CN115350285A - 树枝状聚合物到脑肿瘤的选择性传递 - Google Patents
树枝状聚合物到脑肿瘤的选择性传递 Download PDFInfo
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Abstract
已经研发一种组合物,其包含共价连接于至少一种用于治疗或缓解脑肿瘤的一种或多种症状的治疗剂、预防剂或诊断剂的羟基封端的聚(酰胺基胺)(PAMAM)树枝状聚合物。该等树枝状聚合物包含一个或多个乙二胺核心聚(酰胺基胺)(PAMAM)羟基封端的4、5、6、7、8、9或10级、最优选6级(G4‑10‑OH)树枝状聚合物。G6树枝状聚合物已经展示意外高的脑摄取。树枝状聚合物提供了一种穿过血脑屏障(“BBB”)选择性传递化学治疗剂、免疫治疗剂和缓解剂的方式。树枝状聚合物还具有如下优点:具有一种或多种作用机制的两种不同类别化合物可以结合于树枝状聚合物,提供同时传递。树枝状聚合物可以通过静脉内注射单独投与,或作为与辐射组合的多叉疗法的一部分投与。
Description
相关申请案的交叉参考
本申请案要求以引用的方式并入本文中的于2014年8月13日提交的美国临时专利申请案第62/036,675号、于2014年8月13日提交的美国临时专利申请案第62/036,839号和于2015年10月3日提交的美国临时专利申请案第62/059,240号的优先权。
技术领域
本发明大体上属于传递化学治疗剂、免疫治疗剂和姑息性药物到脑以治疗脑肿瘤和相关症状的领域。
背景技术
脑肿瘤为脑或中央脊柱中组织的异常生长,其会破坏适当脑功能。医生基于肿瘤细胞所来源的位置以及肿瘤细胞是癌性(恶性)还是非癌性(良性)来提及肿瘤。侵袭性最小的脑肿瘤类型常常称为良性脑肿瘤。它们来源于脑内或脑周围的细胞,不含癌细胞,生长缓慢,并且通常具有清晰边界,不扩散到其它组织中。恶性脑肿瘤含有癌细胞并且常常无清晰边界。它们被视为是危及生命的,因为其生长迅速并侵入脑组织周围。在脑细胞中开始的肿瘤称为原发性脑肿瘤。原发性脑肿瘤可以扩散到脑其它部分或脊柱,但很少扩散到其它器官。转移性或继发性脑肿瘤在身体另一部分中开始并接着扩散到脑。这些肿瘤比原发性脑肿瘤更常见,并且由其开始的位置来命名。
存在超过120种脑和中枢神经系统肿瘤。每个人的脑和脊髓肿瘤是不同的。其在不同区域形成,从不同细胞类型发展,并且可能具有不同的治疗选择。无侵袭性的低级肿瘤(I和II级)常常仅仅通过谨慎的监测或手术来治疗。虽然所有肿瘤都通过重复扫描来监测,但II级肿瘤在手术后并随时间推移更紧密地监视,以确保不复发。恶性并且会快速生长的更高级别肿瘤(III和IV级)更难以去除,并需要除手术以外的额外治疗,例如辐射或化学疗法。细微肿瘤细胞可能在手术后残留并最终将生长回来。因此,所有治疗都意图尽可能地延长和提高寿命。
对于低级别脑肿瘤,手术可能是所需要的唯一治疗,尤其在所有肿瘤可去除的情况下。如果手术后剩余可见的肿瘤,那么可以使用辐射和化学疗法。对于更高级肿瘤,治疗通常以手术开始,接着辐射疗法和化学疗法。高级别肿瘤的额外治疗选择包括X射线和破坏肿瘤细胞或延迟肿瘤生长的其它辐射形式;迅速杀死分裂细胞的化学疗法;集中于特定细胞要素,例如细胞生长所需要的分子或路径上,以使用其作为标靶的靶向疗法;以及局部或区域性传递的治疗,其通过产生在不同方向上跨越其使用区域前进的交替“波样”电场,产生破坏癌细胞所展现的快速细胞分裂的电场。
成功治疗脑肿瘤可能是具有挑战性的。身体的血脑屏障通常保护脑和脊髓以防有害化学物质通过血流进入那些结构。但是,此屏障也屏蔽了许多类型化学疗法。如果肿瘤靠近脑或脊髓的易损坏部分,那么手术可能困难。即使外科医生可以完全去除原始肿瘤,但可能剩余部分肿瘤,其太小,以致于在手术期间无法看到或去除。辐射疗法可能损伤健康组织。
脑肿瘤和其治疗常常引起副作用。除减缓、终止或消除肿瘤的治疗外,护理重要的一部分是减轻个人症状和副作用。此方法称为姑息性或支持性护理,并且其包括在患者的身体、情感和社交需求方面予以支持。止痛药帮助管理来自头痛的疼痛(脑肿瘤的一种常见症状)。皮质类固醇常常用于降低脑中肿胀,其可以减轻由肿胀引起的疼痛,而不需要处方止痛药。抗惊厥药物用于帮助控制惊厥。
手术常用于去除全部或部分脑肿瘤。有时,无法进行手术,因为肿瘤位于外科医生无法够到的地方,或靠近重要结构;这些肿瘤称为不可进行手术的。
化学疗法的目标可以是破坏手术后剩余的癌细胞,减缓肿瘤生长,或减少症状。化学疗法方案通常由设定时间段内给予的特定数目周期组成。患者可以一次接受一种药物或同时接受不同药物组合。给予化学疗法的常见方式包括吞咽(经口)的丸剂或胶囊或通过静脉内(IV)。一些药物更擅长穿过血脑屏障,并且这些药物常常因为此能力而用于脑肿瘤。格立得植入剂(Gliadel wafer)是一种给予药物卡莫司汀(carmustine)的方式,其涉及将植入剂放在手术期间去除肿瘤的区域中。对于患有胶质母细胞瘤的人,最新标准护理为每日低剂量替莫唑胺(temozolomide)(特莫多(Temodar))的辐射疗法,接着在辐射疗法后每月剂量的替莫唑胺,历时六个月到一年。已使用三种药物洛莫司汀(lomustine)(CeeNU)、丙卡巴肼(procarbazine)(甲苯肼(Matulane))和长春新碱(vincristine)(维卡萨(Vincasar))的组合与辐射疗法一起。当在辐射疗法前或在辐射疗法后立即给予时此方法帮助延长患有III级少突神经胶质瘤与1p19q共同缺失的患者的寿命。其还展示当在针对可能无法用手术完全移除的低级别肿瘤的辐射疗法后给予时延长患者生命。化学疗法的副作用取决于个体和使用剂量,但其可能包括疲劳、感染风险、恶心和呕吐、脱发、食欲不振和腹泻。这些副作用通常在治疗结束后消失。很少地,某些药物可引起一定听力丧失。其它可能引起肾损伤。患者可以通过IV给予额外流体来保护其肾。癌症药物的完整清单可以在NCI网站上找到。
抗血管生成集中于终止血管生成,血管生成是制造新血管的过程。因为肿瘤需要血管所传递的营养素来生长和扩散,所以抗血管生成疗法的目标是使肿瘤“饥饿”。贝伐单抗(Bevacizumab)(阿瓦斯汀(Avastin))是一种用于在先前治疗尚未起作用时治疗多形性胶质母细胞瘤的抗血管生成疗法。
缓解是当在身体中无法检测到肿瘤。缓解可以是暂时性或永久性的。对于大部分原发性脑肿瘤,尽管成像测试展示肿瘤生长受控制或无肿瘤可见征象,但脑肿瘤常常复发。
在神经胶质瘤中,肿瘤相关的微神经胶质细胞/巨噬细胞(TAM)已展示参与肿瘤生长、肿瘤侵袭、血管生成和免疫系统逃避。TAM在肿瘤微环境中经受再程序化,产生替代性免疫遏制致瘤M2表型(达丰塞卡,巴蒂.临床与发育免疫学2013:264124(da Fonseca AC,Badie B.Clin Dev Immunol 2013:264124))。多种微神经胶质细胞/巨噬细胞调节分子已在临床前研究中展示转变TAM表型并且减弱神经胶质瘤进展并增加存活(安达卢思等人,神经胶质2006;54:526-35(E1Andaloussi A,et,al.Glia 2006;54:526-35);侯赛因等人,癌症研究2007;67:9630-6(Hussain SF,et,al.Cancer Res 2007;67:9630-6);加布瑞思等人,公共科学图书馆·综合2011;6:e23902(Gabrusiewicz K,et,al.PLoS One 2011;6:e23902);马科维奇等人,大脑、行为和免疫2011;25:624-8(Markovic DS,et,al.BrainBehav Immun 2011;25:624-8))。免疫调节分子靶向性传递到TAM可提高功效并降低副作用。
恶性神经胶质瘤是最常见和最具侵袭性的原发性脑肿瘤,并且尽管治疗有所进展,但中位存活期仍在16.4个月。有效疗法的研发中所面对的关键挑战涉及(a)全身性传递的化学治疗剂渗透受损的血脑肿瘤屏障(BBTB)并均匀覆盖整个实体肿瘤的能力以及(b)靶向特定细胞的能力。虽然基于小分子的治疗剂可以有效地分布在肿瘤组织内,但其受快速的肿瘤清除和脱靶外渗限制,可能引起不利影响。近期纳米技术的发展已提供选择性肿瘤累积。但是,大部分纳米粒子的尺寸限制外渗和肿瘤渗透,因此限制均匀覆盖实体肿瘤。已经尝试小心地调整粒径和表面电荷,以增强皮下肿瘤中纳米粒子的分布型态。不幸地,已证实实现原位脑肿瘤均匀覆盖更具挑战性。此可归因于与皮下肿瘤中血液-肿瘤屏障(BTB)相比BBTB的渗透性更低、不均匀的血管间空间和脑肿瘤中高间质压力。虽然,一些策略已尝试经由吸收性摄取使纳米粒子传递穿过BBTB;但仅仅证实在分子小于20nm下被动扩散穿过漏的BBTB穿孔,并且在7nm分子下实现无阻扩散穿过BBTB,因此限制大部分基于纳米粒子的治疗剂的全身投与。
