醚,聚(烯丙胺),聚酐,聚(β-氨基酯),聚(丁二酸丁二酯),聚己内酯,聚碳酸酯,聚对二氧杂环己酮,聚(丙三醇),聚(乙醇酸),聚(3-羟基丙酸),聚(甲基丙烯酸2-羟乙酯),聚(N-(2-羟丙基)甲基丙烯酰胺),聚乳酸,聚(乳酸-乙醇酸共聚物),聚(原酸酯)聚(2-恶唑啉),聚(癸二酸),聚(对苯二甲酸酯-共-磷酸酯)及其共聚物的基团。
聚合物-类黄酮接合物的类黄酮可以选自(-)-表儿茶素,(+)-表儿茶素,(-)-儿茶素,(+)-儿茶素,表儿茶素没食子酸酯,表没食子儿茶素,表没食子儿茶素没食子酸酯,非瑟酮醇,没食子儿茶素,没食子儿茶素没食子酸酯,牧豆树醇和双洋槐儿茶素,鞣花鞣剂,没食子单宁,乌龙茶酮,根皮单宁,单宁,茶柠檬素,茶二苯骈卓酚酮,茶黄素,茶多醌,茶红素,聚酯型儿茶素和其混合物组成的基团。
聚合物可以通过选自硫醚,亚胺,胺,偶氮和1,2,3-三唑基团的连接体与聚合物-类黄酮接合物中的类黄酮接合。连接体可以是烷基。连接体可以存在于聚合物任一部分和类黄酮任一部分之间。连接体可存在于聚合物末端和类黄酮的任一部分之间。
聚合物-类黄酮接合物的聚合物可以是聚(乙二醇),所述聚合物-类黄酮接合物的类黄酮可以是表没食子儿茶素-3-没食子酸酯,并且所述聚合物-类黄酮缀合物的所述连接体可以是硫醚。
聚合物-类黄酮可有下列结构式
[结构式2]
其中,n的范围在20-910。
聚合物-类黄酮接合物的制备方法可以包括在碱性条件下,透过亲核性加成使所述类黄酮与所述聚合物接合的步骤,其中所述聚合物具有游离的亲核基团。
亲核基团可以选自巯基,胺,羰基,羧酸,迭氮化物,卤素,炔烃和烯烃组成的基团。亲核基团可以选自硫醇,胺,重氮烷烃和迭氮化物的基团。
亲核基团可以是硫醇。EGCG可在氧存在下,通过涉及半醌自由基和活性的途径,经氧化形成邻醌。EGCG的缺电子邻醌可与存在于不同生物分子(包括半胱氨酸,谷胱甘肽和蛋白质)中的亲核巯基反应。EGCG可以共价结合到人红血球细胞膜蛋白和甘油醛-3-磷酸脱氢酶(GAPDH)中的半胱氨酸残基。当在半胱氨酸和谷胱甘肽的存在下氧化时,可以形成EGCG的共价加合物。所形成的EGCG的半胱氨酸接合物可以表现出比EGCG更高的促氧化活性,同时保持其生长抑制和抗发炎活性。此外,N-乙酰半胱氨酸接合的EGCG可以增强EGCG于鼠和人肺癌细胞的生长抑制和细胞雕亡诱导作用。
接合步骤的反应时间可以在约1小时至24小时,约1小时至2小时,约1小时至4小时,约1小时至8小时,约1小时至12小时,约2小时约4小时,约2小时至8小时,约2小时至12小时,约2小时至24小时,约4小时至8小时,约4小时至12小时,约4小时至24小时,约8小时至12小时,约8小时至24小时或约12小时至24小时。
该方法可进一步包括,在可实质地预防所述类黄酮聚集的溶液中进行接合步骤。
该方法可以进一步包括添加清除剂以防止H2O2媒介使所述亲核基团氧化,从而提高所述接合步骤的效率。
碱性条件可以在大于7至10,大于8至10,大于9至10,大于7至11,大于8至11,大于9至11,大于10至11,大于7,大于8,大于9,大于10或大于11的pH范围内。
胶球奈米复合物的使用可以包含胶球和包覆在所述胶球内作为药物传送载体的试剂,其中所述胶球包含聚合物-类黄酮接合物,并且其中所述聚合物与所述类黄酮的B环键结。
胶球奈米复合物可以将包覆的药剂递送至体内肿瘤标靶部位。
治疗癌症的方法可以包括向癌症患者施用胶球奈米复合物的步骤。治疗肿瘤的方法可以包括向癌症患者施用胶球奈米复合物的步骤。
胶球奈米复合物可以肠胃外给药,可通过吸入喷雾,局部,直肠,鼻,颊,阴道,通过植入药池,注射,皮下,腹膜内,经粘膜,口服或在眼科制剂中。
肠胃外给药可大体包括皮下,皮内,静脉内,肌内,关节内,动脉内,滑膜内,胸骨内,鞘内,病灶内和通过颅内注射或输注。
存在于所述胶球奈米复合物中的试剂投与剂量可为约1至约80mg/kg/天,约1至约2mg/kg/天,约1至约5mg/kg/天,约1至约10mg/kg/天,约1至约20mg/kg/天,约1至约50mg/kg/天,约2至约5mg/kg/天,约2至约10mg/天,约2至约20mg/kg/天,约2至约50mg/kg/天,约2至约80mg/kg/天,约5至约10mg/kg/天,约5至约20mg/kg/天,约5至约50mg/kg/天,约5至约80mg/kg/天,约10至约20mg/kg/天,约10至约50mg/kg/天,约10至约80mg/kg/天,约20至约50mg/kg/天,约20至约80mg/kg/天或约50至约80mg/kg/天。
癌症患者可能患有选自以下的癌症:肾上腺皮质癌,AIDS相关淋巴瘤,肛门癌,阑尾癌,I级(间变性)星形细胞瘤,II级星形细胞瘤,III级星形细胞瘤,IV级星形细胞瘤,非典型畸形/中枢神经系统的横纹肌瘤,基底细胞癌,膀胱癌,支气管癌,支气管肺泡癌,伯基特淋巴瘤,宫颈癌,结肠癌,结肠直肠癌,颅咽管瘤,皮肤T-细胞淋巴瘤,子宫内膜癌,子宫内膜子宫癌,室管膜母细胞瘤,室管膜瘤,食道癌,嗅神经母细胞瘤,尤因氏肉瘤,颅外生殖细胞肿瘤,性腺外生殖细胞肿瘤,肝外胆管癌,纤维组织细胞瘤,胆囊癌,胃癌,胃肠癌肿瘤,胃肠道间质瘤,妊娠滋养细胞肿瘤,胶质瘤,头颈癌,心脏癌,肝细胞癌,肝门胆管癌,霍奇金淋巴瘤,下咽癌,眼内黑素瘤,胰岛细胞瘤,卡波西肉瘤,朗格汉斯细胞组织细胞增多症,喉癌,唇癌,淋巴瘤,巨球蛋白血症,恶性纤维组织细胞瘤,髓母细胞瘤,髓上皮瘤,黑色素瘤,梅克尔细胞癌,间皮瘤,内分泌肿瘤,多发性骨髓瘤,蕈样肉芽肿,骨髓增生异常,骨髓增生异常/骨髓增生性肿瘤,骨髓增生性疾病,鼻腔癌,鼻咽癌,神经母细胞瘤,非霍奇金淋巴瘤,口腔癌,口咽癌,骨肉瘤,卵巢透明细胞癌,卵巢上皮癌,卵巢生殖细胞瘤,乳头状瘤,鼻旁窦癌,甲状旁腺癌,阴茎癌,咽癌,松果体实质瘤,松果体瘤,垂体瘤,浆细胞瘤,浆细胞瘤,胸膜肺母细胞瘤,原发性中枢神经系统淋巴瘤,前列腺癌,直肠癌,肾细胞癌,具有染色体15变化的呼吸道癌,视网膜母细胞瘤,横纹肌肉瘤,唾液腺癌,塞泽里综合征,小肠癌,软组织肉瘤,鳞状细胞癌,鳞状上颈癌,幕上原始神经外胚层肿瘤,幕上原始神经外胚层肿瘤,睾丸癌,喉癌,胸腺癌,胸腺瘤,甲状腺癌,肾盂癌,尿道癌,子宫肉瘤,阴道癌,外阴癌,华氏巨球蛋白血症,和维尔姆斯肿瘤。
