CN111971038B - 用于双靶向治疗神经内分泌瘤的组合物和方法 - Google Patents
用于双靶向治疗神经内分泌瘤的组合物和方法 Download PDFInfo
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Abstract
化学组合物及其合成方法。所公开和描述的组合物针对结合至去甲肾上腺素转运体(NET)或儿茶酚胺转运体的靶标的甲状腺激素αvβ3整联蛋白受体拮抗剂。该组合物在神经内分泌瘤的治疗、诊断和成像中具有双靶向作用和增强的靶向效率。
Description
技术领域
本发明一般涉及靶向并治疗神经内分泌瘤的组合物。特别是,该组合物可能包括甲状腺激素αvβ3整联蛋白受体拮抗剂(称为“甲状腺整联蛋白拮抗剂”),以及将去甲肾上腺素转运体(NET)或儿茶酚胺转运体(例如苄胍(“BG”)或其衍生物)作为靶的化合物。
背景技术
去甲肾上腺素/儿茶酚胺转运蛋白(“去甲肾上腺素转运体”)对于在突触末端和肾上腺嗜铬细胞上去甲肾上腺素摄取是必不可少的。在神经内分泌瘤中,去甲肾上腺素转运体是高度活跃的,可以靶向用于局部放疗的成像和/或治疗。靶向去甲肾上腺素转运体的最广泛使用的治疗剂之一是间碘苄甲胍(MIBG),其为去甲肾上腺素的胍类似物。123I/131I-MIBG治疗学已用于神经内分泌瘤的临床评估和管理,尤其是应用在成神经细胞瘤、副神经节瘤和嗜铬细胞瘤中。123I-MIBG成像已用于评估成神经细胞瘤,而131I-MIBG则用于治疗复发的高危成神经细胞瘤,然而,结果仍然欠佳。靶向去甲肾上腺素转运体的正电子放射断层造影术(PET)示踪剂及其靶标在成神经细胞瘤、副神经节瘤/嗜铬细胞瘤和类癌治疗后展现为成像和评估的更好选择。
整联蛋白是细胞表面粘附受体的超家族,其控制细胞与固体细胞外环境对细胞外基质(ECM)和其他细胞的粘附。粘附对于细胞是至关重要的;它提供了定位、迁移的线索以及生长和分化的信号。整联蛋白直接参与许多正常和病理情况,因此其本身是治疗干预的主要靶标。整联蛋白是完整的跨膜蛋白,为异二聚体,其结合特异性取决于14条α-链中的哪条与8条β-链中的哪条结合。整联蛋白划分为四个重叠的亚家族,包含β1、β2、β3或αv链。细胞可以表达来自每个亚家族的几种不同的整联蛋白。在过去的几十年中,已经显示整联蛋白是参与细胞粘附的主要受体,因此可能是用于治疗干预的合适靶标。整联蛋白αvβ3调节细胞生长和存活,因为这种受体的连接在某些情况下可以诱导肿瘤细胞凋亡。采用抗αvβ3抗体、RGD肽、肽模拟物或非肽衍生物以及其他整联蛋白拮抗剂来破坏细胞粘附已显示可减缓肿瘤的生长。
已显示甲状腺整联蛋白拮抗剂通过与整联蛋白αvβ3相互作用来影响肿瘤血管生成。甲状腺整联蛋白拮抗剂的作用描述于公开号为2017/0348425,标题为《与αvβ3整联蛋白甲状腺拮抗剂结合的不可裂解的聚合物》的美国专利,其内容通过引用并入本文。
包括甲状腺整联蛋白拮抗剂化合物和去甲肾上腺素转运体靶标化合物的组合物将会在本领域中深受欢迎。
发明内容
根据一个方面,组合物包括N-苄胍和甲状腺整联蛋白αvβ3受体拮抗剂,其中N-苄胍和甲状腺整联蛋白αvβ3受体拮抗剂通过连接体连接。
根据另一方面,组合物包括通式:
或其盐;
其中R1、R2、R3和R4各自独立地选自由氢、碘、氟、溴、甲氧基基团、硝基基团、氨基基团、腈基团所构成的组,其中R5、R6、R7和R8各自独立地选自由氢、碘和烷烃基团所构成的组,且n1≥0;n2≥1,以及
根据另一方面,用于双靶向肿瘤细胞的组合物包括去甲肾上腺素转运体靶标和甲状腺整联蛋白αvβ3受体拮抗剂,其中去甲肾上腺素转运体靶标和αvβ3甲状腺整联蛋白受体拮抗剂通过连接体链接,进一步地,其中组合物设置为通过a)去甲肾上腺素转运体和b)与整联蛋白αvβ3受体反应,来双靶向肿瘤细胞。
附图说明
本专利或本申请文件包括至少一个采用彩色的附图。将根据要求和支付必要的费用由专利局提供带有彩色附图的本专利或本专利申请公开的副本。
将参考以下附图详细描述一些实施例,其中相同的附图标记表示相同的构件,其中:
图1描述了用于双靶向神经内分泌瘤的示范性组合物的通式;
图2a描述了具有带有一元胺的连接体的示范性组合物的另一通式;
图2b描述了具有带有二元胺的连接体的示范性组合物的另一通式;
图2c描述了具有带有三唑的连接体的示范性组合物的另一通式;
图3描述了一种用于双靶向神经内分泌瘤的示范性组合物,其称为组合物300、BG-PEG-TAT、或BG-P-TAT;
图4a描述了来自图3的组合物300的合成路径概述;
图4b描述了图4a的合成路径的详细示意图;
图4c描述了生产称为组合物201(BG-PEG-MAT)和组合物202(BG-PEG-MAT)的两个其他示范性组合物的可能合成路径概述,其中生产使用甲苯磺酸酯基团或乙醛;
图4d描述了生产图4c中所示的组合物的另一种合成路径概述,其中生产使用甲苯磺酸酯基团或乙醛;
图4e描述了使用乙醛的图4c和图4d的合成路径的详细示意图;
图4f描述了使用甲苯磺酸酯基团的图4c和图4d的合成路径的详细示意图;
图5描述了曲线图,该图显示在采用对照或组合物300对老鼠进行多日治疗期间,当以每日1-10mg/kg范围的不同剂量皮下给药持续15天时,老鼠体重没有明显变化;