因此,本发明的一个目标是提供一种改善的传递药物以治疗脑肿瘤的方法和试剂。
发明内容
已经研发一种组合物,其包含共价连接于至少一种用于治疗或缓解脑肿瘤的一种或多种症状的治疗剂、预防剂或诊断剂或与其复合的羟基封端的聚(酰胺基胺)(PAMAM)树枝状聚合物。该组合物含有一个或多个乙二胺核心聚(酰胺基胺)(PAMAM)羟基封端的4、5、6、7、8、9或10级(G4-10-OH)树枝状聚合物。G6树枝状聚合物已证实意外高的摄取和均匀分布在整个脑肿瘤中。该等树枝状聚合物提供一种穿过血脑屏障(“BBB”)选择性传递化学治疗剂、免疫治疗剂及缓解剂的方式。该等树枝状聚合物还具有如下优点:多种治疗剂、预防剂和/或诊断剂可以用同一树枝状聚合物传递。在一个实施例中,树枝状聚合物与两种不同类别的化合物复合或结合,提供同时传递。该等树枝状聚合物可以通过静脉内注射单独投与,或作为与辐射和/或手术组合的多叉疗法的一部分投与。在一个实施例中,树枝状聚合物以有效遏制或抑制增生性疾病中DDX3活性的量共价连接于至少一种辐射增敏剂。在另一实施例中,树枝状聚合物以有效检测个体的肿瘤的量共价连接于至少一种可检测部分。在另一实施例中,树枝状聚合物组合物具有与树枝状聚合物复合或结合的多种药剂,例如化学治疗剂、免疫治疗剂、抗惊厥剂、减少肿胀的类固醇、抗生素、抗血管生成剂和/或诊断剂。
树枝状聚合物组合物优选全身性投与,最优选经由静脉内注射投与。组合物可以在手术、辐射或两者前或紧接在其后投与。组合物可以设计用于治疗特定类型肿瘤,例如神经胶质瘤,或靶向与肿瘤相关的微神经胶质细胞/巨噬细胞(TAM)。
实例证实羟基封端的PAMAM树枝状聚合物在胶质母细胞瘤肿瘤模型中在全身性投与后展现独特的有利药物动力学特征。树枝状聚合物迅速累积并选择性地保留在肿瘤组织中。此至少部分归因于小尺寸和接近中性的表面电荷,从而允许树枝状聚合物均匀分布在整个实体肿瘤上。树枝状聚合物均匀地分布在细胞外基质,到达整个肿瘤和瘤周区域。树枝状聚合物本质上靶向神经发炎并累积在肿瘤相关的微神经胶质细胞/巨噬细胞(TAM)中。树枝状聚合物从4级增加到6级可显著增加树枝状聚合物累积在肿瘤中,而不影响其均匀分布和靶向TAM。4和6级羟基封端的PAMAM树枝状聚合物在全身性投与后可以漏过血脑肿瘤屏障,并选择性地累积在胶质母细胞瘤中而非瘤周区域。但是,树枝状聚合物还累积在瘤周区域,从而对胶质母细胞瘤的转移前沿具有作用。这些树枝状聚合物本质上靶向肿瘤相关的微神经胶质细胞/巨噬细胞并保留在这些细胞中超过至少48小时。树枝状聚合物不显著累积在对侧半球(‘健康’)中,其中树枝状聚合物保持在血管内腔中。
4级(G4)树枝状聚合物尽管快速地从循环中清除,但迅速并选择性地累积并且保留在肿瘤组织中。基于荧光定量和高分辨率荧光显微法,树枝状聚合物在开始8小时内累积并且在48小时仍保留在肿瘤中。树枝状聚合物从4级增加到6级可显著增加肿瘤中树枝状聚合物的累积、AUC和保留约100倍,而不影响其均匀分布和靶向TAM。
附图说明
图1A-1C展示用于将小分子BLZ-945结合于G4羟基封端的树枝状聚合物的合成方案。
图2A和2B为说明啮齿动物9L神经胶质肉瘤模型的脑(肿瘤、瘤周区域和对侧半球)中D-Cy5药物动力学的图。图1A为全身性投与后15分钟、1小时、4小时、8小时、24小时和48小时,脑区域中D-Cy5浓度的图。累积表示为每克组织的D-Cy5微克数。图1B为D-Cy5的曲线下面积(“AUC”)的图。在48小时的AUC证实肿瘤与对侧半球之间的树枝状聚合物暴露的显著差异。
图3A为脑定量数据的线性曲线拟合的图。对侧、瘤周和肿瘤的R2分别是0.98、0.99和0.96。图3B展示基于脑药物动力学数据,肿瘤、瘤周区域和对侧半球中渗透常数(Kin)和初始分布体积(Vi)的计算,组织(t)/血清(t)(mL/g)对比AUC血清t/血清(t)(hr)。
图4A和4B描绘使用Imaris软件,表征9L神经胶质肉瘤接种的啮齿动物脑中微神经胶质细胞(群体和活化)。图4A为肿瘤、同侧半球和对侧半球中基于影像的每平方毫米面积Iba1+微神经胶质细胞/巨噬细胞群体的细胞数的图。图4B为肿瘤接种的脑和肿瘤组织的健康脑、对侧半球和同侧半球中基于影像的微神经胶质细胞表面积体积比的测量值的图,指示微神经胶质细胞/巨噬细胞的活化和吞噬细胞活性。1+细胞D-Cy5与Iba1+TAM共定位,并且D-Cy5与DAPI+细胞共定位。结果表示为全部DAPI+细胞群体的百分比。微神经胶质细胞摄取与细胞摄取之间不存在统计显著性。统计*p<0.05;**p<0.001,统计分析基于3-5个不同切片。
图5为投与后24小时,使用基于影像的Iba-1+细胞D-Cy5与Iba1+TAM共定位和D-Cy5与DAPI+细胞共定位的测量,D-Cy5细胞定位分析的图。结果表示为全部DAPI+细胞群体的百分比。微神经胶质细胞摄取与细胞摄取之间不存在统计显著性。
图6A-6C为基于D-Cy5投与后24小时9L神经胶质肉瘤啮齿动物模型的主要器官(脑、肝、肺、脾、心脏和肾)、血清和尿中D-Cy5的基于荧光的定量的图。图6A为生物分布,其以每个器官所注射的剂量的百分比表示:肾、尿和其它器官中的D-Cy5累积。图6B为脾、肝、肾和血清中D-Cy5的时间依赖性浓度的图。浓度以每克组织所注射的剂量的百分比表示。图6C为基于荧光的D-Cy5的血浆药物动力学的定量的图。
图7A-7C为作为时间的函数的G6与G4树枝状聚合物在负载肿瘤的脑中的累积(树枝状聚合物微克数/脑组织克数)(图7A)之间比较的图。肿瘤/瘤周中G4树枝状聚合物的累积在注射后大约8小时达到峰值,并且逐渐降低,而肿瘤/瘤周中G6树枝状聚合物浓度不断增加。在48小时,肿瘤中G6浓度几乎比G4树枝状聚合物浓度高100倍;曲线下面积(AUC)曲线图(图7B),证实在48小时内G6树枝状聚合物具有比G4树枝状聚合物高大约100倍的脑肿瘤暴露。当脑中树枝状聚合物浓度通过血清中树枝状聚合物浓度标准化时,脑/血清比率指示脑靶向能力。在所有时间点G6树枝状聚合物展示比G4树枝状聚合物更高的肿瘤靶向能力(图7C)。
图8A和8B为展示血清和如下主要器官中作为时间的函数的G4和G6树枝状聚合物浓度的图:肾、肝、脾。图8A展示G6树枝状聚合物展示比G4树枝状聚合物更高的血清浓度和延长的血清半衰期,此引起G6树枝状聚合物的肿瘤累积和靶向更高。树枝状聚合物浓度展示为每毫升血清所注射的全部剂量的百分比。图8B展示对于G4树枝状聚合物,在不同时间点,肾具有大部分树枝状聚合物累积(20%-30%),显著高于肝和脾中树枝状聚合物累积(约0.3%)。对于G6树枝状聚合物,尺寸的增加大大降低肾过滤和肾累积。G6树枝状聚合物的肾浓度比G4树枝状聚合物(约1%)小超过10倍,并且从48小时开始,开始展示从肾清除。G6树枝状聚合物的肝累积类似于G4树枝状聚合物,而脾展示高约5倍的累积,此可能归因于单核细胞摄取增加。
具体实施方式
I.定义
术语“治疗剂”是指可以投与以预防或治疗疾病或病症的一种或多种症状的药剂。实例包括(但不限于)核酸、核酸类似物、小分子、肽模拟物、蛋白质、肽、碳水化合物或糖、脂质或表面活性剂,或其组合。
术语“治疗”是指预防或缓解疾病、病症或病状的一种或多种症状。治疗疾病或病状包括缓解特定疾病或病状的至少一种症状,即使潜在病理生理学不受影响;例如通过投与镇痛剂来治疗个体疼痛,尽管此类药剂不治疗该疼痛的原因。
短语“医药学上可接受”是指组合物、聚合物以及其它材料和/或剂型在合理医学判断的范围内,适合与人类和动物的组织接触使用而不产生过度毒性、刺激、过敏反应或其它问题或并发症,与合理的益处/风险比相称。短语“医药学上可接受的载剂”是指在将任何主题组合物从一个器官或身体部分运载或运输到另一个器官或身体部分中所涉及的医药学上可接受的材料、组合物或媒剂,例如液体或固体填充剂、稀释剂、溶剂或囊封材料。每种载剂在与主题组合物的其它成分相容并且对患者无害的意义上必须是“可接受的”。