肿瘤患者可能患有选自以下的癌症:肾上腺皮质癌,肛门癌,阑尾癌,I级(间变性)星形细胞瘤,II级星形细胞瘤,III级星形细胞瘤,IV级星形细胞瘤,非典型畸形/中枢神经系统,基底细胞癌,膀胱癌,支气管癌,支气管肺泡癌,子宫颈癌,结肠癌,结肠直肠癌,颅咽管瘤,子宫内膜癌,子宫内膜子宫癌,室管膜母细胞瘤,室管膜瘤,食道癌,胚胎母细胞瘤,尤因氏肉瘤,颅外生殖细胞肿瘤,性腺外生殖细胞瘤,肝外胆管癌,纤维组织细胞瘤,胆囊癌,胃癌,胃肠道类癌瘤,胃肠道间质瘤,妊娠滋养细胞瘤,胶质瘤,头颈癌,心脏癌,肝细胞癌,肝门胆管癌,下咽癌,眼内黑素瘤,胰岛细胞瘤,卡波西肉瘤,朗格汉斯细胞组织细胞增多症,喉癌,唇癌,巨球蛋白血症,恶性纤维组织细胞瘤,髓母细胞瘤,髓上皮瘤,黑色素瘤,梅克尔细胞癌,间皮瘤,内分泌肿瘤,多发性骨髓瘤,蕈样内芽肿,脊髓发育不良,脊髓增生异常/骨髓增生性肿瘤,骨髓增殖性疾病,鼻腔癌,鼻咽癌,神经母细胞瘤,口腔癌,口咽癌,骨肉瘤,卵巢透明细胞癌,卵巢上皮癌,卵巢生殖细胞肿瘤,乳头状瘤病,鼻旁窦癌,甲状旁腺癌,阴茎癌,咽癌,松果体实质瘤,松质瘤,垂体瘤,浆细胞瘤,浆细胞瘤,胸膜肺母细胞瘤,前列腺癌,直肠癌,肾细胞癌,具有染色体15变化的呼吸道癌,视网膜母细胞瘤,横纹肌肉瘤,唾液腺癌,塞泽里综合征,小肠癌,软组织肉瘤,鳞状细胞癌,鳞状上颈癌,幕上原始神经外胚层肿瘤,幕上原始神经外胚层肿瘤,睾丸癌,咽喉癌,胸腺癌,胸腺瘤,甲状腺癌,肾盂,尿道癌,子宫肉瘤,阴道癌,外阴癌,华氏巨球蛋白血症和维尔姆斯肿瘤。
胶球奈米复合物可用于治疗癌症。胶球奈米复合物可用于治疗肿瘤。
胶球奈米复合物的使用可用于制备治疗癌症的药物。胶球奈米复合物的使用可用于制备治疗肿瘤的药物。
附图说明
附图示出了所公开的实施例并且用于解释所公开的实施例原理。然而,应当理解,附图仅被设计用于说明目的,而不是作为本发明的限制定义。
图1
[图1]为PEG-mEGCG接合物(108)的合成方案。在DMSO和水1:3(v/v)混合的碱性pH(106)下,将巯基官能化的PEG(PEG-SH)(102)与EGCG接合(104)。
图2
[图2]为PEG-EGCG接合物(202)和PEG(204)以0.5mg/mL的浓度溶解于去离子水中的可见紫外光吸收光谱。
图3
[图3]为EGCG(302)和PEG-mEGCG接合物(304)的HPLC图谱。箭头表示在280nm监测的样品峰。
图4
[图4]为PEG-mEGCG接合物的接合度与反应时间的函数。
图5
[图5]为PEG-mEGCG接合物溶解在D2O中的1H NMR光谱。
图6
[图6]为阿霉素/PEG-mEGCG胶球奈米复合物制备的示意图。
图7
[图7]为不同的阿霉素/PEG-mEGCG重量比,制备阿霉素/PEG-mEGCG胶球纳米复合物的(A)尺寸和(B)ζ电位的图。将制备的奈米复合物(黑色柱状,702)的尺寸和ζ电位与重构的奈米复合物(交叉柱状,704)的尺寸和ζ电位进行比较。
图8
[图8]为不同阿霉素/PEG-mEGCG重量比制备的阿霉素/PEG-mEGCG胶球奈米复合物的(A)药物装载效率和(B)装载含量。
图9
[图9]为在37℃,PEG-mEGCG:阿霉素重量比=1:1下,阿霉素/PEG-mEGCG胶球奈米复合物在PBS(pH7.3)的体外药物释放曲线。
图10
[图10]为SU/PEG-EGCG胶球奈米复合物制备的示意图。
图11
[图11]为不同PEG-EGCG:SU重量比,SU/PEG-EGCG胶球奈米复合物的(A)尺寸,(B)PDI和(C)ζ电位。
图12
[图12]为不同PEG-EGCG:SU重量比制备的SU/PEG-EGCG胶球奈米复合物的(A)药物装载效率和(B)药物装载含量。
图13
[图13]为在37℃,PBS(pH7.3)中不同PEG-EGCG:SU重量比的(A)SU/PEG-mEGCG胶球奈米复合物和(B)SU/PEG-dEGCG胶球奈米复合物的体外药物释放曲线37℃。
图14
[图14]为接受每日口服SU治疗(60mg/kg)与接受SU/PEG-EGCG胶球奈米复合物(具有指定的PEG-EGCG:SU重量比)的小鼠和对照组相比的每周体重测量。
图15
[图15]为经SU/PEG-EGCG胶球奈米复合物(具有指定的PEG-EGCG:SU重量比)、SU治疗或无治疗小鼠的(A)肿瘤大小(通过发光信号定量)和(B)荧光图。
图16
[图16]为接受每日口服SU治疗(40和15mg/kg)与接受SU/PEG-Megcg8:1胶球奈米复合物的小鼠和对照组小鼠体重测量。图17
[图17]为口服SU/PEG-mEGCG 8:1胶球奈米复合物、口服SU治疗和无治疗的老鼠的肿瘤大小。
具体实施方式
通过参考具体实施例进一步详细描述本发明和比较实施例的非限制性实施例,这些实施例不应被解释为以任何方式限制本发明的范围。
实施例1:材料和细胞培养
材料
具硫醇末端的甲氧基-聚乙二醇(PEG-SH,Mw=5000Da)取自键凯科技(中国)。具醛末端的甲氧基-聚乙二醇(PEG-CHO,Mw=5000Da)取自日本日油株式会社。(-)-表没食子儿茶素-3-没食子酸酯(EGCG,纯度>95%)取自栗田工业股份(日本东京)。丙酮酸钠溶液(100mM)取自英杰(新加坡)。不含Ca2+和Mg2+的PBS盐水(150mM,pH 7.3)于新加坡启奥的培养基制备设施制备。DMSO和三乙胺(TEA)购自西格玛奥瑞奇(新加坡)。阿霉素(DOX·HCl)购自保宁制药(韩国)。SU(游离碱形式)购自BioVision(US)。所有其他化学品均为分析等级。
