CN103945869A - 使用h-膦酸酯-烯/-炔的氢膦酸酯化反应进行的靶向纳米颗粒的远程组装 - Google Patents
使用h-膦酸酯-烯/-炔的氢膦酸酯化反应进行的靶向纳米颗粒的远程组装 Download PDFInfo
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Abstract
本发明提供膦酸酯化合物和制备所述膦酸酯化合物的方法,从而例如增加修饰用于靶向药物递送应用的纳米颗粒的能力。
Description
相关申请的交叉参考
本申请要求于2011年8月31日提交的美国临时申请61/529,665的优先权,其全部内容在此引入作为参考。
关于在联邦资助的研究与开发下所作出的发明的专利权的声明
不适用
关于在光盘上提交的“序列表”、表格或计算机程序列表附录
不适用
发明背景
目前,大多数的治疗性和诊断性试剂被全身性地给予至患者。不幸的是,目前的递送方法具有若干缺点,包括降低的治疗功效以及由于例如患者非靶点处药物激活导致的副作用。为了解决其中的一些缺点,与诊断性和治疗性试剂联合的纳米颗粒的靶向递送呈现了一种有希望的药物递送的新方式。对于一些药物递送方法,纳米颗粒如脂质体,可使用连接至脂质体表面的靶向剂而靶向细胞表面受体。例如,在活化的内皮细胞上,αvβ3整合素受体通常是上调的,且可通过将适宜的RGD配体掺合至纳米颗粒的表面靶向该αvβ3整合素受体。(Dubey et al.,“RGD-modified liposomes for tumor targeting”inAmiji,M.M.,Ed.Nanotechnology for Cancer Therapy,CRC Press(2007),pp.643-661)。
尽管在开发靶向药物递送方法中已有一些新近进展,仍需要进一步的改善。例如,将纳米颗粒转变成靶向纳米颗粒的方法是有限的而且通常不能为修饰所述纳米颗粒提供足够的柔性。此外,可用于修饰纳米颗粒的化合物不允许足够的功能性变化范围,例如纳米颗粒表面特性或诊断相容性。本发明解决了这些和其它需要。
发明概述
本发明提供膦酸酯化合物和制备所述膦酸酯化合物的方法,从而例如增加修饰用于靶向药物递送应用的纳米颗粒的能力。
在本发明的一方面中,本发明的化合物可包括下式的化合物:
其中R1、R2、R3、R4、L1、L2和L3各自如下所进一步详述。
在另一方面中,本发明包括制备膦酸酯化合物的方法,所述方法包括:将具有下式的H-膦酸酯化合物:
和具有下式的炔烃化合物混合:
在催化剂存在下形成具有下式的膦酸酯化合物:
其中所述H-膦酸酯化合物、炔烃化合物和本发明的膦酸酯化合物如下所详述。
在另一方面中,本发明的化合物可包括下式的化合物:
其中L1、L2、L4、R1和R2各自如下所进一步详述。
在另一方面中,本发明包括制备具有连接骨架的膦酸酯化合物的方法,所述方法包括:将具有下式的H-膦酸酯化合物:
和具有下式的炔烃化合物混合:
在催化剂存在下形成具有下式的膦酸酯化合物:
其中本发明的H-膦酸酯化合物、炔烃化合物和具有连接骨架的膦酸酯化合物如下所详述。
本发明的膦酸酯化合物和其制备方法为药物递送和诊断成像领域提供了许多独特的方面。例如,本发明提供了制备可促进非靶向纳米颗粒向靶向纳米颗粒转变的化合物的稳健而且简单的方法。此外,可将多种靶向剂、隐形剂(stealth agents)和/或诊断剂的若干组合掺入至多种纳米颗粒如脂质体中。这种在制备经修饰的纳米颗粒中的灵活性可,例如允许定制的纳米颗粒用于特定治疗性和/或诊断性应用(其在给予患者后也可具有长体内半衰期)。
可通过参考本说明书的其余部分和附图进一步理解本发明的性质和优势。