短语“治疗有效量”是指以可适用于任何药物治疗的合理益处/风险比产生某种所需作用的治疗剂的量。有效量可以取决于例如以下的因素而变化:所治疗的疾病或病状、所投与的特定靶向构筑体、个体的体型或疾病或病状的严重性。所属领域的一般技术人员可以在不必进行过度实验的情况下凭经验确定特定化合物的有效量。
II.调配
A.树枝状聚合物
如本文所用的术语“树枝状聚合物”包括(但不限于)以下分子架构,其具有内部核心、规则地附接到此引发剂核心上的重复单元内部层(或“级”)以及附接到最外级上的端基外表面。树枝状聚合物的实例包括(但不限于)PAMAM、聚酯、聚赖氨酸和PPI。PAMAM树枝状聚合物可以具有羧酸、胺和羟基终端,并且可以是任何级的树枝状聚合物,包括(但不限于)1级PAMAM树枝状聚合物、2级PAMAM树枝状聚合物、3级PAMAM树枝状聚合物、4级PAMAM树枝状聚合物、5级PAMAM树枝状聚合物、6级PAMAM树枝状聚合物、7级PAMAM树枝状聚合物、8级PAMAM树枝状聚合物、9级PAMAM树枝状聚合物或10级PAMAM树枝状聚合物。适合使用的树枝状聚合物包括(但不限于)聚酰胺基胺(PAMAM)、聚丙胺(POPAM)、聚乙烯亚胺、聚赖氨酸、聚酯、蝶烯(iptycene)、脂肪族聚(醚)和/或芳香族聚醚树枝状聚合物。树枝状聚合物复合物的每一树枝状聚合物都可以具有与其它树枝状聚合物类似或不同的化学性质(例如,第一树枝状聚合物可以包括PAMAM树枝状聚合物,而第二树枝状聚合物可以包含POPAM树枝状聚合物)。在一些实施例中,第一或第二树枝状聚合物可以进一步包括其它药剂。多臂PEG聚合物包括具有至少两个携带硫氢基或硫吡啶端基的分支的聚乙二醇;然而,本文所公开的实施例不限于此类别,并且可以使用携带其它端基(例如丁二酰亚胺基或顺丁烯二酰亚胺终端)的PEG聚合物。可以使用分子量10kDa到80kDa的PEG聚合物。
树枝状聚合物复合物包括多个树枝状聚合物。举例来说,树枝状聚合物复合物可以包括第三树枝状聚合物;其中该第三树枝状聚合物与至少一种其它树枝状聚合物复合。此外,第三药剂可以与第三树枝状聚合物复合。在另一个实施例中,第一和第二树枝状聚合物各自与第三树枝状聚合物复合,其中该第一和第二树枝状聚合物是PAMAM树枝状聚合物,并且该第三树枝状聚合物是POPAM树枝状聚合物。可以在不脱离本发明精神的情况下并入其它树枝状聚合物。当利用多种树枝状聚合物时,也可以并入多种药剂,不受彼此复合的树枝状聚合物数目限制。
如本文所用,术语“PAMAM树枝状聚合物”意指使用酰胺基胺构建嵌段的聚(酰胺基胺)树枝状聚合物,其可以含有不同核心。其制造方法是所属领域的技术人员已知的,并且一般来说,涉及围绕中央引发剂核心产生树枝状β-丙氨酸单元的同心壳层(级)的两步反复(iterative)反应程序。此PAMAM核-壳架构随壳层(级)增加而在直径上线性生长。同时,表面基团在每一级根据树枝状分支数学以指数方式扩增。其可以呈具有5种不同核心类型和10种官能性表面基团的G0-10级形式获得。树枝状聚合物分支聚合物可以由聚酰胺基胺(PAMAM)、聚酯、聚醚、聚赖氨酸或聚乙二醇(PEG)、多肽树枝状聚合物组成。
根据一些实施例,所用PAMAM树枝状聚合物可以是羟基附接到其表面官能团上的4级或更高级树枝状聚合物。多臂PEG聚合物包含具有2个和更多个携带硫氢基或硫吡啶端基的分支的聚乙二醇;然而,实施例不限于此类别,并且可以使用携带其它端基(例如丁二酰亚胺基或顺丁烯二酰亚胺终端)的PEG聚合物。可以使用分子量10kDa到80kDa的PEG聚合物。
在一些实施例中,树枝状聚合物呈纳米粒子形式,并且详细地描述于国际专利公开案第W02009/046446号中。
PAMAM-BLZ-945的制备
作为非限制性实例,以下为使用乙酸、2-(2-环辛炔-1-基氧基)酸和2-叠氮基乙酸作为连接子将小分子BLZ-945结合于羟基封端的四级PAMAM树枝状聚合物(PAMAM-OH)的合成方案。参见图1A-1C。
最初,使用2-(2-环辛炔-1-基氧基)酸,将羟基封端的四级PAMAM树枝状聚合物(PAMAM-OH)官能化到表面上具有9个可点击基团的可点击双官能树枝状聚合物(中间物1)(图1A)。BLZ-945与2-叠氮基乙酸反应以经由酯键形成叠氮基官能化的中间物(图1B)。2-叠氮基乙酰基连接子上所得叠氮基进一步与双官能树枝状聚合物的可点击基团反应,得到树枝状聚合物-BLZ-945结合物(图1C)。大约九分子BLZ-945结合于一分子树枝状聚合物。
上述方案不限于BLZ-945。其它小分子,例如信号转导子和转录激活子(STAT)蛋白质的小分子抑制剂(例如WP1066)和其它小分子(例如米诺环素和环孢灵A(cyclosporineA))可以作为TAM靶向疗法的免疫调节分子结合于树枝状聚合物。
B.偶合剂和间隔子
树枝状聚合物复合物可以通过治疗活性剂或化合物(在下文中称为“药剂”)结合或附接到树枝状聚合物或多臂PEG上来形成。附接可以经由在药剂与树枝状聚合物之间提供二硫桥键的适当间隔子进行。在身体中所发现的还原条件下,树枝状聚合物复合物能够通过硫醇交换反应来在体内快速释放药剂。
如本文所用的术语“间隔子”打算包括用于将治疗活性剂连接于树枝状聚合物的组合物。间隔子可以是单一化学实体或连接在一起以将聚合物与治疗剂或成像剂桥连的两个或更多个化学实体。间隔子可以包括具有硫氢基、硫吡啶、丁二酰亚胺基、顺丁烯二酰亚胺、乙烯基砜和碳酸酯终端的任何较小化学实体、肽或聚合物。
间隔子可以选自用硫氢基、硫吡啶、丁二酰亚胺基、顺丁烯二酰亚胺、乙烯基砜和碳酸酯基团封端的一类化合物。间隔子可以包含硫吡啶封端的化合物,例如二硫联吡啶、3-(2-吡啶基二硫基)-丙酸N-丁二酰亚胺酯(SPDP)、6-(3-[2-吡啶基二硫基]-丙酰胺基)己酸丁二酰亚胺酯LC-SPDP或磺基-LC-SPDP。间隔子还可以包括肽,其中肽基本上为线性或环状,具有硫氢基,例如谷胱甘肽、高半胱氨酸、半胱氨酸和其衍生物、arg-gly-asp-cys(RGDG)(SEQ ID NO:1)、环(Arg-Gly-Asp-d-Phe-Cys)(c(RGDfC))(SEQ ID NO:2)、环(Arg-Gly-Asp-D-Tyr-Cys)(SEQ ID NO:3)、环(Arg-Ala-Asp-d-Tyr-Cys)(SEQ ID NO:4)。间隔子可以是巯基酸衍生物,例如3巯基丙酸、巯基乙酸、4巯基丁酸、硫杂环戊-2-酮、6巯基己酸、5巯基戊酸以及其它巯基衍生物,例如2巯基乙醇和2巯基乙胺。间隔子可为硫代水杨酸和其衍生物、(4-丁二酰亚胺基氧基羰基-甲基-α-2-吡啶基硫基)甲苯、(3-[2-吡啶硫基]丙酰肼。间隔子可以具有顺丁烯二酰亚胺终端,其中该间隔子包含聚合物或较小化学实体,例如双-顺丁烯二酰亚胺基二乙二醇和双-顺丁烯二酰亚胺基三乙二醇、双-顺丁烯二酰亚胺基乙烷、双顺丁烯二酰亚胺基己烷。间隔子可以包含乙烯基砜,例如1,6-己烷-双-乙烯基砜。间隔子可以包含硫代糖苷,例如硫代葡萄糖。间隔子可以是经过还原的蛋白质,例如牛血清白蛋白和人类血清白蛋白、能够形成二硫键的任何硫醇封端的化合物。间隔子可以包括具有顺丁烯二酰亚胺、丁二酰亚胺基和硫醇终端的聚乙二醇。
治疗活性剂、成像剂和/或靶向部分可以共价附接或分子内分散或囊封。树枝状聚合物优选地是至多10级的具有羧酸、羟基或胺终端的PAMAM树枝状聚合物。PEG聚合物是具有2个或更多个臂并且分子量为10kDa到80kDa的星形聚合物。PEG聚合物具有硫氢基、硫吡啶、丁二酰亚胺基或顺丁烯二酰亚胺终端。树枝状聚合物经由以二硫键、酯键或酰胺键终止的间隔子连接于靶向部分、成像剂和/或治疗剂。
C.治疗剂、预防剂和诊断剂
如本文所用,术语“树枝状聚合物复合物”是指与一种或多种治疗剂、预防剂或诊断剂结合或复合的树枝状聚合物。树枝状聚合物复合物在通过静脉内注射投与时可以仅在患病情况下并且不在正常情况下优先通过血脑屏障(BBB)。优选地,药剂附接或结合于能够在体内发现的还原条件下优先细胞内释放药物的PAMAM树枝状聚合物或多臂PEG。连接于药剂的树枝状聚合物复合物可以用于进行若干功能,包括靶向、定位在患病部位、释放药物和成像目的。树枝状聚合物复合物可以在有或无靶向部分下标记,使得经由间隔子或连接子分子树枝状聚合物与药剂或成像剂之间形成二硫键。