细胞培养
人肾癌细胞A498取自美国典藏培养物保藏中心(ATCC,Manassas,VA,USA),培养于10%胎牛血清,1%青霉素-链霉素,2mM谷胱甘肽和0.1mM非必需氨基酸的DMEM培养基。如所述产生稳定表现荧光酵素基因(A498-luc)的A498细胞株。简言之,将A498细胞以5×105个细胞/孔的密度接种在6孔板中,并使用脂质体(Lipofectamine)2000(英杰,Carlsbad,CA,USA)用pRC-CMV2-luc质体转殖。1天后,将转殖的细胞转移到100-mm细胞培养皿,于培养基中加入1mg ml-1遗传霉素以选择抗性细胞。筛选1周后,将抗性细胞以1个细胞/孔的密度接种在96孔板中以形成聚落。共选择和扩增10个菌落,并在单管发光计(Berthold Lumat LB9507,Bad Wildbad,Germany)中用Promega Kit(Madison,WI,USA)测量荧光酵素活性。选择具最高荧光酵素活性的细胞株,并用500mg m1-1遗传霉素持续培养。
实施例2:PEG-EGCG接合物
在这研究中,两种类型的PEG-EGCG接合物用于制备胶球奈米复合物,PEG-mEGCG和PEG-dEGCG,其分别在PEG的一端具有一个和两个EGCG。
合成PEG-mEGCG接合物
PEG-mEGCG接合物透过将EGCG接合到含巯基末端的PEG合成。通常,将EGCG(18.3mg,40μmol)溶解在20mL的PBS和DMSO的1:1(v/v)混合物中。将PEG-SH(Mw=5000Da,JenKem Technology,China)(100mg,20μmol)独自溶于20mL PBS。将PEG-SH溶液滴加到搅拌的EGCG溶液。将未修饰的PEG溶液加入到相同浓度的EGCG搅拌溶液,作为对照组。所得混合物的pH为8.4。将混合物在25℃下搅拌7小时。于该溶液中加入1.6mL 10%乙酸以将pH调为4,停止反应。将所得溶液转移至截流分子量(MWCO)为1,000Da的透析管中。将管对去离子水透析。将纯化的溶液冻干,得到PEG-mEGCG接合物。用1H NMR光谱证实PEG-mEGCG接合物的结构。将干燥的PEG-mEGCG接合物以20mg/mL的浓度溶于D2O,然后用400MHz的Bruker AV-400NMR光谱仪分析。产率:89%。1H NMR(D2O):δ2.9(t,PEG的H-α),3.4(s,PEG的H-γ),3.5-3.8(m,PEG的质子),5.5(s,C环的H-2),5.85(s,C环的H-3),6.15(d,A环的H-6和H-8),6.9(s,B环的H-6'),7.05(s,D环的H-2”和H-6”)。
图1说明PEG-mEGCG接合物(108)的合成方案。硫醇官能化的PEG(PEG-SH)(102)在碱性pH(106),DMSO和水1:3(v/v)中,与超过2倍摩尔的EGCG共同培养(PEG-SH:EGCG=1:2)(104)。报告指出,pH严重影响EGCG的自氧化过程。在7-9.5的碱性pH范围内,B环上的没食子部分比D环上的没食子酸酯部分更易于自氧化。结果,只有B环上的没食子部分形成邻醌。在强碱性条件(pH>10)下,D环上的没食子酸酯部分也可以被自动氧化以形成邻醌。在本研究中,反应在pH8.4下进行,以允许仅在EGCG的B环上形成邻醌。随后PEG-SH与邻醌的亲核加合反应,产生通过共价硫醚键结的PEG-mEGCG接合物。
值得注意的是,接合反应在二甲基亚砜(DMSO)的存在下进行。因EGCG在与水溶液中的PEG接触时会聚集,应避免EGCG与PEG-SH于接合时发生聚集。发现DMSO可有效地防止聚集。基于此一发现,接合反应在DMSO和水的混合物中进行。此外,丙酮酸钠用以清除EGCG自动氧化期间产生的H2O2。丙酮酸钠用以保护游离巯基免受H2O2介导的氧化,其可增加用于与EGCG行接合的PEG-SH分子数目。将所得的PEG-mEGCG接合物在氮气中透析纯化,然后冻干,得到白色粉末。
PEG-mEGCG接合物的UV-Vis特征
使用可见紫外光(UV-Vis)光谱(图2)分析PEG-mEGCG接合物。
用Hitachi U-2810分光光度计(日本)测量PEG-mEGCG接合物的UV-Vis光谱。利用UV-Vis光谱,将干燥的PEG-mEGCG接合物和PEG以0.5mg mL-1的浓度溶解于去离子水中。与未修饰的PEG(204)不同,PEG-mEGCG接合物(202)在280nm具有强烈的UV吸收峰,表明EGCG成功接合。此外,未观察到对应于EGCG二聚体和其它氧化产物的425nm UV吸收带。
PEG-mEGCG接合物的HPLC特征
PEG-mEGCG接合物也用反相高效液相色谱(HPLC)评估。使用装备有SpiritTMC18层析柱(5μm,4.6×250mm i.d.,AAPPTec)的Waters 2695分离模组进行反相HPLC。EGCG,PEG/EGCG混合物和PEG-mEGCG接合物以1mg mL-1的浓度溶于去离子水。样品用1%乙酸的乙腈溶液和1%乙酸的水溶液混合物在25℃下以1mL/分钟的流速洗脱。关于流动相,乙腈:水的体积比从0分钟的3:7逐渐增加到10分钟的4:6。在280nm监测洗脱的样品。通过积分峰面积与从一系列不同浓度的EGCG标准溶液获得的峰面积进行比较来确定EGCG接合的程度。如图3所示,在4.8分钟的滞留时间洗脱EGCG(302),而在8分钟时洗脱PEG-mEGCG接合物(304)。滞留时间的显著变化可以解释为亲水性PEG链结到EGCG。此外,在PEG-mEGCG接合物的HPLC色谱图中没有观察到EGCG峰,表明未反应的EGCG分子通过透析被完全去除。随着反应时间从6小时增加到7小时,EGCG接合的程度从约63%增加到98%(图4)。然而,当反应时间为8小时时,接合程度略微降低,可能是因为EGCG二聚体和其它氧化产物开始产生。因此,最佳反应时间为7小时。
