CN117750946A - 包括唾液酸结合配体的新型颗粒组合物 - Google Patents
包括唾液酸结合配体的新型颗粒组合物 Download PDFInfo
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- CN117750946A CN117750946A CN202280050112.0A CN202280050112A CN117750946A CN 117750946 A CN117750946 A CN 117750946A CN 202280050112 A CN202280050112 A CN 202280050112A CN 117750946 A CN117750946 A CN 117750946A
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Abstract
本发明提供了在其表面上呈现非缀合唾液酸残基的聚合物颗粒、其组合物和使用方法,以及产生在其表面上具有唾液酸部分的纳米颗粒和微米颗粒的非缀合方法。
Description
相关申请
本申请要求于2021年6月8日提交的第63/208,150号美国临时申请的优先权。以上申请的全部教导通过引用并入本文。
背景技术
唾液酸,也称为N-乙酰神经氨酸,可与唾液酸结合免疫球蛋白样凝集素(Siglec)结合。唾液酸主要有三种衍生物,N-乙酰神经氨酸(Neu5Ac)、N-乙酰神经氨基酸羟烷基(Neu5Gc)和3-脱氧-D-甘油-D-半乳糖基-壬基酮糖(Kdn)。还存在由这些主要衍生物衍生的其他唾液酸衍生物。一种重要的唾液酸衍生物是神经节苷脂,它存在于大脑中。
Siglec,其由各种免疫细胞表达,并具有细胞内免疫受体酪氨酸基抑制基序(ITIM),该基序可以介导与唾液酸结合的抑制信号,并通过酪氨酸磷酸酶SHP-1和SHP-2的募集激活下游抑制信号。唾液酸还可以调节补体激活的替代途径。主要血清蛋白补体因子H将唾液酸识别为“自我”标记物,有助于抑制C1q/C3b片段的激活。此外,唾液酸还结合在几种类型的癌症中过表达的碳水化合物结合凝集素。
唾液酸和Siglec之间的异常相互作用与许多病理相关,包括感染、自身免疫和癌症。因此,将特定类型的细胞上的Siglec与包含唾液酸残基的化学或生物实体结合,以调节免疫抑制或免疫激活,从而治疗包括感染、自身免疫和癌症在内的疾病,这在治疗上是有益的。然而,很难在体内使用唾液酸的这种分子实体递送到靶细胞。一种常见的策略是将唾液酸或聚唾液酸分子附着在纳米颗粒的表面上,使得纳米颗粒可以将唾液酸实体携带到靶细胞上。
此外,当唾液酸与某些类型的免疫细胞上的Siglec结合时,包含唾液酸部分的化学实体可以作为配体附着在颗粒上,以将所述颗粒引导至免疫细胞,并使颗粒与细胞上的Siglec结合。这种结合可以促进颗粒通过受体介导的内吞作用进入细胞。以这种方式,负载有治疗剂及表面涂覆有唾液酸或含唾液酸的实体的纳米颗粒可以靶向免疫细胞并将治疗剂递送到细胞中。
纳米医学是靶向给药的重要工具。理想的是,系统给药的载药纳米颗粒在到达靶向位点之前需要较长的循环时间。目前延长纳米颗粒体内循环的策略是对颗粒表面进行聚乙二醇化(PEGylate),以防止纳米颗粒被网状内皮系统(RES)吸收。然而,聚乙二醇化纳米颗粒可能会导致PEG-特异性抗体的产生,并减轻药物释放和靶细胞相互作用,从而损害治疗效果。因此,需要开发能够在替代聚乙二醇(PEG)的同时延长纳米颗粒在体内循环的新策略。
目前将唾液酸附着到纳米颗粒表面的方法是通过化学缀合。例如,唾液酸分子可以用能够与纳米颗粒表面上的另一个反应性基团形成共价键的反应基团官能化。然而,此方法存在缀合效率低和副反应导致药物制剂中产生不需要的副产物的问题。
因此,对于将含有唾液酸的配体附着到纳米颗粒表面的新方法的需求尚未得到满足。
发明内容
本发明提供了在其表面上呈现非缀合唾液酸残基的聚合物颗粒、其组合物及其使用方法,以及制备在其表面具有唾液酸部分的纳米颗粒和微米颗粒的非缀合方法。
本发明包括一种组合物,所述组合物包括在其表面上呈现唾液酸残基的聚合物颗粒,其中所述颗粒是微米颗粒或纳米颗粒;其中每个颗粒包括可生物降解的聚合物和包括唾液酸残基的聚唾液酸,其中唾液酸残基未缀合到所述颗粒的表面。所述可生物降解的聚合物优选为药学上可接受的可生物降解的聚合物。在有些方面,所述可生物降解的聚合物可选自聚丙交酯(PLA)、聚(丙交酯-共-乙交酯)(PLGA)、乙二醇和丙交酯/乙交酯的共聚物(PEG-PLGA)、乙二醇和丙交酯的共聚物(PEG-PLA)、乙二醇和乙交酯的共聚物(PEG-PGA)、聚(乙二醇)(PEG)、聚己内酯(PCL)、聚酸酐(PANH)、聚(邻酯)、聚氰基丙烯酸酯、聚(羟基链烷酸酯)(PHA)、聚(己酸酯)、聚膦腈、聚磷酸酯、改性聚(糖)及其混合物和共聚物。在某些实施方案中,所述可生物降解的聚合物是PLGA。在另外的方面,可生物降解的聚合物和聚唾液酸形成互穿网络。所述颗粒可进一步包括活性剂,例如活性药物成分。
本发明还包括一种用于将活性剂给药有需要的受试者的方法,其包括向所述受试者给药所述组合物,所述组合物包括在其表面上呈现唾液酸残基的颗粒,其中所述颗粒是微米颗粒或纳米颗粒;其中每个颗粒包括可生物降解的聚合物和包括唾液酸残基的聚唾液酸,其中所述唾液酸残基未缀合到所述颗粒的表面;并且进一步地,其中所述颗粒包括所述活性剂。所述活性剂可以是活性药物成分。在某些方面,活性剂被封装到所述颗粒中。
本发明进一步包括一种治疗有需要的受试者的疾病或紊乱的方法,其包括向所述受试者给药本文所述的颗粒。
本发明包括一种制备在其表面上呈现唾液酸残基的微米颗粒或纳米颗粒的方法,其包括:(1)将可生物降解的聚合物(和任选的活性剂,例如药物成分(API)或难溶于水的化合物)溶于第一溶剂以形成聚合物溶液;(2)在第二溶剂的溶液中乳化所述聚合物溶液以形成乳液,其中所述第一溶剂与所述第二溶剂不混溶或部分混溶,以及其中所述第二溶剂的溶液包括聚唾液酸,所述第二溶剂的溶液任选地进一步包括可溶于所述第二溶剂的表面活性剂和/或API;以及(3)移除所述第一溶剂以形成具有表面唾液酸部分的所述微米颗粒或纳米颗粒。
本申请还提供了一种用于制备在其表面上呈现唾液酸部分的微米颗粒或纳米颗粒的方法,所述方法包括:(1)将可生物降解的聚合物(和任选的活性剂,API,或难溶于水的化合物)溶于第一溶剂以形成聚合物溶液;(2)将第二溶剂的第一溶液添加到所述聚合物溶液中以形成混合物,其中所述第一溶剂与第二溶剂不混溶或部分混溶,以及其中所述第二溶剂的第一溶液任选地包括可能与溶于所述第一溶剂的API相同或不同的活性剂;(3)将所述混合物乳化以形成第一乳液;(4)将所述第一乳液乳化于所述第二溶剂的第二溶液以形成第二乳液,其中所述第二溶剂的第二溶液包括聚唾液酸,且任选地进一步包括表面活性剂;以及(5)移除所述第一溶剂以形成具有表面唾液酸部分的微米颗粒或纳米颗粒。
在其他方面,本发明涉及通过本文描述的方法产生的颗粒。
优选地,所述微米颗粒或纳米颗粒包括活性剂,例如活性药物成分(API)。
优选地,所述API被封装到所述微米颗粒或纳米颗粒中。在某些优选方面,所述颗粒为纳米颗粒。
可替代地或者另外地,所述API共价或离子连接至所述微米颗粒或纳米颗粒的表面。例如,所述API可通过促进体内释放的可水解键共价连接到所述颗粒的表面。
优选地,在乳化过程中将所述第一溶剂中的聚合物溶液添加到所述第二溶剂的第一溶液中之前,所述第二溶剂的溶液进一步包括第一溶剂或被第一溶剂饱和。这可能是有益的,因为当添加到第二溶剂的第一溶液中进行乳化时,所述第一溶剂中的聚合物不太可能沉淀。优选地,第一溶剂是乙酸乙酯,而第二溶剂的溶液(例如,水溶液(water oraqueous solution))包括大约7-8%v/v的乙酸乙酯。
优选地,所述微米颗粒和纳米颗粒基于可生物降解的聚合物,其选自由以下组成的组:聚丙交酯(PLA)、聚(丙交酯-共-乙交酯)(PLGA)、乙二醇和丙交酯/乙交酯的共聚物(PEG-PLGA)、乙二醇和丙交酯的共聚物(PEG-PLA)、乙二醇和乙交酯的共聚物(PEG-PGA)、聚(乙二醇)(PEG)、聚己内酯(PCL)、聚酸酐(PANH)、聚(邻酯)、聚氰基丙烯酸酯、聚(羟基链烷酸酯)(PHA)、聚(己酸酯)、聚膦腈、聚磷酸酯、改性聚(糖)及其混合物和共聚物。在另外优选的方面,所述可生物降解的聚合物是PLGA。任选地,所述微米颗粒和纳米颗粒包括活性剂,例如药物。
在某些优选实施方案中,所述颗粒封装所述活性剂。
优选地,所述聚唾液酸是药学上可接受的聚合物。
优选地,所述唾液酸是唾液酸、其盐、衍生物或模拟物。
优选地,所述聚唾液酸通过非化学方法附着到所述微米颗粒和纳米颗粒的表面,例如包覆、吸收、吸附和乳化。
优选地,所述聚唾液酸持久地附着到所述微米颗粒和纳米颗粒的表面并且可维持多个洗涤循环。
优选地,所述聚唾液酸的分子量为500至50,000,000、1,000至5,000,000和2,000至500,000Da。
在一些实施方案中,所述聚唾液酸是一种仅包括唾液酸重复单元的聚唾液酸。这种类型的聚合物通常称为“均聚物(homopolymer)”。聚唾液酸的此类均聚物的一个实施例是多聚乙酰神经氨酸,可从例如,美国伊利诺伊州Oakbrook Terrace市的Carbosynth购得。多聚乙酰神经氨酸,也称为聚唾液酸,是一种含有α-2,8-连接唾液酸(神经氨酸)的线性小多糖,具有(n=8至>100)残基。
在一些实施方案中,所述聚唾液酸是一种“共聚物”,其包括唾液酸重复单元和至少一个不同化学实体的重复单元。这种共聚物的非限制性实施例包括PLGA-PSia、PEG-PSia、PLGA-PEG-PSia,等等。在这里,PLGA是聚(丙交酯-共-乙交酯),PEG是聚乙二醇,并且PSia是聚唾液酸。
在一些实施方案中,聚唾液酸是唾液酸的低聚物,例如二聚体、三聚体、四聚体、五聚体或六聚体,可用作N-乙酰神经氨酸低聚物或其钠盐,可从美国加利福尼亚州圣地亚哥Nacalai USA有限公司获得。
在一些实施方案中,聚唾液酸是在其化学结构末端具有唾液酸部分的药学上可接受的聚合物。例如,PEG-Sia或PLGA-PEG-Sia,其中Sia代表唾液酸部分。聚唾液酸也可以是神经节苷脂。
具体实施方式
概述
由于唾液酸和Siglec之间的异常相互作用与许多病理学相关,所述病理包括感染、自身免疫疾病和癌症,因此提供能够呈现唾液酸部分的颗粒,将Siglec结合在特定细胞上可能具有治疗作用。例如,包含颗粒的组合物可用于治疗包括感染、自身免疫疾病和癌症在内的病理学。此外,唾液酸和Siglec在特定免疫细胞上的相互作用可用于将包含唾液酸残基的颗粒引导至免疫细胞。因此,包含治疗剂以及唾液酸部分的颗粒可以靶向特异性免疫细胞。
本发明提供了在其表面上具有非缀合唾液酸残基的颗粒、组合物及其使用方法,以及制备在其表面具有唾液酸部分的纳米颗粒和微米颗粒的非缀合方法。本文描述的非缀合方法避免了当使用缀合方法将唾液酸残基附着到颗粒表面时观察到的副反应和副产物。
本文所述的本发明提供了包括在其表面上具有唾液酸残基的微米颗粒和纳米颗粒的药物制剂(具有或不具有药剂/药物/API负载),以及能够生产这种包括微米颗粒和/或纳米颗粒的药物制剂的方法。
本发明包括用于制备在其表面上具有唾液酸残基的微米颗粒和纳米颗粒的方法,所述方法包括疏水性和/或中性生物相容性聚合物(如PLGA或PLA)与聚唾液酸的共沉淀或凝聚。在不受任何理论约束的情况下,人们认为聚合物主链在乳液的有机相中相互缠绕或交织。使用本发明的方法,聚唾液酸紧密结合到所产生的微米颗粒或纳米颗粒中。因此,优选地,聚唾液酸结合到所述微米颗粒或纳米颗粒上,并在所述微米颗粒或纳米颗粒的表面上呈现唾液酸残基。
对于以上一般描述的本发明,本发明的具体方面将在以下章节中进一步描述。
定义
如本文所用,“药学上可接受的”包括在合理的医学判断范围内适合于医学或兽医用途的那些化合物、材料、组合物和/或剂型,当其以在产品中存在的浓度、剂型或者剂量与人和动物的组织接触时不会产生过多的毒性、刺激、过敏反应或其他问题或并发症,与合理的利益/风险比相称。优选地,药学上可接受的材料(例如,聚合物、赋形剂、表面活性剂、溶剂或由其制备的聚合物或微米颗粒/纳米颗粒)适合于或被批准用于人类医学用途。
如本文所述,“微米颗粒”的形状优选为大致圆形、球形或类球形,并且通常在例如约1-1,000μm之间或约10-100μm之间的尺寸范围内,如通过激光衍射测量。本发明的微米颗粒还可以包括在体内不太可能结块或聚集的颗粒。然而,应当理解的是,其他颗粒形态也是可能的,包括棒、板、片和针等。通常,应当理解的是,粒度反映了所测试的产品样品的体积中值几何尺寸。
如本文所用,“纳米颗粒”的形状优选为大致为圆形、球形或类球形,并且通过例如激光衍射测量或者动态光散射测量通常在例如约1-1000nm之间,约10-1000nm之间或约50-1000nm之间或约100-500nm之间的尺寸范围内。所述纳米颗粒还可包括不太可能在体内聚集的颗粒。
颗粒尺寸和粒度分布可通过动态光散射仪器测量,例如使用马尔文纳米粒度仪(Malvern Zsizer)测量。颗粒尺寸通过表示为质量平均直径。替代性技术包括,例如,沉降场流分级、光子相关光谱、光散射、动态光散射、光衍射和盘式离心。术语“微米颗粒”和“纳米颗粒”不旨在表达任何特定的形状限制。这些颗粒包括,但不限于,具有通常的多面体或球形几何形状的颗粒。优选的颗粒的特征在于通常通过基于乳液的包封方法产生的球形几何形状。应理解,术语“微米颗粒”和“纳米颗粒”在本文中可互换使用,除非附有尺寸的具体描述。例如,当称为“微米颗粒和/或纳米颗粒”时,除非上下文另有要求,否则术语“微米颗粒”也旨在包括“纳米颗粒”。
每个微米颗粒或纳米颗粒的尺寸不必是平均的,尽管它们通常具有足以触发抗原呈递细胞(APC)或其他MPS细胞的吞噬作用。优选地,所述微米颗粒和纳米颗粒具有足以引发抗原呈递细胞(APC)或其他MPS细胞的吞噬作用的直径。
术语“颗粒”包括纳米颗粒和微米颗粒。除非另有明确限定,这里使用的“一个”或“一种”指的是一个或者一个以上。
本文所使用的“约”通常指最多为所修饰的特定术语的±10%。
当涉及药物或活性剂被包封在颗粒内时,本文所使用的术语“封装(encapsulate)”、“被封装的(encapsulated)”等是指药物或活性剂更有可能存在于微米颗粒内而不是存在于微米颗粒的表面上。
“聚唾液酸”是包括唾液酸单体的聚合物。聚唾液酸将在下面进行更为详细的描述。
术语“唾液酸残基”和“唾液酸部分”及其复数形式等在本文中可互换使用。
本文所使用的“缀合”或“缀合的”等,在颗粒表面上的唾液酸部分的上下文中是指唾液酸部分(例如,聚唾液酸的唾液酸部分)通过形成共价键与颗粒或可生物降解的聚合物共价结合,例如通过连接体部分或唾液酸残基与能够与纳米颗粒表面上的反应性基团(例如可生物降解的聚合物的反应性基团)形成共价键的反应性基团的官能化。例如,已经描述了使用聚唾液酸的硫代衍生物进行缀合(Bondioli等人(2010年),PLGA纳米颗粒表面用唾液酸,N-乙酰神经氨酸修饰,生物材料,31.3395-403.10.1016/j,生物材料,2010.01.049)。因此,在颗粒表面上的唾液酸残基的上下文中,“未缀合的(not conjugated)”或“非缀合的(non-conjugated)”等意指唾液酸残基或包括唾液酸残基的聚唾液酸不通过在颗粒或可生物降解的聚合物之间形成共价键而与颗粒或可生物降解的聚合物共价结合。例如,通过诸如涂覆、吸收、吸附和/或乳化的过程将聚唾液酸附着到纳米颗粒的表面。在不希望受理论束缚的情况下,认为可生物降解的聚合物,如PLGA和聚唾液酸形成互穿网络,在形成的颗粒表面上呈现唾液酸残基。
本文所用的术语“受试者”是指动物,优选为哺乳动物,包括人或非人动物。术语“患者”和“受试者”可互换使用。
受试者的“治疗”或“疗法”是指对受试者进行的任何类型的干预或介入过程,或向受试者施用活性剂,其目的是逆转、缓解、改善、抑制、减缓或预防症状、并发症、与疾病相关的状况或生化指标的发作、进展、发展、严重程度或复发。如本文所使用的,“治疗”(及其语法变化,例如“处理”或“救治”)包括临床干预,以改变被治疗个体的疾病自然病程,并且可以用于预防或在临床病理学的病程中进行。理想的治疗效果包括但不限于预防疾病的发生或复发、减轻症状、减少疾病的任何直接或间接病理后果、预防转移、降低疾病进展的速度、缓解或减轻疾病状态、缓解或改善预后。在一些实施方案中,本发明的组合用于延迟疾病的发展或减慢疾病的进展。
可生物降解的聚合物
可生物降解的聚合物是一种可以被生物代谢或分解的聚合物。在有些方面,可生物降解的聚合物被分解或代谢而不会引起显著的毒性作用。本发明的可生物降解的聚合物可选自:聚丙交酯(PLA)、聚(丙交酯-共-乙交酯)(PLGA)、乙二醇和丙交酯/乙交酯的共聚物(PEG-PLGA)、乙二醇和丙交酯的共聚物(PEG-PLA)、乙二醇和乙交酯的共聚物(PEG-PGA)、聚(乙二醇)(PEG)、聚己内酯(PCL)、聚酸酐(PANH)、聚(邻酯)、聚氰基丙烯酸酯、聚(羟基链烷酸酯)(PHA)、聚(己酸酯)、聚膦腈、聚磷酸酯、改性聚(糖)及其混合物和共聚物。PLGA是本发明中优选的可生物降解的聚合物。
PLGA
PLGA通常通过丙交酯和乙交酯的开环聚合制备。在这一反应中,通常使用辛酸亚锡作为催化剂,尽管其他催化剂也可以使用。引发剂,例如醇,通常用于引发聚合反应。如果没有有意添加引发剂,则微量的含有活性质子的极性化合物,如醇和水,可以用作引发剂。聚合通常产生在链末端具有羧基的PLGA聚合物,如下图所示:
R-OH+L(丙交酯单体)+G(乙交酯单体)=PLGA-COOH
因此,每个PLGA和/或PLA聚合物分子通常是直链的,并且通常在链末端含有单个COOH基团。除此之外,可能没有足够数量的COOH基团用于将API或其他化学部分例如蛋白质配体或其他靶向剂共价连接至所述微米颗粒和纳米颗粒的表面。此类蛋白质配体或其他靶向剂可以结合至靶向细胞、组织、器官或位置的表面上的受体或结合配体。
本发明提供了用聚唾液酸生产PLGA/PLA颗粒的各种方法或其组合。此类颗粒特别用于,例如,治疗某些疾病(例如炎性疾病、自身免疫性疾病和癌症)和用于递送活性剂。
优选地,所述药学上可接受的聚合物PLGA的平均分子量在期望的范围内。
所述范围的下限优选不小于约100、200、300、400、500、600、700、800、900、1,000、1,200、1,500、2,000、2,500或3,000Da。期望的范围具有上述任何值的下限。