代表性治疗剂(包括前药)、预防剂或诊断剂可以是肽、蛋白质、碳水化合物、核苷酸或寡核苷酸、小分子或其组合。代表性寡核苷酸包括siRNA、微RNA、DNA和RNA。
术语“化学治疗剂”大体上包括通过干扰癌细胞中DNA合成或功能起作用的医药学上或治疗学上活性化合物。基于其在细胞水平下的化学作用,化学治疗剂可归类为细胞周期特异性药剂(在细胞周期的某些阶段期间有效)和细胞周期非特异性药剂(在细胞周期所有阶段期间都有效)。化学治疗剂的实例包括烷基化剂、血管生成抑制剂、肿瘤免疫反应调节剂、芳香酶抑制剂、抗代谢物、蒽环霉素、抗肿瘤抗生素、铂化合物、拓扑异构酶抑制剂、放射性同位素、辐射增敏剂、检查点抑制剂、PD1抑制剂、APRKinase抑制剂、植物碱、糖酵解抑制剂和其前药。
治疗脑肿瘤常用的代表性化学治疗剂包括紫杉醇(例如太平洋紫杉醇)、BCNU、喜树碱、多西环素、顺铂以及其衍生物、类似物和前药。
PD-1抑制剂的实例包括例如MDX-1106,其为一种对人类PD-1具有特异性的基因工程化的完全人类免疫球蛋白G4(IgG4)单株抗体;和近来US FDA批准的派立珠单抗(pembrolizumab)。
治疗剂可以包括增强例如辐射等不同疗法的作用的药剂。如本文所用的术语“辐射剂量敏化剂”意指当与细胞、细胞群体或组织接触时增加该细胞、细胞群体或组织对电离辐射的敏感性的任何药剂。在一些实施例中,辐射增敏剂为DDX3抑制剂,例如化合物RK-33,或其盐、溶剂化物、立体异构体或衍生物。
治疗剂包括缓解脑肿瘤的一种或多种症状的药剂。举例来说,减少与肿瘤相关的肿胀的药剂可以经由树枝状聚合物传递。实例包括消炎剂,例如类固醇,例如甲基泼尼松(methyl prednisone)、地塞米松(dexamethasone)和氟新诺龙丙酮(fluocinoloneacetonide);非类固醇消炎剂,例如COX-2抑制剂;金化合物消炎剂、免疫遏制剂、水杨酸盐消炎剂、兰比珠单抗、米诺环素和雷帕霉素。其它消炎药包括非类固醇药物,例如吲哚美辛(indomethacin)、阿司匹林(aspirin)、乙酰胺苯酚(acetaminophen)、双氯芬酸钠(diclofenac sodium)和布洛芬(ibuprofen)。
肽药物可以是作用于TAM或癌细胞的任何序列。实例包括具有Lys3Gly3Ser连接子和C端生物素标签的肽(具有序列YEQDPWGVKWWY(SEQ ID NO:5)的M2pep和具有序列WEDYQWPVYKGW(SEQ ID NO:6)的scM2pep),以>95%纯度购自以林生物制药公司(ElimBiopharmaceuticals)。合成KLA材料并以>95%纯度如下纯化:M2pepKLA(YEQDPWGVKWWYGGGS-D[KLAKLAK]2(SEQ ID NO:7))、scM2pepKLA(WEDYQWPVYKGWSGGGS-D[KLAKLAK]2(SEQ ID NO:8))和KLA(D[KLAKLAK]2(SEQ ID NO:9))。
靶向TAM的免疫治疗剂的实例可以包括群落刺激因子-1(CSF-1)受体抑制剂,例如BLZ-945和PLX3397;MAP激酶抑制剂,例如PD98059;STAT小分子抑制剂(例如WP1066);米诺环素和环孢灵A。
其它示例性治疗剂包括血管扩张剂和抗感染剂。抗生素包括β-内酰胺,例如青霉素(penicillin)和安比西林(ampicillin);头胞菌素(cephalosporin),例如头孢呋辛(cefuroxime)、头孢克洛(cefaclor)、头孢力新(cephalexin)、头孢羟氨苄(cephydroxil)、头孢泊肟(cepfodoxime)和普塞(proxetil);四环素抗生素,例如多西环素和米诺环素;大环内酯抗生素,例如阿奇霉素(azithromycin)、红霉素(erythromycin)、雷帕霉素和克拉霉素(clarithromycin);氟喹诺酮(fluoroquinolone),例如环丙沙星(ciprofloxacin)、恩氟沙星(enrofloxacin)、氧氟沙星(ofloxacin)、加替沙星(gatifloxacin)、左氧氟沙星(levofloxacin)和诺氟沙星(norfloxacin);托普霉素(tobramycin)、黏菌素(colistin)或氨曲南(aztreonam)以及已知具有消炎活性的抗生素,例如红霉素、阿奇霉素或克拉霉素。还可以投与具有作为抗兴奋毒性剂的活性的其它药剂,例如丙戊酸、D-氨基膦酰基戊酸酯、D-氨基膦酰基庚酸酯、谷氨酸形成/释放抑制剂(例如氯苯胺丁酸(baclofen))和NMDA受体拮抗剂。
在一些实施例中,分子可以包括抗体,例如达利珠单抗(daclizumab)、贝伐单抗兰比珠单抗巴利昔单抗(basiliximab)、兰比珠单抗和哌加他尼钠(pegaptanib sodium);或肽,如SN50;和NF拮抗剂。
示例性诊断剂包括顺磁分子、荧光化合物、磁性分子和放射性核素、x射线成像剂和造影剂。这些也可以是由前述诊断剂标记的配位体或抗体,或结合于可通过所属领域的技术人员已知的方法检测的经过标记的配位体或抗体。
示例性诊断剂包括染料、荧光染料、近红外染料、SPECT成像剂、PET成像剂和放射性同位素。代表性染料包括羰花青、吲哚羰花青、氧杂羰花青、硫杂羰花青和部花青、聚甲炔、香豆素、若丹明、二苯并哌喃、荧光素、硼-联吡咯甲烷(BODIPY)、Cy5、Cy5.5、Cy7、VivoTag-680、VivoTag-8680、VivoTag-S750、AlexaFluor660、AlexaFluor680、AlexaFluor700、AlexaFluor750、AlexaFluor790、Dy677、Dy676、Dy682、Dy752、Dy780、DyLight547、Dylight647、HiLyte Fluor647、HiLyte Fluor 680、HiLyte Fluor 750、IRDye800CW、IRDye 800RS、IRDye 700DX、ADS780WS、ADS830WS和ADS832WS。
代表性SPEGT或PET成像剂包括螯合剂,例如二亚乙基三胺五乙酸(DTPA)、1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)、二胺二硫醇、活化的巯基乙酰基-甘氨酰基-甘氨酰基-甘氨酸(MAG3)和酰肼烟酰胺(HYNIC)。
代表性同位素包括Tc-94m、Tc-99m、In-111、Ga-67、Ga-68、Gd3+、Y-86、Y-90、Lu-177、Re-186、Re-188、Cu-64、Cu-67、Co-55、Co-57、F-18、Sc-47、Ac-225、Bi-213、Bi-212、Pb-212、Sm-153、Ho-166和Dy-i66。
靶向部分包括叶酸、直链或环状的RGD肽、TAT肽、LHRH和BH3。
D.装置和调配物
树枝状聚合物可以通过硬膜下、静脉内、羊膜内、腹膜内或皮下途径不经肠投与。
本文所用的载剂或稀释剂可以是固体载剂或用于固体调配物的稀释剂、用于液体调配物的液体载剂或稀释剂或其混合物。
对于液体调配物,药学上可接受的载剂可以是例如水性或非水性溶液、悬浮液、乳液或油。不经肠媒剂(用于皮下、静脉内、动脉内或组织内注射)包括例如氯化钠溶液、林格氏右旋糖(Ringer's dextrose)、右旋糖和氯化钠、乳酸林格氏溶液和不挥发性油。非水性溶剂的实例为丙二醇、聚乙二醇和可注射有机酯(例如油酸乙酯)。水性载剂包括例如水、醇/水溶液、环糊精、乳液或悬浮液,包括盐水和缓冲介质。
树枝状聚合物也可以在乳液,例如油包水中投与。油的实例是石油、动物、植物或合成来源的油,例如花生油、大豆油、矿物油、橄榄油、葵花油、鱼肝油、芝麻油、棉籽油、玉米油、橄榄油、石蜡油和矿物油。适合用于不经肠调配物中的脂肪酸包括例如油酸、硬脂酸和异硬脂酸。油酸乙酯和肉豆蔻酸异丙酯是适合的脂肪酸酯的实例。
适合于不经肠投药的调配物可以包括抗氧化剂、缓冲剂、抑菌剂和使得调配物与预期接受者的血液等张的溶质,以及可以包括悬浮剂、增溶剂、增稠剂、稳定剂和防腐剂的水性和非水性无菌悬浮液。静脉内媒剂可以包括流体和营养补充剂、电解质补充剂,例如基于林格氏右旋糖的补充剂。一般来说,水、生理盐水、右旋糖水溶液和相关糖的水溶液以及如丙二醇或聚乙二醇等二醇是优选的液体载剂,尤其对于可注射溶液来说。