PEG-mEGCG接合物的1H NMR特征
利用1H核磁共振(NMR)光谱测定PEG-mEGCG接合物的结构。如图5所示,PEG-mEGCG接合物显示A环(δ=6.15处的H-6和H-8),C环(δ=5.5处的H-2和δ=5.85处的H-3)和D环(H-2”和H-6”,在δ=7.1)。由A,C和D环产生的质子信号与未修饰的EGCG相似,表明这些部分在接合反应期间保持不变。相反,接合反应后,B环的质子信号从6.5ppm移动到6.9ppm。质子信号的这种显著变化可能归因于PEG-SH与B环的C2'位置的连接。此外,B环的NMR峰显示具有D环的峰下面积的一半,表明B环上的一个质子在接合反应后消失。观察到的现象与先前的报告一致,其中2'-半胱氨酰EGCG的形成导致H-2'原子从B环消失。上述结果显示,只有一个PEG分子可以特异性地与EGCG的B环C2'位置接合。
PEG-dEGCG接合物的合成
将EGCG与具有醛端基(PEG-CHO)的PEG接合,以合成PEG-dEGCG接合物。将PEG-CHO(Mw=5000Da,NOF Co.,Japan)(1.75g)和EGCG(3.25g,7.09mmol)分别溶于乙酸,水和DMSO的混合物中。滴加PEG-CHO溶液开始反应,并在20℃下进行72小时。将所得溶液对去离子水透析(MWCO=3500Da)。将纯化的溶液冻干以获得PEG-dEGCG接合物。
实施例3:阿霉素/PEG-mEGCG接合物
对于癌症治疗应用,PEG-mEGCG接合物被设计成能够在内部携带大量抗癌药物的胶球奈米复合物。在本实验,PEG-mEGCG胶球奈米复合物作为阿霉素的递送载体。阿霉素是最广泛使用的化疗试剂之一,并且对各种类型的癌症如白血病,乳腺癌,卵巢癌和肺癌表现出强的细胞毒活性。然而,它可引起严重的心脏毒性,并增加充血性心力衰竭,心律失常,低血压和其他副作用的风险。设想PEG-mEGCG胶球奈米复合物可以透过在其内部稳定地包覆药物分子并以持续的方式释放它们而使这种不利的副作用最小化。
阿霉素/PEG-mEGCG胶球奈米复合物的制备
使用透析法制备阿霉素/PEG-mEGCG胶球奈米复合物。简言之,将5mg DOX·HCl溶解在4.5mL二甲基甲酰胺。于该溶液中,以TEA:DOX·HCl摩尔比为5:1加入TEA。将该混合物涡旋搅拌30分钟以形成去质子化的阿霉素(DOX)。将所得DOX溶液与溶解在0.5mL二甲基甲酰胺中的PEG-mEGCG接合物以不同的PEG-mEGCG/DOX重量比混合。将该混合物涡旋搅拌90分钟,然后转移至截流分子量为2,000Da的透析管中。将试管以去离子水透析24小时,以获得阿霉素/PEG-mEGCG胶球奈米复合物。
阿霉素/PEG-mEGCG胶球奈米复合物的特征
利用动态光散射(Zetasizer Nano ZS,Malvern,UK)评估阿霉素/PEG-mEGCG胶球奈米复合物的流体动力学直径,多分散指数和ζ电位。25℃,在水中进行三重复测量。为了测量阿霉素的负载量,将20μL分散在水中的奈米复合物与980μL二甲基甲酰胺混合,以提取阿霉素。使用Hitachi U-2810分光光度计(日本)测量阿霉素在480nm的吸光度。利用吸光度值与从不同浓度获得的一系列阿霉素标准溶液数值进行比较,来确定药物装载效率和装载含量。
图6说明阿霉素/PEG-mEGCG胶球奈米复合物的制备。将PEG-mEGCG接合物(602)和阿霉素(604)共溶于二甲基甲酰胺(606)。将该混合物以蒸馏水透析(608)。当从透析管中除去有机溶剂时,接合物中的疏水性EGCG部分开始自组装以形成被亲水性PEG链壳包围的胶球核(610)。同时,阿霉素分子也被分成疏水胶球核心。报告指出,阿霉素分子容易在水溶液中堆积在一起,因为平面蒽环形环之间的π-π相互作用。由于EGCG具有能够通过π-π堆积与阿霉素相互作用的多酚结构,因此预期在胶球奈米复合物核心中富含的EGCG可为其中的阿霉素包覆提供有利的环境。此外,表面暴露的PEG链可以在胶球奈米复合物周围形成保护壳,以避免被网状内皮系统清除,从而延长血流循环时间。
利用动态光散射(DLS)分析阿霉素/PEG-mEGCG胶球奈米复合物的尺寸和表面电荷特征。图7显示阿霉素/PEG-mEGCG胶球奈米复合物的(A)尺寸和(B)ζ电位。
图7A显示PEG-mEGCG与阿霉素在不同重量比下制备的胶球奈米复合物的流体动力学直径。值得注意的是,奈米复合物的尺寸范围为130-180nm。这种小尺寸有利于通过增强的渗透性和保留(EPR)效应达到延长血流循环和肿瘤靶向。以0.5:1的PEG-mEGCG:阿霉素重量比形成的胶球奈米复合物的直径大于以1:1所形成的。截留更高量的阿霉素可能是形成更大胶球奈米复合物的原因。奈米复合物是高度单分散的,可由小的多分散指数(PDI)值明显落在0.1-0.2的范围内证实。
如图7B所示,胶球奈米复合物具有+15-25mV范围内的正ζ电位。这种阳离子表面电荷归因于带正电荷的阿霉素分子在奈米复合物内的包覆。我们还评估了胶球奈米复合物在冷冻干燥过程中是否保持其结构完整性。冷冻干燥是用于长期储存胶体奈米颗粒最常见的一种技术。将奈米复合物冻干,然后以相同浓度再分散于去离子水。发现重构的奈米复合物即使没有任何冻干保护剂也能保留原始的粒度和表面电荷。这种高胶体稳定性在胶球奈米复合物的临床应用和商业化将是有利的。
图8显示阿霉素/PEG-mEGCG胶球奈米复合物的药物装载效率和装载量。药物负载效率高于75%,表明阿霉素有效地被并入在PEG-mEGCG奈米复合物。由于PEG-mEGCG:阿霉素重量比降低,药物装载效率和装载量均增加。观察到的负载含量(35-50w/w%)显著高于用其它聚合物胶球系统结果的负载量。EGCG和阿霉素之间的π-π堆积和/或疏水相互作用可能在PEG-mEGCG胶球奈米复合物的高药物负载能力中发挥重要作用。
阿霉素释放研究