图6描述了曲线图,该图显示与对照组的肿瘤体积增加相比较,在皮下给药组合物300,以1-10mg/kg进行多日治疗期间,随时间推移(15天),小鼠内的肿瘤体积呈剂量依赖性减少;
图7a显示对照组中的老鼠图像,老鼠具有可视大型皮下肿瘤,以及提示伴有中枢行为改变的异常动物头部运动;
图7b显示用组合物300治疗的老鼠图像,且表明可视皮下肿瘤以剂量依赖性的方式明显减小或消失(肿瘤显著的收缩至消失),连同已观察到的异常动物头部运动也消失;
图8是肿瘤重量与组合物300的剂量函数关系示意图,表示显著的肿瘤收缩至肿瘤完全消失;
图9a是表示相对肿瘤大小和的血行阻断与组合物300的剂量函数关系的肿瘤照片;
图9b是表示绝对肿瘤大小随组合物300的剂量变化的函数关系的肿瘤照片,证明在剂量水平为10mg/kg情况下,从明显的肿瘤收缩至消失;
图10是成神经细胞瘤肿瘤细胞活性随组合物300的剂量变化的函数关系图,表示在剂量水平为10mg/kg情况下,肿瘤细胞从丧失活性至完全丧失;
图11是成神经细胞瘤肿瘤细胞坏死随组合物300的剂量变化的函数关系图,表示在剂量为3mg/kg和10mg/kg情况下,肿瘤细胞坏死增加了80%至100%;
图12a是每日皮下给药3mg/kg,给药15天情况下,肿瘤重量收缩随采用不同苄胍衍生物的治疗变化的函数关系图,该苄胍衍生物包括MIBG、BG以及结合BG的聚合物,与对照(PBS溶媒)相比,该图显示可比较的收缩,范围从40%至50%;
图12b是全部每日皮下给药3mg/kg,给药15天情况下,肿瘤重量收缩随采用苄胍、TAT衍生物或BG和TAT衍生物与BG-P-TAT(组合物300)联合给药的治疗变化的函数关系图(数据证明采用BG、TAT或BG与TAT联合给药使肿瘤收缩40%至50%,与之相比,采用BG-P-TAT(组合物300)使肿瘤收缩80%,且采用BG-P-TAT使肿瘤细胞最大丧失活性);
图13a是在给药Cy5标记的结合TAT的聚合物(组1)、结合BG的聚合物(组2)以及结合BG-TAT的聚合物(组合物300)(组3)的1小时和2小时后,各种老鼠的荧光图像照片;以及
图13b是在给药4小时、6小时以及24小时后图13a的老鼠的荧光图像照片(数据清楚表示在成神经细胞瘤中明显且最高浓度聚集(描述和成像),且用Cy5标记的结合BG-P-TAT的聚合物(组合物300))布满。
具体实施方式
本文通过举例而非限制的方式参照附图给出了所公开的组合物和方法的以下描述的实施例的详细描述。尽管示出并详细描述了某些实施例,但是应当理解,在不脱离权利要求的范围的情况下,可以进行各种改变和修改。本发明的范围绝不限于构成部件的数量、材料、形状、颜色、相对布置等,并且仅作为本发明的实施例的实例来公开。通过参考以下结合附图的描述,可以获得对本发明实施例及其优点的更完整的理解,其中,相同的附图标记表示相同的特征。
作为详细描述的前言,应当注意,除非上下文明确指出,在本说明书和权利要求书中使用的单数形式“一个”,“一种”和“该”包括复数所指事物。
概述
本发明的实施例描述了新的化学组合物以及其合成方法。本文中公开及描述的组合物可能针对抗血管生成剂,特别是甲状腺整联蛋白拮抗剂,其能够与整联蛋白αvβ3受体家族中的一种或更多种细胞表面受体相互作用。本文中公开及描述的组合物也可能针对去甲肾上腺素转运体(称为儿茶酚胺转运体)的靶标。去甲肾上腺素转运体靶标可作为成神经细胞瘤肿瘤细胞靶向药剂。
本文中公开及描述的组合物可针对包括甲状腺整联蛋白拮抗剂和去甲肾上腺素转运体靶标的组合物。此外,该组合物可以使用聚合物或其他连接体,以连接甲状腺整联蛋白拮抗剂和去甲肾上腺素转运体靶标。
去甲肾上腺素转运体是儿茶酚胺正常生理摄取的调节子,且高度表达并过度活跃于神经内分泌瘤中,例如成神经细胞瘤中。虽然去甲肾上腺素类似物,即间碘苯甲胍(MIBG)是去甲肾上腺素转运体已确定的底物,但是如(123)I/(131)I-MIBG的类似物或用氟(F18)替代碘(放射性的)的类似物也可能用于成神经细胞瘤和其他神经内分泌瘤的诊断性影像学。
研究表明多种成神经细胞瘤细胞株高度表达αvβ3整联蛋白受体(90%-95%)。然而,在肿瘤生长速率和肿瘤活性抑制方面,高亲和力αvβ3整联蛋白受体拮抗剂显示疗效受限(40-50%)。同样地,尽管苄胍及其衍生物(90%-100%)最大摄入到成神经细胞瘤和其他神经内分泌瘤中,但被证明其对成神经细胞瘤的抗肿瘤疗效有限。此外,如苄胍或其衍生物的去甲肾上腺素转运体靶标与如三唑四碘甲腺乙酸衍生物的甲状腺整联蛋白拮抗剂的治疗结合没有超过对成神经细胞瘤的生长和活性的50%抑制。
相反且出乎意料地,通过例如聚乙二醇(PEG)的不同聚合物连接体,将例如苄胍衍生物的去甲肾上腺素转运体靶标以及如三唑四碘甲腺乙酸衍生物的甲状腺整联蛋白蛋白拮抗剂结合到单个新化学实体中,导致不同剂量下的最大摄入到成神经细胞瘤和其他神经内分泌瘤中,以及最大肿瘤生长抑制且活性降低(80-100%)。通过连接体,与去甲肾上腺素/儿茶酚胺转运体靶标化合物结合的甲状腺整联蛋白拮抗剂可能提供对神经细胞瘤靶向具有双靶向效果的组合物。例如,根据本发明的一个实施例,该组合物可能包括连接至苄胍(或苄胍衍生物)的α-V-β-3(αvβ3)整联蛋白-甲状腺激素受体拮抗剂。