所属领域的一般技术人员熟知用于可注射组合物的可注射医药载剂(参见例如制药学和药学实践,利平科特公司,费城,宾夕法尼亚州,班克和查默斯编,第238-250页(1982)(Pharmaceutics and Pharmacy Practice,J.B.Lippincott Company,Philadelphia,PA,Banker and Chalmers,eds.,pages 238-250(1982));和可注射药物的ASHP手册,托塞尔,第4版,第622-630页(2009))(ASHP Handbook on Injectable Drugs,Trissel,15th ed.,pages 622-630(2009)))。
用于对流增强型传递(“CED”)的调配物包括低分子量盐和例如甘露糖醇等糖的溶液。
III.治疗方法
A.待治疗的病症或疾病
包括连接于一种或多种治疗剂、预防剂和/或诊断剂的树枝状聚合物的树枝状聚合物复合物组合物可以选择性地靶向微神经胶质细胞和星形胶质细胞。有效血脑肿瘤屏障(BBTB)渗透和均匀的实体肿瘤分布显著地增强治疗剂传递到脑肿瘤。羟基官能化的4或6级聚(酰胺基胺)(PAMAM)树枝状聚合物因小尺寸、接近中性的表面电荷而选择性地定位在与神经发炎相关的细胞中。
如本文所用,术语“增生性疾病”包括癌症和其它疾病,例如良性和恶性赘瘤和增生。术语癌症包括CNS和脑的癌症,包括(但不限于)神经胶质瘤、胶质母细胞瘤、神经胶质肉瘤、星形细胞瘤、少突神经胶质瘤、室管膜瘤、脑膜瘤、成神经管细胞瘤、神经节瘤、神经鞘瘤、颅咽管瘤、脊索瘤和垂体肿瘤。
肿瘤也可以来自与脑不同的来源。举例来说,肿瘤可以起源于腺泡状横纹肌肉瘤、骨癌、乳癌、肛门、肛管或肛门直肠的癌症、眼癌、肝内胆管癌、关节癌、颈、胆囊或胸膜的癌症、鼻、鼻腔或中耳的癌症、口腔癌、外阴癌、结肠癌、食道癌、子宫颈癌、胃肠道类癌肿瘤、霍奇金淋巴瘤、喉咽癌、肾癌、喉癌、肝癌、肺癌、恶性间皮瘤、黑色素瘤、多发性骨髓瘤、鼻咽癌、非霍奇金淋巴瘤、卵巢癌、胰腺癌、腹膜、网膜和隔膜癌、咽癌、前列腺癌、直肠癌、肾癌(例如肾细胞癌(RCC))、小肠癌、软组织癌、胃癌、睾丸癌、甲状腺癌、输尿管癌和膀胱癌。
树枝状聚合物的投与剂量取决于肿瘤尺寸和类型、位置和其它治疗以及待传递的药剂。通常,主治医生将在考虑到多种因素,例如年龄、体重、总体健康、饮食、性别、待投与的化合物、投药途径和所治疗病状的严重性的情况下决定用于治疗每一个别个体的组合物剂量。一般来说,将调节投药的时间安排和频率以使既定治疗或诊断时程的功效与既定递送系统的副作用平衡。示例性给药频率包括连续输注;单次和多次投药,例如每小时、每日、每周、每月或每年给药。
所属领域的技术人员应了解给药方案可为足够治疗脑肿瘤以减小尺寸、癌转移或生长速率或缓解例如肿胀、疼痛或癫痫等一种或多种症状的任何量和任何时间长度。医师按常规确定待投与的疗法的长度和量。
B.辅助或组合疗法
树枝状聚合物复合物可以与一种或多种已知能够治疗脑肿瘤或与之相关联的症状的其它治疗活性剂组合投与。
举例来说,树枝状聚合物可以经由静脉内投与或在去除所有或一部分肿瘤的手术期间投与脑。树枝状聚合物可以用于传递化学治疗剂、免疫治疗剂、增强例如进行辐射疗法的个体的辅助疗法的药剂,其中羟基封端的聚(酰胺基胺)(PAMAM)树枝状聚合物以有效遏制或抑制脑中增生性疾病中DDX3活性的量,共价连接于至少一种辐射增敏剂。
所属领域的技术人员应了解除化学疗法之外,手术介入和辐射疗法也用于治疗CNS癌症。如本文所用,辐射疗法意指在接近个体的癌症的位置,向该个体给予电离辐射。在一些实施例中,辐射增敏剂投与2剂或更多剂,且随后在个体中接近癌症的位置,向该个体给予电离辐射。在其它实施例中,先投与辐射增敏剂并随后进行电离辐射,可重复2个或更多个周期。
通常,电离辐射剂量随着肿瘤尺寸和位置而变化,但剂量在0.1Gy到约30Gy范围内,优选在5Gy到约25Gy范围内。
在一些实施例中,电离辐射呈立体定向消融辐射疗法(SABR)或立体定向身体辐射疗法(SBRT)形式。
C.成像和诊断学
树枝状聚合物还可用于一种使与个体的增生性疾病相关的TAM成像的方法。树枝状聚合物连接于至少一种可检测部分,以有效检测个体的TAM的量静脉内投与该个体。
树枝状聚合物组合物可以出于治疗诊断学目的进行调配。换句话说,树枝状聚合物组合物可以包含包括至少一种生物活性剂和至少一种可检测部分的多种组合物。在一些情况下,至少一种生物活性剂和至少一种可检测部分可以是相同的分子实体。因此,树枝状聚合物组合物可以用于检测个体体内的增生性疾病或肿瘤并同时传递生物活性剂到肿瘤或TAM。
将通过参考以下非限制性实例进一步理解本发明。
实例1:投与荧光标记的树枝状聚合物到大鼠的神经胶质瘤
材料与方法
购买以下试剂:羟基封端的乙二胺核心PAMAM树枝状聚合物(除非另外说明,否则通篇称为树枝状聚合物)(密歇根州米德兰的德曲科技(Dendritech,Midland,MI))、甲醇(HPLC级)、DMF(HPLC级)、不锈钢珠粒(马萨诸塞州沃尔瑟姆的飞世尔科技公司(FisherScientific,Waltham,MA));以及花青5(Cy5)(宾夕法尼亚州匹兹堡的通用电气医疗集团生命科学部(GE Healthcare Life Science,Pittsburgh,PA))。对于共聚焦显微法:核对比染色、4',6-二甲脒基-2-苯基吲哚二盐酸盐(DAPI)、594山羊抗兔IgG(H+L)抗体(俄勒冈州尤金的分子探针公司(Molecular Probes,Eugene,Oregon));荧光淬灭介质(加利福尼亚州圣克拉拉的达科公司(Dako,Santa Clara,CA));抗Iba1,兔(日本大阪的和光(Wako,Osaka,Japan));来自西非单叶豆凝集素(Bandeiraea simplicifolia)(BSI-B4)的凝集素(密苏里州圣路易斯的西格玛-奥德里奇公司(Sigma-Aldrich,St.Louis,MO));抗GFAP 488(加利福尼亚州圣地亚哥的电子生物科学(eBioscience,San Diego,CA));异硫氰酸荧光素聚葡萄糖(FITC-聚葡萄糖),平均分子量为70,000(密苏里州圣路易斯的西格玛-奥德里奇公司)。
合成树枝状聚合物Cy5(D-Cy5)结合物
D-Cy5根据分子药剂学,10:4560(2013)(Mol Pharmaceutics,10:4560(2013))的方法通过两个步骤制备。简单来说,羟基封端的PAMAM树枝状聚合物表面经氨基改性,以制备双官能树枝状聚合物。6-(Fmoc-氨基)己酸用于产生经Fmoc保护的双官能树枝状聚合物中间物,其通过再溶解于哌啶/DMF混合物而最终脱除保护基。具有N-羟基丁二酰亚胺单酯的Cy5染料与双官能树枝状聚合物的表面上的氨基反应。‘粗’产物通过透析进一步充分纯化。使用1H NMR、高效液相色谱法(HPLC)和凝胶渗透色谱法(GPC)表征最终D-Cy5结合物。结合物呈固体粉末存储在-20℃下并在投与当天用无菌0.9%NaCl以10mg/ml复原。
肿瘤接种
将各自重达125-175g的雌性费舍尔(Fischer)344大鼠(印第安纳州印地安那的哈兰生物产品公司)圈养在标准设施中并自由取用食物和水。9L神经胶质肉瘤颅内植入如神经外科2010,66,530-7(Neurosurgery 2010,66,530-7);神经外科杂志2010,113,210-7(J.Neurosurg.2010,113,210-7)中所述进行。简单来说,9L神经胶质肉瘤(获自加利福尼亚州旧金山UCSF的脑肿瘤研究中心(Brain Tumor Research Center,UCSF,San Francisco,CA))维持在F344的腰窝中。肿瘤以外科手术方式从运载动物的腰窝切除,切成1mm3片并放在冰上无菌0.9%NaCl中供颅内植入。将大鼠麻醉并内侧切开头皮以确定径向和冠状缝合线。在径向缝合线外侧3mm处以及冠状缝合线后部5mm处钻孔。切开硬脑膜,并使用手术显微镜和缓缓抽汲,切除小皮质区域。将肿瘤片放在切除空腔中并使用外科封缝钉闭合皮肤。所有动物都根据约翰霍普金斯大学动物护理与使用委员会(Johns Hopkins UniversityAnimal Care and Use Committee)的策略和准则处理。