所述范围的上限优选不超过50,000、40,000、35,000、30,000、25,000、20,000、15,000、10,000、7,500或5,000Da。期望的范围具有上述任何值的上限。
例如,期望的范围可为约500至约50,000Da,或者约1,000至约30,000Da。
优选地,PLGA的平均分子量为约500至约1,000,000Da,优选约1,000至约50,000Da。
PLGA可以包含多个带负电的末端基团。
对于PLGA,平均分子量可以用其他物理性质来表示,例如比浓对数粘度(inherentviscosity)。比浓对数粘度(IV)是一种用于测量分子大小的粘度测量方法。IV是基于聚合物溶液通过窄毛细管的流动时间相对于纯溶剂通过毛细管的流动时间。对于本申请中的确定性测量,所使用的溶剂通常是氯仿,并且聚合物浓度为约0.5%(w/v)。测量粘度的温度为约30℃。IV的单位通常以分升每克(dL/g)为单位。因此,例如,本发明中使用的PLGA可具有约0.01至约20dL/g,或约0.05至2.0dL/g。
所述PLGA聚合物的组成和可生物降解性部分地由聚合物中丙交酯(L)与乙交酯(G)单元的摩尔比或L/G比决定。本发明中PLGA聚合物的L/G比可以从100/0至0/100。如本文所用的,“100/0”的L/G比指的是聚丙交酯或PLA,而“0/100”的L/G比指的是聚乙交酯或PGA。优选地,所述PLGA聚合物的所述L/G比为约100/0至0/100,或者约95/5至5/95,更为优选地为约85/15至15/85。本发明中最优选的L/G比为约50/50。
在制备PLGA微米颗粒和纳米颗粒时,可以将其他聚合物与所述PLGA聚合物混合。例如,通常将聚乙二醇或PEG添加到PLGA中以增强性能。聚乙二醇化的颗粒是很有用的,因为它们通常可以增加在人体或动物体内的循环时间。
优选地,还可以使用PEG和PLGA的共聚物。
由PEG和PLGA混合物或PEG和PLGA共聚物制备的微米颗粒和纳米颗粒被称为PEG化(聚乙二醇化)的PLGA微米颗粒和纳米颗粒。
这种“PEG化(PEGylation)”过程也可以在形成微米颗粒和纳米颗粒之后进行。在这种情况下,PEG聚合物或含有PEG单元的其他聚合物通过物理吸收被涂覆到PLGA微米颗粒和纳米颗粒上。
所述的PEG单元也可以通过共价键附着到PLGA微米颗粒或纳米颗粒的表面。这种过程通常被称为“缀合(conjugation)”。在缀合过程中,含有PEG单元的活性实体与微米颗粒和纳米颗粒表面的某些官能团发生反应形成化学键。
因此,优选地,药学上可接受的聚合物是PLGA,并且微米颗粒或纳米颗粒是PEG化的。所述微米颗粒或纳米颗粒可以通过在微米颗粒和纳米颗粒的制备过程中混合聚乙二醇(PEG)或含有PEG的实体来进行PEG化。所述微米颗粒或纳米颗粒也可以通过使用PEG和PLGA的共聚物来进行PEG化。通过将PEG聚合物或含有PEG单元的聚合物物理吸收到PLGA微米颗粒和纳米颗粒上,可以进一步对微米颗粒或纳米颗粒进行PEG化。可以通过将PEG单元经由共价键缀合到PLGA微米颗粒或纳米颗粒的表面来另外对微米颗粒或纳米颗粒进行PEG化。
优选地,可生物降解的聚合物具有约500至约1,000,000Da,优选为约1,000至约200,000Da。
优选地,可生物降解的聚合物是PLGA并且具有约100/0至0/100、约95/5至5/95、约85/15至15/85和约50/50的L/G比。
聚唾液酸
聚唾液酸(PSia)包括唾液酸的均聚物。天然存在的PSia最早在大肠杆菌中发现,是细菌荚膜材料的成分之一,如小脑膜炎奈瑟菌B、头蟹沙门氏菌048和弗氏柠檬酸杆菌05。PSia可以是α-2,8(下图中的A)或α-2,9连接体(下图中的B)或α-2,8和α-2,9的混合物。PSia由α-2,8键具有非免疫原性和生物可降解性,可降低蛋白质多肽的免疫原性。PSia具有逃逸吞噬细胞和延长体内循环时间的性质。
因此,表面上具有唾液酸部分的纳米颗粒也可以促进RES逃逸,并使纳米颗粒和微米颗粒在血液中的循环延长。此外,由于唾液酸还与肿瘤细胞上的多种受体结合,因此唾液酸包覆的纳米颗粒和微米颗粒可以通过唾液酸与凝集素的高亲和力结合来靶向肿瘤部位。
如上所述,聚唾液酸是包含唾液酸单体链的聚合物。在某些方面,所述聚合物是均聚物(例如,所有唾液酸单体单元都相同)。在其他方面,所述聚合物是杂聚物(例如,聚唾液酸包含至少两种不同的唾液酸单体单元)。在其他方面,聚合物包含至少10个、至少15个、至少20个、至少30个、至少40个、至少50个、至少60个、至少75个、至少100个、至少200个或至少300个唾液酸单体。唾液酸单体可以是神经氨酸的任何衍生物。唾液酸单体包括,例如,N-乙酰基神经氨酸(Neu5Ac)、N-甘醇基神经氨甲酸(Neu5Gc)或脱氨基神经氨酸(Kdn;3-脱氧-D-丙三基-D-半乳糖醛酸。所述唾液酸单体如式(I)所示:
在Neu5Ac中,R是-NH-C(O)-CH3。在Neu5Gc中,R是-NH-C(O)-CH2-OH。在Kdn中,R是OH。唾液酸单体的其它实施例是N-唾液酸、O-唾液酸、9-O-乙酰基-8-O-甲基-N-乙酰基神经氨酸(Neu5,9Ac28Me)和7,8,9-三-O-乙酰基-N-甘醇基神经氨甲酸(Neu5Gc7,8,9Ac3),Neu4,5Ac2;Neu5,7Ac2;Neu5,8Ac2;Neu5,9Ac2;Neu4,5,9Ac 3;Neu5,7,9Ac 3;Neu5,8,9Ac3;Neu5,7,8,9Ac 4;Neu5Ac9Lt;Neu4,5Ac 29Lt;Neu5Ac8Me;Neu5,9Ac28Me;Neu5Ac8S;Neu5Ac9P;Neu2en5Ac;Neu2en5,9Ac2;Neu2en5Ac9Lt;Neu2,7an5Ac;Neu5Gc;Neu4Ac5Gc;Neu7Ac5Gc;Neu8Ac5Gc;Neu9Ac5Gc;Neu7,9Ac 25Gc;Neu8,9Ac25Gc;Neu7,8,9Ac 35Gc;Neu5Gc9Lt;Neu5Gc8Me;Neu9Ac5Gc8Me;Neu7,9Ac 25Gc8Me;Neu5Gc8S;Neu5GcAc;Neu5GcMe;Neu2en5Gc;Neu2en9Ac5Gc;Neu2en5Gc9Lt;Neu2en5Gc8Me;Neu2,7an5Gc;Neu2,7an5Gc8Me;和Knd9Ac。
如上所述,唾液酸单体可以通过α-2,8-,α-2,9或者α-2,8/α-2-9-酮糖苷键连接,例如。α-2,4-酮糖苷键和α-2,5-酮糖苷键也被报道过(Janas et al.(2011),Biochimicaet Biophysica Acta 1808:2923-2932)。唾液酸单体可以以任何结合排列方式连接。在某些实施方案中,聚唾液酸包含如下单体:2→8连接的单体,2→9连接的单体,或者其结合。在依旧另一个方面,所述单体都是2→8连接的或者都是2→9连接的。在进一步方面,聚唾液酸包括2→8连接的或者2→9连接的或者二者的组合连接的Neu5Ac单体。在依旧其他方面,所述聚唾液酸包括2→8连接的或者2→9连接的或者二者的组合连接的Neu5Gc单体。在进一步的实施方案中,所述聚唾液酸包括2→8连接的或者2→9连接的或者二者的组合连接的Kdn单体。所述聚唾液酸可以是均聚物,所述均聚物选自以下单体:Neu5Ac、Neu5Gc和Kdn,或者所述聚唾液酸还可以是包括选自Neu5Ac、Neu5Gc和Kdn中两个或者三个单体的杂均聚物。在某些特定的实施方案中,所述均聚物包括Neu5Ac单体。所述均聚物可以是聚(Neu5Ac)n,聚(Neu5Gc)n,或者聚(Kdn)n聚合物,其中,n是大于10的整数,是大于15的整数,或者是大于20的整数;或者任选的其中,所述单体是2→8连接的或者2→9连接的,或者是二者的组合。在依旧另一个具体的实施方案中,所述杂均聚物包括Neu5Ac和Neu5Gc单体。
聚唾液酸可以是支链或非支链聚合物。一种“非支链”聚合物是直链聚唾液酸聚合物,包括单体的线性序列。“支链”聚合物是一种聚唾液酸聚合物,它包括一个带有一个或多个取代基侧链的主链。支链聚合物的实施例是包含与三个或更多个不同唾液酸单元结合的唾液酸单元,从而在聚唾液酸内产生分支点的聚合物。
聚唾液酸可以具有例如至少1kDa、至少3kDa、至少5kDa、至少10kDa、至少20kDa、至少25kDa、至少30kDa、至少40kDa、至少50kDa、至少60kDa、至少70kDa、至少75kDa、至少80kDa、至少90kDa、至少100kDa等的分子量。
优选的,所述聚唾液酸的分子量在500到50,000,000之间,在1,000到5,000,000之间,或者在2,000到500,000Da之间。
在一些实施方案中,聚唾液酸是仅包含唾液酸重复单元的聚唾液酸。这种类型的聚合物通常被称为“均聚物”。聚唾液酸的这种均聚物的一个实施例是可从Carbosynth,Oakbrook Terrace,IL,USA商业上购买的多聚乙酰神经氨酸。所述多聚乙酰神经氨酸,也称为聚唾液酸,是一种含有α-2,8-连接唾液酸(神经氨酸)的线性小多糖,具有(n=8至>100)个残基。
在一些实施方案中,聚唾液酸是包含唾液酸重复单元和至少一种不同化学部分重复单元的“共聚物”。这种共聚物的非限制性实施例包括PLGA-PSia、PEG-PSia、PLGA-PEG-PSia等。这里,PLGA是聚(丙交酯-乙交酯),PEG是聚乙二醇,PSia是聚唾液酸。所述的聚唾液酸也可以是神经节苷脂。
在一些实施方案中,所述聚唾液酸是唾液酸的低聚物,例如二聚体、三聚体、四聚体、五聚体和六聚体,可用作N-乙酰神经氨酸低聚物或其钠盐,可从美国加利福尼亚州圣地亚哥的Nacalai USA.,Inc.获得。
在一些实施方案中,所述聚唾液酸是在其化学结构末端具有唾液酸部分的药学上可接受的聚合物。例如,PEG-Sia或PLGA-PEG-Sia,其中Sia表示唾液酸部分。
唾液酸也可以是唾液酸的水溶性盐和水溶性衍生物。例如,唾液酸盐可以是钠盐、钾盐、镁盐、钙盐或锌盐。如上所述,聚唾液酸可以包括一种以上类型唾液酸的组合。
在一组实施方案中,聚唾液酸内的一种或多种唾液酸单体被修饰。例如,一个或多个唾液酸单体可以通过连接到聚乙二醇或烷基来修饰。在其他实施方案中,聚唾液酸未被修饰。
除了唾液酸单体之外,聚唾液酸还可以包括其他单体或单元。在某些实施方案中,聚唾液酸是唾液酸单体单元的聚合物和另一种聚合物的缀合物,例如合成聚合物,包括例如聚乙二醇(PEG)(例如聚唾液酸-PEG共聚物)。例如,在Zhang等人(2018),Drug Deliveryand Translational Research 8602-616中描述了这种缀合物的实例。PEG可以具有式:H-(O-CH2-CH2)n-OH,其中n是表示PEG聚合度的整数。例如,n为至少2、至少4、至少6、至少8、至少10、至少15、至少20、至少25、至少30、至少40、至少50、至少75、至少100、至少200、至少300、至少400或至少500。在一些情况下,n不超过1000、不超过500、不超过200、不超过100、不超过50、不超过30或不超过10。
在颗粒中的聚唾液酸可以是相同的或者不同的。
此外,聚唾液酸可以沿着链的长度或在链的末端被共价取代或离子取代。例如,一个或多个单体单元可以被靶向部分取代,例如细胞配体(或片段)、肽或碳水化合物。靶向部分的取代或缀合步骤可以在微米颗粒形成之前或之后发生。
在一些实施例中,基于制剂中使用的PLGA的重量,本发明中使用的聚唾液酸的量可以是0.01%至30%,优选为0.1%至15%。
活性剂
这里所描述的颗粒可以进一步包括活性剂。该组合物可以包括API,并且API可以通过共价键或离子键,例如在蛋白质的酰胺基和微米颗粒或纳米颗粒表面上的羧基之间形成的键,共价连接或离子连接到微米颗粒或纳米颗粒的表面。API也可以封装在微米颗粒或纳米颗粒内。API的量可以占所述微米颗粒或纳米颗粒的约0.01至约50%(w/w),或占所述微米颗粒或纳米颗粒的大约0.05至约25%、大约0.1至大约10%、大约0.2至大约5%、大约0.5至大约3%、大约1%至大约5%或大约2%至大约5%(w/w)。
在某些方面,所述活性剂优选是药物(本文中也称为活性药物成分或API)。然而,根据所述方法,非治疗性的活性剂也可以作为颗粒的一部分包括在内,例如,用于诊断、农业、化妆品、个护产品、家用产品、工业化学品、染料、荧光剂或着色剂等用途的试剂。优选的活性成分包括小分子和大分子。例如,生物分子,如肽、拟肽、寡核苷酸、核酸分子及其模拟物,如DNA、RNA、PNA、siRNA、微小RNA、反义、蛋白质、抗体及其抗原结合片段、酶、激素、生长因子、抗原、新抗原、糖类、低聚糖、多糖及其组合。该组合物可以不含其他活性药物成分或API,例如附着的肽或抗原部分。可以理解,API可以被非治疗性化合物取代,例如诊断剂、农业剂或化学剂。因此,在使用API一词的每种情况下,应理解为术语“活性剂”,包括诊断剂、农业剂或化学剂,可以用来代替API。术语“API”和“药物”在本文中可互换使用。
所述API可以是水溶性的或者具有相对较差的水溶性。例如,在API溶液与包括PLGA的第一溶剂混合之前,水溶性差的API可以溶解在与溶解PLGA相同的第一溶剂中,或者溶解在合适的溶剂(可以与第一溶剂相同或不同)中以形成API溶液,使得API和PLGA都保留在所得溶液中。在将API溶液添加到第二溶剂之前,水溶性API可以首先溶解在其自身的溶剂(其可与第二溶剂相同或不同)中以形成API溶液。
API或活性剂可以包括多种不同的化合物,包括化合物和化合物的混合物,例如小的有机或无机分子;糖精;低聚糖;多糖;生物大分子,例如肽、蛋白质以及肽类似物和衍生物;拟肽制剂;抗体及其抗原结合片段;核酸;核酸类似物和衍生物;由细菌、植物、真菌或动物细胞等生物材料制成的提取物;动物组织;天然存在的或合成的组合物;以及它们的任何组合。优选地,所述治疗剂是小分子。
如本文所用,术语“小分子”可以指“类天然产物”的化合物,然而,术语“小分子”不限于“类天然产品”的化合物。相反,小分子的典型特征在于它含有几个碳-碳键,并且分子量小于5000道尔顿(5kDa),优选小于3kDa,还更优选小于2kDa,并且最优选小于1kDa。在一些情况下,优选小分子具有等于或小于700道尔顿的分子量。
如本文所用,“肽”是寡肽,例如,2至25个氨基酸的序列。除非另有规定,否则术语“肽”在其范围内包括一种肽,所述肽含有天然存在氨基酸的已知类似物,以及具有天然存在氨基酸的功能的肽。“蛋白质”包含一个或多个肽(多肽)链,并且可以包含比肽更多的氨基酸。术语“肽”、“多肽”和“蛋白质”在本文中可以互换使用。
示例性治疗剂包括,但不限于,经FDA批准的治疗剂、向FDA提出新药申请的治疗剂、处于临床试验或临床前研究中的治疗剂。
API包括本文公开的类别和具体的实施例。所述类别不受具体实施例的限制。根据本发明,本领域普通技术人员还将确认属于这些类别并且有用的许多其他化合物。实施例包括放射增敏剂、类固醇、黄嘌呤、β-2-激动剂支气管扩张剂、抗炎剂、镇痛剂、钙拮抗剂、血管紧张素转换酶抑制剂、β-阻断剂、中枢活性α-激动剂、α-1-拮抗剂、抗胆碱能/解痉剂、加压素类似物、抗心律失常药、抗帕金森病药、抗心绞痛/抗高血压药、抗凝血剂、抗血小板药、镇静剂、溶血剂、肽剂、生物聚合剂、抗肿瘤药、缓泻药、止泻剂、抗微生物剂、抗真菌剂、疫苗、蛋白质或核酸。另一方面,药物活性剂可以是香豆素,白蛋白,类固醇(例如倍他米松、地塞米松、甲基强的松龙、泼尼松龙、泼尼松、曲安奈德、布地奈德、氢化可的松和药学上可接受的氢化可的松衍生物);黄嘌呤(例如茶碱和多索可可碱);β-2-激动剂支气管扩张剂(例如沙丁胺醇、非诺特罗(fenterol)、克伦特罗、班布特罗、沙美特罗、酚丙喘宁(fenoterol);抗炎药,包括抗哮喘抗炎药、抗关节炎抗炎药和非甾体抗炎药,其实施例包括但不限于硫化物、美沙拉嗪、布地奈德、柳氮磺吡啶、双氯芬酸、药学上可接受的双氯芬酸盐、尼美舒利、萘普生、对乙酰氨基酚、布洛芬、酮洛芬和吡罗昔康;镇痛剂,例如水杨酸盐;钙通道阻滞剂,例如硝苯地平、氨氯地平和尼卡地平;血管紧张素转换酶抑制剂,例如卡托普利、盐酸贝那普利、福辛普利钠、群多普利、雷米普利、赖诺普利、依那普利、盐酸喹那普利和盐酸莫西普利;β受体阻滞剂(即β-肾上腺素能阻滞剂),例如盐酸索他洛尔、马来酸噻吗洛尔、盐酸艾司洛尔、卡替洛尔、盐酸普萘洛尔、盐酸倍他洛尔、硫酸巴替洛尔、酒石酸美托洛尔、琥珀酸美托洛尔、盐酸醋丁洛尔、阿替洛尔、吲哚洛尔和富马酸比索洛尔;中枢活性α-2-激动剂,例如可乐定;α-1-拮抗剂,例如多沙唑嗪和哌唑嗪;抗胆碱能/抗痉挛药,例如盐酸双环胺、氢溴酸东莨菪碱、格隆溴铵、克利溴铵、黄酮酸盐和奥昔布宁;加压素类似物,例如加压素和去氨加压素;抗心律失常药,例如奎尼丁、利多卡因、盐酸托西坦、盐酸美西律、地高辛、盐酸维拉帕米、盐酸普罗帕酮、醋酸氟卡尼、盐酸普鲁卡因胺、盐酸莫雷西嗪和磷酸二丙酰胺等;抗帕金森病药,例如多巴胺、左旋多巴/卡比多巴、司来吉兰、二氢麦角环肽、培高利特、麦角乙脲、阿扑吗啡和溴隐亭;抗心绞痛药和抗高血压药,例如单硝酸异山梨酯、硝酸异山梨酯、心得安、阿替洛尔和维拉帕米;抗凝血剂和抗血小板药,例如香豆素、华法林、乙酰水杨酸和噻氯匹定;镇静剂,例如苯二氮卓类和巴比妥类;溶血剂,例如劳拉西泮、溴西泮和地西泮;肽剂和生物聚合剂,例如降钙素、亮丙瑞林和其他LHRH激动剂、水蛭素、环孢菌素、胰岛素、生长抑素、普罗瑞林、干扰素、去氨加压素、生长激素、胸腺五肽、匹多莫德、促红细胞生成素、白细胞介素、褪黑激素、粒细胞/巨噬细胞-CSF和肝素;抗肿瘤药,例如依托泊苷、依托泊苷磷酸盐、环磷酰胺、甲氨蝶呤、5-氟尿嘧啶、长春新碱、多柔比星、顺铂、羟基脲、甲酰四氢叶酸钙、他莫昔芬、氟他胺、天冬酰胺酶、六甲蜜胺、米托坦和盐酸丙卡巴肼;缓泻药,例如番泻叶浓缩物、鼠李蒽酚、比沙可啶和匹可硫酸钠;止泻剂,例如盐酸地诺考因、盐酸洛哌丁胺、呋喃唑酮、盐酸地芬诺酯和微生物;疫苗,例如细菌疫苗和病毒疫苗;抗微生物剂,例如青霉素、头孢菌素和大环内酯类;抗真菌剂,例如咪唑和三唑衍生物;和核酸,例如编码生物蛋白质的DNA序列和反义寡核苷酸。
合适的API的实施例包括英夫利昔单抗、依那西普、贝伐单抗、雷珠单抗、阿达木单抗、赛妥珠单抗、戈利木单抗、白细胞介素1(IL-1)阻断剂(例如阿那白滞素)、T细胞共刺激阻断剂(例如阿巴西普)、白细胞介素6(IL-6)阻断剂(例如托珠单抗);白细胞介素l3(IL-13)阻滞剂(例如罗氏单抗lebrikizumab);干扰素α(IFN)阻断剂(例如罗利珠单抗(Rontalizumab));β7整合素阻断剂(例如rhuMAbβ7);IgE途径阻断剂(例如抗-M1Prime);分泌的同源三聚体LTa3和膜结合的异源三聚体LTα1/β2阻断剂,例如抗淋巴毒素α(Lta)或抗VEGF剂等。