本文中描述的组合物可能包括化合物,例如甲状腺整联蛋白拮抗剂或其衍生物,其以共价键连接至去甲肾上腺素转运体的靶标上,形成单个化学实体。通过连接体,将甲状腺整联蛋白拮抗剂和去甲肾上腺素靶标结合。
可参照特定的甲状腺整联蛋白化合物和去甲肾上腺素化合物,例如四碘甲腺乙酸、三碘甲腺乙酸和苄胍。这些短语包括根据本发明全部教导的这类化合物的衍生物,即使没有将这类衍生物在本发明中特定列出。
参照附图,图1描述了通式100的实施例,该通式100包括通过连接体130连接至去甲肾上腺素转运体靶标120的甲状腺整联蛋白拮抗剂110。该组合物可被称为通过连接体130结合至苄胍衍生物的甲状腺整联蛋白拮抗剂衍生物,或用连接体130修饰结合至苄胍衍生物的甲状腺整联蛋白拮抗剂衍生物。图1描述了通式100的羧酸形式。对于本领域技术人员显而易见的是可以使用通式100的盐(例如钠盐)。
连接体130包括间隔基132和聚合物131。连接体130抗生物降解,如此使得连接体在生理条件下保持为不会裂解的。在一个实施例中,间隔基132包括CH2单元和毗邻的亚甲基(CH2)单元的重复连接,其可通过n1个重复进行限定,其中n1是≥0的整数。在其他实施例中,n1可以是≥1、≥2或≥3。连接体130还包括部分“Y”。在某些情况中,部分“Y”的实施例可以是胺。例如,通式的部分Y可以是具有一个氨基基团的二价烷烃,或具有两个氨基基团的二价烷烃,如图2a和2b的通式200a和200b的实例所示。在另一个实施例中,部分Y可以是三唑,如图2c所示的通式200c的实例所示。聚合物131可能包括聚醚,例如聚乙二醇(PEG)。可使用其他聚合物,包括壳聚糖、海藻酸、透明质酸和其他聚合物。在使用PEG作为聚合物131的实施例中,该聚合物可能具有的分子量为200g/mol至4000g/mol。
本文中术语甲状腺拮抗剂描述了具有本领域技术人员已知的抑制或对抗一种或多种甲状腺激素受体的能力的化合物,例如甲状腺激素受体的整联蛋白家族,像甲状腺激素细胞表面受体αvβ3。甲状腺整联蛋白拮抗剂110可以是抗血管生成的甲状腺激素或甲状腺激素受体拮抗剂。例如,甲状腺整联蛋白拮抗剂110可以是α-V-β-3(αvβ3)整联蛋白-甲状腺激素受体拮抗剂。
甲状腺整联蛋白拮抗剂110的特定实施例可能包括四碘甲腺乙酸(tetrac)、三碘甲腺乙酸(triac)、其衍生物和其变体。在一些实施例中,包括tetrac和triac的甲状腺整联蛋白拮抗剂的的一种或多种变体的实例可能包括二氨基四碘甲腺乙酸(DAT)、或二氨基三碘甲腺乙酸(DATri)(在下文中可以互换地称为“DAT”)、一元胺四碘甲腺乙酸(MAT)或一元胺三碘甲腺乙酸(MATri)(在下文中可以互换地称为“MAT”)、三唑四碘甲腺乙酸(TAT)或三唑三碘甲腺乙酸(TATri)(在下文中可以互换地称为“TAT”),及其衍生物或本领域技术人员已知的其他甲状腺拮抗剂。甲状腺整联蛋白拮抗剂可能是在公开号为2017/00348425,标题为《与αvβ3甲状腺整联蛋白拮抗剂结合的不可裂解的聚合物》的美国专利中所述的类型,其内容通过引用并入本文。
基于图1的一般结构100的示范性甲状腺整联蛋白拮抗剂在下面的表1中示出。
表1
在甲状腺整联蛋白拮抗剂110的一些实施例中,描述为R5、R6、R7和R8的变量可能各自独立地被例如氢、碘和烷烃的分子取代。在一些实施例中,烷烃具有四个或更少的碳。例如,如表1所示,在甲状腺整联蛋白拮抗剂110的一些实施例中,被描述为R5、R6、R7和R8的变量可能各自独立地被例如氢、碘和例如异丙基或异丁基的烷烃基团的分子取代。在表1的实施例中,烷烃具有四个或更少的碳。
去甲肾上腺素转运体靶标120可能是神经内分泌瘤细胞靶向剂。作为一个实例,去甲肾上腺素转运体靶标120可能是苄胍或苄胍衍生物。作为又一实例,去甲肾上腺素转运体靶标120可能是N-苄胍或其衍生物。
基于来自图1的通式100的示范性去甲肾上腺素转运体靶标120在下面的表2中示出。
表2
在去甲肾上腺素转运体靶标120的一些实施例中,描述成R1、R2、R3和R4的变体可能各自独立地被例如氢、碘、氟、溴、甲氧基基团、硝基基团、氨基基团和腈基团的分子取代。例如,在去甲肾上腺素转运体靶标120的一些实施例中,描述成R1、R2、R3和R4的变体可能各自独立地被例如氢、碘、氟、溴、甲氧基基团、硝基基团、氨基基团和腈类基团的分子取代,如表2中所描述。还可使用其他实施例和取代基。在一个实施例中,R1、R2、R3和R4中的至少一个是放射性标记。合适的放射性标记的实例包括I(123)、I(131)和F(18)。该化合物可以施用于人类或动物。
通过连接体130,可将任何示范性的甲状腺整联蛋白拮抗剂110(以及本文中教导的任何其他甲状腺整联蛋白拮抗剂实施例)连接至任何示范性的去甲肾上腺素转运体靶标120(以及本文中教导的其他任何去甲肾上腺素转运体靶实施例),来形成组合物。
从表1和表2清楚看到,在组合物中,有许多可用作甲状腺整联蛋白拮抗剂110的化合物以及有许多可用作去甲肾上腺素转运体靶标120的化合物。此外,多种甲状腺整联蛋白拮抗剂110可以与多种去甲肾上腺素转运体靶标120结合,从而导致本文中所述组合物具有许多可能的化学结构。