投与D-Cy5用于定量和免疫荧光
为进行尾静脉注射,将动物固定并将其尾部加热以诱发血管扩张。每只动物投与3mg/300μl树枝状聚合物-Cy5溶液。为进行树枝状聚合物和聚葡萄糖分布的成像,将3只动物共同注射300μl中2mg D-Cy5和2mg聚葡萄糖-FITC的0.9%NaCl溶液。
为了研究肿瘤脑中树枝状聚合物累积的动力学,当平均肿瘤直径尺寸为6mm时,将D-Cy5注射到27只肿瘤接种大鼠中并且接着在固定时间点(15分钟、1小时、4小时、8小时、24小时和48小时)处死动物。磁共振成像用于测量颅内肿瘤尺寸。通过心脏穿刺来抽血并立即离心以收集血浆。收获大脑并速冻于干冰上,以基于荧光光谱分析进行定量或放在4%福马林溶液中用于免疫荧光。
为了研究树枝状聚合物的细胞摄取,在3只肿瘤接种大鼠和3只健康大鼠中进行D-Cy5注射,并且在注射后24小时处死动物。收获大脑并放在4%福马林中用于免疫荧光研究。
为了研究血浆和全身器官中树枝状聚合物的药物动力学和生物分布,将D-Cy5注射到放在代谢笼中以收集尿的15只肿瘤接种大鼠中,随后在固定时间点(15分钟、1小时、4小时、8小时、24小时和48小时)处死动物。收获器官并速冻于干冰上,以基于荧光光谱分析进行定量或放在4%福马林溶液中用于免疫荧光。
荧光光谱分析
基于荧光的D-Cy5结合物定量根据莱斯尼克,分子药剂学2013年12月2日;10(12):4560-71(Lesniak,Mol Pharm.2013 Dec 2;10(12):4560-71)中的方案。简单来说,使用均质器(TissueLyser LT,凯杰(Giagen)),在2ml DNA LoBind Eppendorf管中,在1ml甲醇中将100-150mg冷冻组织均质化,并随后进行声波处理。悬浮液稀释到100mg/ml并在15,000rpm下在4℃下离心15分钟。所得上清液经受荧光光谱分析。重要的是,先前的研究展示D-Cy5在血浆中稳定,并且可以从组织完整回收,不明显释放结合的Cy5。
对于脑组织,精确切开肿瘤并且瘤周区域被界定为距离肿瘤切开平面多达1mm。在对侧半球中,将100mg具有周围白质区域的尾壳核解剖并用于分析。对于血浆和尿样品,将100μl血浆和尿的样品与900μl磷酸盐缓冲液(0.1M)混合并用荧光光谱分析进行分析。
使用岛津(Shimadzu)RF-5301荧光分光光度计(日本京都(Kyoto,Japan))记录D-Cy5结合物和获自组织提取物的D-Cy5结合物的荧光谱图。根据每个实验,在不同缝隙宽度下,在645nm的激发波长下记录从650nm到720nm的谱图后,使用662nm的最大发射波长,构筑D-Cy5校准曲线。在甲醇或磷酸盐缓冲液(0.1M)中在1ng/ml到100μg/ml范围内的溶液中测量D-Cy5浓度。基于不同样品组所观测到的荧光水平,选择缝隙宽度。对于具有低水平D-Cy5的生物样品(即脑、肺、心脏),激发和发射缝隙宽度设定在10下;对于具有高水平D-Cy5的生物样品(即尿和肾),激发和发射缝隙宽度设定在3下。对于剩余的生物样品,使用激发缝隙宽度5和发射缝隙宽度10。所有校准曲线均展现线性,R2为约0.99。从对注射D-Cy5组织的样品观测到的值减去从未注射D-Cy5的健康大鼠和肿瘤接种大鼠的组织登记的荧光,以解释组织自身荧光。
脑中D-Cy5结合物的浓度以每克组织的微克数表示。其它器官中D-Cy5结合物的浓度以每克组织所注射的剂量的百分比(%)或每个器官所注射的剂量的%表示。尿和血液中D-Cy5结合物的浓度以每毫升尿或血浆总量所注射的剂量的%或尿或血浆总量中所注射的剂量的%表示。基于动物重量计算总血浆浓度(核医学杂志,1985,26,72-6(J.Nucl.Med.,1985,26,72-6))。分析脑和血浆定量数据以计算曲线下面积(AUC)和脑/血清比率。
在脑肿瘤中计算渗透常数(Kin)和初始分布体积(Vi)(纳米医学(伦敦)2013,9,111-21(Nanomedicine(Lond)2013,9,111-21);脑血流与代谢杂志1983,3,8-32(J.Cereb.Blood Flow Metab.1983,3,8-32))。针对每个时间点,计算脑/血清比率和血清(AUC(血清)(t))对血清浓度(血清(t))的曲线下面积,并进行线性回归分析,以基于以下等式得到Kin和Vi:
对于脑中的所有三个区域,多个时间点回归分析展示良好线性,对侧半球、瘤周和肿瘤区域的R2分别等于0.98、0.99和0.96(图3A)。
免疫荧光
将刚收获的组织固定在4%福马林中24小时,接着蔗糖溶液的梯度,随后冷冻切片。接着使用徕卡(Leica)CM 1905低温恒温器,将组织横向切成30μm厚的切片。切片用DAPI(核)、针对微神经胶质细胞/巨噬细胞的兔抗Iba1抗体和山羊抗兔595二级抗体染色。一些切片用针对内皮细胞染色的异凝集素染色。接着使用共焦LSM 710显微镜(卡尔蔡司(CarlZeiss);英国赫特福德郡(Hertfordshire,UK))在5X、20X、40X和63X放大率下使切片成像。对于肿瘤接种大脑的每个切片,获得肿瘤、肿瘤边界和对侧半球的影像。对于对照(非肿瘤)大脑,获得1-3个代表性影像。基于未注射的对照大鼠大脑将设置最佳化以避免背景荧光。针对每个放大率,分开选择激光功率、针孔、增益、偏移和数位增益,并在整个研究中保持恒定。
软件
为处理影像,使用Zen软件,在整个相同放大率影像中。亮度和对比度的任何调整保持恒定。对Cy5通道不进行调整。Imaris软件用于细胞计数、共定位和微神经胶质细胞表面积与体积比的测量。微软Excel 2010和KaleidaGraph 4.0用于与药物动力学研究相关的所有计算、曲线拟合和绘图。
细胞计数和共定位
为进行微神经胶质细胞/巨噬细胞的细胞计数,分析20X 13×13平铺扫描影像并且每个区域分析3-5个切片。功能‘点’用于鉴别Iba1+微神经胶质细胞/巨噬细胞。设定4.15μm的直径阈值以消除小于微神经胶质细胞的物体,并且基于‘质量’分析设定26.801的强度阈值以消除背景信号。
为研究共定位,使用40X 4×4平铺扫描影像,并且每个区域分析3-5个载片。功能‘点’用于鉴别DAPI+核、Iba1+微神经胶质细胞/巨噬细胞和D-Cy5+细胞。对于摄取D-Cy5的细胞,计数具有D-Cy5和DAPI共定位的点;对于摄取D-Cy5的微神经胶质细胞,计数具有DAPI、抗Iba1和D-Cy5共定位的点。应用估计直径以消除尺寸小于细胞的点,并且基于‘质量’分析应用信号阈值。通过计数其中D-Cy5信号和细胞信号彼此相距10μm内的点,使用功能共定位点。
为对微神经胶质细胞进行表面积与体积比分析,在共焦显微镜中,使用40X放大率,在3×3平铺扫描下,在z堆叠中在z方向上延伸10μm,获得微神经胶质细胞形态的3D图示。使用功能‘表面’,并且针对每个细胞的表面和体积,分析个别Iba1+微神经胶质细胞/巨噬细胞。分析肿瘤区域、同侧(非肿瘤区域)、对侧区域和非肿瘤大脑,每个区域包括大约150个细胞。阈值的设置是基于细胞的直径(自然神经科学2009,12,872-8(Nat.Neurosci.2009,12,872-8))
统计分析
根据需要,通过斯图登氏t检验(student's t-test)和单向ANOVA,接着盖姆斯-豪厄尔检验(Games-Howell test),使用SPSS 18.0(IBM公司(IBM,Inc.))进行数据的统计分析。认为在p<0.05下差异为统计学上显著的。
结果
颅内脑肿瘤中全身性传递的D-Cy5的药物动力学
图2A和2B展示负载肿瘤的啮齿动物脑的不同区域中D-Cy5的药物动力学分析:肿瘤、瘤周和对侧半球。分开列出在48小时的AUC以证实肿瘤与对侧半球之间的巨大差异。基于荧光共聚焦显微镜,树枝状聚合物早在全身性投与后十五分钟,就迅速地累积在整个5mm肿瘤中。
相比之下,使用肿瘤接种的啮齿动物脑的共聚焦显微影像,在全身性投与D-Cy5后,在‘健康’对侧半球中,树枝状聚合物囊括在血管中,并且在薄壁组织中未观测到。影像指示D-Cy5均匀分布在肿瘤中并且树枝状聚合物限制在血管内腔中。全身性投与后十五分钟,树枝状聚合物分散在整个颅内肿瘤薄壁组织中。此分布不受肿瘤薄壁组织的不均匀性影响。此时,无明显的细胞摄取。在全身性投与树枝状聚合物后4小时,肿瘤区域中的细胞外分布降低,伴随着Iba1+发炎性细胞的摄取增加。对侧半球展示所有时间点相对最少的D-Cy5荧光。