药物或API包括蛋白质或肽,包括但不限于单克隆抗体(例如人源化单克隆抗体、人和/或小鼠/人嵌合的单克隆抗体)、多克隆抗体和抗体-药物缀合物。示例性的肽/蛋白质疗法包括胰岛素、依那西普、培非司汀、鲑鱼降钙素、环孢菌素、奥曲肽、利拉鲁肽、比伐卢定、去氨加压素、C1酯酶抑制剂人葡糖脑苷酶/>人类源化抗CD20单克隆抗体/>VEGFR-Fc融合/>胰高血糖素样肽-1受体激动剂Fc融合/>VEGFR Fc-融合肽(ZALTRAP)、重组因子IX-Fc融合肽(ALPLOLIX)、重组因子VIII-Fc融合肽(ELOCTATE),GLP-1受体拮抗-白蛋白融合肽重组因子IX白蛋白融合肽/>聚乙二醇化的IFNb-1a聚乙二醇化的重组因子VIII/>人源化的抗-HER2/neu与埃姆坦辛的缀合物/>贝利木单抗、易普利木单抗、布伦妥昔单抗、阿氟西普、贝拉西普、菊欧文氏菌天门冬酰胺酶、胰高血糖素酶、水解溶酶体糖脑苷脂特异性酶(taliglucerase alfa)、帕妥株单抗、阿柏西普(ziv-afilbercept),菲戈斯汀(tbo-filgrastm)、奥克纤溶酶(ocriplasmin)、拉西巴库单抗、恩美曲妥珠单抗(ado-trastuzmabemtansine)、戈利木单抗(golimumab)、塔西单抗、奥比努珠单抗,艾洛磺胺酶、美他列汀、阿白鲁肽、拉穆丘单抗、沙妥昔单抗、韦多利珠单抗、聚乙二醇干扰素β-1a、培溴利珠单抗和杜拉鲁肽(dulaglutide)、双肿瘤单抗、尼沃单抗、司库奇尤单抗、甲状旁腺激素、非格司亭(filgrastim sndz)、丁妥昔单抗、阿利罗库单抗、埃沃洛单抗、依达拉西珠单抗、非格司亭、美波珠单抗,德拉图单抗、奈西图单抗、埃洛妥珠单抗、西贝利帕-阿法、奥比托克沙单抗、艾西单抗、雷西珠单抗、英夫利昔单抗-dyyb、阿替唑珠单抗、达珠单抗、埃坦西普-szzs、凝血因子IX重组人、抗血友病因子(重组),凝血因子XIII A亚单位(重组)、凝血因子IX(重组),Fc融合蛋白、抗高温因子(重组)和Fc融合蛋白质,C1酯酶抑制剂重组,抗高温因子猪,B结构域截短重组,凝血因子IX,血管性血友病因子(重组)、凝血因子IX重组人和抗血友病因子(重组的)。
本发明特别适用于抗癌试剂的给药。例如,所述试剂可以是DNA去甲基试剂5-氮胞苷(氮胞苷)或5-氮杂-2'-脱氧胞苷(地西他滨),(阿糖胞苷或ara-C);伪异胞苷(psi-ICR);5-氟-2'-脱氧胞苷(FCdR);2'-脱氧-2',2'-二氟胞苷(吉西他滨);5-氮杂-2'-脱氧-2',2'-二氟胞苷;5-氮杂-2'-脱氧-2'-氟胞苷;胞苷脱氨酶抑制剂(Zebularine);2',3'-二脱氧-5-氟-3'-噻胞苷(Emtriva);2'-环胞苷(安替他滨);法扎拉宾或ara-C;6-氮杂胞苷(6-aza-CR);5,6-二氢-5-氮杂胞苷(dH-aza-CR);N.sup.4-戊氧基-羰基-5'-脱氧-5-氟胞苷(卡培他滨);N4十八烷基阿糖胞苷;或反油酸阿糖胞苷。胞苷类似物也可在结构上与胞苷或脱氧胞苷相关,并在功能上模拟和/或拮抗胞苷或脱氧胞苷的作用。这些药物还可以包括5-氟尿嘧啶、阿非他尼、阿帕霉素、阿那曲唑、蒽环类药物、阿昔替尼、AVL-101、AVL-291、苯达莫司汀、博莱霉素、硼替佐米、博斯汀尼、苔藓虫素-1、白消安、卡利霉素、喜树碱、卡铂、10-羟基喜树碱、卡莫司汀、塞来昔布、氯霉素、顺铂、COX-2抑制剂、伊立替康(CPT-11)、SN-38、卡铂、克拉屈滨、喜树碱、环唑替尼、环磷酰胺、阿糖胞苷、达卡巴嗪、达沙替尼、地那昔布、多西紫杉醇、达卡霉素、柔红霉素、DM1、DM3、DM4、阿霉素、2-吡咯烷多柔比星(2-PDox),2-PDox(pro-2-PDox)的前药型式,氰基吗啉多柔比星,阿霉素葡醛酸苷,内皮抑制素,表柔比星葡醛酸苷,厄洛替尼,雌孕酮,表鬼臼毒素,厄洛替尼,恩替诺司他,雌激素受体结合剂,足叶乙甙(VP16),足叶乙甙葡醛酸苷,磷酸足叶乙甙,依西美坦,芬戈利莫,氟尿苷(FUdR),3',5'-O-二油酰基-FudR(FudR-dO),氟达拉宾,氟他胺,法尼基蛋白转移酶抑制剂,黄吡利多,福斯他马替尼,甘尼替匹布,GDC-0834,GS-1101,吉非替尼,吉西他滨,羟基脲,伊布替尼,伊达柔比星,依地拉利昔布,异环磷酰胺,伊马替尼,拉帕替尼,来诺达胺,亚叶酸,LFM-A13,洛莫司汀,甲雷他明,美法仑,巯基嘌呤、6-巯基嘌呤、甲氨蝶呤、米托蒽醌、密特拉霉素、丝裂霉素、丝裂坦、一甲基奥斯汀F(MMAF)、一甲基奥斯汀D(MMAD)、一甲基奥斯汀E(MMAE)、纳维本、奈拉替尼、尼罗替尼、硝基苏拉、奥拉帕利、普利康霉素、原卡巴嗪、紫杉醇、PCI-32765、戊他汀、PSI-341、雷洛昔芬、塞莫司汀、SN-38、,索拉非尼、链脲佐菌素、SU11248、舒尼替尼、三苯氧胺、替马唑胺、反铂、沙利度胺、硫鸟嘌呤、硫替帕、替尼泊苷、拓扑替康、尿嘧啶芥子气、瓦塔拉尼、长春瑞滨、长春花碱、长春新碱和ZD1839或其药学上可接受的盐。
抗癌试剂包括,但不限于,基因、配体、受体、蛋白质、因子的抑制剂、激动剂、拮抗剂、配体、调节剂、刺激剂、阻滞剂、激活剂或抑制剂,所述基因、配体、受体、蛋白质、因子例如腺苷受体(例如A2B、A2a、A3)、Abelson鼠白血病病毒癌基因同源物1基因(ABL,例如ABL1),乙酰辅酶A羧化酶(如ACC1/2)、促肾上腺皮质激素受体(ACTH)、活化CDC激酶(ACK,如ACK1)、腺苷脱氨酶、腺苷酸环化酶、ADP核糖环化酶-1、溶氧素、血管紧张素原(AGT)基因、小鼠胸腺瘤病毒癌基因同源物1(AKT)蛋白激酶(如AKT1、AKT2、AKT3)、AKT1基因、碱性磷酸酶、α1肾上腺素受体、α2肾上腺素受体、α酮戊二酸脱氢酶(KGDH),氨基肽酶N、精氨酸脱氨酶、β肾上腺素受体、间变性淋巴瘤激酶受体、间变性淋巴瘤激酶(ALK,如ALK1)、ALK-5蛋白激酶、AMP活化蛋白激酶、雄激素受体、血管生成素(如配体-1、配体-2)、载脂蛋白A-I(APOA1)基因、凋亡信号调节激酶(ASK,如ASK1),凋亡诱导因子、凋亡蛋白(如1,2)、精氨酸酶(I)、天冬酰胺酶、小行星同源物1(ASTE1)基因、共济失调毛细血管扩张症和Rad 3相关(ATR)的丝氨酸/苏氨酸蛋白激酶、Axl酪氨酸激酶受体、芳香化酶、极光蛋白激酶(如1,2)、碱性蛋白酶、BCR(断点簇区)蛋白和基因,B细胞淋巴瘤2(BCL2)基因、Bc12蛋白、Bc12结合成分3、BCL2L11基因、杆状病毒IAP重复序列5(BIRCS)基因、B-Raf原癌基因(BRAF)、Brc-Abl酪氨酸激酶、β-连环蛋白、B-淋巴细胞抗原CD19、B-淋巴细胞抗原CD20、B-淋巴细胞刺激配体、B-淋巴细胞粘附分子、骨形态发生蛋白-10配体、骨形态发生蛋白-9配体调节剂、短链蛋白、缓激肽受体、布鲁顿酪氨酸激酶(BTK)、溴多巴胺和外域(BET)含溴多巴胺的蛋白质(如BRD2、BRD3、BRD4)、钙调素、钙调素依赖性蛋白激酶(CaMK,如CAMKII)、癌睾丸抗原2、癌睾丸抗原NY-ESO-1、,大麻素受体(如CB1、CB2)、碳酸酐酶、半胱氨酸蛋白酶8凋亡相关半胱氨酸肽酶CASP8 FADD样调节因子、半胱氨酸蛋白酶(如半胱氨酸蛋白酶-3、半胱氨酸蛋白酶-7、半胱氨酸蛋白酶-9),半胱氨酸蛋白酶募集结构域蛋白-15、组织蛋白酶G、趋化因子(C-C基序)受体(如CCR2、CCR4、CCR5)、CCR5基因、趋化因子CC21配体、分化簇(CD)如CD4、CD27、CD29、CD30、CD33、CD37、CD40、CD40受体、CD40配体、CD40LG基因、CD44、CD45、CD47、CD49b、CD51、CD52、CD55、CD58、CD66e、CD70基因、CD74、CD79、CD79b、CD79b基因、CD80、CD95、CD99、CD117、CD122、CDw123、CD134、CDw137、CD158a、CD158b1、CD158b2、CD223、CD276抗原;绒毛膜促性腺激素,细胞周期蛋白G1,细胞周期蛋白D1、细胞周期素依赖性激酶(CDK,如CDK1、CDK1B、CDK2-9)、酪蛋白激酶(CK,如CM、CMI)、c-Kit(酪氨酸蛋白激酶试剂盒或CD117)、c-Met(肝细胞生长因子受体(HGFR))、CDK激活激酶(CAK)、检查点激酶(如CHK1、CHK2)、胆囊收缩素CCK2受体、连接蛋白(如6、18)、凝聚素、补体C3、COP9信号体亚单位5、CSF-1(集落刺激因子1受体)、CSF2基因、凝聚素(CLU)基因、结缔组织生长因子、环氧合酶(如1、2)、癌/睾丸抗原1B(CTAG1)基因、CTLA-4(细胞毒性T淋巴细胞蛋白4)受体、CYP2B1基因、半胱氨酸棕榈酰转移酶豪猪、细胞因子信号-1、细胞因子信号-3,细胞色素P450 11B2,细胞色素P450还原酶,细胞色素P450 3A4、细胞色素P450 17A1、细胞色素P450 17、细胞色素P450 2D6(前提是它们是抗癌剂或细胞色素修饰剂,而不是化学抑制剂),细胞质异柠檬酸脱氢酶、胞嘧啶脱氨酶、胞嘧啶DNA甲基转移酶、细胞毒性T淋巴细胞蛋白-4、趋化因子(C--X--C基序)受体(如CXCR4、CXCR1和CXCR2),δ样蛋白配体(如3,4),脱氧核糖核酸酶,Dickkopf-1配体,二氢嘧啶脱氢酶,DNA结合蛋白(如HUβ),DNA依赖性蛋白激酶,DNA旋转酶,DNA甲基转移酶,DNA聚合酶(如α),DNA引物,盘状结构域受体(DDR,如DDR1),DDR2基因,二氢叶酸还原酶(DHFR)、二肽基肽酶IV、左旋多巴胺互变异构酶、dUTP焦磷酸酶、棘皮动物微管样蛋白4、表皮生长因子受体(EGFR)基因、EGFR酪氨酸激酶受体、真核细胞翻译起始因子5A(EIFSA)基因、弹性蛋白酶、延伸因子1α2、延伸因子2、内切胶质、内切核酸酶、内质素、内切唾液酸、内皮抑素、内皮素(如ET-A、ET-B)、玉米淀粉同源物2增强子(EZH2)、表皮生长因子、表皮生长因子受体(EGFR)、上皮细胞粘附分子(EpCAM)、肝配蛋白(EPH)酪氨酸激酶(如Epha3、Ephb4)、肝配蛋白B2配体、Epigen、Erb-B2(v-Erb-B2禽红细胞白血病病毒癌基因同源物2)酪氨酸激酶受体、Erb-b3酪氨酸激酶受体、Erb-b4酪氨酸激酶受体、细胞外信号调节激酶(ERK)、E-选择素、雌二醇17β脱氢酶、雌激素受体(如α、β)、雌激素相关受体、出口蛋白1、细胞外信号相关激酶(如1、2)、因子(如Xa、VIIa)、Fas配体、脂肪酸合成酶、铁蛋白、粘着斑激酶(FAK,如FAK2)、成纤维细胞生长因子(FGF,如FGF1、FGF2、FGF4)、FGF-2配体、FGF-5配体、纤维连接蛋白、,Fms相关酪氨酸激酶3(Flt3)、法尼类x受体(FXR)、叶酸、叶酸转运体1、叶酸受体(如α)、叶酸水解酶前列腺特异性膜抗原1(FOLH1)、成对碱性氨基酸裂解酶(FURIN)、FYN酪氨酸激酶、半乳糖基转移酶、半乳糖基转移酶-3、,糖皮质激素诱导的TNFR相关蛋白GITR受体、糖皮质激素、β-葡萄糖醛酸酶、谷氨酸羧肽酶II、谷氨酰胺酶、谷胱甘肽S-转移酶P、磷脂酰肌醇蛋白聚糖3(GPC3)、糖原合成酶激酶(GSK,如3-β)、粒细胞集落刺激因子(GCSF)配体、粒细胞-巨噬细胞集落刺激因子(GM-CSF)受体、促性腺激素释放激素(GNRH)、生长因子受体结合蛋白2(GRB2)、分子伴侣GREL2基因、Grp78(78kDa葡萄糖调节蛋白)钙结合蛋白、印迹母体表达转录本(H19)基因,热稳定肠毒素受体,乙酰肝素酶,肝细胞生长因子,热休克蛋白基因,热休克蛋白(如27,70,90α,β),刺猬蛋白,HERV-H LTR结合蛋白2,己糖激酶,酪氨酸蛋白激酶HCK,组胺H2受体,组蛋白脱乙酰酶(HDAC,如1,2,3,6,10,11)组蛋白H1、组蛋白H3、组蛋白甲基转移酶(DOT1L)、人类白细胞抗原(HLA)、HLA I类抗原(A-2α)、HLA II类抗原、同源框蛋白NANOG、丝裂原活化蛋白激酶激酶1(MAP4K1、HPK1)、HSPB1基因、人乳头瘤病毒(如E6、E7)蛋白、透明质酸酶、透明质酸、缺氧诱导因子-1α、细胞间粘附分子-1(ICAM-1)、免疫球蛋白(如G、G1、G2、K、M)、吲哚胺2,3-双加氧酶(IDO,如IDO1)、吲哚胺吡咯2,3-双加氧酶1抑制剂、I-κB激酶(IKK,如IKKβε)、免疫球蛋白Fc受体、免疫球蛋白γFc受体(如I、III、IIIA),白介素1配体,白介素2配体,白介素2,白介素2基因,白介素1α,白介素1β,白介素2,白介素2受体α亚单位,白介素3受体,白介素4,白介素6,白介素7,白介素8,白介素12,白介素15,白介素12基因,白介素17,白介素13受体α2,白介素29配体,白介素1受体相关激酶4(IRAK4),胰岛素样生长因子(如1,2),胰岛素受体,整合素α-V/β-3,整合素α-V/β-5,整合素α-V/β-6,整合素α-5/β-1、整合素α-4/β-1、整合素α-4/β-7、黑色素瘤2中缺失的干扰素诱导蛋白(AIM2)、干扰素(如α、α2、β、γ)、干扰素I型受体、异柠檬酸脱氢酶(如IDH1、IDH2)、Janus激酶(JAK,如JAK1、JAK2)、Jun N末端激酶、激酶插入域受体(KDR),杀伤细胞免疫球蛋白样受体,吻素(KISS-1)受体,v-kit Hardy-Zuckerman 4猫肉瘤病毒癌基因同源物(kit)酪氨酸激酶,KIT基因,驱动蛋白样蛋白KIF11,激肽释放酶相关肽酶3(KLK3)基因,Kirsten大鼠肉瘤病毒癌基因同源物(KRAS)基因,乳铁蛋白,淋巴细胞激活基因3蛋白(LAG-3),溶酶体相关膜蛋白家族(LAMP)基因,羊毛甾醇-14去甲基化酶,LDL受体相关蛋白-1,白三烯A4水解酶,李斯特菌溶素,L-选择素,黄体生成素受体,裂解酶、淋巴细胞抗原75、赖氨酸脱甲基酶(如KDM1、KDM2、KDM4、KDM5、KDM6、A/B/C/D)、淋巴细胞功能抗原-3受体、淋巴细胞特异性蛋白酪氨酸激酶(LCK)、淋巴细胞趋化素、Lyn(LCK/是新的)酪氨酸激酶、溶血磷脂酸-1受体、赖氨酰氧化酶蛋白(LOX)、赖氨酰氧化酶样蛋白(LOXL,如LOXL2),赖氨酰氧化酶同系物2,巨噬细胞迁移抑制因子,黑色素瘤抗原家族A3(MAGEA3)基因,MAGEC1基因,MAGEC2基因,主要穹窿蛋白,肉豆蔻酰化富含丙氨酸蛋白激酶C底物(MARKS)蛋白,Melan-A(MART-1)黑色素瘤抗原,肿瘤相关G蛋白偶联受体、基质金属蛋白酶(MMP,如MMP2、MMP9)、髓细胞白血病1(MCL1)基因、Mcl-1分化蛋白、巨噬细胞集落刺激因子(MCSF)配体、黑色素瘤相关抗原(如1、2、3、6)、黑素细胞刺激素配体、黑素细胞蛋白Pmel17、膜铜胺氧化酶、间皮素、代谢型谷氨酸受体1、丝裂原活化蛋白激酶(MEK,如MEK1、MEK2)、肝细胞生长因子受体(MET)基因、MET酪氨酸激酶、甲硫氨酸氨基肽酶-2、丝裂原活化蛋白激酶(MAPK)、Mdm2 p53结合蛋白、Mdm4蛋白、金属还原酶1(前列腺1的六种跨膜上皮抗原),转移抑素、甲基转移酶、线粒体3酮酰辅酶A硫酶、MAPK活化蛋白激酶(如MK2)、mTOR(雷帕霉素的机械靶点(丝氨酸/苏氨酸激酶)、mTOR复合物(如1,2)、粘蛋白(如1,5A,16)、mut T同源物(如MTH,如MTH1),Myc原癌基因蛋白,NAD ADP核糖基转移酶,利钠肽受体C,神经细胞粘附分子1,神经激肽受体,神经激肽2,一氧化氮合酶,核因子(NF)κB,NFκB激活蛋白,神经激肽1(NK1)受体,NK细胞受体,NK3受体,NKG2 A B激活NK受体,NIMA相关激酶9(NEK9)、去甲肾上腺素转运体、Notch(如Notch-2受体、Notch-3受体)、核磷蛋白间变性淋巴瘤激酶(NPM-ALK)、2,5-寡腺苷酸合成酶、核红系2-相关因子2、核仁磷脂、核磷蛋白、O-甲基鸟嘌呤DNA甲基转移酶、鸟氨酸脱羧酶、乳清酸磷酸核糖转移酶、孤儿核激素受体NR4A1、阿片受体(如δ)、骨钙素、破骨细胞分化因子、骨桥蛋白、OX-40(肿瘤坏死因子受体超家族成员4TNFRSF4或CD134)受体、2-氧谷氨酸脱氢酶、嘌呤能受体P2X配体门控离子通道7(P2X7)、甲状旁腺激素配体、p53抑癌蛋白、P3蛋白、程序性细胞死亡1(PD-1)、原癌基因丝氨酸/苏氨酸蛋白激酶(PIM,如PIM-1、PIM-2、PIM-3)、聚ADP核糖聚合酶(PARP,如PARP1、2和3)、p38激酶、p38MAP激酶、血小板衍生生长因子(PDGF,如α、β)、P糖蛋白(如1)、血小板衍生生长因子(PDGF,如α、β)、PKN3基因、P-选择素、磷脂酰肌醇3-激酶(PI3K)、磷脂酰肌醇3激酶(PI3K,如α、δ、γ)、磷酸化酶激酶(PK)、胎盘生长因子、多效性耐药转运体、丛蛋白B1、Polo样激酶1、过氧化物酶体增殖物激活受体(PPAR,如α、δ、γ),在黑色素瘤(PRAME)基因中优先表达抗原,可能的转录因子PML,程序性细胞死亡配体1抑制剂(PD-L1),孕酮受体,前列腺特异性抗原,前列腺酸性磷酸酶,前列腺样受体(EP4),蛋白酶体,蛋白法尼基转移酶、蛋白激酶(PK,如A、B、C)、蛋白E7、蛋白酪氨酸激酶、蛋白酪氨酸磷酸酶β、polo样激酶(PLK)、PLK1基因、丙炔基结合蛋白(PrPB)、原卟啉原氧化酶、原载脂蛋白(PSAP)基因、磷酸酶和张力蛋白同系物(PTEN)、嘌呤核苷磷酸化酶、丙酮酸激酶丙酮酸脱氢酶(PDH),丙酮酸脱氢酶激酶,Raf蛋白激酶(如1,B)、RAF1基因、Ras GTP酶、Ras基因、5-α-还原酶、RET基因、RET酪氨酸激酶受体、视网膜母细胞瘤相关蛋白、维甲酸受体(如γ)、维甲酸X受体、Rheb(富含脑的Ras同源物)GTPase、Rho(Ras同源物)相关蛋白激酶2、核糖核酸酶、,核糖核苷酸还原酶(如M2亚单位)、核糖体蛋白S6激酶、RNA聚合酶(如I、II)、Ron(受体)酪氨酸激酶、ROS1(ROS原癌基因1、受体酪氨酸激酶)基因、Ros1酪氨酸激酶、Runt相关转录因子3、5100钙结合蛋白A9、肉瘤内质钙ATP酶、γ分泌酶、分泌型卷曲相关蛋白-2、信号素-4D、SL细胞因子配体、丝氨酸蛋白酶、信号淋巴细胞激活分子(SLAM)家族成员7、脾酪氨酸激酶(SYK)、Src酪氨酸激酶、,肿瘤进展基因座2(TPL2)、丝氨酸/苏氨酸激酶(STK)、信号转导和转录(STAT,如STAT-1、STAT-3、STAT-5)、第二线粒体衍生的半胱天冬酶激活剂(SMAC)蛋白、平滑(SMO)受体、磷酸钠协同转运体2B、碘化钠协同转运体、生长抑素受体(如1、2、3、4、5)、音速刺猬蛋白、特异蛋白1(Sp1)转录因子、鞘磷脂合酶、鞘氨醇-1-磷酸受体-1、鞘氨醇激酶(如1、2)、SRC基因、STAT3基因、前列腺六种跨膜上皮抗原(STEAP)基因、类固醇硫酸酯酶、干扰素基因刺激因子蛋白、干扰素基因刺激因子(STING)受体、,基质细胞衍生因子1配体,SUMO(小泛素样修饰物),超氧化物歧化酶,维持素蛋白,突触蛋白3,粘结蛋白聚糖-1,突触核蛋白α,丝氨酸/苏氨酸蛋白激酶(TBK,如TBK1),TATA盒结合蛋白相关因子RNA聚合酶I亚单位B(TAF1B)基因,T细胞表面糖蛋白CD8,T细胞CD3糖蛋白ζ链、T细胞分化抗原CD6、T细胞表面糖蛋白CD28、Tec蛋白酪氨酸激酶、Tek酪氨酸激酶受体、端粒酶、Tenascin、端粒酶逆转录酶(TERT)基因、转化生长因子(TGF,如β)激酶、TGFβ2配体、T细胞免疫球蛋白和粘蛋白结构域含-3(TIM-3)、组织因子、,肿瘤坏死因子(TNF,如α、β)、TNF相关凋亡诱导配体、TNFR1相关死亡域蛋白、TNFSF9基因、TNFSF11基因、滋养层糖蛋白(TPBG)基因、转铁蛋白、原肌球蛋白受体激酶(Trk)受体(如TrkA、TrkB、TrkC)、滋养层糖蛋白、胸苷酸合成酶、具有免疫球蛋白样和EGF样结构域(TIE)受体的酪氨酸激酶、Toll样受体(TLR如1-13)、拓扑异构酶(如I、II、III)、肿瘤蛋白53(TP53)基因、转录因子、转移酶、转化生长因子TGF-β。受体激酶、转谷氨酰胺酶、易位相关蛋白、跨膜糖蛋白NMB、肿瘤坏死因子13C受体、胸苷激酶、胸苷磷酸化酶、胸苷酸合成酶、胸腺肽(如α1)、甲状腺激素受体、Trop-2钙信号转换器、促甲状腺激素受体、,色氨酸5-羟化酶,酪氨酸酶,酪氨酸激酶(TK),酪氨酸激酶受体,酪氨酸蛋白激酶ABL1抑制剂,坦克结合激酶(TBK),血小板生成素受体,TNF相关凋亡诱导配体(TRAIL)受体,微管蛋白,肿瘤抑制候选基因2(TUSC2),酪氨酸羟化酶,泛素结合酶E2I(UBE2I,UBC9),泛素,泛素羧基水解酶同工酶L5,泛素硫酯酶-14,尿素酶,尿激酶纤溶酶原激活剂,子宫珠蛋白,香草醛VR1,血管细胞粘附蛋白1、血管内皮生长因子受体(VEGFR)、T细胞活化V域Ig抑制因子(VISTA)、VEGF-1受体、VEGF-2受体、VEGF-3受体、VEGF-A、VEGF-B、波形蛋白、维生素D3受体、原癌基因酪氨酸蛋白激酶是、Wee-1蛋白激酶、威尔姆斯肿瘤蛋白、威尔姆斯肿瘤抗原1、凋亡蛋白X-连锁抑制剂、锌指蛋白转录因子或其任何组合。