附图简述
图1描述了根据本发明的一项例示性实施方案,使用纳米颗粒(包括炔烃化合物)制备膦酸酯化合物的合成方法。
图2描述了根据本发明的一项例示性实施方案,使用纳米颗粒(包括H-膦酸酯化合物)制备膦酸酯化合物的合成方法。
图3显示根据本发明的一项例示性实施方案,制备辛-1-烯-2-基膦酸双十八烷基酯的一般反应流程。
图4显示根据本发明的一项例示性实施方案,制备5-(双(十八烷基氧基)磷酰基)己-5-烯酸的一般反应流程。
图5显示根据本发明的一项例示性实施方案,将5-(双(十八烷基氧基)磷酰基)己-5-烯酸与PEG1000-NH2偶联的一般反应流程。
图6显示根据本发明的一项例示性实施方案,制备5-(双(十八烷基氧基)磷酰基)己-5-烯酸叔丁酯的方法。
图7显示根据本发明的一项例示性实施方案,制备5,7-双(双(十八烷基氧基)磷酰基)庚酸的方法。
图8提供根据本发明的一项例示性实施方案,5,7-双(双(十八烷基氧基)磷酰基)庚酸与PEG1000-NH2的一般反应。
图9显示根据本发明的一项例示性实施方案,制备庚烷-1,3-二基双膦酸四(十八烷基)酯。
图10显示根据本发明的一项例示性实施方案,制备2,5,8,11,14,17,20,23,26,29-十氧杂三十三碳-31-烯-31-基膦酸双十八烷基酯的一般反应流程。
图11显示根据本发明的一项例示性实施方案,制备2,5,8,11,14,17,20,23,26,29-十氧杂三十三烷-32,33-二基双膦酸四(十八烷基)酯的一般反应流程。
图12显示根据本发明的一项例示性实施方案,制备1,1'-(1,3-亚苯基)双(乙烯-1,1-二基)双膦酸四(十八烷基)酯的一般反应流程。
图13显示制备1-环己烯基乙烯基膦酸双十八烷基酯和(E,Z)-(2-(环己-1-烯-1-基)乙烯基)膦酸双十八烷基酯的反应流程。
发明详述
I.定义
如本文所用,符号“-”意指单键,“=”意指双键,“≡”意指叁键,而意指单键或双键。
如本文所用,术语“烷基”,独自或作为另一取代基的部分,除非另有所指,否则意指具有指定碳原子数(即,C10-24意指10至24个碳)的直链或支链烃基。在一些实施方案中,烷基的范围可为1至36个碳。在一些实施方案中,烷基的范围可为10至24个碳。在一些实施方案中,所述烷基可为饱和的或不饱和的,以及取代的或未取代的。
如本文所用,术语“取代的”指的是结合至母体分子或基团的基团。例如,具有甲基取代基的烷基为甲基取代的烷基。适宜的取代基包括但不限于,卤代、氰基、烷基、氨基、羟基、烷氧基和酰胺基。
如本文所用,术语“H-膦酸酯化合物”指的是具有通式为H-P(O)(OL1-R1)(OL2-R2)的化合物,并在本文有所详述。
如本文所用,术语“炔烃化合物”通常指的是具有至少一个碳碳叁键的化合物。在一些实施方案中,本发明中所用的炔烃化合物具有初级炔烃(primaryalkynes)。本发明的炔烃化合物在本文进一步描述。
如本文所用,术语“靶向递送组合物”指的是连接至本发明的膦酸酯化合物的纳米颗粒的组合物,其种类在本文进一步描述。本发明的组合物可用作治疗性组合物、诊断性组合物,或同时用作治疗性和诊断性组合物。在一些实施方案中,所述组合物可靶向受试者或测试样品中的特定靶点,如本文所进一步描述。
如本文所用,术语“催化剂”指的是用于化学反应中促进本发明的一些膦酸酯化合物合成的试剂。在一些实施方案中,催化剂可用于氢膦酸酯化(hydrophosphonylation)反应,如本文所进一步描述。适宜的催化剂包括但不限于顺式PdMe2(PPh2Me)2、顺式PdMe2(PPh3)2、Pd(CH2=CH2)(PPh3)2、Pt(CH2=CH2)(PPh3)2、Pd(PPh3)4、Pt(PPh3)4、Pd(OAc)2。