关于释放实验,将0.5mL负载阿霉素的奈米复合物(2mg mL-1)置于截流分子量为2,000Da的透析管中。将管浸入25mL PBS的37℃振荡培养箱。在给定的时间点,收集1mL释放培养基,然后用等体积的新鲜PBS代替。使用Hitachi U-2810分光光度计(日本)测量阿霉素的480nm吸光度,测定释放到培养基中的阿霉素含量。
在生理温度和pH下研究阿霉素/PEG-mEGCG胶球奈米复合物的药物释放曲线。如图9所示,胶球奈米复合物显示阿霉素在PBS中持续释放。大约11%负载的阿霉素在7天内释放。观察到的释放速率显著低于之前其他报告的阿霉素递送系统的释放速率。这种持续的药物释放可能是由胶球奈米复合物中EGCG和阿霉素之间的强相互作用引起的。此外,仅在初始阶段观察到边缘爆发释放,这表示阿霉素分子稳定地包覆在胶球奈米复合物中。这种低药物渗漏对于以最小的副作用确保最大治疗功效是必要的,因为包覆在奈米复合物中的药物分子在血流循环期间不会过早地渗漏。总之,这些结果证明PEG-mEGCG胶球奈米复合物可以应用于阿霉素的全身性癌症治疗。
实施例4:SU/PEG-EGCG接合物
制备SU/PEG-EGCG胶球奈米复合物
图10说明使用固体分散方法形成SU/PEG-EGCG接合物。简言之,将2mg的SU(1006)溶解在1mL的氯仿。然后将SU溶液以不同的PEG-EGCG:SU重量比(1008)加到玻璃小瓶中的PEG-EGCG接合物(PEG-mEGCG(1002)或PEG-dEGCG(1004))中并涡旋搅拌,然后减压(1010)蒸发氯仿溶液,加入2mL水于所得的PEG-EGCG和SU混合物(1012)的薄膜表面(1014),进行水合,并在室温反应24小时,当所得固体膜水合后,自水合PEG链中分离SU和EGCG,PEG-EGCG自组装形成胶球奈米复合物。然后利用0.8-μm过滤器(Sartorius Stedim)过滤(1016)SU/PEG-EGCG胶球奈米复合物溶液,移除剩下游离的药物试剂,产生透明的SU/PEG-EGCG胶球奈米复合物溶液(1018)。关于体内研究样品,使用0.2-μm过滤器(Sartorius Stedim BiotechGmbH,德国)进一步过滤SU/PEG-EGCG胶球奈米复合物溶液。
应当注意,除非另有说明,PEG-EGCG接合物是指PEG-mEGCG和PEG-dEGCG。
由于EGCG具有能透过疏水相互作用和π-π堆积与SU相互作用的多酚结构,预期在胶球奈米复合物的核中富含的EGCG将为SU包埋提供有利的环境。此外,表面暴露的PEG链将在胶球奈米复合物周围形成高度水合的壳以避免RES的清除,从而允许延长血流中的循环和副作用的减少。
SU/PEG-mEGCG胶球奈米复合物的特征
利用动态光散射(DLS)(Zetasizer Nano ZS,Malvern,UK)评估SU/PEG-mEGCG胶球奈米复合物的流体动力学直径,尺寸分布和表面电荷。在25℃下在水中进行三重复测量。图11A显示在不同PEG-EGCG:SU重量比下制备的胶球奈米复合物的流体动力学直径。值得注意的是,在130-250nm的尺寸范围内产生的胶球奈米复合物。奈米尺寸将有利于通过EPR效应延长循环和肿瘤靶向。通过改变PEG-EGCG:SU重量比控制胶球奈米复合物的特性。图11B显示在PEG-EGCG:SU重量比为8和16所形成的胶球奈米复合物是高度单分散的。当PEG-EGCG:SU重量比增加时,胶球奈米复合物的正电荷降低(图11C)。略带正电的表面电荷归自其包覆带正电荷的SU分子。
为了测量药物装载效率和量,将10μL在水中的胶球奈米复合物溶解于990μL的DMF中,使用Hitachi U-2810可见紫外(UV-Vis)分光光度计(UV-Vis)在431nm测量SU的吸光度(日本)。用SU标准溶液获得的校正曲线决定装载效率和量。
图12显示SU/PEG-EGCG胶球奈米复合物的药物装载效率和药物装载量。随着PEG-EGCG:SU重量比从1增加到16,药物负载效率从增加到 SU/PEG-dEGCG胶球奈米复合物的负载效率高于SU/PEG-mEGCG胶球奈米复合物,表示与PEG-mEGCG相比,SU与PEG-dEGCG有更大的相互作用。还发现胶球奈米复合物的负载效率与过滤前未负载的SU沉淀物的量相关。当PEG-EGCG:SU重量比增加到8时,没有发现SU沉淀。如所预期的,由于PEG-EGCG:SU重量比增加,由于胶球奈米复合物中PEG-EGCG的含量较高,胶球奈米复合物的负载量降低。
SU释放研究
在生理条件(磷酸盐缓冲盐水(PBS),pH 7.3,37℃)下进一步研究SU/PEG-EGCG胶球奈米复合物的药物释放曲线。SU释放实验,将0.5mL的SU/PEG-EGCG胶球奈米复合物(0.4mg mL-1)置于透析管(截流分子量=2,000Da)中。将管浸入25mL PBS,置于37℃振荡培养箱。在给定的时间点,收集1mL释放培养基,然后用等体积的新鲜PBS代替。利用HitachiU-2810分光光度计测量431nm的吸光度来测量释放到培养基中的SU含量。
如图13所示,胶球奈米复合物在PBS中表现出SU的持续释放,这可归因于EGCG和SU间在胶球奈米复合物中的强相互作用。此外,几乎没有观察到任何爆发释放,这表明SU分子稳定地包覆在胶球奈米复合物中。由于SU和mEGCG之间相互作用较弱,SU/PEG-mEGCG胶球奈米复合物显示出比SU/PEG-dEGCG胶球纳奈米复合物更快和更多的SU释放。释放速率和量也取决于PEG-EGCG:SU重量比。对于SU/PEG-mEGCG胶球奈米复合物而言,释放速率和量随着PEG-EGCG:SU重量比增加而降低。除了较慢和较低的释放与PEG-EGCG:SU重量比为8相关之外,PEG-EGCG:SU重量比不显著影响SU/PEG-dEGCG在胶球奈米复合物中的释放速率和量。
体内治疗研究