抗癌试剂包括根据其作用机制或类别定义的制剂,包括:抗代谢产物/抗癌试剂,例如嘧啶类似物氟尿苷、卡培他滨、阿糖胞苷、CPX-351(阿糖胞苷脂质体、柔红霉素)、TAS-118;嘌呤类似物、叶酸拮抗剂(如普拉特雷酯)和相关抑制剂;抗增殖/抗有丝分裂剂,包括天然产物,如长春花生物碱(长春花碱、长春新碱)和微管,如紫杉烷(紫杉醇、多西紫杉醇)、长春花素、诺可达唑、埃博噻隆、长春瑞滨(长春花碱)和附睾毒素(依托泊苷、替尼泊苷);DNA损伤剂,如放线菌素、氨沙林、白消安、卡铂、氯霉素、顺铂、环磷酰胺(环磷酰胺)(环磷酰胺)、达克霉素、柔红霉素、阿霉素、表阿霉素、异环磷酰胺、美法仑、甲胺汞、丝裂霉素C、米托蒽醌、亚硝基脲、丙卡巴嗪、紫杉醇、泰索帝、替尼泊甙、足叶乙甙、和三乙烯基硫代磷酰胺;DNA低甲基化剂,如胍地西他滨(SGI-110)抗生素,如达卡霉素、柔红霉素、阿霉素、伊达霉素、蒽环类、米托蒽醌、博莱霉素、褶皱霉素(密特拉霉素)和;酶,例如系统代谢L-天冬酰胺并剥夺细胞合成自身天冬酰胺能力的L-天冬酰胺酶;抗血小板药物;靶向Bcl-2的DNAi寡核苷酸,如PNT2258;激活或重新激活潜在人类免疫缺陷病毒(HIV)的试剂,如帕诺比诺司他或罗米地蛋白酶天冬酰胺酶刺激剂,如克立他酶(crisantaspase)(Erwinase.RTM.)和GRASPA(ERY-001,ERY-ASP);pan-Trk、ROS1和ALK抑制剂,如恩曲替尼间变性淋巴瘤激酶(ALK)抑制剂,如阿雷替尼抗增殖/抗有丝分裂烷基化剂,如氮芥、环磷酰胺和类似物(美法仑、氯苯脲、六甲基三聚氰胺和硫替帕)、烷基亚硝基脲(卡莫司汀)和类似物,链脲佐菌素和三氮烯(达卡巴嗪);抗增殖/抗有丝分裂抗代谢物,如叶酸类似物(甲氨蝶呤);铂配合物(顺铂、奥昔洛铂和卡铂)、丙卡巴嗪、羟基脲、米托坦和氨基谷氨酰胺;激素、激素类似物(雌激素、三苯氧胺、戈舍雷林、比卡鲁胺和尼鲁他胺)和芳香化酶抑制剂(来曲唑和阿那曲唑);抗凝剂,如肝素、合成肝素盐和其他凝血酶抑制剂;组织纤溶酶原激活剂、链激酶、尿激酶、阿司匹林、双嘧达莫、噻氯匹定和氯吡格雷等纤溶剂;抗迁移剂;抗分泌剂(breveldin);免疫抑制剂他克莫司、西罗莫司、硫唑嘌呤和霉酚酸酯;化合物(TNP-470,染料木素)和生长因子抑制剂(血管内皮生长因子抑制剂和成纤维细胞生长因子抑制剂,如FPA14;血管紧张素受体阻滞剂,一氧化氮供体;反义寡核苷酸,如AEG35156;DNA干扰寡核苷酸,如PNT2258,AZD-9150抗体,如曲妥珠单抗和利妥昔单抗;抗HER3抗体,如LJM716抗HER2抗体,如玛格妥昔单抗(margetuximab);抗HLA-DR抗体,如IMMU-114;抗IL-3抗体,如JNJ-56022473;抗OX40抗体,如MEDI6469抗EphA3抗体,如KB-004;抗CD20抗体,如阿托珠单抗(obinutuzumab);抗程序性细胞死亡蛋白1(抗PD-1)抗体,如纳武单抗(nivolumab)(OPDIVO,BMS-936558,MDX-1106),帕博丽珠单抗(pembrolizumab)(KEYTRUD,MK-3477,SCH-900475,派姆单抗(lambrolizumab,CAS注册号1374853-91-4),匹迪利珠单抗和抗程序性死亡配体1(抗PD-L1)抗体,如BMS-936559,阿替唑珠单抗(MPDL3280A),杜瓦鲁单抗(MEDI4736),阿维鲁单抗(MSB0010718C)和MDX1105-01,CXCR4拮抗剂如BL-8040;CXCR2拮抗剂如AZD-5069;GM-CSF抗体,例如仑兹鲁单抗(lenzilumab)。选择性雌激素受体下调因子(SERD),如氟维司坦(Faslodex);转化生长因子-β(TGF-β)激酶拮抗剂,如galunisertib;一种双特异性抗体,如MM-141(IGF-1/ErbB3)、MM-111(Erb2/Erb3)、JNJ-64052781(CD19/CD3)。突变选择性EGFR抑制剂,如PF-06747775、EGF816、ASP8273、ACEA-0010、BI-1482694。α-酮戊二酸脱氢酶(KGDH)抑制剂如CPI-613,XPO1抑制剂如塞利尼索(selinexor)(KPT-330)。异柠檬酸脱氢酶2(IDH2)抑制剂如依那西替尼(AG-221),IDH1抑制剂如AG-120和AG-881(IDH1和IDH2)。靶向白细胞介素-3受体(IL-3R)的药物,如SL-401。精氨酸脱氨酶刺激剂,如聚乙二醇亚胺酶(ADI-PEG-20)抗体-药物结合物,如MLN0264(抗GCC,鸟苷酸环化酶C)、T-DM1(曲妥珠单抗-美坦新偶联物,Kadcycla)、米拉组单抗(milatuzumab-doxorubicin)(hCD74-DOX)、维布妥昔单抗(brentuximab-vedotin)、DCDT2980S、波妥珠单抗维多丁(Polatuzumabvedotin)、SGN-CD70A、SGN-CD19A、奥英妥珠单抗(InotuzumabOzogamicin)、莫星-洛沃妥珠单抗(lorvotuzumabmertansine)、SAR3419、isactuzumabgovitecan、抗连接蛋白-18.2抗体,如IMAB362。β-连环蛋白抑制剂,如CWP-291和CD73拮抗剂,如MEDI-9447;c-PIM抑制剂,如PIM447,BRAF抑制剂,如达布拉非尼、维穆拉非尼,鞘氨醇激酶-2(SK2)抑制剂,如耶利娃。(ABC294640)细胞周期抑制剂,如塞洛美替尼(MEK1/2),沙巴替滨,AKT抑制剂,如MK-2206,依帕替尼,阿富列西替布,抗CTLA-4(细胞毒性T淋巴细胞蛋白-4)抑制剂,如银耳单抗,c-MET抑制剂,如AMG-337,萨沃利替尼,替凡尼(ARQ-197),卡马替尼,CSF1R/KIT和FLT3的替泊替尼抑制剂,如PLX3397,激酶抑制剂,如樊得他尼;E选择素拮抗剂如GMI-1271,分化诱导剂如维甲酸;表皮生长因子受体(EGFR)抑制剂,如奥西米替尼(AZD-9291)拓扑异构酶抑制剂(阿霉素、柔红霉素、达卡霉素、伊尼泊苷、表阿霉素、依托泊苷、伊达柔比星、伊立替康、米托蒽醌、哌蒽醌、索布唑嗪、拓扑替康和伊立替康,MM-398(伊立替康脂质体),沃沙罗辛和皮质类固醇(可的松、地塞米松、氢化可的松、甲基强的松龙、强的松和强的松龙);生长因子信号转导激酶抑制剂;功能障碍诱导剂;核苷类似物,如DFP-10917 Axl抑制剂,如BGB-324;BET抑制剂,如INCB-054329,PARP抑制剂,如奥拉帕利,鲁卡帕利,维利帕尼(Veliparib),蛋白酶体抑制剂,如伊沙佐米(Ixazomib),卡非佐米(carfilzomib)(商品名为凯洛斯(Kyprolis));谷氨酰胺酶抑制剂,如CB-839;疫苗,如肽疫苗TG-01(RAS),细菌载体疫苗,如CRS-207/GVAX,自体Gp96疫苗,树突状细胞疫苗,OncQuest-L疫苗,DPX-生存素,ProstAtak,DCVAC,ADXS31-142,登赛珠单抗(抗DLL4,δ样配体4,Notch途径),纳巴布卡西(BBI-608)平滑(SMO)受体抑制剂,例如Odomzo.RTM。(索尼德吉(Sonidegib(商品名Odomzo)),前身为LDE-225)、LEQ506、维莫德吉(Vismodegib)(GDC-0449)、BMS-833923、格拉吉布(glasdegib)(PF-04449913)、LY2940680和伊曲康唑;干扰素α配体调节剂,如干扰素α-2b、干扰素α-2a生物类似物(生物基因组学)、罗布金特费隆α-2b(AOP-2014、P-1101、聚乙二醇干扰素α-2b),多重干扰素(阿尔法那特、维拉根)、干扰素α1b、干扰素-A(坎弗隆、Ro-25-3036)、干扰素α-2a后续生物制剂(Biosidus)(Inmutag、INTR 2a)、干扰素α-2b后续生物制剂(BiosidusBiosifon、Citopheron、Ganapar)(北京卡文科技有限公司卡弗隆)(AXXO干扰素α-2b)、干扰素α-2b、聚乙二醇化干扰素α-1b、,聚乙二醇干扰素α-2b后续生物制剂(Amega)、重组人干扰素α-1b、重组人干扰素α-2a、重组人干扰素α-2b、维妥珠单抗(veltuzumab)干扰素α-2b结合物、Dynavax(SD-101)和干扰素α-n1(Humoferon,SM-10500,Sumiferon);干扰素-γ配体调节剂,如干扰素-γ(OH-6000,Ogamma 100);IL-6受体调节剂,如托昔单抗、西妥昔单抗、as-101(CB-06-02,IVX-Q-101);端粒酶调节剂,如特托莫肽(GV-1001,HR-2802,Riavax)和伊美司他(GRN-163,JNJ-63935937)DNA甲基转移酶抑制剂,如替莫唑胺(CCRG-81045),地西他滨,胍地西他滨(S-110,SGI-110),KRX-0402和阿扎胞苷;DNA回旋酶抑制剂,如哌蒽醌和索布唑烷;Bcl-2家族蛋白抑制剂ABT-263、维奈托克(venetoclax)(ABT-199)、ABT-737和AT-101;Notch抑制剂,如LY3039478、塔替单抗(抗Notch2/3)、BMS-906024抗肌生长抑制素抑制剂,如兰度戈组单抗、透明质酸酶刺激剂,如PEGFH-20、Wnt途径抑制剂,如SM-04755、PRI-724、伽马分泌酶抑制剂,如PF-03084014、IDO抑制剂,如吲哚昔莫、Grb-2(生长因子受体结合蛋白-2)抑制剂BP1001(脂质体Grb-2)、TRAIL途径诱导化合物(如ONC201)、粘着斑激酶抑制剂(如VS-4718)、德法替尼、刺猬抑制剂(如沙利吉布、索尼地吉布(LDE225)、格拉斯吉布和维斯莫吉布、极光激酶抑制剂(如阿利替布)(MLN-8237)、HSPB1活性调节剂(热休克蛋白27、HSP27),如溴夫定、阿托森、ATR抑制剂如AZD6738和VX-970、mTOR抑制剂如Sapaniertib、Hsp90抑制剂如AUY922。小鼠双分钟(mdm2)癌基因抑制剂,例如DS-3032bCD137激动剂,比如脲单抗,抗KIR单克隆抗体,例如利利单抗(IPH-2102)。抗原CD19抑制剂,例如MOR208、MEDI-551、AFM-11、CD44结合物,例如A6、CYP17抑制剂,例如VT-464、ASN-001、ODM-204。RXR激动剂,例如IRX4204,TLRs(Toll样受体)激动剂,例如IMO-8400,刺猬/平滑(hh/Smo)拮抗剂,例如taladegib。免疫调节剂,如补体C3调节剂,如Imprime PGG。瘤内免疫肿瘤药物,如G100(TLR4激动剂)、IL-15激动剂,如ALT-803EZH2(zeste同源物2增强子)抑制剂,如他泽米司他。溶瘤病毒,如Pelarorep和talimogenelaherparepvec)。DOT1L(组蛋白甲基转移酶)抑制剂,如美托司他(EPZ-5676),毒素,如霍乱毒素、蓖麻毒素、假单胞菌外毒素、百日咳杆菌腺苷酸环化酶毒素、白喉毒素和半胱天冬酶激活剂;染色质。DNA质粒,如BC-819。PLK 1、2和3的PLK抑制剂,如伏拉色替(PLK1)。凋亡信号调节激酶(ASK)抑制剂:ASK抑制剂包括ASK1抑制剂。ASK1抑制剂的示例包括但不限于WO 2011/008709(吉利德科学)和WO2013/112741(吉利德科学)中所述的抑制剂。布鲁顿酪氨酸激酶(BTK)抑制剂:BTK抑制剂的示例包括但不限于,(s)-6-氨基-9-(1-(但-2-炔酰基)吡咯烷基-3-基)-7-(4-苯氧基苯基)-7H-pur-in-8(9H)-酮、阿卡鲁替尼(ACP-196)、BGB-3111、HM71224、伊布替尼、M-2951、ONO-4059、PRN-1008、司布替尼(CC-292)、TAK-020。细胞周期素依赖性激酶(CDK)抑制剂:CDK抑制剂包括CDK 1、2、3、4、6和9的抑制剂,如阿贝马西林、阿维西肽(HMR-1275,黄吡利多)、AT-7519、FLX-925、LEE001、帕博西林、核糖环利布、里戈西替布、塞林索、UCN-01和TG-02。盘状结构域受体(DDR)抑制剂:DDR抑制剂包括DDR1和/或DDR2抑制剂。DDR抑制剂的实例包括但不限于WO 2014/047624(Gilead Sciences公司)、US 2009-0142345(武田制药)、US2011-0287011(肿瘤学制药)、WO 2013/027802(Chugai制药)和WO 2013/034933(帝国创新)中披露的抑制剂。组蛋白去乙酰化酶(HDAC)抑制剂:HDAC抑制剂的实施例包括,但不限于,阿贝西诺司他、ACY-241、AR-42、BEBT-908、贝尼司他、CKD-581、CS-055(HBI-8000)、CUDC-907、恩替诺特、吉维司他、莫西汀、帕诺比诺司他、普拉西诺司他、奎西诺司他(JNJ-26481585)、雷斯米诺司他、利可林司他、SHP-141、丙戊酸(VAL-001),伏立诺斯塔。詹讷斯激酶(JAK)抑制剂:JAK抑制剂抑制JAK1、JAK2和/或JAK3。JAK抑制剂的实例包括但不限于AT9283、AZD1480、巴利西替尼、BMS-911543、非拉替尼、非戈替尼(GLPG0634)、甘多替尼(LY2784544)、INCB039110、莱索替尼、莫莫莫洛替尼(CYT0387)、NS-018、帕西替尼(SB1518)、培非替尼(ASP015K)、鲁索利替尼、托法替尼(以前的塔西替尼)和XL019。赖氨酰氧化酶样蛋白(LOXL)抑制剂:LOXL抑制剂包括LOXL1、LOXL2、LOXL3、LOXL4和/或LOXL5的抑制剂。LOXL抑制剂的实例包括但不限于WO 2009/017833(Arresto Biosciences公司)中描述的抗体。LOXL2抑制剂的实例包括但不限于WO 2009/017833(Arresto Biosciences公司)、WO 2009/035791(Arresto Biosciences公司)和WO 2011/097513(Gilead Biosics公司)中所述的抗体。基质金属蛋白酶(MMP)抑制剂:MMP抑制剂包括MMP1至10的抑制剂。MMP9抑制剂的示例包括但不限于马马司他(BB-2516)、西马司他(Ro32-3555)和WO 2012/027721(Gilead Biologics)中所述的抑制剂。丝裂原活化蛋白激酶(MEK)抑制剂:MEK抑制剂包括安托喹诺尔、比尼替尼、科比替尼(GDC-0973、XL-518)、MT-144、塞洛替尼(AZD6244)、索拉非尼、曲美替尼(GSK1120212)、乌罗西替尼+曲美替尼。磷脂酰肌醇3-激酶(PI3K)抑制剂:PI3K抑制剂包括PI3Kγ、PI3Kδ、PI3β、PI3Kα和/或pan-PI3K的抑制剂。PI3K抑制剂的示例包括但不限于ACP-319、AEZA-129、AMG-319、AS252424、BAY 10824391、BEZ235、布帕尼盘(BKM120)、BYL719(alpelisib)、CH5132799、科潘利西(BAY 80-6946)、杜维利西、GDC-0941、GDC-0980、GSK2636771、GSK2269557、Idelisib(Zydelig.RTM.)、IPI-145、IPI-443、KAR4141、LY294002、Ly-3023414、MLN111A、,PA799、PX-866、RG7604、rigosertib、RP5090、taselisib、TG100115、TGR-1202、TGX221、WX-037、X-339、X-414、XL147(SAR245408)、XL499、XL756、wortmannin、ZSTK474以及WO 2005/113556(ICOS)、WO 2013/052699(Gilead Calistoga)、WO 2013/116562(Gilead Calistoga)、WO 2014/100765(Gilead Calistoga)、WO 2014/100767中描述的化合物(基列卡利斯托加)和WO 2014/201409(基列科学)。