如本文所用,术语“纳米颗粒”指的是各种大小、形状、类型和用途的颗粒,其在本文有进一步描述。本领域的普通技术人员应当理解,所述纳米颗粒的特征,例如大小,可取决于所述纳米颗粒的类型和/或用途以及本领域公知的其它因素。通常,纳米颗粒的大小范围可为约1nm至约1000nm。在其它实施方案中,纳米颗粒的大小范围可为约10nm至约200nm。在另一些实施方案中,纳米颗粒的大小范围为可约50nm至约150nm。在一些实施方案中,所述纳米颗粒的大小大于肾脏排泄的限制,例如直径大于约6nm。在其它实施方案中,所述纳米颗粒足够小以避免通过肝脏从血流中清除,例如直径小于1000nm。纳米颗粒可包括球形、锥形、椭球形,以及本领域公知的其它形状。纳米颗粒可为中空的(例如,实体外核,中空内核)或实体的或为具有中空和实体层或多个实体层的多层。例如,纳米颗粒可包括实体核区和实体外层包封区,两者可以是交联的。纳米颗粒可由一种物质或多种物质的任意组合组成,其包括脂质、聚合物、磁性材料,或金属材料如二氧化硅、金、氧化铁等。脂质可包括脂肪、蜡类、甾醇类、胆固醇、脂溶性维生素、甘油一酯、甘油二酯、磷脂类、鞘脂类、糖脂类、阳离子或阴离子脂质、衍生脂质、心磷脂等。聚合物通常可包括嵌段共聚物、聚(乳酸)、乳酸-乙醇酸共聚物、聚乙二醇、丙烯酸聚合物、阳离子聚合物,以及本领域已知的用于制备纳米颗粒的其它聚合物。在一些实施方案中,所述聚合物可以是生物可降解的和/或生物相容的。纳米颗粒可包括脂质体、胶束、脂蛋白、脂包衣囊泡(lipid-coated bubble)、嵌段共聚物胶束、聚合物泡囊(polymersome)、类脂囊泡(niosome)、量子点、氧化铁颗粒、金颗粒、树枝状聚合物(dendrimer)或二氧化硅颗粒。在一些实施方案中,脂单层或双层能够全部或部分地包被由能够被脂质包被的材料组成的纳米颗粒,例如聚合物纳米颗粒。在一些实施方案中,脂质体可包括多室脂质体(MLV)、大单室脂质体(LUV)和小单室脂质体(SUV)。
如本文所用,术语“治疗剂”指的是当以有效量存在时,可对有需要的受试者产生所需的治疗性作用的化合物或分子。本发明涵盖范围广泛的治疗剂及其在与纳米颗粒和膦酸酯化合物结合中的用途,如本文进一步所描述。
如本文所用,术语“诊断剂”指的是可在受试者或测试样品中检测的组分且在本文有进一步描述。
如本文所用,术语“连接基团”指的是连接化合物各个部分的膦酸酯化合物的部分。例如,连接基团L1,可将R1(例如,一种靶向试剂)连接至与所述膦酸酯化合物的磷结合的氧。取决于所制备的膦酸酯化合物和该化合物所需的性质,所述连接基团可从方便获得的单体组分组装以实现靶向剂和膦酸酯化合物(其可例如联接至纳米颗粒)的其它部分的适当分离。
如本文所用,术语“靶向剂”指的是对靶点具有特异性的分子。在一些实施方案中,靶向剂可包括靶配体(例如,肽模拟配体)的小分子模拟物、靶配体(例如,含肽或叶酸酰胺(folate amide)的RGD肽),或对特定靶点具有特异性的抗体或抗体片段。靶向剂可结合很多种靶点,包括器官、组织、细胞、细胞外基质组分,和/或细胞内区室中可能与疾病的特定发展阶段有关的靶点。在一些实施方案中,靶点可包括癌症细胞,特别是癌症干细胞。靶点还可包括细胞表面的抗原,或与正常组织相比在癌症细胞上为抗原呈递或更普遍的肿瘤标记物。在一些实施方案中,靶向剂还可包括叶酸衍生物、B-12衍生物、整合素RGD肽、RGD模拟物、NGR衍生物、生长抑素衍生物或结合生长抑素受体的肽,例如奥曲肽和octreotate等。在一些实施方案中,靶向剂可以是适体(其由核酸(例如,DNA或RNA)组成),或肽(其结合具体靶点)。可将靶向剂设计成特异性或非特异性结合受体靶点,特别是其表达与肿瘤有关的受体靶点。受体靶点的实例包括但不限于,MUC-1、EGFR、Claudin4、MUC-4、CXCR4、CCR7、FOL1R、生长抑素受体4、Erb-B2(成红细胞白血病致癌基因同源物2)受体、CD44受体和VEGF受体-2激酶。