为了评估脑中树枝状聚合物累积的动力学,使用近来研发的基于荧光的半定量方法用于D-Cy5。使用近红外Cy5波长克服了组织自身荧光的挑战。此方法的高灵敏度(0.1ng/g组织)允许在特定解剖位置检测树枝状聚合物的累积。根据共聚焦显微法结果,树枝状聚合物迅速地累积在肿瘤和瘤周区域中,峰值浓度出现在8小时。参见图3A。树枝状聚合物以~0.01微克/克/小时的速率从肿瘤逐渐清除,并以~0.007微克/克/小时的速率从瘤周区域逐渐清除,在初始全身性注射后48小时,到达0.2μg/g组织的浓度。在对侧半球中,树枝状聚合物累积也在8小时达到峰值,浓度比在肿瘤区域中发现的浓度低~8倍。在24小时,可以在对侧半球中检测到痕量树枝状聚合物(0.03μg/g)并且观测到在肿瘤中的累积高~14倍。在48小时,与对侧半球相比,肿瘤区域中AUC高10倍,表明树枝状聚合物显著更高(p<0.05)地整体暴露于肿瘤。在投与树枝状聚合物后24小时,在针对星形胶质细胞染色的肿瘤的低放大率影像中,目测树枝状聚合物高度和选择性地保留在肿瘤和瘤周区域中。
已经证明肿瘤核心与肿瘤边界之间,血管和BBTB破坏的量显著地不同,此可能在药物累积中起到显著的作用。因此,将血管内皮细胞染色,以检查肿瘤与瘤周区域之间血管的差异并且因此检查灌注的差异。如所预期,瘤周区域和肿瘤边界展示比肿瘤核心显著更致密的血管。但是,树枝状聚合物分布在肿瘤中呈现均一。
为了进一步了解肿瘤中树枝状聚合物渗透的动力学,计算肿瘤、瘤周区域和对侧半球中的渗透常数(Kin)和初始分布体积(Vi)。参见图3B。Kin描述树枝状聚合物从血液到脑的流入,并且与对侧半球比较,肿瘤和瘤周区域中高10倍,表明树枝状聚合物的渗透增加以及对肿瘤组织的渗透性和灌注增加。Vi表示与血浆快速平衡的脑隔室的体积,在肿瘤与瘤周区域之间显著不同,表明肿瘤核心中快速平衡的体积更大。在肿瘤异种移植物中,与肿瘤边界相比,低氧的肿瘤核心增加血管渗透性,并且在胶质母细胞瘤中,具体地说,已经展示肿瘤核心与瘤周区域之间的BBTB形态的明显差异,相较于瘤周区域,此可能影响肿瘤核心中的快速分布。
D-Cy5的生物分布:颅内脑肿瘤中基于成像的研究
为了研究肿瘤和瘤周区域中的树枝状聚合物分布,D-Cy5与尺寸是树枝状聚合物尺寸的大约两倍的线性聚葡萄糖-FITC(70kDa,~6.5nm半径)共同注射。基于增加的DAPI阳性核的密度,清楚鉴别肿瘤。参见图4A和图4B。在每个时间点,树枝状聚合物均匀分布在整个肿瘤区域中并且在注射后24小时观测到信号显著降低。参见图5。相比之下,仅仅在肿瘤边界周围观测到来自聚葡萄糖-FITC的信号,而肿瘤核心中未观测到,即使激光功率和增益设置增加到在FITC通道中看到背景信号。更高放大率的影像展示树枝状聚合物迅速分布并且划定细胞外基质(ECM)界限,引起分布的网状模式和逐渐累积在细胞中。相反地,聚葡萄糖展示有限分布在细胞外基质中,但在注射后十五分钟,可以在血管内腔内看到高度信号。在后来时间点,可能由于低细胞摄取,有限量的聚葡萄糖保留在组织中。
肿瘤相关的微神经胶质细胞/巨噬细胞的表征和树枝状聚合物的细胞摄取
神经胶质瘤产生促进微神经胶质细胞/巨噬细胞募集和增殖的化学引诱剂和生长因子。在人类胶质母细胞瘤中,多达30%的细胞可能为肿瘤相关的巨噬细胞。在9L肿瘤模型的不同解剖位置中测定微神经胶质细胞分布,此表明此肿瘤模型中TAM的浓度类似于人类胶质母细胞瘤中所见到的浓度。与对侧半球相比,肿瘤内每平方毫米的微神经胶质细胞群体高9倍,并且与对侧相比,同侧半球的健康脑组织中每平方毫米的微神经胶质细胞群体高2.5倍。
TAM在肿瘤微环境中再程序化,产生替代性免疫抑制M2表型。但是,许多研究已经表明神经胶质瘤中持续的TAM的吞噬细胞活性。已经表明TAM的吞噬细胞活性在纳米粒子摄取中起到关键作用。当微神经胶质细胞/巨噬细胞从静息形式变成活化形式时,其形态从分支状改变成似变形虫,表明其吞噬细胞活性增加。为了评估9L肿瘤模型中TAM的形态,表征不同解剖位置的免疫细胞群体(Iba1+)的表面积与体积比。表面积与体积比(S/V比率)被认为是微神经胶质细胞活化的‘量度’。结果表明与对侧半球中和健康脑中的免疫细胞相比,肿瘤内和肿瘤周围的微神经胶质细胞/巨噬细胞具有显著(p<0.001)较低的S/V比率。肿瘤相关的微神经胶质细胞的平均S/V比率低于1,表明其类变形虫状态和吞噬细胞活性。基于影像,对肿瘤、同侧半球和对侧半球中每平方毫米面积的Iba1+微神经胶质细胞/巨噬细胞群体进行细胞计数。基于影像的微神经胶质细胞的表面积体积比的测量表明肿瘤接种的脑和肿瘤组织的健康脑、对侧半球和同侧半球中微神经胶质细胞/巨噬细胞的活化和吞噬细胞活性。1+细胞D-Cy5与Iba1+TAM共定位,并且D-Cy5与DAPI+细胞共定位。结果表示为全部DAPI+细胞群体的百分比。微神经胶质细胞摄取与细胞摄取之间不存在统计显著性。统计*p<0.05;**p<0.001,统计分析基于3-5个不同切片。参见图4A和图4B。
接着计算Iba1+微神经胶质细胞/巨噬细胞中D-Cy5的定位。在全身性投与后24小时,树枝状聚合物定位于Iba1+TAM中。计算Iba1+微神经胶质细胞/巨噬细胞,占全部肿瘤细胞群体的38%(图5)。共定位表明大约一半的TAM群体吸收树枝状聚合物并且树枝状聚合物阳性细胞的全部群体与树枝状聚合物阳性Iba1+微神经胶质细胞/巨噬细胞的群体在数量上没有不同。因此,树枝状聚合物几乎完全被肿瘤组织内的肿瘤相关的巨噬细胞吸收,而肿瘤区域内的其它细胞无可测量的树枝状聚合物摄取。在肿瘤边界(基于DAPI染色,离肿瘤边缘1mm)中,树枝状聚合物阳性微神经胶质细胞/巨噬细胞基本上减少,反映了肿瘤核心与肿瘤边界之间的生物过程差异。在同侧非肿瘤区域中或在对侧半球中不存在树枝状聚合物。
在投与后24小时,使用基于影像的Iba1+细胞D-Cy5与Iba1+TAM共定位和D-Cy5与DAPI+细胞共定位的测量,进行D-Cy5细胞定位分析。结果表示为全部DAPI+细胞群体的百分比。微神经胶质细胞摄取与细胞摄取之间不存在统计显著性。9L神经胶质肉瘤接种的脑的不同解剖位置的高放大率(40X)荧光共焦成像。
D-Cy5的全身性生物分布
全身性投与24小时后,所提取的D-Cy5的荧光定量表明56%的树枝状聚合物通过尿排出,而32%保持在肾中。此与同一时间点的低血清含量(0.66%,图6A)非常相关。全身性投与24小时后,仅仅2.5%的树枝状聚合物累积在其它主要器官中。1.5%的这些树枝状聚合物保留在肝和脾中,表示被网状内皮系统(RES)消除。痕量累积在脑、肺和心脏中。
为了更好地了解动力学,随时间推移测量血清和主要器官中的树枝状聚合物浓度(图6B)。在长达24小时的所有选择时间点下,肾的累积递增。全身性投与后48小时,肾中树枝状聚合物的量开始下降。树枝状聚合物血清含量迅速下降,在全身性注射后15分钟观测到仅仅4%的所注射的剂量(图8A)。
图6A展示在D-Cy5投与后24小时9L神经胶质肉瘤啮齿动物模型的主要器官(脑、肝、肺、脾、心脏和肾)、血清和尿中D-Cy5的基于荧光的定量。生物分布以每个器官所注射的剂量的百分比表示;(插图):肾、尿和其它器官中的D-Cy5累积。(6B)脾、肝、肾和血清中D-Cy5的时间依赖性浓度。浓度以每克组织所注射的剂量的百分比表示。(57C)基于荧光的D-Cy5的血浆药物动力学的定量
肾累积和分布
肾系统中高浓度的树枝状聚合物引起对肾中分布的研究,以评估累积部位。基于荧光显微法,树枝状聚合物累积在肾皮质中。树枝状聚合物与染色肾小管周边成纤维细胞的抗GFAP抗体共定位。在肾小球中未观测到树枝状聚合物的存在。在健康和负载肿瘤的大鼠中肾清除率无显著差异。
概述和结论
恶性神经胶质瘤是最常见的原发性脑肿瘤并且引起的寿命损失比任何其它肿瘤都多。在临床前和临床试验中多个传统小分子化学治疗药物无法对天然病史产生强有力的影响,因为其在全身性投与后累积低并且从肿瘤快速清除。
在48小时,脑肿瘤中的树枝状聚合物累积比对侧半球中高11倍。与其它非靶向性纳米粒子相比,此比率突出,并与主动靶向性磁性纳米粒子相当。重要的是,还观测到高度保留在瘤周区域中。胶质母细胞瘤细胞具有高度浸润性并且可以在具有完整血脑屏障的解剖位置中发现;因此,实现高度保留在瘤周区域对于设计有效的治疗媒剂来说显然是重要的。树枝状聚合物选择性保留在肿瘤和瘤周区域中与低循环半衰期组合允许化学治疗剂特异性传递以及有限的脱靶作用。