脾脏酪氨酸激酶(SYK)抑制剂:SYK抑制剂的实施例包括但不限于6-(1H-吲唑-6-基)-N-(4-吗啉苯基)咪唑[1,2-吡嗪-8-胺,BAY-61-3606,赛度替尼(Cerdulatinib)(PRT-062607),内抑素,福他替尼(R788),HMPL-523,NVP-QAB 205AA,R112,R343,他马替尼(R406)酪氨酸激酶抑制剂(TKIs):TKIs可靶向表皮生长因子受体(EGFR)和成纤维细胞生长因子(FGF)、血小板衍生生长因子(PDGF)和血管内皮生长因子(VEGF)受体。TKIs的示例包括但不限于:阿法替尼、博司替尼、百加替尼、卡波坦替尼、克洛替尼、达考替尼、达沙替尼、多维替尼、E-6201、厄洛替尼、吉非替尼、吉替替尼(ASP-2215)、HM61713、伊科替尼、伊马替尼、KX2-391(Src)、拉帕替尼、列斯托替尼、米多司他林、尼答尼布、奥西替尼、奥西替尼(AZD-9291)波那替尼、波齐奥替尼、奎扎替尼、拉多替尼、罗西替尼、舒尼替尼和TH-4000。其他抗癌试剂包括:烷基化剂,如硫替帕和环磷酰胺(环磷酰胺);烷基磺酸盐,如白消安、英普苏凡和皮普苏凡;氮丙啶类化合物,如苯并噻吩、碳醌、二甲双胍和脲;亚乙基胺和甲胺,包括奥替瑞胺、三乙烯基三聚氰胺、三乙烯基磷酰胺、三乙烯基硫代磷酰胺和三甲基甲酰胺;丙酮类,尤其是牛拉他星和牛拉他星酮;一种喜树碱,包括合成模拟物拓扑替康;苔藓虫素、胼胝抑素;CC-1065,包括其阿多来新、卡折来新和比折来新合成类似物;隐藻毒素,尤其是隐藻毒素1和隐藻毒素8;多拉他汀;杜卡霉素,包括合成类似物KW-2189和CBI-TMI;埃列瑟罗宾;5-氮胞苷;胰抑素;肉蜥蜴;海绵素;氮芥,如氯苯脲、氯丙嗪、环磷酰胺、葡糖酰胺、吴茱萸酰胺、苯达莫司汀、雌霉素、异环磷酰胺、甲氯乙胺、甲氯乙胺氧化物盐酸盐、美法仑、新比钦、苯酯酶、泼尼莫司汀、特罗福胺和尿嘧啶芥末;亚硝基脲,如卡莫司汀、氯唑霉素、福莫司汀、洛莫司汀、尼莫司汀和雷尼霉素;抗生素,如烯二炔类抗生素(例如,卡利霉素,尤其是卡利霉素gammaII和卡利霉素phiI1),强尼霉素,包括强尼霉素A,双磷酸盐,如氯膦酸盐,一种埃斯帕米星,新卡那他丁生色团和相关生色蛋白烯二炔类抗生素生色团,阿克拉霉素,放线菌素,阿曲霉素,阿扎丝氨酸、博莱霉素、仙人掌毒素、carabicin、洋红霉素、嗜癌素、色霉素、放线菌素、柔红霉素、地托比星、6-重氮-5-氧代-L-去甲亮氨酸、多柔比星(包括吗啉-多柔比星、氰基吗啉-多柔比星、2-吡咯-多柔比星和脱氧多柔比星)、表阿霉素、埃索比星、伊达柔比星、马塞霉素;丝裂霉素,如丝裂霉素C、霉酚酸、诺加霉素、橄榄霉素、培洛霉素、波罗霉素、嘌呤霉素、奎拉霉素、罗托霉素、链霉素、链脲佐菌素、结核菌素、乌本美司、吉诺他丁和唑柔比星;抗代谢产物如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,如去甲蝶呤、甲氨蝶呤、蝶呤和三甲氧基苯甲酸;嘌呤类似物,如氟达拉滨、6-巯基嘌呤、噻咪嗪和硫鸟嘌呤;嘧啶类似物,如安西他滨、阿扎胞苷、6-阿扎尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、多西氟啶、依诺西他滨和氟尿苷;雄激素,如卡卢斯酮、丙酸屈莫司他龙、表雄醇、甲匹噻烷和睾丸内酯;抗肾上腺药物,如氨基谷氨酰胺、米托坦和曲洛坦;叶酸补充剂,如弗罗林酸;放射治疗剂,如镭-223;毛霉素,尤其是T-2毒素、维拉库林A、罗立定A和胍;紫杉醇(紫杉醇)、艾布拉烷、多西紫杉醇(泰索帝)、卡巴齐他塞尔、BIND-014等紫杉类;铂类似物,如顺铂和卡铂,NC-6004纳米铂;乙酰甲胺酮;醛缩磷苷;氨基乙酰丙酸;依那普利;氨吖啶;海斯特拉布西;双芳烯;依达拉奉;毁林饥荒;德梅科辛;二嗪醌;艾尔福霉素;乙酸椭圆铵;埃博噻隆;依托胶酸;硝酸镓;羟基脲;香菇多糖;亚叶酸;洛尼达明;美丹素类化合物,如美丹素和安萨米托素;米托瓜宗;米托蒽醌;莫匹达莫;硝胺;抑制素;非那米特;吡柔比星;洛沙坦酮;氟嘧啶;叶酸;鬼臼酸;2-乙基肼;丙卡巴嗪;多糖-K(PSK);唑烷;根霉素;西索菲兰;螺旋锗;噻诺酮酸;曲白细胞素,三嗪醌;2,2',2”-三氟三胺;聚氨酯;长春地辛;达卡巴嗪;甘露霉素;米托溴醇;米托内酯;哌泊溴烷;胞嘧啶;阿糖胞苷(“Ara-C”);环磷酰胺;硫花瓣;苯丙胺;吉西他滨(GEMZARTM);6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;二尖瓣环酮;香草碱;长春瑞滨(NAVELBINETM);诺凡特罗;替尼泊甙;乙氨蝶呤;柔红霉素;氨基蝶呤;塞奥洛达;伊班膦酸钠;CPT-11;拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(DFMO);维甲酸等维甲酸;卡培他滨;FOLFIRI(氟尿嘧啶、亚叶酸和伊立替康);以及上述任何一种的药学上可接受的盐、酸或衍生物。
抗癌试剂的定义中还包括抗激素剂,如抗雌激素和选择性雌激素受体调节剂(SERM)、芳香化酶抑制剂、抗雄激素以及上述任何一种药物上可接受的盐、酸或衍生物,其作用是调节或抑制激素对肿瘤的作用。抗雌激素和血清的实例包括,例如,三苯氧胺(包括诺瓦德)、雷洛昔芬、屈洛昔芬、4-羟基三苯氧胺、三羟昔芬、凯奥昔芬、LY117018、奥那普利斯通和托瑞米芬(法雷斯顿)。芳香化酶抑制剂调节肾上腺中雌激素的产生。实施例包括4(5)-咪唑类、氨基谷丙酰胺类、醋酸甲地孕酮类(MEGACE)、依西美坦类、福美坦(formestan)类、法曲唑类、伏罗唑类(RIVISOR)、来曲唑类(FEMARA)和阿那曲唑类(ARIMIDEX)。抗雄激素的实例包括阿扑鲁胺、阿比特龙、恩扎鲁胺、氟他胺、加列特酮、尼鲁他胺、比卡鲁胺、亮丙瑞林、戈舍瑞林、ODM-201、APC-100、ODM-204。孕酮受体拮抗剂的实施例包括奥那普利斯通。
抗血管生成药物包括但不限于维甲酸及其衍生物、2-甲氧基雌二醇、血管抑制素、内皮抑制素、雷戈拉非尼、奈库帕拉尼、苏拉明、角鲨胺、金属蛋白酶组织抑制剂-1、金属蛋白酶组织抑制剂-2、纤溶酶原激活物抑制剂-1、纤溶酶原激活物抑制剂-2、,软骨衍生抑制剂、紫杉醇(nab紫杉醇)、血小板因子4、硫酸鱼精蛋白(clupeine)、硫酸化几丁质衍生物(从皇后蟹壳制备)、硫酸化多糖肽聚糖复合物(sp-pg)、星形孢菌素、基质代谢调节剂,包括脯氨酸类似物,如1-氮胞苷-2-羧酸(LACA),顺羟脯氨酸,d,I-3,4-脱氢丙氨酸,硫脯氨酸,α,α'-联吡啶,β-氨基丙腈富马酸,4-丙基-5-(4-吡啶基)-2(3h)-恶唑酮,甲氨蝶呤,米托蒽醌,肝素,干扰素,2-巨球蛋白血清,鸡金属蛋白酶抑制剂-3(ChIMP-3),凝乳抑素,β-环糊精-十四硫酸酯,依泊霉素,富马西林、硫代苹果酸金钠、d-青霉胺、β-1-抗胶原酶-血清、α-2-抗血浆蛋白、双香菇烯、洛贝扎利二钠、n-2-羧基苯基-4-氯代蒽酸二钠或“CCA”、沙利度胺、血管抑制剂类固醇、羧基氨基咪唑、金属蛋白酶抑制剂(如BB-94)、S100A9抑制剂(如塔奎尼莫)。其他抗血管生成剂包括抗体,优选针对这些血管生成生长因子的单克隆抗体:β-FGF、α-FGF、FGF-5、VEGF亚型、VEGF-C、HGF/SF和Ang-1/Ang-2。
抗纤维化试剂包括但不限于一些化合物,例如β-氨基丙腈(BAPN),以及美国专利申请第4965288号中公开的关于赖氨酰氧化酶抑制剂及其在治疗与胶原异常沉积相关的疾病和条件中的应用,以及美国专利第4997854号中公开的涉及抑制LOX用于治疗各种病理性纤维化状态的化合物,其通过引用并入本文。进一步的示例性抑制剂描述在美国专利第4943593号中,其中涉及化合物,例如2-异丁基-3-氟、氯或溴代烯丙胺;美国专利第5021456号;美国专利第5059714号;美国专利第5120764号;美国专利第5182297号;美国专利第5252608号,涉及2-(1-萘氧基甲酰基)-3-氟烯丙胺和美国专利号2004-0248871,通过引用并入本文。示例性抗纤维化剂还包括伯胺,所述伯胺与赖氨酰氧化酶活性部位的羰基发生反应,更具体地说,包括那些在与羰基结合后产生产物的伯胺,所述产物可以通过共振稳定,例如以下伯胺:烯丙基胺、肼、苯肼,及其衍生物;氨基脲和尿素衍生物;氨基腈,如BAPN或2-硝基乙胺;不饱和或饱和卤胺,例如2-溴乙胺、2-氯乙胺、2-三氟乙胺、3-溴丙胺和对卤苄胺;硒单半胱氨酸内酯。其他抗纤维化剂是渗透或不渗透细胞的铜螯合剂。示例性化合物包括间接抑制剂,所述间接抑制剂阻断醛衍生物,所述醛衍生物是通过赖氨酰和羟基赖氨酰残基被赖氨酰氧化酶氧化脱氨基而产生的。实施例包括硫胺,尤其是D-青霉胺,及其类似物,例如2-氨基-5-巯基-5-甲基己酸、D-2-氨基-3-甲基-3-((2-乙酰胺基)二硫代)丁酸、p-2-氨基-3-甲基-3-((2-氨基乙基)二硫代)丁酸、钠-4-((p-1-二甲基-2-氨基-2-羧乙基)二硫代)丁烷磺酸,2-乙酰胺乙基-2-乙酰胺乙硫醇硫酸盐和4-巯基丁烷磺酸钠三水合物。
所述API可以是免疫治疗剂。免疫治疗剂包括但不限于适合治疗患者的治疗性抗体。治疗性抗体的一些实例包括辛妥单抗、阿巴戈单抗、阿德卡妥单抗、阿富图单抗、阿来单抗、阿他单抗、阿那图单抗、阿西图单抗、巴维妥昔单抗、贝伐单抗、比伐单抗、布利那单抗、布伦图单抗、坎图单抗、卡妥单抗、西妥昔单抗、西他单抗、西妥单抗、西妥单抗、西妥单抗、西妥单抗、西妥单抗、克伐珠单抗、康那单抗、达鲁珠单抗、,多利戈图单抗、杜西吉单抗、德妥单抗、达曲单抗、达洛妥单抗、迪诺妥昔单抗、埃洛妥单抗、埃米贝图单抗、增敏妥昔单抗、厄尔妥单抗、埃塔曲单抗、法利妥单抗、菲卡曲珠单抗、菲格妥单抗、法洛妥单抗、富妥昔单抗、甘尼妥单抗、吉伦妥昔单抗、格列巴妥单抗、伊布妥单抗、伊格妥单抗、伊格妥单抗、伊诺妥单抗、伊妥单抗、伊诺妥单抗、,伊普利单抗(YERVOY、MDX-010、BMS-734016和MDX-101),伊拉图单抗、拉贝珠单抗、来沙木单抗、林妥珠单抗、洛沃妥珠单抗、卢卡木单抗、马帕木单抗、马妥珠单抗、米拉组单抗、明瑞莫单抗、米妥莫单抗、莫格利组单抗、Moxetumab、pasudotox、那呐妥单抗、卡伦达珠单抗、耐昔妥珠单抗、尼妥珠单抗、若莫单抗、奥滨尤妥珠单抗、奥比图单抗、奥卡妥珠单抗、奥法图单抗、奥法木单抗、奥法木单抗、欧伐托单抗(Ofatumab)、奥兰替珠单抗(Oratuzumab)、Olaraturatumab、Oratumab,帕萨图单抗、帕特里图单抗、培瘤单抗、培瘤单抗、平瘤单抗、普瑞图单抗、瑞曲单抗、瑞曲单抗、瑞曲单抗(Cyramza.RTM.)、利曲单抗、利妥昔单抗、瑞曲单抗、利妥昔单抗、沙曲单抗、西布罗单抗、沙曲单抗、索洛单抗、他卡图单抗、塔普利单抗、替那图单抗、替罗单抗、替加单抗、妥昔单抗、曲单抗、曲珠单抗、ABP-980、图可单抗、ubilituximab、维妥珠单抗、沃斯妥珠单抗、伏妥莫单抗、扎鲁木单抗、CC49、OBI-833和3F8。利妥昔单抗可用于治疗惰性B细胞癌,包括边缘区淋巴瘤、WM、CLL和小淋巴细胞淋巴瘤。利妥昔单抗和化疗药物的联合使用尤其有效。
示例性的治疗性抗体可进一步标记或与诸如铟-111、钇-90(90Y-克利妥珠单抗)或碘-131的放射性同位素粒子组合。
该组合物包括取代API或除此之外的靶向部分,如共价连接到微米颗粒或纳米颗粒表面的靶向部分,例如肽或蛋白质配体或结构域,该靶向部分特异性或优先结合到靶位点(如靶向部分的细胞表面受体或结合部分),使得携带这种靶向部分的微米颗粒或纳米颗粒将在体内特异性地或优先地指向靶点。携带靶向部分的微米颗粒或纳米颗粒可以进一步包括API,该API被封装或嵌入在微米颗粒或纳米颗粒内,该API可以在靶点释放或以其他方式发挥作用。事实上,唾液酸本身可以成为癌细胞的一个靶向部分。
通过具有靶向部分,靶点特异性纳米颗粒能够有效地结合生物实体或以其他方式与生物体关联,例如膜成分或细胞表面受体。治疗剂的靶向性(例如,针对特定组织或细胞类型,针对特定疾病组织,但不针对正常组织等)对于治疗组织特定疾病,例如癌症(例如,前列腺癌症)是理想的。例如,与细胞毒性抗癌药物的全身给药相比,靶向给药可以阻止该药物杀死健康细胞。
此外,靶向传递将允许给予较低剂量的药剂,这可以减少通常与传统化疗相关的不良副作用。如上所述,本发明的纳米颗粒的靶点特异性将通过优化纳米颗粒上的配体密度而最大化。靶向部分可以共价结合到纳米颗粒或微米颗粒的表面。例如,靶向部分可以共价结合到阴离子聚合物(例如,通过偶联一个或多个羧酸或其他官能团部分)、PLGA/PLA(例如,经由聚合物末端)或通过另一分子或聚合物结合到互穿网络中。例如,靶向部分可以公假连接到聚乙二醇(PEG)分子或PLGA-PEG二嵌段,并与阴离子聚合物一起添加到乳液中。
例如,靶向部分可以是能够结合或以其他方式与生物实体相关联的部分,例如,膜成分、细胞表面受体、前列腺特异性膜抗原等。如本文所使用的术语“结合(bind)”或“结合(binding)”是指表现出相互亲和力或结合能力的对应分子对或其部分之间的相互作用,通常由于特定或非特异性结合或相互作用,包括,但不限于,生化相互作用、生理相互作用和/或化学相互作用。
“生物结合”定义了一种发生在成对分子之间的相互作用,所述成对分子包括蛋白质、核酸、糖蛋白、碳水化合物、激素等。
术语“结合伙伴”指能够与特定分子结合的分子。“特异性结合”是指能够结合或识别结合伙伴(或有限数量的结合伙伴)的分子,如多核苷酸,其结合程度远远高于其他类似生物实体。在一组实施方案中,靶向部分具有小于约1微摩尔、至少约10微摩尔或至少约100微摩尔的亲和力(通过解离常数测量)。
在优选的实施方案中,本发明的靶向部分为小分子。在某些实施方案中,术语“小分子”是指具有相对低分子量且不是蛋白质、多肽或核酸的有机化合物,所述有机化合物既可以是自然存在的也可以是人工产生的(例如,通过化学合成)。小分子通常具有多个碳-碳键。在某些实施方案中,小分子的尺寸小于约2000g/mol。在一些实施方案中,小分子小于约1500g/mol或小于约1000g/mol。在一些实施方案中,小分子小于约800g/mol或小于约500g/mol。
在特别优选的实施方案中,小分子靶向部分靶向前列腺癌肿瘤,并且具体而言,小分子靶向部分是PSMA肽酶抑制剂。这些部分在本文中也称为“低分子量PSMA配体”。与正常组织中的表达相比,前列腺特异性膜抗原(PSMA)在恶性前列腺中的表达比正常组织高至少10倍,并且随着疾病进展到转移期,PSMA表达水平进一步上调(Silver等人,1997年,临床癌症研究,3:81),如美国专利申请第2014/0235706号所述。
在一些实施方案中,可用于靶向与前列腺癌肿瘤相关的细胞的小分子靶向部分包括PSMA肽酶抑制剂,例如2-PMPA、GPI5232、VA-033、苯基烷基膦酰胺(Jackson et al.,2001,Curr.Med.Chem.,8:949;Bennett et al,1998,J.Am.Chem.Soc.,120:12139;Jacksonet al.,2001,J.Med.Chem.,44:4170;Tsulcarnoto et al,2002,Bioorg.Med.Chem.Lett.,12:2189;Tang et al.,2003,Biochem.Biophys.Res.Commun.,307:8;Oliver et al.,2003,Bioorg.Med.Chem.,11:4455;和Maung et al.,2004,Bioorg.Med.Chem.,12:4969),及其类似物和衍生物。在一些实施方案中,可用于靶向与前列腺癌肿瘤相关的细胞的小分子靶向部分包括硫醇和吲哚硫醇衍生物,例如2-MPPA和3-(2-巯基乙基)-1H-吲哚-2-羧酸衍生物(Majer et al.,2003,J.Med.Chem.,46:1989;和美国专利申请公开号第2005/0080128号)。在一些实施方案中,小分子靶向部分可以被用于靶向与前列腺癌肿瘤相关的细胞,这种小分子靶向部分包括羟肟酯衍生物(Stoermer et al.,2003,Bioorg.Med.Chem.Lett.,13:2097)。在一些实施方案中,小分子靶向部分可以被用于靶向与前列腺癌肿瘤相关的细胞,这种小分子靶向部分包括PBDA-基抑制剂和尿素-基抑制剂,例如,ZJ 43、ZJ 11、ZJ 17、ZJ 38(Nan et al.2000,J.Med.Chem.,43:772;和Kozikowskiet al.,2004,J.Med.Chem.,47:1729),和/或其类似物和衍生物。在某些实施方案中,小分子靶向部分可以被用于靶向与前列腺癌肿瘤相关的细胞,这种小分子靶向部分包括腐胺、精胺和亚精胺,雄激素受体靶向剂(ARTAs),例如在以下专利中的描述:美国专利7,026,500;7,022,870;6,998,500;6,995,284;6,838,484;6,569,896;6,492,554;和美国申请公开号2006/0287547;2006/0276540;2006/0258628;2006/0241180;2006/0183931;2006/0035966;2006/0009529;2006/0004042;2005/0033074;2004/0260108;2004/0260092;2004/0167103;2004/0147550;2004/0147489;2004/0087810;2004/0067979;2004/0052727;2004/0029913;2004/0014975;2003/0232792;2003/0232013;2003/0225040;2003/0162761;2004/0087810;2003/0022868;2002/0173495;2002/0099096;2002/0099036.本发明的一个相关方面提供了一种药物组合物,其包含上述组合物和医药上可接受的载体或赋形剂。下文在单独一部分中更详细地描述药物组合物。
本发明还提供了用于递送核酸以增强体外和体内细胞摄取和转染的载体。核酸的实施例包括DNA、RNA、PNA、siRNA、微小RNA、反义核酸等。
颗粒的制备
本文所述的本发明提供了用于制备在其表面上呈现唾液酸残基的颗粒的几种基本方法。