本文中所述的每种组合物的实施例可能具有多种类型的用于治疗由血管生成或其抑制所调节的若干种不同疾病的效用。鉴于在所述组合物中存在甲状腺整联蛋白拮抗剂110,本发明中描述的每种组合物可能具有针对靶向整联蛋白受体αvβ3的高度亲力,所述整联蛋白受体αvβ位于遍及人体和多种动物体中的众多类型细胞上。
此外,在本发明中所述的每种组合物的实施例可能具有治疗以去甲肾上腺素转运体的活性为特征的多种不同疾病的功用。鉴于在所述组合物中存在去甲肾上腺素转运体靶标120,本发明中所述的每种组合物可能各自对使用去甲肾上腺素转运体的,在人体和多种动物体中到处发现的众多靶向类型细胞具有高度亲和力。本发明中所述的每种组合物可能对表现出去甲肾上腺素转运体,例如神经内分泌肿瘤细胞的增强的或高于平均活性的靶向细胞具有增强的亲和力。作为更具体的实例,该组合物对靶向成神经细胞瘤、嗜铬细胞瘤、胰腺神经内分泌肿瘤和类癌肿瘤细胞可具有增强的亲和力。
更进一步,由于组合物一起使用甲状腺整联蛋白拮抗剂110和去甲肾上腺素转运体靶标120,该组合物对于对抗某些疾病和/或情况具有增强的功用和疗效。例如,神经内分泌瘤对用甲状腺整联蛋白拮抗剂进行治疗敏感,同时还表明去甲肾上腺素转运体的活性增加。本文中所述的组合物使用两个化合物,在对神经内分泌瘤细胞治疗中具有双靶向疗效。此外,增加的疗效超过通过用甲状腺整联蛋白拮抗剂和去甲肾上腺素转运体靶标的同时单独治疗所预期或实现的任何增加疗效。关于有益功效的更多细节将在下面在实验研究方面进行讨论。
如图1的通式100的化学结构所示,化学结构的实施例可能包括一个或多个变体,该变体限定通式100的甲状腺整联蛋白拮抗剂110的额外特征。例如,在甲状腺整联蛋白拮抗剂110的一些实施例中,描述成R5、R6、R7和R8的变体可能各自独立地是上述表1中所示的氢、碘和烷烃。
因此,有很多种可用作通式100的甲状腺整联蛋白拮抗剂110的甲状腺整联蛋白拮抗剂化合物。例如,如图2a所示,甲状腺整联蛋白拮抗剂110a可能包括用于R5-R8的碘取代基,导致形成具有3碳连接体和一元胺作为Y部分的四碘甲腺乙酸(tetrac)衍生物。通式200a可能称为通过PEG连接至苄胍或苄胍衍生物的一元胺四碘甲腺乙酸(MAT)。同样地,在图2b中,四碘甲腺乙酸分子还包括连接至碳连接体的二元胺Y部分。该通式200b可能称为通过PEG结合至苄胍或苄胍衍生物的二元胺四碘甲腺乙酸(DAT)。在图2c的另一实施例中,通式200c可包括连接至碳连接体的单个碳的三唑基团。该通式200c可称为通过PEG结合至苄胍或苄胍衍生物的三唑四碘甲腺乙酸(TAT)。
其他甲状腺整联蛋白拮抗剂化合物可以用于本文中所述组合物的形成。例如,可使用甲状腺整联蛋白拮抗剂110a、110b和110c的一般结构,其中仅R5-R7包括碘,从而提供类似的三碘甲腺乙酸衍生物。此外,如上表1所示,可使用类似的结构,其中甲状腺整联蛋白拮抗剂包括其他元素或官能团的取代基,用于R5-R8中的任意一个和/或全部。
去甲肾上腺素转运体靶标120可能包括苄胍或苄胍衍生物。去甲肾上腺素转运体靶标120的化学结构的实施例可能包括一个或多个变体,限定如图1所示的通式100的去甲肾上腺素转运体靶标120的额外特征。例如,在去甲肾上腺素转运体靶标120的一些实施例中,描述成R1、R2、R3和R4的变体可能各自独立地被上述表2中的氢、碘、氟、溴、甲氧基、硝基基团、氨基基团、和腈基团分子所取代。
图3描述了通式100的示范性组合物300。组合物300包括结合至苄胍修饰的PEG的三唑四碘甲腺乙酸。组合物300也可称为BG-PEG-TAT或BG-P-TAT。
下面将主要参照图3中所示的示范性组合物,即组合物300来展示本文中所述组合物的合成。类似组合物,即组合物201和组合物202(见图4c-f4)的合成也被提供为实例,并且不限制本发明于此类组合物。
实例1a:示范性组合物300的合成
该实例提供了制备图3中所示组合物300的取样方法。组合物300被称为BG-PEG-TAT或BG-P-TAT。组合物300具有的化学名称为2-(4-(4-(1-(20-(4-(胍基甲基)苯氧基)-3,6,9,12,15,18-六氧二十烷基)-1H-1,2,3-三唑-4-基)甲氧基-3,5-二碘苯氧基)-3,5-二碘苯基)乙酸,或[4-(4-{1-[2-(2-{2-[2-(2-{2-[2-(4-胍基甲基-苯氧基)-乙氧基]-乙氧基}-乙氧基)-乙氧基]-乙氧基}-乙氧基)-乙基]-1H-[1,2,3]三唑-4-基甲氧基}-3,5-二碘-苯氧基)-3,5-二碘-苯基]-乙酸。组合物300的分子量为1284.44g/mol。