为了研究毒性和治疗效果,用胶球奈米复合物进行体内研究。建立皮下肾细胞癌模型。使用成年雌性Balb/c无胸腺无免疫功能的裸鼠(平均体重=19g,年龄=6-8周)
为了研究静脉内注射SU/PEG-EGCG胶球奈米复合物的治疗效果,将6×106个A498-luc细胞皮下接种到小鼠左大腿的根部,建立异种移植肿瘤模型。肿瘤接种后第6天,将动物分为四组,每周两次于尾静脉注射各种溶液(每组数量=8),持续5周,而一组接受每日60mg/kg的SU。尾静脉注射,使用200μl样品溶液体积。
为了监测A498-luc细胞的生物发光信号,将异氟醚气体麻醉的动物腹膜内注射200μl溶于PBS的D-荧光素(5mg ml-1,Promega),并置于相机箱内的温热阶段(30℃)的IVIS成像系统(Xenogen,Alameda,CA,USA)。在荧光素注射20分钟后获取发光图像,采集30秒。A498-luc细胞发射的光被数字化并作为伪彩色覆盖物以电子显示在动物的灰度图像上。获取发光信号的图像和测量,并用Xenogen成像软件v3.2进行分析并定量为光子/s。每周测量肿瘤大小和体重。动物的所有处理和护理根据遵照新加坡国家实验动物研究咨询委员会发布的用于科学目的的动物的护理和使用指南进行。
所有数据以平均值±标准误差(SEM)表示。利用Student's t-统计检定平均值之间差异的显著性。利用SigmaStat 3.5的Bonferroni's和ANOVA进行多重比较检定。P值<0.05被认为是具统计显著意义。
根据胶球奈米复合物尺寸、尺寸分布和表面电荷,选择SU/PEG-mECGC胶球奈米复合物(PEG-EGCG:SU重量比为8和16)和SU/PEG-dEGCG胶球奈米复合物(PEG-EGCG:SU重量比为8)做体内实验。每周静脉内注射两次SU/PEG-mEGCG胶球奈米复合物,持续5周,一组每天灌食SU60mg/kg。基于先前报告选择60mg/kg/天的口服药物剂量,其证明了在小鼠中最佳临床前抗肿瘤功效的SU剂量为40-80mg/kg/天。关于我们的研究,以每天60mg/kg代表有效的抗肿瘤剂量,因为其它研究表明每天<40mg/kg的剂量是低效的,且每天120mg/kg的剂量将测试进一步提高药物施用的效果。
图14显示在开始治疗后一周,接受口服游离SU组别的体重显著减轻。这在接受SU/PEG-EGCG胶球奈米复合物的其他组中没有观察到。与每日口服SU治疗相比,当每周施用两次SU/PEG-EGCG胶球纳奈米复合物时,抗肿瘤效应增强(图15)。使用SU/PEG-EGCG胶球奈米复合物的这种抗肿瘤作用约为口服剂量近十分之一的浓度。即使治疗在5周后停止,SU/PEG-EGCG胶球奈米复合物的抑制作用也维持相当长的时间。与接受胶球奈米复合物治疗的组别相比,接受口服治疗组的肿瘤再生长的速度明显快得多。
为了研究口服SU/PEG-mEGCG MNC的治疗效果,将悬浮在100μlPBS和100μl基质胶(Matrigel)(BD Bioscience)的4×106个ACHN细胞经皮下接种到右大腿根部,建立老鼠异种移植肿瘤模型。一旦肿瘤体积达到200mm3,将动物分成四组,每天口服灌胃各种溶液(每组数量=8),持续5周:对照组(pH=5的柠檬酸盐缓冲液),SU/PEG-mEGCG 8:1(SU为15mg/kg),15和40mg/kg的SU。使用数字卡尺每周测量肿瘤两次,并由下式计算肿瘤体积(mm3):体积=(长度×宽度2)/2(图16和17)。
由于每日60mg/kg的口服SU剂量已显示太毒,在本公开中,每日口服SU剂量减少至40mg/kg。根据之前的报告,每天40mg/kg的口服剂量是小鼠抗肿瘤功效的最佳临床前剂量(40-80mg/kg/天)。图16显示在治疗期间接受40mg/kg SU的组别体重显著减轻。这在接受SU/PEG-mEGCG MNC 8:1和SU以15mg/kg治疗的其他组中没有观察到。在与15mg/kg相同的SU剂量下,与单独的SU相比,SU/PEG-mEGCG MNC显著显示更高的治疗效果(图17)。使用SU/PEG-mEGCG MNC的抗肿瘤效果约为小于最佳口服剂量40mg/kg的一半浓度。即使治疗在5周后停止,SU/PEG-mEGCG MNC的抑制作用也维持了相当长的时间。
考量肿瘤血管的解剖生理性质的EPR效应,有利大于40kDa的大分子选择性地从肿瘤血管中渗出并在肿瘤组织中积累的传送。大多数固态瘤具有血管结构缺陷,这通常导致大量的血管通透性。这在正常组织中不会发生。本发明公开了通过静脉内和口服给药的SU/PEG-mEGCG胶球奈米复合物作为第一次用于ccRCC可能疗法的用途。已经观察到EGCG与SU相互作用,并且在大鼠中的药代动力学研究显示施用EGCG显著降低SU的血浆浓度。被报告过的绿茶与SU的相互作用,和胶球奈米颗粒在各种肿瘤中的EPR效应,表明使用PEG-EGCG作为递送SU的奈米颗粒载体的可能性。在胶质母细胞瘤,高度血管生成的肿瘤中,抗血管生成治疗已显示显著但短暂的功效。这种肿瘤主要通过由VEGF驱动的过程刺激新血管的形成,但所得血管在结构和功能上异常。在这种情况下使用SU/PEG-EGCG胶球奈米复合物具增强抗血管生成活性的潜力。
产业应用
胶球奈米复合物可以应用于全身施用阿霉素的癌症治疗。胶球奈米复合物可作为传送SU的奈米颗粒载体。在胶质母细胞瘤,高度血管生成的肿瘤,抗血管生成治疗已显示有用但短暂的功效。这种肿瘤主要通过由VEGF驱动的过程刺激新血管生成,但新生血管的结构和功能异常。利用包覆SU的胶球奈米复合物,可潜在地增强抗血管生成活性。胶球奈米复合物可作为全身施用治疗剂时的持续释放,或当作传送治疗剂到靶位的运送系统。胶球奈米复合物可用于包覆治疗不同种类癌症的各种试剂。胶球奈米复合物也可用于包覆非癌性治疗的各种试剂。这可包括用于抗生素和其他医疗应用的小分子。显而易见的,在不脱离本发明的精神和范围的情况,在阅读前述公开内容之后,本领域技术人员就本发明的各项修改和调整将是容易的,且修改和调整的意图应属专利申请范围。