如本文所用,术语“隐形剂”指的是可修饰纳米颗粒的表面性质的分子且在本文有进一步描述。
如本文所用,术语“嵌入”指的是试剂的位置在纳米颗粒表面上或邻近纳米颗粒表面。例如,嵌入纳米颗粒的试剂可位于脂质体的双层膜内或位于纳米颗粒的外层聚合物壳内以包含在该壳内。
如本文所用,术语“包封在”指的是试剂的位置被包在纳米颗粒内部或完全包含于纳米颗粒内部。对于脂质体,例如,可将治疗性和/诊断性试剂包封以使其存在于该脂质体的水性内部。然后,可通过一些意图使该脂质体不稳定或其它影响该包封试剂释放的条件触发这些包封试剂的释放。
如本文所述,术语“束缚至(tethered to)”是指一种组分连接至另一组分以使一种或多种组分可在空间中自由地到处移动。在某些示例性实施方案中,联接组分可束缚至纳米颗粒以使得在纳米颗粒周围的溶液中自由地到处移动。在一些实施方案中,联接组分可束缚至纳米颗粒的表面,延伸至该表面之外。
如本文所述,术语“脂质”是指脂质分子,其可包括脂肪、蜡、固醇、胆固醇、胆固醇衍生物、脂溶性维生素、甘油一酯、甘油二酯、磷脂、鞘脂、糖脂、阳离子或阴离子脂质、衍生的脂质等。脂质可形成胶束、单层和双层膜。在某些实施方案中,脂质可自组装为脂质体。在其它实施方案中,脂质可作为单层或双层涂覆纳米颗粒的表面。
如本文所述,术语“适体”是指特异结合至具体靶点的非天然存在的寡核苷酸(通常20-200个核苷酸)。“非天然存在的”包括天然核苷酸(A,T,C,G,U)的非天然存在的序列,以及具有非天然存在的或修饰的核苷酸的寡核苷酸。例如,为具有镜像核酸的适体,即,具有L手性构型而非天然存在的D构型。适体可通过分子内相互作用形成独特的三维结构,和/或在结合至靶点时改变结构,例如,通过诱导契合机理从主要或次级结构改变。结合至靶点的适体不通过常规互补核酸杂交,例如,双重或三重螺旋形成而介导,尽管部分适体可参与该杂交。例如,适体通常形成分子内发夹(hairpin)结构和其它三维结构。适体可根据任何方法或方法的组合而选择。通过指数式富集配体系统进化(Systematic Evolution of Ligands by ExponentialEnrichment)(SELEXTM)或其变体,在本领域是通常使用的。基本的SELEX TM 方法描述于例如,美国专利5,567,588。也可使用多种基本方法的变体,例如,体内SELEX TM ,如美国申请2010015041所述。MONOLEX TM 为另一选择方法,其例如描述于Nitsche等人(2007)BMC Biotechnology7:48和WO02/29093。使用注入肿瘤细胞的核酸库的体内选择也是可能的(参见,例如,Mi等人,(2010)Nat.Chem.Biol.1:22)。用于本发明的适体可设计为结合至多种靶点,包括但不限于MUC-1、EGFR、Claudin4、MUC-4、CXCR4、CCR7、FOL1R、生长抑素受体4、Erb-B2(成红细胞白血病致癌基因同源物2)受体、CD44受体、VEGF受体-2激酶和核仁素。
如本文所述,术语"受试者"是指在生命任何阶段的任何哺乳动物,特别是人。
如本文所述,术语“给药”、“给予”或“施用”是指给药本发明的靶向递送组合物的方法。本发明的靶向递送组合物可以多种方式给药,包括局部、肠胃外、静脉内、皮内、肌内、结肠、直肠或向腹膜内。肠胃外给药和静脉内给药为优选给药方法。该靶向递送组合物也可作为组合物或制剂的部分给予。