所有可商购的化合物无需进一步纯化而使用。干燥所有溶剂,使用激活的分子筛(0.3nm或0.4nm,取决于溶剂的类型)来获得无水溶剂。所有反应(如非特别包含作为反应物、溶剂或共溶剂的水)均在Ar或N2气氛下,在烘干的玻璃器皿中进行。所有新的化合物均提供令人满意的1H HMR和质谱分析结果。熔点在电热熔点测定仪上测定,接着在Thomas HOOVER Uni-mel毛细管熔点测定仪上测定。在Thermo Electron NicoletAvatar330FT-IR设备上记录红外光谱。紫外光谱是从SHIMADZU UV-1650P紫外-可见分光光度计上获得。全部溶液态NMR试验都在伦斯勒理工学院(RPI,Troy,NY)生物技术跨学科研究中心,由配备有z轴梯度(Bruker BioSpin,Billerica,MA)低温冷却探针(TCI)的BrukerAdvance II 800MHz分光仪执行。使用的所有管的外直径为5mm。NMR数据将参照三氯甲烷(CDCl3;7.27ppm 1H,77.20ppm 13C)或DMSO-d6(=2.50ppm,38.92ppm 13C)作为内部标准。化学位移δ以ppm为单位;重数表示为s(单峰)、d(双峰)、t(三峰)、q(四峰)、m(多重峰)和br(宽泛);耦合常数J用Hz表示。在具有荧光指示剂的硅胶板上进行薄层色谱。可视化是通过紫外光(254nm和/或365nm)和/或通过在钼酸铈铵或硫酸溶液中染色实现的。跟随J.Org.Chem.43,14,1978,2923-2925中指示步骤,用230-400目硅胶执行快速柱层析。在应用生物系统API4000 LC/MS/MS或应用生物系统QSTAR XL质谱仪上执行高分辨率质谱分析。
该实例使用精氨酸丙酯化四碘甲腺乙酸(PGT)。在公开号为2017/0348425,标题为《与αvβ3整联蛋白甲状腺拮抗剂结合的不可裂解的聚合物》的美国专利中描述了由四碘甲腺乙酸制备PGT或其衍生物,其内容通过引用并入本发明。
图4a描述了组合物300的合成路径概述。
图4b描述了来自图4a的合成路径的详细示意图。图4a显示了合成组合物300的方案,以通过链接化学,将四碘甲腺乙酸类似物结合到苄胍修饰的PEG作为实例。可使用其他合成路径。
下面将更详细描述图4b中所示组合物300的合成方案的各个步骤,其中中间产物用在链接化学方案中所示的数字表示。
异源双功能的PEG的合成。虽然异源双功能的连接体是可商购的,但是出于本实例的目的,使用下列合成路线进行制备:
产物2,即[(4-羟苯基)-甲基]氨基甲酸叔丁酯2的合成。
根据先前公开的保护方法{1)ACS Medicinal Chemistry Letters,8(10),1025-1030;2017.2)European Journal of Medicinal Chemistry,126,384-407;2017.3)Tetrahedron Letters,47(46),8039-8042;3006}来合成[(4-羟苯基)-甲基]氨基甲酸叔丁酯,其内容在此通过引用的方式并入。在室温和搅拌下,将产物1,4-羟苯基胺(0.62g,5mmol)缓慢加入至二碳酸二叔丁酯(1.2g,5.1mmol)溶液中。在搅拌反应混合物8小时后,通过柱层析[SiO2:EtOAc/己烷(1:4)],将油状残留物纯化,以得到0.82g无色油状物N-Boc-4-羟基苄胺,产率71%。
产物3的合成将叔丁氧羟基-4-羟基苄胺醚化成溴代-叠氮修饰的PEG(400)3
在室温、搅拌下,将CsCO3(867mg,2.67mmol,3eq)添加至溶解于CAN(25mL)的叔丁氧羰基-1-4-羟基苄胺(300mg,0.896mmol,1eq)溶液中。将反应混合物搅拌30分钟后,将溴代-叠氮修饰的PEG(400)(445mg,1.05mmol,1.2eq)添加至混合物中,然后升温直至回流24小时。过滤,移除过量CsCO3。在减压下,移除溶剂,然后通过柱层析[SiO2:EtOAc/己烷(5:5)]纯化油状残留物,以得到黄色油状物产物3。产量:433mg,87%。
产物4的合成。BOC去保护
在室温下,将产物3(100mg,0.179mmol,3eq)溶解于3ml的无水1,4-二氧己环中,添加3ml的HCl(4N,溶于二氧己环)并搅拌。24小时后,在减压下移除溶剂,纯化油状残留物,以定量得到黄色油状产物4(产量:73g,90%)
产物5的合成。产物4的胍基化反应
将产物4(85mg,0.17mmol,1eq)N,N’-双-Boc-1H-吡唑-1-甲脒(54mg,17mg,1eq)溶解于3ml至4ml无水二乙碳二亚胺“DCM”,然后将三乙胺“TEA”(48μl,0.35mmol,2eq)添加至溶液中。在室温下搅拌反应混合物12小时。完成反应后,在减压下移除溶剂,残留物溶解于EtOAc(30ml)。用%5HCl(25ml)和卤水(25ml)清洗,接着干燥(Mg2SO4)。在减压下,移除溶剂,获得产物5,通过柱层析[SiO2:EtOAc/己烷(2:8)]纯化,产量:92mg,80%。
产物6的合成
将产物5(100mg,1eq)和1eq的PGT溶解于THF中,搅拌5分钟,然后将0.5eq抗坏血酸钠和溶于2ml水的0.5eq硫酸铜添加至混合物中,在65℃下搅拌24小时。24小时后,在减压下,移除溶剂,纯化产物6,产率:65%。
组合物300,即2-(4-(4-((1-(20-(4-(胍基甲基)苯氧基)-3,6,9,12,15,18-六氧二十烷基)-1H-1,2,3-三唑-4-基)甲氧基-3,5-二碘苯氧基)-3,5-二碘苯基)乙酸的合成
将产物6(50mg)溶解于3ml无水1,4-二氧己环中,添加3ml HCl(4N,溶于二氧己环),在40℃下搅拌。24小时后,在减压下,移除溶剂,纯化油状残留物,以得到黄色粉末状的组合物300.