所述颗粒可由疏水性和/或中性生物相容性聚合物(如PLGA或PLA)与聚唾液酸的共沉淀或凝聚来制造。在不受任何理论约束的情况下,人们认为聚合物主链在乳液的有机相中相互缠绕或交织。
如本文所述,“少量”是指与具有PLGA聚合物的第一溶剂的体积相比,第二溶剂的第一溶液的量/体积相对较小,从而使第二溶剂的第一溶液乳化在第一溶剂中的聚合物溶液中形成乳液(即,第一乳液),其中连续相是聚合物溶液。通常,少量的第二溶剂的第一溶液与第一溶剂之间的体积比为至少约1:n,其中n可以是1、2、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90或100。
如本文所述,“大量”是指与第一乳液的体积相比,第二溶剂的第二溶液的量/体积相对较大,使得第一乳液在第二溶剂的第二溶液中乳化形成乳液(即,第二乳液),其中连续相是第二溶剂的第二溶液。通常,第一乳液与大量第二溶剂的第二溶液之间的体积比为至少约1:m,其中m可以是1、2、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90或100。
使用本文描述的制备方法,将聚唾液酸紧密结合到所产生的微米颗粒或纳米颗粒中。
将聚唾液酸掺入到微米颗粒或纳米颗粒中可以是稳定且紧密的。因此,优选地,所述方法进一步包括洗涤所述微米颗粒或纳米颗粒,和/或将所述微米颗粒或者纳米颗粒浓缩到所需体积。
乳液法可用于制备本文所述的颗粒。本发明包括一种制备在其表面上呈现唾液酸部分的微米颗粒或纳米颗粒的方法,其包括:(1)将可生物降解的聚合物(以及任选的活性剂,例如药物成分(API)或水溶性差的化合物)溶于第一溶剂中以形成聚合物溶液;(2)在第二溶剂的溶液中乳化所述聚合物溶液以形成乳液,其中所述第一溶剂与所述第二溶剂不混溶或部分混溶,且其中所述第二溶剂的溶液包括聚唾液酸,所述第二溶剂的溶液任选地进一步包括溶于第二溶剂的表面活性剂和/或API;以及(3)除去第一溶剂以形成具有表面唾液酸部分的所述微米颗粒或纳米颗粒。
本发明还提供了一种用于制备具有表面唾液酸部分的微米颗粒或纳米颗粒的双乳化方法,所述方法包括:(1)将可生物降解的聚合物(和任选的活性剂、API或难溶于水的化合物)溶于第一溶剂中以形成聚合物溶液;(2)将第二溶剂添加到聚合物溶液中以形成混合物,其中第一溶剂与第二溶剂不混溶或部分混溶,并且其中第二溶剂的第一溶液任选地包括活性剂,所述活性剂与溶于所述第一溶剂中的所述API相同或不同;(3)乳化所述混合物以形成第一乳液;(4)将所述第一乳液在所述第二溶剂的第二溶液中乳化以形成第二乳液,其中所述第二溶剂的第二溶液包括聚唾液酸,且任选地进一步包括表面活性剂;以及(5)除去所述第一溶剂以形成具有表面唾液酸部分的微米颗粒或纳米颗粒。
本发明中的API可以是核酸治疗剂。示例性的核酸治疗剂包括但不限于经美国食品药品监督管理局(FDA)批准的、经FDA新药申请的、在临床试验或临床前研究中的核酸治疗剂。核酸分子包括编码治疗蛋白、抗原分子和抑制分子的分子。例如,能够介导RNA干扰的核酸分子包括在RNA干扰中具有活性的分子(RNAi分子),包括双链RNA,例如反义、核酶、siRNA(小干扰RNA)、miRNA(微RNA)、shRNA(短发夹RNA)、短聚体、抗逆转录病毒、mRNA、tRNA、ddRNA(DNA导向的RNA)、piRNA(Piwi相互作用RNA)或rasiRNA(重复相关的siRNA)及其修饰形式。分子还可包括DNA、质粒、载体、杂合寡核苷酸、催化DNA或适体。
编码核酸和多核苷酸可包括编码感兴趣的多肽的区域(例如,编码区域)、第一区域的5’-末端(例如5’-UTR)、第一区域的3’-末端(例如3’-UTR)、至少一个5’-帽区域和/或3’-稳定区域。核酸可包括多聚腺苷酸区域(poly-Aregion)或Kozak序列(例如,在所述5’-UTR中)、能够从多核苷酸上切除的一个或多个内含子核苷酸序列、5’帽结构、链终止核苷酸、茎环、多聚腺苷酸序列和/或多聚腺苷酸化信号。核酸可包括一种或多种替代组分(例如,替代核苷)。例如,所述的3’-稳定区域可含有替代核苷,例如L-核苷、反式胸苷或2’-O-甲基核苷,和/或所述编码区域、5’-UTR、3'-UTR或帽区域可包括替代核苷,例如5-取代尿苷(如,5-甲氧基尿苷)、1-取代假尿苷(如,1-甲基-假尿苷或1-乙基-假尿苷)、5-取代胞苷(如,5-甲基-胞苷)和/或肌肽和丝氨酸。
多核苷酸序列的长度足以编码二肽或多肽,例如三肽、四肽、五肽、六肽、七肽、八肽、九肽或十肽。在一些情况下,多核苷酸的长度大于30个核苷酸,例如大于35个核苷酸、至少40个核苷酸、至少45个核苷酸、至少55个核苷酸、至少60个核苷酸、至少80个核苷酸、至少90个核苷酸、至少100个核苷酸或更多。
核酸和多核苷酸包括一种或多种天然存在的组分,包括任何规范核苷酸A(腺苷)、G(鸟苷)、C(胞嘧啶)、U(尿苷)或T(胸苷)。在一个实施方案中,包含(a)5’-UTR、(b)开放阅读框(ORF)、(c)3’-UTR、(d)多聚腺苷酸尾部,以及包括天然存在的规范核苷酸A(腺苷)、G(鸟苷)、C(胞嘧啶)、U(尿苷)或T(胸苷)的(上述a、b、c或d)的任何组合。
核酸和多核苷酸可以包括一种或多种组分以增加稳定性,减少引入多核苷酸的细胞的先天免疫应答的实质性诱导,增强蛋白质生产的效率,多个苷酸的胞内滞留,接触的细胞的活力,和/或降低免疫原性。
多核苷酸和核酸可以是天然存在的或非天然存在的。多核苷酸和核酸可以包括一种或多种修饰的(如,改变的或替代的)核碱基、核苷、核苷酸或其组合。可用于纳米颗粒组合物的核酸和多核苷酸可包括任何有用的修饰或改变,例如,对核碱基、糖或核苷间连结(例如,对连接的磷酸盐/对磷酸二酯键/对磷酸双酯主链)的修饰或改变。改变(例如,一个或多个改变)存在于核碱基、糖和核苷间连结的每一个中。根据本申请公开的改变可以是核糖核酸(RNA)到脱氧核糖核酸(DNA)的改变,例如呋喃核糖基环的2’-OH到2’-H、苏氨酸核酸(TNA)、乙二醇核酸(GNA)、肽核酸(PNA)、锁核酸(LNA)或其杂合体。
多核苷酸和核酸可以沿着分子的整个长度均匀地改变,也可以不均匀地改变。举例来说,一种或多种或所有类型的核苷酸(例如嘌呤或嘧啶,或者A、G、U、C中的任意一种或多种或全部)可以在多核苷酸或核酸中或在其给定的预定序列区域中均匀地改变,也可以不均匀地改变。在一些情况下,多核苷酸(或其给定序列区域)中的所有核苷酸X都被改变,其中X可以是核苷酸A、G、U、C中的任意一种,或组合A+G、A+U、A+C、G+U、G+C、U+C、A+G+U、A+G+C、G+U+C或A+G+C中的任意一种。
不同的糖改变和/或核苷间连结(例如,骨架结构)可能存在于多核苷酸的不同位置。本领域普通技术人员将理解,核苷酸类似物或其他改变可以位于多核苷酸的任何位置,使得多核苷酸的功能不会显著降低。改变也可以是5’-末端或3’-末端改变。在一些实施方案中,所述的多核苷酸包括在3’-末端的改变。
在一些情况下,核酸基本上不会诱导引入多核苷酸(例如,mRNA)的细胞的先天免疫应答。诱导的先天免疫应答的特征包括1)促炎细胞因子的表达增加,2)细胞内PRR(RIG-I、MDA5等)的激活,和/或3)蛋白质翻译的终止或减少。
所述的核酸可以任选地包括其他试剂(如,RNAi-诱导剂、RNAi试剂、siRNA、shRNA、miRNA、反义RNA、核酶、催化DNA、tRNA、诱导三螺旋形成的RNA、适体、载体)。在一些实施方案中,所述的核酸可以包括一个或多个信使RNA(mRNA),其具有一个或多个替代核苷或核苷酸(即替代mRNA分子)。
在一些实施方案中,可以在封装之前使用阳离子络合剂来络合所述核酸货物。
本发明中的阳离子络合剂可以是含氮、硫或磷的分子,例如小分子化合物、脂质体、聚合物或树枝状聚合物。该分子优选为两亲性的,具有一个或多个阳离子部分和一个或更多个疏水部分。阳离子部分可以是含氮、硫或磷的基团。优选的阳离子部分包括伯胺或仲胺、铵或膦。疏水部分可以是有机或无机基团。优选的疏水基团包括取代的或未取代的、饱和的或不饱和的高级烷基、酰基或酯(C3-C20或更多)。疏水基团可以是直链、支链或环化的(例如芳基或胆固醇及其类似物)。
用于本发明的小分子络合剂通常是含氮、硫或磷的化合物或其盐。小分子络合剂的非限制性实施例包括十二烷基精氨酸乙酯HCl(LAE)、三丙基胺、三丁基胺、三苯基胺、十六烷基胺、己胺、二十二烷基二甲基溴化铵、十二烷基三甲基溴化胺(DTAB)、溴化十六烷基铵(CTAB)、苯甲基、二甲基二十八烷基溴化铵、苯乙苄胺、海巴明(hydrabamine)、硬质烷铵、DC-胆固醇·HCl、氯化十六烷基吡啶、1,2-二硬脂酰-3-二甲基氨基丙烷、DODMA、脂质等。
可在本发明中用作络合剂的脂质可以是阳离子脂质或可电离脂质。
阳离子脂质是两亲性分子,其具有通过稳定或可降解键连接的阳离子头部基团和疏水性内酰胺基。胍、咪唑、吡啶、哌啶和氨基酸(如赖氨酸、精氨酸、鸟氨酸和色氨酸)是脂质修饰中常用的头部基团。可在本发明中用作络合剂的脂质包括但不限于在其头部基团中具有单胺官能团的单价脂族脂质,例如N[1-(2,3-二聚氧基)丙基]-N,N,N-三甲基氯化铵(DOTMA),)、N-(2-羟乙基)-N,N-二甲基-2,3-双(十四烷氧基-L-丙胺溴化物)(DMRIE),在头部基团中具有多个胺官能团的多价脂族脂质,例如精胺基团,例如二十八烷基酰胺甘氨酰精胺(DOGS),或阳离子胆固醇衍生物,例如3b-[N-(N0,N0-二甲基氨基乙烷)氨基甲酰基]胆固醇(DC-Chol)、双-鸟嘌呤-tren-胆固醇(BGTC),以及中性辅助脂质,例如l,2-二油基-sn-甘油-3-磷酸乙醇胺(DOPE)或胆固醇,将其添加到DNA和RNA以及阳离子脂质的复合物中以提高转染效率。
可电离脂质是一类脂质分子,这类脂质分子在生理pH值下是中性和非离子的,但在较低pH值下会质子化而带正电荷。电离脂质也可以与含SA的实体形成复合物,同时促进内体逃逸并降低毒性。市售可电离脂质的实例包括DLin-KC2-DMA、DLin-MC3-DMA、DLin-DMA、DODMA和DODAP。
为了增加RNA-脂质复合物的稳定性、功能性和其他性能表现,可将脂质纳米粒子(LNP)制剂中常用的其他化学部分,例如结构脂质、聚乙二醇化脂质、胆固醇、磷脂等添加到本发明的纳米粒子制剂中。
聚合物络合剂可以是包括一种或多种阳离子单体的阳离子聚合物,并且包括聚赖氨酸、细胞穿透肽(例如,聚精氨酸)、聚乙烯亚胺、壳聚糖和聚(氨基酯)。
聚赖氨酸是一种阳离子同型多肽,其可以是α-聚赖氨酸或ε-聚赖氨酸。聚赖氨酸在中性pH值下含有带正电荷的氨基。α-聚赖氨酸是一种合成聚合物,可以分别以聚-L-赖氨酸(PLL)和聚-D-赖氨酸的形式存在。ε-聚赖氨酸(ε-聚-L-赖氨酸,EPL)通常以约25-30个L-赖氨酸残基的同型多肽形式产生。本发明中使用的聚赖氨酸可以是赖氨酸和其他化学实体的共聚物。聚赖氨酸也可以被修饰以具有特定的性质。例如,修饰的聚赖氨酸可以通过例如将一个或多个赖氨酸上的胺基烷基化或酰化而变得更加疏水。
细胞穿透肽(CPP)具有转运质膜并促进各种分子货物递送到细胞质或细胞器的能力。一些细胞穿透肽,如聚精氨酸,是阳离子的,适合作为核酸的络合剂。
聚乙烯亚胺(PEI)是一种具有由胺基和二碳脂族(CH2CH2)间隔体组成的重复单元的聚合物。PEI有直链和支链之分。直链结构有利于聚合物的结晶,因此直链PEI在室温下可以是结晶的和固体的。支链PEI在室温下可以是液体。直链PEI主要含有仲胺,而支链PEI则含有伯氨基、仲氨基和书氨基。
壳聚糖是由随机分布的β-(1→4)-连接的D-葡糖胺(脱乙酰基单元)和N-乙酰基-D-葡糖胺组成的线性多糖。壳聚糖中的氨基的pKa值约为~6.5,这导致在中性溶液中发生显著的质子化并带正电荷。因此,壳聚糖可用于通过离子相互作用于核酸形成复合物。
优选的聚(氨基酯)是可生物降解的和生物相容的聚合物。聚(氨基酯)的一个实施例是聚[α-(4-氨基丁基)-1-乙醇酸]。
聚(β-氨基酯)(PBAE)是由二丙烯酸酯和包括伯胺和仲胺的官能胺获得的一类聚合物,优选通过迈克尔加成反应形成。PBAE对pH敏感、可生物降解且具有生物相容性。PBAE的pH缓冲能力是由于PBAE结构中存在叔胺而引起的,有助于内体逃逸,从而促进治疗剂的细胞内递送。
阳离子络合剂也可以进行改性,以获得其他所需的性质。例如,阳离子络合剂,如PBAE,可以进行聚乙二醇化,从而延长体内循环时间。阳离子络合剂,尤其是聚合物,可以针对分子量、降解曲线、体内半衰期、pH响应性和特定应用可能需要的其他性质进行优化。
优选地,在乳化过程中,PLGA溶液与水溶液的重量比通常为1:1,000至10:1,优选为1:100至1:1。
如本文所使用的,混溶性定义为液体以所有比例混合形成均匀溶液的性质。如果按照一定比例,它们不会形成溶液,则物质/液体被称为不混溶或不能混溶。
可与水混溶的示例性溶剂包括丙酮、四氢呋喃(THF)、乙腈、二甲基亚砜(DMSO)、二甲基甲酰胺(DMF)。
当活性剂,例如药物或活性药物成分(API),例如在水溶液中制备的基于蛋白质的治疗剂,首先用药学上可接受的聚合物溶液乳化以形成第一乳液,使得API包封在聚合物溶液内。然后,在形成微米颗粒或纳米颗粒之前,将聚合物和包封在其中的治疗剂再次在较大体积的溶剂中乳化,以形成第二乳液(例如,水包油包水或w/o/w型双乳液)。
举例来说,在上述w/o/w技术中,可以将相对少量的第二溶剂(例如,蛋白质水溶液)的第一溶液(例如,有机溶液的约20%、15%、10%、5%v/v)引入相对大量的溶解疏水性聚合物PLGA的第一溶剂(例如,有机溶剂)中,例如二氯甲烷或乙酸乙酯。然后使用合适的方法形成第一乳液,例如探针超声处理或均质化。在形成第一乳液之后,通过将第一乳液引入更大体积的含有乳化剂(例如,聚乙烯醇)的第二溶剂的第二溶液(例如,第一乳液的至少2倍、3倍、4倍、5倍、6倍、10倍)中,形成第二乳液。同样,可以使用均质化方法来形成第二乳液。接下来是一段时间的溶剂蒸发,导致所述聚合物的硬化,通常通过搅拌几小时。结果,所述的蛋白质溶液被捕获到PLGA聚合物的相对疏水基质中,形成小的内含物。最后,通过重复离心或过滤洗涤(例如,用蒸馏水),然后脱水,一般通过冷冻干燥,收集形成的微米颗粒或纳米颗粒。
在上述任一方面中,优选地,第一溶剂是二氯甲烷、乙酸乙酯或氯仿。优选地,第二溶剂的第二溶液包括表面活性剂,所述表面活性剂包含有机或无机的药用赋形剂;各种聚合物;低聚物;天然产物;非离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂或离子表面活性剂;以及它们的混合物。表面活性剂可以包括聚乙烯醇(PVA)、聚乙烯吡咯烷酮(PVP)、聚山梨醇酯(吐温系列)表面活性剂、PEO-PPO-PEO(聚环氧乙烷-聚环氧丙烷-聚环氧乙烷)三嵌段共聚物(Pluronic系列或Poloxamer系列)表面活性剂或叔辛基苯基-聚乙二醇(Triton X-100)表面活性剂或其盐、衍生物、共聚物或混合物。优选地,所述的表面活性剂是PVA(参见实施例)。
优选地,所述的乳化步骤包括均质化、机械搅拌和/或微流化。
优选地,通过溶剂交换和/或蒸发来去除第一溶剂。
在聚合物溶解步骤中使用的溶剂可以是溶解聚合物的任何类型的溶剂(例如,PLGA)。然而,优选使用挥发性溶剂来实现溶剂的去除。例如,用于形成PLGA溶液的优选溶剂包括二氯甲烷、乙酸乙酯和氯仿。
在乳化步骤中,所述(水)溶液可以含有表面活性剂或表面稳定剂。表面活性剂通常包括降低液体的表面张力、两种液体之间的界面张力或液体和固体之间的界面张力的化合物。表面活性剂可充当洗涤剂、润湿剂、乳化剂、发泡剂和分散剂。表面活性剂通常是两亲性的有机化合物,既含有疏水集团(通常是支链、直链或芳香烃链、氟碳链或硅氧烷链作为“尾部(tail)”),也含有亲水基团(通常为头部(head))。表面活性剂最常见的是根据其极性头部基团进行分类:非离子表面活性剂的头部没有电荷基团;离子表面活性剂携带净电荷-如果电荷为负,则表面活性剂为阴离子,如果电荷为正,则表面活性剂为阳离子。如果表面活性剂包含带有两个相反电荷的基团的头部,则其被称为两性离子。优选在本发明中使用阴离子表面活性剂或两性离子表面活性剂,例如含有羧基的表面活性剂(“羧酸盐”)。羧酸盐是最常见的表面活性剂,包括烷基羧酸盐,如硬脂酸钠、月桂酰肌氨酸钠和基于羧酸盐的含氟表面活性剂,如全氟辛酸盐、全氟辛酸酯(PFOA或PFO)。
尽管不希望受到任何特定理论的束缚,表面活性剂可用于乳液液滴的形成和稳定。表面活性剂也可以包括有机或无机药物赋形剂、各种聚合物、低聚物、天然产物、非离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂和离子表面活性剂,以及它们的混合物。
可用于制备本发明的(PLGA)微米颗粒或纳米颗粒的表面活性剂包括聚乙烯醇、聚乙烯吡咯烷酮、吐温系列、Pluronic系列、Poloxamer系列、Triton X-100等。下文提供了其他合适的表面活性剂。
乳化过程可以通过任何本领域公知的方式进行,例如均质化、超声处理、机械搅拌、微流化或其组合。
通常通过例如溶剂交换和蒸发来实现溶剂的去除。
一种以上表面活性剂的组合可用于本发明。可用于本发明的有用的表面活性剂或表面稳定剂包括,但不限于,已知的有机药物赋形剂和无机药物赋形剂。这些赋形剂包括各种聚合物、低分子量低聚物、天然产物和表面活性剂。表面活性剂或表面稳定剂包括非离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂和离子表面活性剂。