如本文所述,术语“治疗”病症、疾病、障碍或综合征包括(i)抑制该疾病、障碍或综合征,即,阻止其发展;和(ii)缓解该疾病、障碍或综合征,即,引起疾病、障碍或综合征的消退。如本领域已知的,对于全身和局部递送的调整,年龄、体重、一般健康、性别、饮食、给药时间、药物相互作用和病症严重性可能是需要考虑的,且其可通过本领域技术人员使用常规实验而确定。
如本文所述,术语“制剂”是指给药至受试者的组分的混合物。适合肠胃外给药的制剂,例如,关节内(关节中)、静脉内、肌内、瘤内、皮内、腹腔内和皮下途径的制剂,包括水性和非水性、等渗无菌注射溶液,其可包含抗氧化剂、缓冲剂、抑菌剂和使得制剂与预期接受者的血液等渗的溶质,和水性和非水性无菌悬浮液,其可包括助悬剂、增溶剂、增稠剂、稳定剂和防腐剂。注射溶液和悬浮液也可由无菌粉末、颗粒和片剂制备。靶向递送组合物的制剂可存在于单位剂量或多剂量密封容器中,如安瓿和小瓶。靶向递送组合物,在单独或与其它合适的组分组合时,可制备成气溶胶制剂(即,它们可被"雾化")以经由吸入通过口或鼻给药。气溶胶制剂可置于加压可接受的推进剂中,如二氯二氟甲烷、丙烷、氮气等。用于直肠给药的合适的制剂包括,例如,栓剂,其包含有效量的靶向递送组合物和栓剂基质。合适的栓剂基质包括天然或合成的甘油三酯或烷属烃。此外,也可使用明胶直肠胶囊,其包含靶向递送组合物和基质的组合,所述基质包括,例如,液体甘油三酯、聚乙二醇和烷属烃。在某些实施方案中,制剂可局部给药或以滴眼剂形式给药。
本发明的实施方案
II.概要
本发明提供膦酸酯化合物和使用涉及H-膦酸酯化合物和炔烃化合物的氢膦酸酯化(hydrophosphonylation)反应制备所述膦酸酯化合物的方法。在一些实施方案中,本发明的膦酸酯化合物可用于转变纳米颗粒的特性。例如,所述膦酸酯化合物可将非靶向纳米颗粒转变成靶向纳米颗粒,或隐形剂可连接至纳米颗粒以例如改善给予至患者后所述纳米颗粒的体内半衰期。
此外,所述用于制备膦酸酯化合物的氢膦酸酯化化学反应提供若干独特的方面。例如,H-膦酸酯化合物可连接至纳米颗粒从而使所述纳米颗粒在其表面显示所述H-膦酸酯化合物的反应性部分。后续的反应步骤可提供炔烃化合物(其包括例如靶向剂)并与H-膦酸酯化合物反应以形成所述膦酸酯化合物,从而将所述纳米颗粒从非靶向纳米颗粒转变成显示靶向剂的靶向纳米颗粒,其中所述靶向剂可结合感兴趣的特定靶点。
所述膦酸酯化合物和其制备方法为生产纳米颗粒或其它可用于递送诊断性和/或治疗性试剂至患者的组合物提供了多种选择。在一些实施方案中,纳米颗粒可包括具有例如2个或4个联接组分的膦酸酯化合物的锚固组件,其可用于生产更稳定的系统以用于例如将靶向剂和/或隐形剂连接至纳米颗粒表面。或者,呈现组件(presentation assemblies)可在纳米颗粒表面产生并呈现例如2种或4种可促进治疗性和/或诊断性试剂靶向递送的靶向剂。
III.膦酸酯化合物
在一方面中,本发明的化合物可包括下式的化合物:
其中标识为的键为单键或双键;L1、L2和L3各自为键或连接基团;R1、R2和R3各自独立地选自纳米颗粒、联接组分、靶向剂、诊断性试剂和隐形剂;且R4为选自H和-P(=O)(OL1-R1)(OL2-R2)的一员,其中当R4不为H时,所述标识为的键为单键。
在另一方面中,本发明的化合物可包括具有下式的化合物:
其中R1和R2各自为联接组分。在一些实施方案中,所述联接组分选自饱和或不饱和的C10-24烷基、取代的饱和或不饱和的C10-24烷基和胆固醇;且L1和L2各自为键。在一些实施方案中,这些化合物可提供纳米颗粒锚固组件,其中所述膦酸酯化合物包括4个可与纳米颗粒结合的联接组分(2×R1和2×R2)。例如,所述4个联接组分可与脂质体的脂质双层的表面相互作用,从而使得R3可显示在所述脂质体的表面并呈现例如靶向剂、诊断性试剂或隐形剂。
在另一方面中,本发明的化合物可包括具有下式的化合物:
其中R3为联接组分。在一些实施方案中,所述联接组分可选自饱和或不饱和的C10-24烷基、取代的饱和或不饱和的C10-24烷基和胆固醇。在一些实施方案中,R1和R2可各自独立地选自靶向剂、诊断性试剂和隐形剂。在这些实施方案中,所述化合物可提供呈现组件,其中R3可例如与脂质双层相互作用并且可选择R1和R2从而呈现例如靶向剂、诊断性试剂、隐形剂或其组合。
在另一方面中,本发明的化合物可包括具有下式的化合物:
其中L1和L2各自为键或连接基团;R1和R2各自独立地选自纳米颗粒、联接组分、靶向剂、诊断性试剂和隐形剂;且L4选自亚芳基、亚烷基或其组合。
如本领域的普通技术人员应当理解的,上文所述的锚固组件和呈现组件也可应用于以下化合物,其中标识为的键为单键,且R1、R2和R3的每一个存在于所述化合物中。在这些实施方案中,2个联接组分(例如,R1和R2)可用于将所述化合物连接至纳米颗粒,或者R3可连接于所述纳米颗粒而R1和R2可作为例如靶向剂、诊断性试剂、隐形剂或其组合呈现。而此外,如本文进一步所述,取决于本发明的膦酸酯化合物所需的特征或结构特性,L1、L2和L3可为键或连接基团。
纳米颗粒
多种纳米颗粒可用于本发明。本领域的普通技术人员应当理解,所述纳米颗粒的特征,例如大小,可取决于所述纳米颗粒的类型和/或用途以及本领域公知的其它因素。合适的颗粒可为球体、椭圆体、扁平的、板形的、管状、立方体、长方体、卵形(oval)、椭圆形(ellipse)、圆柱体、锥体或角锥。合适的纳米载体的最大尺寸范围(例如,直径)可为约1nm至约1000nm,约10nm至约200nm,和约50nm至约150nm。
合适的纳米颗粒可由多种本领域通常已知的材料制备。在一些实施方案中,纳米颗粒可包括一种物质或多种物质的任意组合,这些物质包括脂质、聚合物,或金属材料,如二氧化硅、金、氧化铁等。纳米颗粒的实例可包括但不限于脂质体、胶束、脂蛋白、脂质涂覆的泡囊、嵌段共聚物胶束、聚合物泡囊、类脂囊泡、氧化铁颗粒、金颗粒、二氧化硅颗粒、树枝状聚合物或量子点。
在一些实施方案中,该纳米颗粒为部分或完全由饱和或不饱和的脂质构成的脂质体。合适的脂质可包括但不限于脂肪、蜡、固醇、胆固醇、胆固醇衍生物、脂溶性维生素、单甘油酯、二甘油酯、磷脂、鞘脂、糖脂、衍生的脂质等。在一些实施方案中,合适的脂质可包括两亲的、中性的、非阳离子的、阴离子的、阳离子的或疏水的脂质。在某些实施方案中,脂质可包括细胞膜中通常存在的那些,如磷脂和/或鞘脂。合适的磷脂包括但不限于磷脂酰胆碱(PC)、磷脂酸(PA)、磷脂酰乙醇胺(PE)、磷脂酰甘油(PG)、磷脂酰丝氨酸(PS)和磷脂酰肌醇(PI)。合适的鞘脂包括但不限于鞘氨醇、神经酰胺、鞘磷脂、脑苷脂、硫脂、神经节苷脂和植物鞘氨醇。其它合适的脂质可包括脂质提取物,如蛋PC、心脏提取物、脑提取物、肝提取物和大豆PC。在一些实施方案中,大豆PC可包括Hydro大豆PC(HSPC)。阳离子脂质包括但不限于N,N-二油酰基-N,N-二甲基氯化铵(DODAC)、N,N-二硬脂基-N,N-二甲基溴化铵(DDAB)、N-(1-(2,3-二油酰基氧基)丙基)-N,N,N-三甲基氯化铵(DOTAP)、N-(1-(2,3-二油基氧基)丙基)-N,N,N-三甲基氯化铵(DOTMA)和N,N-二甲基-2,3-二油基氧基)丙基胺(DODMA)。