可使用其他合成方法,来得到组合物300或得到其他具有图1中所示的通式100的组合物。
实例1b:其他示范性组合物的合成
图4c和4d描述了其他示范性组合物的合成路径概述,例如使用甲苯磺酸酯基团或乙醛,遵循通式200a的组合物201,和遵循通式200b的组合物202。
组合物201可称为BG-P-MAT、BG-PEG-MAT或通过PEG结合至一元胺四碘甲腺乙酸的苄胍。组合物202可称为BG-P-DAT、BG-PEG-DAT或通过PEG结合至二元胺四碘甲腺乙酸的苄胍。如本文中所描述的,可使用苄胍衍生物或其他去甲肾上腺素转运体靶标。如本文中所描述的,也可使用四碘甲腺乙酸衍生物或其他甲状腺整联蛋白拮抗剂,包括但并不限于三碘甲腺乙酸和三碘甲腺乙酸衍生物。
图4e和4f描述了来自图4c和图4d的合成路径详细示意图。图4e和4f显示了组合物201和201的合成方案,其作为通过链接化学将四碘甲腺乙酸结合至苄胍修饰的PEG的另外的实例。此外,可使用其他合成路径。
使用方法
本文中公开的组合物(包括但并非限制于示范性组合物,如组合物300、组合物201、和组合物202)在治疗癌症细胞和肿瘤,特别是治疗神经内分泌肿瘤,例如成神经细胞瘤、嗜铬细胞瘤、胰腺神经内分泌肿瘤和类癌肿瘤中表现出新型的双靶向性。此外,当与单独使用给药的甲状腺整联蛋白拮抗剂或去肾上腺素转运体靶标,即没有结合成单个组合物相比较,组合物显示对抗神经内分泌瘤肿瘤细胞增强的疗效。
还可将组合物用于对癌细胞/肿瘤成像。例如,可使用本文中所描述的组合物,对成神经细胞瘤、嗜铬细胞瘤、胰腺神经内分泌肿瘤和类癌肿瘤成像。成像对于诊断和/或治疗监控可能是令人期望的。此外,可将组合物同时用于治疗和成像。例如,组合物可显示出在靶向的癌细胞/肿瘤中增加保留,使得能够强化治疗且更有效成像。
实例2:对雌性裸鼠皮下移植瘤的影响
使用移植到裸的雌性小鼠的成神经细胞瘤SKNF2细胞,测试组合物300(BG-P-TAT)的疗效。
移植十五只(15)裸的雌性小鼠两次,每次植入106细胞。将SKNF2细胞株与异种皮下移植一起使用。
移植八(8)天后,小鼠被划分成四组,接受下列治疗15天:
组别 | 治疗化合物 | 剂量 |
组1 | 对照–PBS | |
组2 | 组合物300(BG-PEG-TAT) | 1mg/kg |
组3 | 组合物300(BG-PEG-TAT) | 3mg/kg |
组4 | 组合物300(BG-PEG-TAT) | 10mg/kg |
在治疗十五(15)天后,收集肿瘤,以便评估组织病理学,并收集下列结果:
图5显示对照和组合物300(BG-PEG-TAT)治疗对移植有SKNF2细胞株的小鼠体重的影响。如图所示,所有组的体重是一致的。数据表明每日用1、3和10mg/kg的不同剂量的组合物300(BG-PEG-TAT)进行每日治疗持续15天,与对照组动物相比动物体重没有影响。
图6显示组合物300(BG-PEG-TAT)治疗与对照对移植有SKNF2细胞株的小鼠的肿瘤体积的影响。如图所示,在治疗15天后,对照组显示出肿瘤体积从大约825mm3增加至1050mm3。接受用组合物300(BG-PEG-TAT)治疗的所有组显示肿瘤大小减小。此外,接受用组合物300(BG-PEG-TAT)治疗的组显示肿瘤大小呈剂量依赖性减小,采用10mg/kg的组显示肿瘤大小从大约825mm3减小至100mm3。
图7a-7b包括来自每个治疗组的小鼠的照片,在其中可以在视觉上比较皮下肿瘤70。如图7a中所示,对照组显示大且清晰可见的肿瘤70。对照动物还显示异常的盘旋(头部旋转)79,这在所有治疗组中都没有。异常的盘旋被认为是肿瘤对中枢神经系统的影响。
如图7b中所示,治疗组在10mg/kg剂量下,显示肿瘤70大小呈明显的剂量依赖性减小,直至完全消失。如图所示,在10mg/kg治疗组中,在位于肿瘤位置70’处没有任何可见的肿瘤。
图8显示对照与组合物300(BG-PEG-TAT)治疗对移植有SKNF2细胞株的小鼠的肿瘤重量的影响。可以看到,与对照组相比,治疗组显示肿瘤重量呈剂量依赖性减少。数据显示在剂量为1、3和10mg/kg下,肿瘤收缩分别为60%、80%和100%。
图9a和图9b显示对照与组合物300(BG-PEG-TAT)治疗对移植有SKNF2细胞株的小鼠的脉管系统和肿瘤大小的影响。如图所示,对照组显示出随着血管形成的增加,肿瘤70的大小显著增加。对照组肿瘤70的血管化区域90清晰可见。相反,治疗组显示肿瘤70的大小呈剂量依赖性减小,包括在剂量为10mg/kg下的肿瘤收缩。如图所示,肿瘤脉管系统还清楚地减少了。实际上,如图9b所示,对于10mg/kg的组,在植入肿瘤70’处(见图7b)只有坏死的皮肤75需要去除以进行病理组织学检查;此剂量的治疗证明肿瘤收缩。
图10显示对照与组合物300(BG-PEG-TAT)治疗对移植有SKNF2细胞株的小鼠的肿瘤细胞活性的影响。如所示,治疗组显示出肿瘤细胞活性呈剂量依赖性减小。对照中,显示细胞活性为70%-75%,肿瘤中心为20%-30%的坏死。相反,以1、3和10mg/kg的不同剂量下进行组合物300(BG-PEG-TAT)每日治疗,治疗15天,显示出细胞活性丧失分别至50%、20%和0.00%。在治疗15天后,10mg/kg剂量组证明全没有可视肿瘤细胞。