其它有用的表面活性剂或表面稳定剂的代表性实施例包括羟丙基甲基纤维素、羟丙基纤维素、聚乙烯吡咯烷酮、十二烷基硫酸钠、二辛基硫代琥珀酸钠、明胶、酪蛋白、卵磷脂(磷脂)、葡聚糖、阿拉伯树胶、胆固醇、黄蓍胶、硬脂酸、苯扎氯铵、硬脂酸钙、单硬脂酸甘油酯、十六十八醇、聚西托醇(cetomacrogol)乳化蜡、脱水山梨糖醇酯、聚氧乙烯烷基醚(例如,聚乙二醇醚,例如聚西托醇1000)、聚氧乙烯蓖麻油衍生物、聚氧乙烯失水山梨醇脂肪酸酯(例如市售的例如,/>和/>(ICI专用化学品));聚乙二醇类(例如,CARBOWAXS/>和/>(联合碳化物公司))、聚氧乙烯硬脂酸酯、胶体二氧化硅、磷酸盐、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、非结晶纤维素、硅酸铝镁、三乙醇胺、聚乙烯醇(PVA)、4-(1,1,3,3-四甲基丁基)-酚与环氧乙烷和甲醛的聚合物(也称为泰洛沙泊、superione和曲通)、泊洛沙姆(例如,PLURONICS/>和/>它们是环氧乙烷和环氧丙烷的嵌段共聚物);泊洛沙胺(例如/>也叫做泊洛沙胺/>其是一种四官能嵌段共聚物,由环氧丙烷和环氧乙烷顺序加成到乙二胺而得到(巴斯夫怀恩多特公司(BASFWyandotte Corporation),帕西波尼,新泽西州));TETRONIC/>(T-1508)(巴斯夫怀恩多特公司),TRITONS/>(其是烷基芳基聚醚磺酸盐(罗门哈斯公司));CRODESTAS(其是蔗糖硬脂酸酯和蔗糖二硬脂酸酯的混合物(禾大公司));对-异壬基苯氧基聚(缩水甘油),也称为/>或者SURFACTANT/>(奥林化学品公司(OlinChemicals),斯坦福,康涅狄格州);Crodestas SL-40(禾大公司);SA9OHCO(其为C18H37CH2(CON(CH3)-CH2(CHOH)4(CH2OH)2(伊斯曼柯达公司));癸酰基-N-甲基葡糖酰胺;正癸基β-D-吡喃葡萄糖苷;正癸基β-D-吡喃麦芽糖苷;正十二烷基β-D-吡喃葡萄糖苷;正十二烷基β-D-麦芽糖苷;庚酰基-N-甲基葡糖酰胺;正庚基-p-D-吡喃葡萄糖苷;正庚基β-D-硫代葡糖苷;正己基β-D-吡喃葡萄糖苷;壬酰基-N-甲基葡糖酰胺;正壬基β-D-吡喃葡萄糖苷;辛酰基-N-甲基葡糖酰胺;正辛基β-D-吡喃葡萄糖苷;辛基β-D-硫代吡喃葡萄糖苷;PEG衍生的磷脂、PEG-衍生的胆固醇、PEG衍生的胆固醇衍生物、PEG衍生的维生素A、PEG衍生的维生素E、溶菌酶、乙烯基吡咯烷酮和乙酸乙烯酯的无规共聚物等等。
有用的阳离子表面活性剂或表面稳定剂的实施例包括但不限于聚合物、生物聚合物、多糖、纤维素、藻酸盐、磷脂和非聚合化合物,例如两性离子稳定剂、聚-n-甲基吡啶鎓、蒽基吡啶鎓氯化盐、阳离子磷脂、壳聚糖、聚赖氨酸、聚乙烯基咪唑、聚凝胺、聚甲基丙烯酸甲酯三甲基溴化铵(PMMTMABr)、己基二苯乙酮基三甲基溴化铵(HDMAB)、聚乙烯吡咯烷酮-2-二甲基氨基乙基甲基丙烯酸二甲基硫酸酯、1,2-双棕榈酰基-sn-丙三氧基-3-磷酸乙醇胺-N-[氨基(聚乙二醇)(2000)](钠盐)(也称为DPPE-PEG(2000)-胺钠)(阿凡提极性脂质(Avanti Polar Lipids),阿拉巴斯特,阿拉巴马州)、聚(2-甲基丙烯酰氧基乙基三甲基溴化铵)(Polysciences公司,沃灵顿,宾夕法尼亚州)(也称为S1001)、泊洛沙胺(例如,TETRONIC也被称为POLOXAMINE/>),是一种四官能嵌段共聚物,由环氧丙烷和环氧乙烷到乙二胺的顺序加成得到(巴斯夫怀恩多特公司,帕西波尼,新泽西州))、溶菌酶、长链聚合物(例如海藻酸、角叉菜胶(FMC公司)和保益乐(POLYOX,陶氏公司,米德兰德,密歇根州))。
其它有用的阳离子稳定剂包括但不限于阳离子脂质、锍、鏻和季铵化合物,例如硬脂基三甲基氯化铵、苄基-二(2-氯乙基)乙基溴化铵、椰子三甲基氯化铵或椰子三甲基溴化铵、椰子甲基二羟乙基氯化铵或椰子甲基二羟乙基溴化铵、癸基三乙基氯化铵、癸基二甲基羟乙基氯化铵或癸基二甲基羟乙基溴化铵、C12-15二甲基羟乙基氯化铵或C12-15二甲基羟乙基溴化铵、椰子二甲基羟乙基氯化铵或椰子二甲基羟乙基溴化铵、肉豆蔻基三甲基铵甲基硫酸盐、月桂基二甲基苄基氯化铵或月桂基二甲基苄基溴化铵、月桂基二甲基(乙烯氧基)4氯化铵或月桂基二甲基(乙烯氧基)4溴化铵、N-烷基(C12-18)二甲基苄基氯化铵、N-烷基(C14-18)二甲基苄基氯化铵、N-十四烷基二甲基苄基氯化铵一水合物、二甲基二癸基氯化铵、N-烷基和(C12-14)二甲基1-萘甲基氯化铵、三甲基卤化铵、烷基-三甲基铵盐和二烷基二甲基铵盐、十二烷基三甲基氯化铵、乙氧基化烷基酰氨基烷基二烷基铵盐和/或乙氧基化三烷基铵盐、二烷基苯二烷基氯化铵、N-二癸基二甲基氯化铵、N-十四烷基二甲基苄基氯化铵一水合物、N-烷基(C12-14)二甲基1-萘基甲基氯化铵和十二烷基二甲基苄基氯化铵、二烷基苯烷基氯化铵、月桂基三甲基氯化铵、烷基苄基甲基氯化铵、烷基苄基二甲基溴化铵、C12、C15、C17三甲基溴化铵、十二烷基苄基三乙基氯化铵、聚二烯丙基二甲基氯化铵(DADMAC)、二甲基氯化铵、烷基二甲基卤化铵、三鲸蜡基甲基氯化铵、癸基三甲基溴化铵、十二烷基三乙基溴化铵、十四烷基三甲基溴化铵、甲基三辛基氯化铵(ALIQUAT 336TM)、POLYQUAT 10TM、四丁基溴化铵、苄基三甲基溴化铵、胆碱酯(例如脂肪酸胆碱酯)、苯扎氯铵、硬脂酰氯化合物(例如硬脂基三甲基氯化铵和二硬脂基二甲基氯化铵)、十六烷基吡啶溴化物或十六烷基吡啶氯化物、季铵化聚氧乙基烷基胺的卤化物盐、MIRAPOLTM和ALKAQUATTM(购自Alkaril化学公司)、烷基吡啶盐;胺类(例如烷基胺、二烷基胺、链烷醇胺、聚乙烯多胺、N,N-二烷基氨基烷基丙烯酸酯和乙烯基吡啶)、胺盐(例如月桂基胺乙酸盐、十八烷基胺乙酸盐、烷基吡啶鎓盐和烷基咪唑鎓盐)以及氧化胺;咪唑啉盐(imide azoliniumsalt);质子化的四级丙烯酰胺;甲基化四级聚合物,例如聚[二烯丙基二甲基氯化铵]和聚[N-甲基乙烯基吡啶氯化物];和阳离子瓜尔胶。
这种示例性阳离子表面活性剂或表面稳定剂和其它有用的阳离子表面活性剂或表面稳定剂描述于以下文献中:J.Cross and E.Singer,Cationic Surfactants:Analytical and Biological Evaluation(Marcel Dekker,1994);P.andD.Rubingh(Editor),Cationic Surfactants:Physical Chemistry(Marcel Dekker,1991);和J.Richmond,CationicSurfactants:Organic Chemistry,(Marcel Dekker,1990),以上各文献通过引用整体并入本文。
非聚合阳离子表面活性剂或表面稳定剂为任何非聚合化合物,例如苯扎氯铵、碳鎓化合物、鏻化合物、氧鎓化合物、卤鎓化合物、阳离子有机金属化合物、季磷化合物、吡啶鎓化合物、苯铵化合物、铵化合物、羟基铵化合物、伯铵化合物、仲铵化合物、叔铵化合物和式NR1R2R3R4(+)的季铵化合物。对于式NR1R2R3R4(+)的化合物作如下说明:(i)R1-R4均不是CH3;(ii)R1-R4中的一个是CH3;(iii)R1-R4中的三个是CH3;(iv)所有R1-R4均为CH3;(v)R1-R4中的两个是CH3,R1-R4中的一个是C6H5CH2,R1-R4中的一个是具有7个或更少的碳原子的烷基链;(vi)R1-R4中的两个是CH3,R1-R4中的一个是C6H5CH2,并且R1-R4中的一个是具有十九个碳原子或更多个碳原子的烷基链;(vii)R1-R4中的两个是CH3并且R1-R4中的一个是C6H5(CH2)n,其中,n>1;(viii)R1-R4中的两个是CH3,R1-R4中的一个是C6H5CH2,并且R1-R4中的一个包含至少一个杂原子;(ix)R1-R4中的两个是CH3,R1-R4中的一个是C6H5CH2,并且R1-R4中的一个包含至少一个卤素;(x)R1-R4中的两个是CH3,R1-R4中的一个是C6H5CH2,并且R1-R4中的一个包含至少一个环状片段;(xi)R1-R4中的两个是CH3并且R1-R4中的一个是苯环;或(xii)R1-R4中的两个是CH3,并且R1-R4中的两个是纯脂肪族片段。
这些化合物包括但不限于山嵛基苄基二甲基氯化铵(behenalkonium chloride)、苄索氯铵、氯化十六烷基吡啶、山嵛基三甲基氯化铵、劳拉氯铵、西他氯铵、西曲溴铵、西曲氯铵、十六烷基胺氢氟化物(cethylaminehydrofluoride)、氯化氯烯丙基六亚甲基四胺(季铵盐-15)、二硬脂基二甲基氯化铵(季铵盐-5)、十二烷基二甲基乙基苄基氯化铵(季铵盐-14)、季铵盐-22、季铵盐-26、季铵盐-18锂蒙脱石、二甲基氨基乙基氯化物盐酸盐、半胱氨酸盐酸盐、二乙醇铵POE(10)油醚磷酸酯、二乙醇铵POE(3)油醚磷酸酯、牛脂基二甲基苄基氯化铵(tallow alkonium chloride)、二甲基二十八烷基铵膨润土、司拉氯铵、溴化度米芬、苯酸苄铵酰铵、肉豆蔻基苄基二甲基氯化铵、月桂基三甲基氯化铵、二盐酸乙二胺、盐酸胍、盐酸吡哆醇、盐酸碘非他胺、盐酸葡甲胺、氯化苄乙氧铵、肉豆蔻基三甲基溴化铵、油基三甲基氯化铵、聚季铵盐-1、盐酸普鲁卡因、椰油基甜菜碱、司拉氯铵膨润土、司拉氯铵水辉石、硬脂基三羟乙基丙二胺二氢氟化物、牛脂基三甲基氯化铵和十六烷基三甲基溴化铵。
这些表面活性剂或表面稳定剂中的大多数是已知的药物赋形剂,并且详细描述于下述文献中:《药物赋形剂手册》(Handbook of Pharmaceutical Excipients),由美国药物协会和大不列颠药物协会联合出版(The Pharmaceutical Press,2000),特别地,该文献通过引用并入本文。
表面活性剂或表面稳定剂可从商业上购买获得和/或可通过本领域已知的技术制备。
优选地,本发明的微米颗粒或纳米颗粒的表面由颗粒表面和间质之间的非特异性或不需要的生物相互作用最小化的材料组成,例如,颗粒表面可以涂覆有防止或减少非特异性相互作用的物质。通过用亲水层如聚乙二醇(PEG)及其共聚物如PLURONICS(包括聚(乙二醇)-bl-聚(丙二醇)-bl-聚(乙二醇)的共聚物)涂覆颗粒实现空间稳定,可以减少与间质蛋白质的非特异性相互作用,皮下注射后淋巴吸收的改善证明了这一点。
如本文所述,“少量”是指与具有PLGA聚合物的第一溶剂的体积相比,第二溶剂的第一溶液的量/体积相对较小,从而使第二溶剂的第一溶液乳化在第一溶剂中的聚合物溶液中形成乳液(即,第一乳液),其中连续相是聚合物溶液。通常,少量的第二溶剂的第一溶液与第一溶剂之间的体积比为至少约1:n,其中n可以是1、2、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90或100。
如本文所述,“大量”是指与第一乳液的体积相比,第二溶剂的第二溶液的量/体积相对较大,使得第一乳液在第二溶剂的第二溶液中乳化形成乳液(即,第二乳液),其中连续相是第二溶剂的第二溶液。通常,第一乳液与大量第二溶剂的第二溶液之间的体积比为至少约1:m,其中m可以是1、2、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90或100。
将聚唾液酸掺入颗粒中可以是稳定和紧密的。因此,优选地,该方法进一步包括洗涤所述微米颗粒或纳米颗粒,和/或将所述微米颗粒或纳米颗粒浓缩到所需体积。
使用本发明的方法制备的微米颗粒和纳米颗粒可以常规地进行洗涤,作为去除杂质和/或浓缩按照本发明方法制备所述微米颗粒和纳米颗粒的纯化过程的一部分。
使用本发明的方法制备的微米颗粒和纳米颗粒也可以经过更严格的洗涤测试,例如,作为质量控制过程的一部分,以确保聚唾液酸残基稳定地结合到如此制备的微米颗粒和纳米颗粒中。
优选地,所述的洗涤测试使用与下面举例说明的条件相同或相似的条件。优选地,所述聚唾液酸持久地附着在微米颗粒和纳米颗粒的表面,并且能够维持多个洗涤循环。
优选地,在颗粒表面上的所述聚唾液酸可以承受某些洗涤测试,例如本文举例说明的洗涤测试,而不会显著损失聚唾液酸的量。
优选地,洗涤之后,所述微米颗粒或纳米颗粒保留唾液酸部分的至少约50%、60%、75%、80%、85%、90%、95%或99%的量。
颗粒尺寸
所述微米颗粒和纳米颗粒的尺寸为约1nm至约1000μm,优选为约10nm至约100μm,更优选为约20nm至约5μm,最优选为约50nm至约2μm。例如,微米颗粒和纳米颗粒的平均尺寸可以在约100和900nm之间,例如约100、300、500、700或900nm。
如本文所用,颗粒尺寸可通过本领域技术人员熟知的任何常规的颗粒尺寸测量技术来测定。这些技术包括,例如,沉降场流分级、光子相关光谱、光散射、动态光散射、光衍射和盘式离心。
其他组分
优选地,本发明的颗粒还可含有其他组分。例如,载体可以具有掺入或缀合到载体的成像剂。具有目前可商购的成像剂的载体纳米球的实施例是Kodak X-sight纳米球。无机量子限制发光纳米晶体,称为量子点(QD),已成为荧光共振能量转移(FRET)应用中的理想供体:它们的高量子产率和可调的尺寸依赖性斯托克斯位移使得不同尺寸能够在单一紫外激发下发射蓝色到红外光(Bruchez et al.,Science,1998,281:2013;Niemeyer,C.M.,Angew.Chem.Int.Ed.,2003,42:5796;Waggoner,A.Methods Enzymol.,1995,246:362;Brus,L.E.,J.Chem.Phys.,1993,79,5566)。
量子点,例如基于一类称为树枝状聚合物的混合有机/无机量子点,可用于生物标记、成像和光学生物传感系统(Lemon et al.,J.Am.Chem.Soc.,2000,122:12886)。与传统的无机量子点的合成不同,这些混合量子点纳米颗粒的合成不需要高温或高毒性、不稳定的试剂(Etienne et al.,Appl.Phys.Lett.,87:181913,2005)。
示例性应用
所述颗粒及其组合物具有许多应用,包括在治疗方法中。
优选地,所述纳米颗粒和微米颗粒或包含所述颗粒的组合物可用于治疗有需要的主体的疾病或病症的方法,或用于减少有需要的主体所患疾病或病症持续时间或严重程度的方法,其中所述疾病或病症可用所述颗粒(以及任选地用特定API)治疗,包括向所述主体施用包含所述颗粒的组合物或药物组合物,从而治疗所述疾病或病症。在所述颗粒包括API的情况下,所述颗粒可用于向需要API的主体施用或传递所述API的方法中,和/或所述颗粒可用于治疗患有可用所述API治疗的疾病或病症的主体的方法中。例如,当API是抗炎剂时,可以将颗粒给予患有炎症的主体。
在其他方面,所述颗粒包括免疫治疗剂并且可以用于免疫治疗。
本文所述的微米颗粒和纳米颗粒可用于治疗炎症性疾病。此类疾病和病症的实施例包括但不限于自身免疫性溶血性贫血、特发性血小板减少性紫癜、类风湿性关节炎、乳糜泻、高IgM免疫缺陷、动脉硬化、动脉粥样硬化、冠状动脉疾病、败血症、心肌炎、脑炎、移植排斥反应、肝炎、甲状腺炎(例如桥本甲状腺炎、格雷夫斯病)、骨质疏松症、多发性肌炎、皮肌炎、I型糖尿病、II型糖尿病、痛风、皮炎、斑秃、系统性红斑狼疮、干燥综合征、硬化性地衣、硬皮病、溃疡性结肠炎、糖尿病视网膜病变、盆腔炎、牙周病、关节炎、青少年慢性关节炎(如慢性虹膜睫状体炎)、银屑病、骨质疏松症、糖尿病肾病、哮喘、盆腔炎、慢性炎性肝病、慢性炎症性肺病、肺纤维化、肝纤维化、慢性发炎性肺病、炎症性肠病(IBD)、克罗恩病、溃疡性结肠炎、腹膜炎、心血管疾病、再灌注损伤、缺血性损伤、中风、烧伤以及中枢神经系统(CNS;例如多发性硬化症)、胃肠系统、皮肤和相关结构、免疫系统、肝胆系统或身体中炎症成分可能发生病理的任何部位的其他急性和慢性炎症性疾病。炎症性疾病还包括涉及胃肠道和相关组织的疾病(如肠梗阻、阑尾炎、消化性溃疡、胃和十二指肠溃疡、腹膜炎、胰腺炎、溃疡性、伪膜性、急性和缺血性结肠炎、憩室炎、会厌炎、贲门失弛缓症、胆管炎、胆囊炎、腹腔疾病、肝炎、克罗恩病、肠炎和惠普尔病);全身或局部炎症性疾病和病症(如哮喘、过敏、过敏性休克、免疫复合物疾病、器官缺血、再灌注损伤、器官坏死、花粉热、败血症、败血性疾病、内毒素休克、恶病质、高热、嗜酸性肉芽肿、肉芽肿病和结节病);涉及泌尿生殖系统和相关组织的疾病(如感染性流产、附睾炎、阴道炎、前列腺炎和尿道炎);涉及呼吸系统和相关组织的疾病(如支气管炎、肺气肿、鼻炎、囊性纤维化、肺炎、成人呼吸窘迫综合征、尘肺、肠炎、毛细支气管炎、咽炎、胸膜炎和鼻窦炎);由各种病毒(如流感、呼吸道合胞病毒、艾滋病毒、乙型肝炎病毒、丙型肝炎病毒和疱疹)、细菌(如播散性菌血症、登革热)、真菌(如念珠菌感染)以及原生动物和多细胞寄生虫感染引起的疾病(如疟疾、丝虫病、阿米巴病和包虫囊肿);皮肤病和皮肤状况(如烧伤、皮炎、皮肌炎、晒伤、荨麻疹、疣和风团);涉及心血管系统和相关组织的疾病(如狭窄、再狭窄、血管炎、心内膜炎、动脉炎、动脉粥样硬化、血栓性静脉炎、心包炎、充血性心力衰竭、心肌炎、自身免疫性心肌炎、心肌缺血、结节性动脉周围炎和风湿热);涉及中枢或外周神经系统和相关组织的疾病(如阿尔茨海默病、脑膜炎、脑炎、多发性硬化症、脑梗死、脑栓塞、格林-巴利综合征、神经炎、神经痛、脊髓损伤、瘫痪和葡萄膜炎);骨骼、关节、肌肉和结缔组织疾病(如各种关节炎和关节痛、骨髓炎、筋膜炎、佩吉特病、痛风、牙周病、类风湿性关节炎和滑膜炎);其他自身免疫性和炎症性疾病(如重症肌无力、甲状腺炎、系统性红斑狼疮、Goodpaste综合征、Behcets综合征、同种异体移植物排斥反应、移植物抗宿主病、I型糖尿病、强直性脊柱炎、Berger病和Retier综合征);以及各种癌症、肿瘤和增殖性疾病(如霍奇金斯病);以及在任何情况下对任何原发性疾病的炎症或免疫宿主反应。
可以治疗或预防的疾病还包括过敏性疾病或病症,包括过敏性、变态反应、湿疹、哮喘、过敏性鼻炎或皮肤超敏反应。
待治疗的疾病也可以是病毒感染,包括例如肝炎病毒感染、西尼罗河病毒感染、黄病毒、流感感染、鼻病毒感染、乳头瘤病毒感染、副粘病毒感染或副流感病毒感染。优选地,病毒感染感染所述受试者的中枢神经系统。优选地,病毒感染引起病毒性脑炎或病毒性脑膜炎。在另一个方面,待治疗的疾病是细菌感染。示例性细菌感染是葡萄球菌感染、链球菌感染、分枝杆菌感染、芽孢杆菌感染、沙门氏菌感染、弧菌感染、螺旋体感染和奈瑟菌感染。优选的是感染受试者的中枢神经系统的细菌。最优选的是引起脑炎或脑膜炎的细菌。
在要求保护的发明中使用的优选条件是治疗癌症。本文治疗的患者和癌症包括伯基特淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、惰性非霍奇金淋巴瘤(iNHL)、难治性iNHL、多发性骨髓瘤(MM)、慢性髓系白血病(CML)、急性淋巴细胞白血病(ALL)、B细胞ALL、急性髓系白血病(AML)、慢性淋巴细胞白血病(CLL),小淋巴细胞淋巴瘤(SLL)、骨髓增生异常综合征(MDS)、骨髓增生性疾病(MPD)、套细胞淋巴瘤(MCL)、滤泡性淋巴瘤(FL)、瓦尔德斯特罗姆巨球蛋白血症(WM)、T细胞淋巴瘤、B细胞淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)或边缘区淋巴瘤(MZL)。在一个实施方案中,癌症是最小残留疾病(MRD)。在其他实施方案中,所述癌症选自霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、惰性非霍奇金淋巴瘤(iNHL)和难治性iNHL。在某些实施方案中,所述癌症为惰性非霍奇金淋巴瘤(iNHL)。在一些实施方案中,所述癌症是难治性iNHL。在一个实施方案中,所述癌症为慢性淋巴细胞白血病(CLL)。在另一实施方案中,癌症为弥漫性大B细胞淋巴瘤(DLBCL)。