非阳离子脂质包括但不限于二肉豆蔻酰基磷脂酰胆碱(DMPC)、二硬脂酰基磷脂酰胆碱(DSPC)、二油酰基磷脂酰胆碱(DOPC)、二棕榈酰基磷脂酰胆碱(DPPC)、二肉豆蔻酰基磷脂酰甘油(DMPG)、二硬脂酰基磷脂酰甘油(DSPG)、二油酰基磷脂酰甘油(DOPG)、二棕榈酰基磷脂酰甘油(DPPG)、二肉豆蔻酰基磷脂酰丝氨酸(DMPS)、二硬脂酰基磷脂酰丝氨酸(DSPS)、二油酰基磷脂酰丝氨酸(DOPS)、二棕榈酰基磷脂酰丝氨酸(DPPS)、二油酰基磷脂酰乙醇胺(DOPE)、棕榈酰基油酰基磷脂酰胆碱(POPC)、棕榈酰基油酰基-磷脂酰乙醇胺(POPE)和二油酰基-磷脂酰乙醇胺4-(N-马来酰亚胺基甲基)-环己烷-1-羧酸酯(DOPE-mal)、二棕榈酰基磷脂酰乙醇胺(DPPE)、二肉豆蔻酰基磷酸乙醇胺(DMPE)、二硬脂酰基-磷脂酰-乙醇胺(DSPE)、16-O-单甲基PE、16-O-二甲基PE、18-1-反PE、1-硬脂酰基-2-油酰基-磷脂酰基乙醇胺(SOPE)、1,2-二反油酰(dielaidoyl)-sn-甘油基-3-磷酸乙醇胺(反DOPE)和心磷脂。在某些实施方案中,脂质可包括衍生的脂质,如聚乙二醇化脂质。衍生的脂质可包括,例如,DSPE-PEG2000、胆固醇-PEG2000、DSPE-聚甘油,或其它本领域通常已知的衍生物。
任何脂质的组合可用于构造纳米颗粒,如脂质体。在某些实施方案中,脂质体的的脂质组合物,可定制以影响脂质体的特征,如泄漏率、稳定性、颗粒尺寸、ζ电势、蛋白质结合、体内循环和/或组织(如肿瘤、肝、脾)等中的聚集。例如,DSPC和/或胆固醇可用于减少从脂质体的泄漏。可包括带负电或带正电的脂质,如DSPG和/或DOTAP,以影响脂质体的表面电荷。在一些实施方案中,脂质体可包括约10种或更少种类的脂质,或约5种或更少种类的脂质,或约3种或更少种类的脂质。在一些实施方案中,存在的具体类型的脂质的摩尔百分比(mol%)通常占纳米颗粒(如脂质体)中存在的总脂质的约0%至约10%、约10%至约30%、约30%至约50%、约50%至约70%、约70%至约90%、约90%至100%。本文所述的脂质可包含在脂质体中,或该脂质可用于涂覆本发明的纳米颗粒,如聚合物纳米颗粒。涂层可部分或完全围绕纳米颗粒且可包括单层和/或双层。
在其它实施方案中,部分或全部纳米颗粒可包括聚合物,如嵌段共聚物或本领域已知的用于制备纳米颗粒的其它聚合物。在一些实施方案中,该聚合物可为生物可降解的和/或生物相容的。合适的聚合物可包括但不限于聚乙烯、聚碳酸酯、聚酐、聚羟酸、聚丙基富马酸酯、聚己内酯、聚酰胺、聚缩醛、聚醚、聚酯、聚(原酸酯)、聚氰基丙烯酸酯、聚乙烯醇、聚氨酯、聚磷腈、聚丙烯酸酯、聚甲基丙烯酸酯、聚氰基丙烯酸酯、聚脲、聚苯乙烯、聚胺及其组合。在一些实施方案中,示例性颗粒可包括壳交联的Knedels,其在以下文献进一步描述:Becker等人,U.S.Appl.No11/250830;Thurmond,K.B.等人,J.Am.Chem.Soc.,119(28)6656–(1997));Wooley,K.L.,Chem.Eur.J.,3(9):1397-1399(1997);Wooley,K.L.,J.Poly.Sci.:Part A:Polymer Chem.,38:1397-1407(2000)。在其它实施方案中,合适的颗粒可包括乳酸-羟基乙酸共聚物(PLGA)(Fu,K.等人,Pharm Res.,27:100-106(2000)。