图11显示对照与组合物300(BG-PEG-TAT)治疗对移植有SKNF2细胞株的小鼠的肿瘤细胞坏死的影响。可以看出,治疗组显示肿瘤细胞坏死呈剂量依赖性增加。10mg/kg组表明肿瘤细胞坏死率接近100%,3mg/kg组表明肿瘤细胞坏死率大约为80%,1mg/kg组表明肿瘤细胞坏死率大约为50%。
实例3:比较实例
图12a和12b显示与采用组合物300(BG-PEG-TAT)治疗相比较,对照和采用BG、BG衍生物、例如TAT衍生物的甲状腺整联蛋白拮抗剂,及其组合物(联合给药)治疗对移植有SKNF2细胞株的小鼠的肿瘤细胞坏死的影响。
总之,与组合物300(BG-PEG-TAT)相比较,已知的治疗肿瘤细胞的甲状腺整联蛋白拮抗剂获得实质上较差的结果。例如,每日以3mg/kg皮下输送三唑四碘甲腺乙酸衍生物,持续三(3)周,已显示肿瘤生长降低大约为40%-50%,且肿瘤活性降低大约为40%-50%。类似地,三唑四碘甲腺乙酸衍生物显示肿瘤生长降低大约40%-50%,且使肿瘤活性降低大约40%-50%。此外,即使每日以3mg/kg皮下输送两种三唑四碘甲腺乙酸衍生物的组合进行联合治疗,持续三(3)周也仅实现将肿瘤生长和肿瘤活性降低40%-50%。使用苄胍和苄胍衍生物治疗获得类似的结果。此外,即使苄胍和甲状腺素整联蛋白拮抗剂进行联合治疗也无法表明增加的疗效超过40%-50%的关口。
相反,采用组合物300(BG-PEG-TAT)的治疗导致肿瘤减少80%,其中残余的肿瘤活性降低了80%。
比较实例3a:TAT衍生物对肿瘤重量的影响:
在神经内分泌瘤,例如成神经细胞瘤、嗜铬细胞瘤、胰腺神经内分泌肿瘤和类癌肿瘤的情况中,就肿瘤生长速率和肿瘤活性抑制方面而言,αvβ3整联蛋白受体拮抗剂(甲状腺整联蛋白拮抗剂)显示有限的功效(40%-50%)。例如,图12b的图包括当与对照组(磷酸盐缓冲液“PBS”)相比较时,三唑四碘甲腺乙酸衍生物(被称为TAT)对肿瘤体重的影响。被测试的特定衍生物为β环糊精三唑四碘甲腺乙酸。如图所示,3mg/kg剂量导致肿瘤重量大约降低40%-50%。
比较实例3b:苄胍及其衍生物对肿瘤重量的影响
类似地,在神经内分泌瘤,例如成神经细胞瘤、嗜铬细胞瘤、胰腺神经内分泌肿瘤和类癌肿瘤的情况中,就肿瘤生长速率和肿瘤活性抑制方面而言,苄胍和其衍生物显示有限的功效(40%-50%)。例如,图12a中的图包括当与对照组(PBS)相比较时,苄胍(BG)和苄胍衍生物(例如MIBG和结合苄胍的聚合物(特别是PLGA-PEG-BG,被称为聚合物-BG))对肿瘤体重的影响。尽管治疗化合物的最大量(90%-100%)被摄入到成神经细胞瘤和其他神经内分泌瘤中,但其表现出有限的成神经细胞瘤的抗癌疗效。
比较实例3c:分开的去甲肾上腺素转运体靶标和甲状腺整联蛋白拮抗剂的联合给药的影响
此外,包括如苄胍或其衍生物的去甲肾上腺素转运体靶标与如三唑四碘甲腺乙酸衍生物甲状腺整联蛋白拮抗剂的共同给药的联合治疗对成神经细胞瘤生长和活性的抑制不超过40%-50%。例如,如图12b中所示,通过使用任一化合物单独进行治疗(BG+TAT)显示,苄胍联合四碘甲腺乙酸衍生物的一起给药(BG+TAT)没有超过40%-50%的疗效。此外,β环糊精三唑四碘甲腺乙酸为已使用的四碘甲腺乙酸衍生物。
比较实例3d:组合物300(BG-P-TAT)(通过PEG结合至TAT的苄胍)的影响
此外,与图12b中所示的对照组和其他类型治疗相比较,采用组合物300(BG-P-TAT)治疗导致肿瘤重量显著提高的效果。组合物300实现了肿瘤大约80%的减少。此外,残留肿瘤的活性下降了80%。实际上,组合物300(结合至BG的TAT)显示出显著增加的疗效,甚至超过了分别单独给药TAT和BG(BG+TAT)的联合给药。
在下列表3中总结来自图12a和12b的比较实例:
表3
实例4:在无胸腺雌性小鼠中皮下移植肿瘤的成像
对无胸腺雌性小鼠移植两次,每次106细胞/移植。SKNF1细胞株与皮下异种移植一起使用。
组1由三只小鼠构成,采用PEG-TAT-染料(Cy5)治疗。组2由三只小鼠构成,采用PEG-BG-染料(Cy5)治疗。组3由三只小鼠构成,采用TAT-PEG-BG-染料(Cy5)治疗,其中TAT和BG用PEG连接体共价连接,作为化合物300。治疗组如下所示:
组别 | 治疗组合物 |
组1 | 有Cy5染料的PEG修饰的三唑四碘甲腺乙酸衍生物 |
组2 | 有Cy5染料的PEG修饰的苄胍衍生物 |
组3 | 有Cy5染料的组合物300 |
在给药后1小时、2小时、4小时、6小时和24小时进行荧光成像(Cy5)。图13a和13b中示出成像结果,其中肿瘤位置用黄色圈出,Cy5染料呈现为红色。如这些图中所示,当TAT和BG共价连接时,荧光信号有急剧增加,当与单独的三唑四碘甲腺乙酸衍生物或单独的苄胍衍生物相比较时,组合物300显示SKNF1成神经细胞瘤内的摄取和在肿瘤内的保留时间均显著提高。