Claims (50)
1.一种胶球奈米复合物,包含一胶球和包覆在所述胶球内的试剂,所述胶球包含聚合物-类黄酮接合物,其中所述聚合物为与所述类黄酮的B环键结的亲水性聚合物。
2.如权利要求1所述的胶球奈米复合物,其中至少有一类黄酮与所述聚合物结合。
3.如权利要求1或2所述的胶球奈米复合物,其中所述聚合物通过连接体与所述类黄酮结合。
4.如权利要求3所述的胶球奈米复合物,其中所述连接体选自以下所组成的组:硫醚,亚胺,胺,偶氮和1,2,3-三唑基团。
5.如权利要求1所述的胶球奈米复合物,其中所述类黄酮是单体类黄酮或双体类黄酮。
6.如权利要求2所述的胶球奈米复合物,当其中所述接合物存在不只一个类黄酮时,所述类黄酮的至少有一通过所述B环与所述聚合物键结。
7.如权利要求6所述的胶球奈米复合物,其中所述的至少一个类黄酮外的另一个通过A环与所述聚合物键结。
8.如权利要求1所述的胶球奈米复合物,其中所述亲水性聚合物包含选自以下组中的单体:烷基,恶唑啉,烯基,亚胺,丙烯酸,环氧乙烷,醇,胺,酸酐,酯,羧酸,羟基,磷酸盐,对苯二甲酸盐,酰胺和醚。
9.如权利要求8所述的胶球奈米复合物,其中所述醇为二醇,或者其中所述酯为甲基丙烯酸酯、内脂、碳酸酯或丙烯酸酯,或者所述酰胺为丙烯酰胺。
10.如权利要求1所述的胶球奈米复合物,其中所述亲水性聚合物选自以下组中的物质及其共聚物:聚丙烯酰胺,聚(N-异丙基丙烯酰胺),聚(恶唑啉),聚乙烯亚胺,聚(丙烯酸),聚甲基丙烯酸酯,聚(乙二醇),聚(环氧乙烷),聚(乙烯醇)聚(乙烯基吡咯烷酮),聚醚,聚(烯丙基胺),聚酐,聚(β-氨基酯),聚(丁二酸丁二醇酯),聚己内酯,聚碳酸酯,聚二氧杂环己酮,聚(丙三醇),聚乙醇酸,聚(3-羟基丙酸),聚(甲基丙烯酸-2-羟基乙酯),聚(N-(2-羟丙基)甲基丙烯酰胺),聚乳酸,聚(乳酸-共-乙醇酸),聚(原酸酯),聚(癸二酸)和聚(对苯二甲酸酯-共-磷酸酯)。
11.如权利要求1所述的胶球奈米复合物,其中所述亲水性聚合物是多糖。
12.如权利要求1所述的胶球奈米复合物,其中所述亲水性聚合物是选自以下组成的组:透明质酸,葡聚醣,脱乙酰壳多糖,纤维素,淀粉,明胶,角叉菜胶,环糊精,结冷胶,瓜尔胶,果胶,聚蔗糖,黄原胶,和藻酸盐。
13.如权利要求12所述的胶球奈米复合物,其中所述淀粉为支链淀粉或直链淀粉,或者所述葡聚糖为硫酸葡聚糖、硬葡聚糖或木葡聚糖,或者其中所述聚蔗糖为蔗糖多聚体。
14.如权利要求1所述的胶球奈米复合物,其中所述类黄酮选自以下组成的组:黄酮,异黄酮,黄烷,原花青素和花青素。
15.如权利要求14所述的胶球奈米复合物,其中,所述黄烷选自以下物质组成的组:(-)-表儿茶素,(+)-表儿茶素,(-)-儿茶素,(+)-儿茶素,表儿茶素没食子酸酯,表没食子儿茶素,表没食子儿茶素没食子酸酯,非瑟酮醇,没食子儿茶素,没食子儿茶素没食子酸酯,牧豆树醇和双洋槐儿茶素,乌龙茶酮,单宁,茶柠檬素,茶二苯骈卓酚酮,茶黄素,茶多酮,茶红素,聚酯型儿茶素和其混合物。
16.如权利要求15所述的胶球奈米复合物,其中所述单宁为根皮单宁、鞣花单宁或没食子单宁。
17.如权利要求1所述的胶球奈米复合物,其中所述试剂是治疗剂。
18.如权利要求17所述的胶球奈米复合物,其中所述治疗剂是选自以下化疗试剂组成的组:烷化剂,蒽环霉素,埃博霉素,组蛋白脱乙酰酶抑制剂,拓扑异构酶I抑制剂,拓扑异构酶II抑制剂,激酶抑制剂,单株抗体,抗体-药物接合物,核苷酸类似物,胜肽抗生素,铂基剂,类视黄醇,细胞激素,以及抗代谢物。
19.如权利要求18所述的胶球奈米复合物,其中所述化疗试剂为长春花生物碱,或长春花生物碱衍生物。
20.如权利要求18所述的胶球奈米复合物,其中所述化疗剂选自以下组成的组:放线菌素,阿法替尼,全反式视黄酸,阿西替尼,阿扎胞苷,硫唑嘌呤,贝伐单抗,博来霉素,博素替尼,硼替佐米,卡铂,卡培他滨,西妥昔单抗,顺铂,苯丁酸氮芥,克里唑蒂尼,环磷酰胺,阿糖胞苷,达沙替尼,柔红霉素,多西他赛,去氧氟尿苷,阿霉素,表柔比星,埃博霉素A(C26H39NO6S),埃博霉素B(C27H41NO6S),埃博霉素C(C26H39NO5S),埃博霉素D(C27H41NO5S),埃博霉素E(C26H39NO7S),埃博霉素F(C27H41NO7S),埃罗替尼,依托泊苷,氟尿嘧啶,福莫替尼,吉非替尼,吉西他滨,羟基脲,伊达比星,伊马替尼,伊立替康,拉帕替尼,乐伐替尼,氮芥,巯嘌呤,氨甲蝶呤,米托蒽醌,尼罗替尼,奥沙利铂,太平洋紫杉醇,帕尼单抗,帕唑帕尼,哌加他尼,培美曲塞,雷珠单抗,瑞格菲尼,鲁索替尼,索拉非尼,舒尼替尼,曲妥珠单抗,替尼泊苷,硫鸟嘌呤,托法替尼,托泊替康,伐卢替尼,维莫司尼,长春花碱,长春新碱,长春地辛,长春瑞滨。
21.如权利要求1所述的胶球奈米复合物,其中所述胶球奈米复合物的尺寸在30至300nm。
22.如权利要求1所述的胶球奈米复合物,其中存在于所述胶球奈米复合物的所述试剂,其负载效率大于30%。
23.如权利要求1所述的胶球奈米复合物,其中存在于所述胶球奈米复合物的所述试剂,其加载含量在1至50w/w%。
24.一种制备胶球奈米复合物的方法,所述胶球奈米复合物包含胶球和包覆在所述胶球的试剂,所述方法包括以下步骤:
a.在合适的溶剂中,将所述试剂加入聚合物-类黄酮接合物,其中所述聚合物为与所述类黄酮的B环键结的亲水性聚合物;和
b.使包含所述聚合物-类黄酮接合物的胶球自组装,并将所述试剂包覆在所述胶球内,从而形成所述胶球奈米复合物。
25.如权利要求24所述的方法,其中步骤a.还包括以下步骤:
a1.除去所述溶剂,以形成所述试剂和所述聚合物-类黄酮缀合物的干膜;和
a2.用水性溶剂水合所述干膜。
26.如权利要求24或25所述的方法,还包括利用过滤分离所形成胶球奈米复合物的步骤。
27.如权利要求24所述的方法,其中步骤a.还包括在合适的溶剂中透析所述试剂的步骤。