在某些实施方案中,所述癌症为实体肿瘤且选自由以下所组成的组中:胰腺癌;膀胱癌;结直肠癌;乳腺癌,包括转移性乳腺癌;前列腺癌,包括雄激素依赖性和雄激素非依赖性前列腺癌;肾癌或肾癌,包括转移性肾细胞癌等;肝细胞癌;肺癌,包括非小细胞肺癌(NSCLC)、细支气管肺泡癌(BAC)和肺腺癌;卵巢癌,包括进行性上皮癌或原发性腹膜癌;宫颈癌;胃癌;食管癌;头颈癌,包括,例如,头颈部鳞状细胞癌等;黑色素瘤;神经内分泌癌,包括转移性神经内分泌肿瘤;脑肿瘤,包括胶质瘤、间变性少突胶质细胞瘤、成人多形性胶质母细胞瘤和成人间变性星形细胞瘤;骨癌;软组织肉瘤、肝癌、直肠癌、阴茎癌、外阴癌、甲状腺癌、涎腺癌、子宫内膜癌或子宫癌、肝癌、肝细胞癌、肝癌、胃癌或胃癌,包括胃肠道癌、腹膜癌、肺鳞癌、胃食管癌、胆道癌、胆囊癌、结直肠癌/阑尾癌、鳞状细胞癌(如上皮鳞状细胞癌)。
所提供的任何治疗方法都可用于治疗不同阶段的癌症。
举例来说,癌症阶段包括但不限于早期、晚期、局部晚期、缓解、难治性、缓解后复发期和进行期。
优选地,本发明的微米颗粒或纳米颗粒可与第二治疗剂结合使用,该第二治疗剂可有效治疗任何一种可治疗病症。
优选地,所述主体是人类患者。优选地,所述主体是非人哺乳动物,例如非人灵长类动物、家畜动物(马、骡、牛、牛、羊、山羊、猪、骆驼等)、啮齿动物(兔子、仓鼠、老鼠、老鼠等)或宠物(猫、狗)。
优选地,该方法包括通过任何合适的手段或途径,例如通过口服给药、鼻内给药、静脉内给药、肌肉内给药、眼内给药、经皮给药、皮下给药、肿瘤内给药、膀胱内给药,关节内给药、颅内给药和腹腔内给药包含所述微米颗粒或纳米颗粒的主体组合物或药物组合物。
优选的,对个体给药大约102到大约1020的颗粒。优选的,提供了大约103到大约1015个颗粒。优选的,提供了大约106到大约1012个颗粒。优选的,提供了大约108到大约1010个颗粒。优选的,优选剂量是0.1%固体/ml。因此,对于0.5μm的小珠,优选的剂量是大约4×109个小珠,对于直径为0.05μm的小珠,优选的剂量是大约4×1012个小珠,对于直径为3μm的小珠,优选的剂量是2×107的小珠。但是,本发明还包括能够有效治疗待治疗的特定病况的有效剂量。
本文所述的微米颗粒和纳米颗粒对可治疗的疾病和条件的有效性可以使用许多有效性测试方法来测试,包括合适的动物模型。
药物组合物
本发明的一个方面提供药物组合物,该药物组合物包含所述微米颗粒和纳米颗粒,并且任选地包含药学上可接受的载体或赋形剂。优选地,这些组合物任选进一步包含一种或多种其他的治疗剂。或者,本发明的所述颗粒可以与一种或多种其他治疗剂组合施用给有需要的患者。例如,用于联合施用或包含在具有本发明化合物的药物组合物中的其他治疗剂可以是经批准的抗炎剂、免疫治疗剂或化疗剂,或者所述其他治疗剂可以是经美国食品药品监督管理局批准的多种药剂中的任何一种。还应理解,本发明的某些所述颗粒可以以游离形式存在,或在适当情况下,以其药学上可接受的衍生物的形式存在,以用于治疗。
优选地,本发明的药物组合物另外包含药学上可接受的载体,如本文所用,所述载体包括适合于所需的特定剂型的任何和所有溶剂、稀释剂或其他液体载体、分散助剂或悬浮助剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。用于配制药物组合物及其制备的已知技术的各种载体公开于Remington’s PharmaceuticalSciences,Sixteenth Edition,E.W.Martin(Mack Publishing Co.,Easton,Pa.,1980)。除非任何常规载体介质与本发明的化合物不相容,例如通过产生任何不希望的生物效应或以有害方式与药物组合物的任何其他组分相互作用,否则其使用被认为是在本发明的范围内。
可用作药学上可接受的载体的材料的一些实施例包括但不限于糖,例如乳糖、葡萄糖和蔗糖;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;粉末黄蓍胶;麦芽;明胶;滑石;赋形剂,例如可可脂和栓剂蜡;油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二羟基醇,例如丙二醇;酯类,例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,例如氢氧化镁和氢氧化铝;海藻酸;无热原水;等渗盐水;林格氏液;乙醇、磷酸盐缓冲溶液以及其他无毒相容润滑剂(例如十二烷基硫酸钠和硬脂酸镁)以及着色剂、释放剂、涂层剂、甜味剂、调味剂和芳香剂,根据配方设计师的判断,防腐剂和抗氧化剂也可以包括在组合物中。
用于口服给药的液体剂型包括但不限于药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除活性化合物外,液体剂型可含有本领域常用的惰性稀释剂,例如水或其它溶剂、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄基醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇脂肪酸酯及它们的混合物。除惰性稀释剂外,口服组合物还可包括佐剂,例如润湿剂、乳化剂和悬浮剂,甜味剂,调味剂和芳香剂。
用于口服给药的固体剂型包括胶囊、片剂、丸剂、散剂和颗粒剂。在这种固体剂型中,将改性的颗粒与至少一种惰性的药学上可接受的赋形剂或载体(例如柠檬酸钠或磷酸二钙)和/或以下物质混合:a)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;b)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;c)保湿剂,例如甘油;d)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶液缓凝剂,例如石蜡;f)吸收促进剂,例如季铵化合物;g)润湿剂,例如鲸蜡醇和甘油单硬脂酸酯;h)吸收剂,例如高岭土和膨润土;和i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠、以及它们的混合物。在胶囊、片剂和丸剂的情况下,剂型还可包含缓冲剂。
类似类型的固体组合物也可用作使用诸如乳糖以及高分子量聚乙二醇等赋形剂的软填充明胶胶囊和硬填充明胶胶囊中的填充剂。片剂、糖衣丸、胶囊、丸剂和颗粒剂的固体剂型可以用包衣和外壳(例如药物配制领域熟知的肠溶包衣和其它包衣)来制备。它们可以任选地含有遮光剂,并且还可以是这样的组合物,其中它们仅在肠道的某一部分或优选地在肠道的某一部分任选地以延迟的方式释放活性成分的组合物。可以使用的包埋组合物的实例包括聚合物质和蜡。类似类型的固体组合物也可用作使用诸如乳糖或奶制品糖以及高分子量聚乙二醇等赋形剂的软填充明胶胶囊和硬填充明胶胶囊中的填充剂。
颗粒也可以是具有一种或多种上述赋形剂的微胶囊形式。片剂、糖衣丸、胶囊、丸剂和颗粒剂的固体剂型可以用包衣和外壳(例如药物配制领域熟知的肠溶包衣、释放控制包衣和其它包衣)来制备。在这种固体剂型中,活性化合物可以与至少一种惰性稀释剂例如(蔗糖、乳糖和淀粉)混合。
正常情况下,这些剂型还可包含除惰性稀释剂以外的其它物质,例如压片润滑剂和其它压片助剂,例如硬脂酸镁和微晶纤维素。在胶囊、片剂和丸剂的情况下,剂型还可包含缓冲剂。它们可以任选地含有遮光剂,并且还可以是这样的组合物,其中它们仅在肠道的某一部分或优选地在肠道的某一部分任选地以延迟的方式释放改性的颗粒。可以使用的包埋组合物的实例包括聚合物质和蜡。
还应理解,本发明的纳米颗粒和微米颗粒和药物组合物可以配制并用于联合治疗,即,所述化合物和药物组合物可以与一种或多种其他所需的治疗剂或医疗程序一起配制或同时施用,或在一种或多种其他所需的治疗剂或医疗程序之前或之后施用。在联合治疗方案中使用的特定疗法组合(治疗剂或程序)将考虑所需治疗剂和/或程序的相容性以及要实现的所需治疗效果。还应当理解,所采用的疗法可以对相同的病症实现期望的效果(例如,本发明的化合物可以与另一种抗炎剂同时施用),或者它们可以实现不同的效果(例如,控制任何不利的效果)。
优选地,含有本发明的颗粒的药物组合物还包含一种或多种其他的治疗活性成分(例如,抗炎和/或姑息治疗)。出于本发明的目的,术语“姑息治疗(Palliative)”是指集中于缓解疾病症状和/或治疗方案的副作用的治疗,但不是治愈性的。例如,姑息治疗包括止痛药、抗恶心药物和抗病药物。
给出以下实施例以说明本发明。然而,应该理解,本发明不限于这些实施例中描述的具体条件或细节。
实施例
实施例1.表面具有聚唾液酸的PLGA纳米颗粒的制备
将200mg PLGA溶解在8ml乙酸乙酯中以形成PLGA溶液,所述的PLGA溶液与40ml含有40mg多聚乙酰神经氨酸的0.5%聚乙烯醇(PVA)溶液混合,并使用均质机在25,000rpm下均质化1分钟。将所得的乳液倒入玻璃容器中,并以400rpm的速度磁力搅拌3小时以使溶剂蒸发。然后在冻干前用蒸馏水洗涤纳米颗粒三次。将冻干颗粒在蒸馏水中重构,用于测量颗粒尺寸、粒度分布、ζ电位和表面上聚唾液酸的量。
实施例2.通过双乳液法制备表面具有聚唾液酸的蛋白质负载PLGA纳米颗粒
将200mg PLGA溶解在4mL乙酸乙酯中以形成PLGA溶液。制备由35ml 2%聚乙烯醇(PVA)溶液(在水中)、1.5ml乙酸乙酯和40mg多聚乙酰神经氨酸组成的混合溶液。将4mg牛血清蛋白(BSA,一种模型治疗蛋白)溶于0.4mL水性缓冲液中以形成蛋白溶液。将BSA溶液与PLGA溶液混合,并使用探针超声仪将所得混合物均质化30秒。将所得乳液与PVA/聚唾液酸溶液混合,并使用均质机在18,000rpm下均质化1分钟。将所得的最终乳液倒入250mL玻璃烧瓶中,并通过在50mbar的真空下的转子蒸发去除溶剂。将负载BSA的颗粒用蒸馏水洗涤三次并冻干。将冻干颗粒在蒸馏水中重构,用于测量颗粒尺寸、粒度分布、ζ电位、蛋白质封装效率和表面上聚唾液酸的量。
实施例3.通过单乳液法制备表面上具有聚唾液酸的紫杉醇负载PLGA纳米颗粒
将200mg PLGA和4mg紫杉醇溶解在4mL乙酸乙酯中,以形成PLGA-紫杉醇溶液。将PLGA紫杉醇溶液与含有40mg聚唾液酸的16mL 2.5%聚乙烯醇溶液混合,并使用均质机在24,000rpm下均质化1分钟。将所得的乳液倒入玻璃容器中,并以400rpm的速度磁力搅拌4小时以使溶剂蒸发。然后将负载紫杉醇的纳米颗粒用蒸馏水洗涤三次并冻干。将冻干颗粒在蒸馏水中重构,用于测量颗粒尺寸、粒度分布、ζ电位、药物封装效率和表面上聚唾液酸的量。
实施例4.表面具有聚唾液酸的聚己内酯纳米颗粒的制备
将100mg聚己内酯(PCL)溶解在6ml二氯甲烷(DCM)中,形成PCL溶液,将其与含有40mg多聚乙酰神经氨酸的40ml 5%聚乙烯醇(PVA)溶液混合,并使用均质机在25,000rpm下均质化1分钟。将所得的乳液倒入玻璃容器中,并以400rpm的速度磁力搅拌3小时以使DCM蒸发。然后在冻干前用蒸馏水洗涤纳米颗粒三次。将冻干颗粒在蒸馏水中重构,用于测量颗粒尺寸、粒度分布、ζ电位和表面上聚唾液酸的量。
实施例5.荧光标记寡核苷酸的制备
从马萨诸塞州剑桥市Boston Open Labs获得了一种靶向非编码核RNA转移相关肺腺癌转录物1(MALAT1)的反义寡核苷酸(ASO),其在5’-位置添加了伯胺基团(见图1)。将这种MALAT1-ASO-5’-胺与等摩尔量的用NHS酯官能化的Cy7近红外荧光染料反应。所得到的反应产物称为ASO-Cy7缀合物。
实施例6.负载有ASO-Cy7缀合物且表面存在聚唾液酸的纳米颗粒的制备
将约50mg实施例5中制备的ASO-Cy7缀合物溶解在1mL蒸馏水中以形成ASO溶液。将100mg聚(丙交酯-乙交酯)(PLGA,酯封端)溶解在1mL乙酸乙酯中以形成聚合物溶液。将63.75mg月桂酰精氨酸乙酯(ELA)溶于1mL苯甲醇中以形成ELA溶液。将0.5mL聚合物溶液、0.2mLELA溶液、0.3mL乙酸乙酯和0.1mLASO溶液在8mL玻璃瓶中混合。以90%的振幅对8mL小瓶中的所得混合物进行30秒的探针超声处理,以产生第一乳液,将其转移到含有5mL水溶液的15mL玻璃瓶中,所述水溶液由0.5%聚乙烯醇(PVA,89%水解)、0.2%Brij-S100-PA-SG(Brij-S100)和用适量的乙酸乙酯饱和的0.5%聚唾液酸组成。立即以90%振幅对整个混合物进行60秒的探针超声处理,形成第二乳液,将其转移到30mL烧杯中,并在化学通风橱中磁力搅拌2小时。一旦颗粒形成并硬化,用50mL磷酸盐缓冲盐水洗涤悬浮液,然后用50mL蒸馏水使用切向流过滤洗涤两次。纯化后,将纳米颗粒冻干,发现所得到的纳米颗粒的平均粒径为155.6nm,ASO-Cy7的负载为3.9%,表面ζ电位为-33.0MV。
实施例7.洗涤测试
将如实施例1中所制备的50mg PLGA纳米颗粒在30mL去离子水中重构。经过短暂的超声处理后,颗粒充分悬浮。取样用于测量ζ电位。
然后向这种纳米颗粒悬浮液中添加300mL去离子水。使用切向流过滤(TFF)装置将所得混合物浓缩至30mL,并再次测量ζ电位。所述洗涤步骤再重复四次,并测量和记录每次洗涤后产生的ζ电位。
虽然已经参考优选实施方案具体说明和描述了本发明,但是本领域的技术人员将理解,在不脱离所附权利要求所包含的本发明的范围的情况下,可以在形式上和细节上进行各种改变。
应当理解,本文所述的本发明的任何优选特征可以与任何其他优选特征相结合,包括仅在本发明的一个方面下描述的优选特征,以及仅在实施例中描述的优选特点。在整个说明书中,对公开可获得的文件的任何和所有引用,包括任何美国专利或专利申请出版物,都通过引用的方式具体并入本文。
Claims (26)
1.一种组合物,其包括在其表面上呈现唾液酸残基的颗粒,其中每个颗粒包括可生物降解的聚合物和聚唾液酸,其中所述聚唾液酸包括所述唾液酸残基,其中所述唾液酸残基存在于所述颗粒的表面上并且不与其缀合;以及其中所述颗粒是微米颗粒或纳米颗粒。
2.根据权利要求1所述的组合物,其中所述可生物降解的聚合物选自以下:聚丙交酯(PLA)、聚(丙交酯-共-乙交酯)(PLGA)、乙二醇和丙交酯/乙交酯的共聚物(PEG-PLGA)、乙二醇和丙交酯的共聚物(PEG-PLA)、乙二醇和乙交酯的共聚物(PEG-PGA)、聚(乙二醇)(PEG)、聚己内酯(PCL)、聚酸酐(PANH)、聚(邻酯)、聚氰基丙烯酸酯、聚(羟基链烷酸酯)(PHA)、聚(己酸酯)、聚膦腈、聚磷酸酯、改性聚(糖)及其混合物和共聚物。
3.根据权利要求2所述的组合物,其中所述可生物降解的聚合物为PLGA。
4.根据权利要求1或权利要求3所述的组合物,其中所述颗粒是纳米颗粒。
5.根据权利要求1所述的组合物,其中所述可生物降解的聚合物和所述聚唾液酸形成互穿网络。
6.根据权利要求3所述的组合物,其中所述PLGA和所述聚唾液酸形成互穿网络。
7.根据权利要求1所述的组合物,其中所述唾液酸残基选自由以下所组成的组:Neu5Ac、Neu5Gc和Kdn,或其组合。
8.根据权利要求1所述的组合物,其中所述聚唾液酸是均聚物。
9.根据权利要求1所述的组合物,其中所述聚唾液酸是多聚乙酰神经氨酸。
10.根据权利要求1所述的组合物,其中所述颗粒进一步包括活性剂。
11.根据权利要求10所述的组合物,其中所述活性剂是活性药物成分,其选自由小分子、肽、蛋白质和核酸所组成的组。
12.根据权利要求11所述的组合物,其中所述活性剂是核酸,其选自由DNA、RNA和反义寡核苷酸所组成的组。
13.根据权利要求12所述的组合物,进一步包括阳离子络合剂,所述阳离子络合剂选自由小分子阳离子试剂、阳离子或可电离脂质和阳离子聚合物组成的组。
14.根据权利要求10所述的组合物,其中所述活性剂被封装在所述颗粒中。
15.根据权利要求1所述的组合物,其中所述组合物进一步包括药学上可接受的赋形剂。
16.一种向有需要的受试者给药活性剂的方法,其包括向所述受试者给药权利要求10所述的组合物。
17.根据权利要求16所述的方法,其中所述活性剂是活性药物成分。
18.根据权利要求16所述的方法,其中所述活性剂被封装在所述颗粒中。
19.一种治疗有需要的受试者的疾病或病症的方法,其包括向所述受试者给药权利要求11所述的组合物。
20.根据权利要求19所述的方法,其中所述疾病是癌症。
21.根据权利要求19所述的方法,其中所述活性药物成分是抗癌剂或免疫治疗剂。
22.根据权利要求19所述的方法,其中所述疾病是自身免疫性疾病。
23.一种用于制备在其表面上呈现唾液酸残基的颗粒的方法,其中每个颗粒包括可生物降解的聚合物和聚唾液酸,其中所述唾液酸残基存在于所述颗粒的表面且不与其缀合,以及其中所述颗粒是微米颗粒或纳米颗粒;所述方法包括以下步骤:
i.将所述可生物降解的聚合物和任选的活性剂溶解在第一溶剂中以形成聚合物溶液;
ii.将所述聚合物溶液在第二溶剂的溶液中乳化以形成乳液,其中所述第一溶剂与第二溶剂不混溶或部分混溶,并且其中所述第二溶剂的溶液包括所述聚唾液酸,所述第二溶剂的溶液任选地进一步包括可溶于第二溶剂的表面活性剂和/或活性剂;以及
iii.去除所述第一溶剂以形成所述颗粒。
24.根据权利要求23所述的方法制备的所述颗粒。
25.一种用于制备在其表面上呈现唾液酸残基的颗粒的方法,其中每个颗粒包括可生物降解的聚合物和聚唾液酸,其中所述唾液酸残基存在于所述颗粒的表面且不与其缀合,以及其中所述颗粒是微米颗粒或纳米颗粒;所述方法包括以下步骤:
i.将所述可生物降解的聚合物和任选的活性剂、API溶解在第一溶剂中以形成聚合物溶液;
ii.将第二溶剂的第一溶液添加到所述聚合物溶液中以形成混合物,其中所述第一溶剂与第二溶剂不混溶或部分混溶,并且其中所述第二溶剂的第一溶液任选地包括与溶解在所述第一溶剂中的所述API相同或不同的活性剂;乳化所述混合物以形成第一乳液;
iii.在第二溶剂的第二溶液中乳化所述第一乳液以形成第二乳液,其中所述第二溶剂的第二溶液包括所述聚唾液酸,并且任选地进一步包括表面活性剂;以及
iv.去除所述第一溶剂以形成所述颗粒。
26.根据权利要求25所述的方法制备的所述颗粒。
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