成神经内分泌瘤肿瘤细胞用于所述治疗实例中。对于本领域技术人员可以理解这些实例是用于治疗其他肿瘤类型的有效模型,特别是其他神经内分泌瘤肿瘤的有效模型。此外,可通过公开组合物治疗任何表示出去甲肾上腺素转运体的活性增加的肿瘤或疾病状态,其中期望甲状腺整联蛋白降低抗血管生成的活性。
根据这些实例,本文中所所述的组合物显示对肿瘤细胞,特别是神经内分泌瘤的疗效增加。例如通过注射、局部、舌下、口服和其他给药路线,可使用这些组合物治疗神经内分泌瘤,例如成神经细胞瘤、嗜铬细胞瘤、胰腺神经内分泌肿瘤和类癌肿瘤。
出于说明的目的,这里提供了对本发明的各种实施例的描述,但是这些描述并非意图是详尽的或限于所公开的实施例。在不脱离所描述的实施例的范围和精神的情况下,许多修改和变型对于本领域普通技术人员而言将是显而易见的。本文中所选择使用的术语是为了最好地解释实施例的原理、对市场上存在的技术的实际应用或技术上的改进,或者使本领域的其他普通技术人员能够理解本文所公开的实施例。
Claims (7)
1.一种组合物,其包括:
通式:
或其盐;
其中R1、R2、R3和R4各自独立地选自由氢、碘、氟、溴、或甲氧基基团所构成的组;
其中R5、R6、R7和R8各自独立地是碘;且n1≥0;n2≥1;以及
2.根据权利要求1所述的组合物,其特征在于,所述组合物具有选自由下列组构成的化学式:
以及
3.根据权利要求1所述的组合物,其特征在于,所述组合物具有的化学式为:
4.根据权利要求1所述的组合物,其特征在于,所述的组合物包括去甲肾上腺素转运体靶标,所述去甲肾上腺素转运体靶标具有的结构为:
其中,R1、R2、R3和R4中至少一个选自由I-123、I-131和F-18所构成的组。
5.一种根据权利要求1所述的组合物在制备成像神经内分泌瘤的药物中的应用。
6.一种根据权利要求1所述的组合物在制备通过给药治疗剂量来治疗神经内分泌瘤的药物中的应用。
7.一种根据权利要求1所述的组合物在制备同时成像和治疗神经内分泌瘤的药物中的应用。
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US11351137B2 (en) * | 2018-04-11 | 2022-06-07 | Nanopharmaceuticals Llc | Composition and method for dual targeting in treatment of neuroendocrine tumors |
US10961204B1 (en) * | 2020-04-29 | 2021-03-30 | Nanopharmaceuticals Llc | Composition of scalable thyrointegrin antagonists with improved blood brain barrier penetration and retention into brain tumors |
JP2024520888A (ja) * | 2021-06-07 | 2024-05-24 | ナノファーマスーティカルス エルエルシー | 神経内分泌腫瘍の治療における二重標的化のための組成物および方法 |
US11723888B2 (en) | 2021-12-09 | 2023-08-15 | Nanopharmaceuticals Llc | Polymer conjugated thyrointegrin antagonists |
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JP2021521185A (ja) | 2021-08-26 |
MX2020010539A (es) | 2020-11-06 |
CN111971038A (zh) | 2020-11-20 |
US20190314314A1 (en) | 2019-10-17 |
AU2019250980A1 (en) | 2020-10-29 |
CA3095074A1 (en) | 2019-10-17 |
WO2019199532A1 (en) | 2019-10-17 |
BR112020020546A2 (pt) | 2021-01-12 |
KR20200142053A (ko) | 2020-12-21 |
US10328043B1 (en) | 2019-06-25 |
EP3773540B1 (en) | 2024-07-03 |
EP3773540A1 (en) | 2021-02-17 |
US11077082B2 (en) | 2021-08-03 |
SG11202009554UA (en) | 2020-10-29 |
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