28.一种聚合物-类黄酮接合物,其包含与类黄酮B环键结的聚合物,其中所述聚合物为亲水性聚合物。
29.如权利要求28所述的聚合物-类黄酮接合物,其中所述亲水性聚合物选自以下组中的物质及其共聚物:多糖,聚丙烯酰胺,聚(N-异丙基丙烯酰胺),聚(恶唑啉),聚乙烯亚胺,聚(丙烯酸),聚甲基丙烯酸酯,聚(乙二醇),聚(环氧乙烷),聚乙烯醇,聚(乙烯吡咯烷酮),聚醚,聚(烯丙胺),聚酐,聚(β-氨基酯),聚(丁二酸丁二醇酯),聚己内酯,聚碳酸酯,聚对二氧杂环己酮,聚(丙三醇),聚(乙醇酸),聚(3-羟基丙酸),聚(2-羟乙基甲基丙烯酸酯),聚(N-(2-羟丙基)甲基丙烯酰胺),聚乳酸,聚(乳酸-乙醇酸共聚物),聚(原酸酯),聚(2-恶唑啉),聚(对苯二甲酸酯-共-磷酸酯)。
30.如权利要求28或29所述的聚合物-类黄酮接合物,其中所述类黄酮选自物质组成的组:(-)-表儿茶素,(+)-表儿茶素,(-)-儿茶素,表儿茶素没食子酸酯,表儿茶素,儿茶素,非瑟酮,没食子儿茶素,没食子儿茶素没食子酸酯,牧豆树醇和双洋怀儿茶素,乌龙茶酮,单宁,茶柠檬素,茶二苯骈卓酚酮,茶黄素,茶多醌,茶红素,聚酯型儿茶素及其混合物组成的基团。
31.如权利要求30所述的聚合物-类黄酮接合物,其中所述单宁为根皮单宁、鞣花单宁或没食子单宁。
32.如权利要求28所述的聚合物-类黄酮接合物,其中所述聚合物通过选自以下组中硫醚,亚胺,胺,偶氮和1,2,3-三唑基团的连接体与类黄酮接合。
33.如权利要求32所述的聚合物-类黄酮接合物,其中所述聚合物是聚(乙二醇),所述类黄酮是表没食子儿茶素-3-没食子酸酯,所述连接体是硫醚。
35.如权利要求28所述聚合物-类黄酮接合物的一种制备方法,包括在碱性条件通过亲核加成将所述类黄酮与所述聚合物接合的步骤,其中所述聚合物为亲水性聚合物并且具有游离的亲核基团。
36.如权利要求35所述的方法,其中所述接合步骤在1至24小时的反应时间进行。
37.如权利要求35或36所述的方法,还包括在防止所述类黄酮聚集的溶剂中进行接合的步骤。
38.如权利要求35所述的方法,还包括添加清除剂以防止所述亲核基团经H2O2介导的氧化,从而提高所述接合效率的步骤。
39.如权利要求35所述的方法,其中所述碱性条件在大于7至10的pH范围。
40.如权利要求35所述的方法,其中所述亲核基团选自以下组成的组:硫醇,胺,重氮烷烃和迭氮化物。
41.包含胶球和包封在所述胶球内的试剂的胶球奈米复合物在制备药物传送载体中的应用,其中所述胶球包含聚合物-类黄酮接合物,且其中所述聚合物为与所述类黄酮的B环键结的亲水性聚合物。
42.如权利要求41所述的应用,其中所述胶球奈米复合物在体内将包覆的药剂传送至肿瘤标靶部位。
43.如权利要求1所述的胶球奈米复合物在制备用于治疗肿瘤的药物中的应用。
44.如权利要求43所述的应用,其中所述胶球奈米复合物适于胃肠外给药或者局部给药。
45.如权利要求43所述的应用,其中所述胶球奈米复合物适于口服或者经颊给药。
46.如权利要求44所述的应用,其中所述胶球奈米复合物适于胃肠外给药,所述胃肠外给药包括皮下,皮内,静脉内,肌内,腹膜内,关节内,动脉内,滑膜内,胸骨内,鞘内,病灶内和颅内,经鼻,经粘膜,经阴道,通过注射,植入药池,吸入喷雾或输注技术。
47.如权利要求44所述的应用,其中所述胶球奈米复合物适于局部给药,所述局部给药包括直肠给药,皮下给药或眼科给药。
48.如权利要求43至47中任一项所述的应用,其中存在于所述胶球奈米复合物中的所述试剂将以每天1至80mg/kg的剂量施用。
49.如权利要求1所述的胶球奈米复合物在制备用于治疗选自以下组中的癌症的药物中的应用:肾上腺皮质癌,肛门癌,阑尾癌,I级星形细胞瘤,II级星形细胞瘤,III级星形细胞瘤,IV级星形细胞瘤,非典型畸形/中枢神经系统的横纹肌瘤,基底细胞癌,膀胱癌,支气管癌,支气管肺泡癌,宫颈癌,结肠癌,颅咽管瘤,子宫内膜癌,室管膜母细胞瘤,室管膜瘤,食管癌,神经母细胞瘤,尤因肉瘤,颅外生殖细胞肿瘤,性腺外生殖细胞肿瘤,肝外胆管癌,纤维组织细胞瘤,胆囊癌,胃癌,胃肠道间质肿瘤,妊娠滋养细胞肿瘤,神经胶质瘤,头颈癌,心脏癌,肝细胞癌,肝门胆管癌,眼内黑色素瘤,胰岛细胞瘤,卡波西肉瘤,朗格汉斯细胞组织细胞增多症,喉癌,唇癌,淋巴瘤,巨球蛋白血症,髓母细胞瘤,髓上皮瘤,黑色素瘤,梅克尔细胞癌,间皮瘤,内分泌肿瘤,多发性骨髓瘤,蕈样肉芽肿,骨髓增生异常,骨髓增生性肿瘤,鼻腔癌,成神经细胞瘤,口腔癌,骨肉瘤,卵巢透明细胞癌,卵巢上皮癌,卵巢生殖细胞肿瘤,乳头状瘤,鼻窦癌,甲状旁腺癌,阴茎癌,咽癌,垂体瘤,浆细胞瘤,胸膜肺母细胞瘤,前列腺癌,直肠癌,肾细胞癌,具有染色体15改变的呼吸道癌,视网膜母细胞瘤,横纹肌肉瘤,唾液腺癌,塞泽里综合症,小肠癌,软组织肉瘤,鳞状细胞癌,鳞状颈癌,幕上原始神经外胚层肿瘤,睾丸癌,胸腺癌,胸腺瘤,甲状腺癌,肾盂癌,尿道癌,子宫肉瘤,阴道癌,外阴癌,肺癌,华氏巨球蛋白血症和肾母细胞瘤。
50.如权利要求49所述的应用,其中所述淋巴瘤为AIDS相关淋巴瘤、伯基特淋巴瘤、皮肤T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤或原发性中枢神经系统淋巴瘤,或者其中所述咽癌为下咽癌、鼻咽癌或口咽癌,或者其中所述纤维组织细胞瘤为恶性纤维组织细胞瘤。
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KR101810156B1 (ko) * | 2017-02-27 | 2017-12-19 | 인제대학교 산학협력단 | 폴리에틸렌 글리콜 및 플라보노이드 나노복합체를 유효성분으로 함유하는 안구 건조증 예방 또는 치료용 조성물 |
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