实例2:羟基封端的6级PAMAM树枝状聚合物作为治疗胶质母细胞瘤的治疗媒剂
材料与方法
除了利用4级和6级羟基封端的PAMAM树枝状聚合物,材料和方法如实例1中所述。
为了研究肿瘤脑中树枝状聚合物累积的动力学,当平均肿瘤直径尺寸为6mm时,将树枝状聚合物注射到肿瘤接种的大鼠,并接着在不同时间点处死动物。
结果
化学治疗剂的功效直接与肿瘤中累积量量相关。树枝状聚合物尺寸从4级增加到6级使得其流体动力学直径从约4.3nm增加到约6.7nm,而不显著影响其ζ电位(表1)。使用动态光散射,在PBS pH 7.4中在室温下测量流体动力学直径(尺寸)和表面电荷(ζ电位)。分子量由供应商提供。
表1:4级(G4-OH)和6级(G6-OH)羟基封端的树枝状聚合物的物理化学特性
树枝状聚合物MW(kDa)尺寸+SEM(nm)ζ–电位+SEM(mV)
实例1展示当全身性投与9L神经胶质肉瘤接种的大鼠时,在D-Cy5投与后24小时,G4树枝状聚合物选择性地累积在TAM中。但是,尺寸的增加使得G6树枝状聚合物避免了由肾过滤所引起的快速清除并且在血液中循环更长时间,从而更好地定位和保留。G6树枝状聚合物展示比G4树枝状聚合物更高的血清浓度和延长的血清半衰期,此引起G6树枝状聚合物更高的肿瘤累积和靶向。
图7A-7C为作为时间的函数的G6与G4树枝状聚合物在负载肿瘤的脑中之间的累积(树枝状聚合物微克数/脑组织克数)(图7A)比较的图。肿瘤/瘤周中G4树枝状聚合物的累积在注射后大约8小时达到峰值,并且逐渐降低,而肿瘤/瘤周中G6树枝状聚合物浓度不断增加。在48小时,肿瘤中G6浓度几乎比G4树枝状聚合物浓度高100倍;曲线下面积(AUC)曲线图(图7B),证实在48小时内G6树枝状聚合物具有比G6树枝状聚合物高大约100倍的脑肿瘤暴露。
当脑中树枝状聚合物浓度通过血清中树枝状聚合物浓度标准化时,脑/血清比率指示脑靶向能力。在所有时间点G6树枝状聚合物展示比G4树枝状聚合物更高的肿瘤靶向能力(图6C)。树枝状聚合物浓度展示为每毫升血清所注射的全部剂量的百分比。对于G4树枝状聚合物,在不同时间点,肾具有大部分的树枝状聚合物累积(20%-30%),显著高于肝和脾中的树枝状聚合物累积(约0.3%)。对于G6树枝状聚合物,尺寸的增加大大降低肾过滤和肾累积。G6树枝状聚合物的肾浓度比G4树枝状聚合物(约1%)小超过10倍,并且从48小时开始,开始展示从肾清除的证据。G6树枝状聚合物的肝累积类似于G4树枝状聚合物,而脾展示高约5倍的累积,此可能归因于单核细胞摄取增加。高血清浓度提供G6树枝状聚合物跨越血脑肿瘤屏障扩散并更好地靶向肿瘤的动力,同时以比G4树枝状聚合物高100倍的浓度和AUC(在48小时)累积在肿瘤中(图7B)。
胶质母细胞瘤复发高频率地发生在侵袭性治疗后存活的个别细胞中。出于此原因,任何治疗媒剂能够到达每个肿瘤细胞是重要的。纳米技术领域中的近期研究已经强调纳米粒子在整个肿瘤组织中的有效分布是功效的先决条件。大部分这些研究揭露了当投与肿瘤时尺寸范围在10-50nm之间的纳米粒子可以均匀地分布在实体肿瘤中。尺寸低于100nm的更大纳米粒子不大可能均匀分布在整个肿瘤床中,因为其中不存在血管的纤维组织交织在癌细胞巢之间,形成分子均匀分布的扩散屏障。但是,纳米粒子的均匀分布还需要其在无任何阻碍下从血管均一外渗。在胶质母细胞瘤的情况下,考虑到与皮下肿瘤相比,颅脑肿瘤中更小的穿孔和孔径,此需要将尺寸截止值的上限进一步降至10nm。7nm的分子已实现无阻扩散穿过BBTB。
电荷密度也影响纳米粒子的渗透。对于纳米粒子,重要的是维持中性或微正电荷而非强阳离子,以防止静电产生的结合位点屏障作用。结果,具有4.3nm的流体动力学直径和中性表面电荷的G4 OH PAMAM树枝状聚合物可以在15分钟内迅速地穿过维管间空间分布并均匀涵盖整个5mm肿瘤。级数增加到G6不仅保留树枝状聚合物均匀分布在脑肿瘤中的能力,而且还防止树枝状聚合物从肿瘤薄壁组织迅速地清除。
G4和G6树枝状聚合物通过尾静脉在静脉内共同注射到负载肿瘤的大鼠中。将脑固定并轴向冷冻切片。参见图8A和8B。图8A和8B为展示血清和如下主要器官中作为时间的函数的G4和G6树枝状聚合物浓度的图:肾、肝、脾。图8A展示G6树枝状聚合物展示比G4树枝状聚合物更高的血清浓度和延长的血清半衰期,此引起G6树枝状聚合物的肿瘤累积和靶向更高。树枝状聚合物浓度展示为每毫升血清所注射的全部剂量的百分比。G6树枝状聚合物的肝累积类似于G4树枝状聚合物,而脾展示高约5倍的累积,此可能归因于单核细胞摄取增加。
G4树枝状聚合物具有比G6树枝状聚合物更快的分泌速率。图8B展示对于G4树枝状聚合物,在不同时间点,肾具有大部分树枝状聚合物累积(20%-30%),显著高于肝和脾中树枝状聚合物累积(~0.3%)。对于G6树枝状聚合物,尺寸的增加大大降低肾过滤和肾累积。G6树枝状聚合物的肾浓度比G4树枝状聚合物(~1%)小超过10倍,并且从48小时开始,开始展示从肾清除。对于G4树枝状聚合物,在静脉内注射后,立即(~15分钟)开始从血管分泌到肿瘤组织,接着在8小时后从肿瘤清除。注射后24小时后,G4树枝状聚合物保留在细胞中。对于G6树枝状聚合物,在投与后未立即观测到肿瘤组织中树枝状聚合物的存在。在整个观测时间段中G6树枝状聚合物的浓度逐渐增加。在投与后48小时,G6树枝状聚合物展示在肿瘤区域中浓度最高。其均匀分布在胶质母细胞瘤中,包括肿瘤细胞的迁移前沿,以及其保留在肿瘤中至少48小时,证实树枝状聚合物适宜有效传递治疗剂。
除在全身性投与时跨越肿瘤床均匀分布外,树枝状聚合物还可以累积在其中神经胶质瘤细胞深度、活性地经血管周和神经周侵袭到正常神经组织中的瘤周区域中。各种技术已经应用于靶向瘤周区域,例如使用GFAP特异性单株抗体以改变纳米粒子的表面特性,以及使用磁场引导磁性纳米粒子累积。对于树枝状聚合物,在不对靶向配位体进行任何修饰或添加下,瘤周区域中曲线下面积(AUC)达到肿瘤区域中曲线下面积的60%,表明树枝状聚合物能够在本质上靶向瘤周区域。
最后,树枝状聚合物靶向神经发炎细胞并且基本上以及仅仅定位在TAM中,而非肿瘤区域中的静息分支状微神经胶质细胞不吸收树枝状聚合物。树枝状聚合物特异性累积在TAM中与低累积在网状内皮系统中以及从快速清除提供了传递靶向TAM的抗神经胶质瘤疗法的独特优点。
对于所属领域的技术人员来说,本文所述的方法和材料的修改和变化将是显而易知的,并且意图涵盖于权利要求书内。
Claims (10)
1.一种治疗个体的增生性疾病的方法,其包含以有效遏制或抑制所述个体的所述增生性疾病的一种或多种症状或使所述增生性疾病成像的量,向所述个体全身性投与包含与至少一种治疗剂、预防剂或诊断剂共价连接或复合的羟基封端的聚(酰胺基胺)(PAMAM)树枝状聚合物的组合物。
2.根据权利要求1所述的方法,其中所述树枝状聚合物为共价连接于至少一种治疗剂的4-10级羟基封端的聚(酰胺基胺)(PAMAM)树枝状聚合物。
3.根据权利要求1所述的方法,其中所述PAMAM树枝状聚合物为6级PAMAM树枝状聚合物。
4.根据权利要求1至3中任一权利要求所述的方法,其中所述树枝状聚合物结合于第一治疗剂和选自由治疗剂、预防剂和诊断剂组成的群组的第二药剂。
5.根据权利要求4所述的方法,其中所述树枝状聚合物结合于两种治疗剂。
6.根据权利要求5所述的方法,其中所述树枝状聚合物结合于化学治疗剂和消炎剂和/或抗兴奋性毒性剂。
7.根据权利要求1至6中任一权利要求所述的方法,其中所述树枝状聚合物复合物包括用于定位和靶向微神经胶质细胞和星形胶质细胞的治疗活性剂。
8.根据权利要求1至7中任一权利要求所述的方法,其中所述增生性疾病在所述个体的脑中。
9.根据权利要求1至8中任一权利要求所述的方法,其中结合于治疗剂的所述树枝状聚合物在单位剂量中以有效缓解所述增生性病症的量存在。
10.根据权利要求1至9中任一权利要求所述的方法,其中所述药剂选自由以下组成的群组:肽、蛋白质、碳水化合物、核苷酸或寡核苷酸、小分子以及其组合。
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