在其它实施方案中,该纳米颗粒可部分或完全由金属性质的材料构成,如二氧化硅、金、氧化铁等。在一些实施方案中,二氧化硅颗粒可为中空的、多孔的和/或介孔的(Slowing,I.I.,等人,Adv.Drug Deliv.Rev.,60(11):1278-1288(2008))。金颗粒是本领域通常已知的,如通过以下示例性文献提供:Bhattacharya,R.&Mukherjee,P.,Adv.Drug Deliv.Rev.,60(11):1289-1306(2008))。氧化铁颗粒或量子点也可使用且是本领域熟知的(vanVlerken,L.E.&Amiji,M.M.,Expert Opin.Drug Deliv.,3(2):205-216(2006))。纳米颗粒还包括但不限于病毒颗粒和陶瓷颗粒。
对纳米颗粒的连接
在某些实施方案中,该联接组分可包括官能团,其可用于将联接组分共价连接至纳米颗粒上存在的反应性基团。该官能团可位于联接组分上的任何位置,如联接组分的末端位置。多种官能团是本领域通常已知的且可在多种类型的反应下反应,如但不限于亲核取代(例如,胺和醇与酰卤或活性酯的反应)、亲电取代(例如,烯胺反应)和向碳-碳和碳-杂原子重键的加成(例如,Michael反应或Diels-Alder加成)。这些和其它有用的反应公开于,例如,March,Advanced Organic Chemistry,3rd Ed.,John Wiley&Sons,New York,1985;和Hermanson,Bioconjugate Techniques,Academic Press,San Diego,1996。合适的官能团可包括,例如:(a)羧基及其多种衍生物,包括,但不限于,N-羟基琥珀酰亚胺酯、N-羟基苯并三唑酯、酰基卤、酰基咪唑、硫酯、对硝基苯基酯、烷基、烯基、炔基和芳族酯;(b)可转化为酯、醚、醛等的羟基;(c)卤代烷基,其中该卤化物随后可被亲核基团代替,例如,胺、羧酸根阴离子、硫醇阴离子、负碳离子或烷氧离子,从而导致新的基团在卤素原子的位点的共价连接;(d)亲二烯体基团(dienophile group),其可参与Diels-Alder反应,例如,马来酰亚氨基;(e)醛或酮基团,使得随后的衍生化是可能的,其通过形成羰基衍生物,例如,亚胺、腙、缩氨基脲或肟,或通过如Grignard加成或烷基锂加成的反应;(f)磺酰卤基团,用于随后的与胺的反应,例如,形成磺酰胺;(g)硫醇(thiol),其可转化为二硫化物或与酰卤反应;(h)氨基或巯基(sulfhydryl),其可,例如,酰基化、烷基化或氧化;(i)烯烃,其可经历,例如,环加成、酰化、Michael加成等;和(j)环氧化物,其可例如,与胺和羟基化合物反应。在一些实施方案中,基于点击化学(click chemistry)的平台可用于将联接组分连接至纳米颗粒(Kolb,H.C.等人M.G.Finn and K.B.Sharpless,Angew.Chem.Int’l.Ed.40(11):2004–(2001))。在一些实施方案中,该联接组分可包括一个官能团或多个官能团(其导致与纳米颗粒的多个共价键)。
表1提供了可用于本发明的官能团的另外的非限制性、代表性实例。
表1.用于缀合化学的示例性官能团对
在其它实施方案中,联接组分可通过非共价相互作用连接至纳米颗粒,该非共价相互作用可包括但不限于亲和力相互作用、金属配位、物理吸咐、疏水相互作用、范德华相互作用、氢键合相互作用、磁性相互作用、静电相互作用、偶极-偶极相互作用、抗体-结合相互作用、互补DNA之间的杂交相互作用等。在一些实施方案中,联接组分可存在于纳米颗粒的脂质双层部分,其中在某些实施方案中该纳米颗粒为脂质体。例如,联接组分可为部分或完全与脂质双层的疏水和/或亲水性区域互相作用的脂质或磷脂(例如,饱和或不饱和的C8-C36烷基)。在一些实施方案中,该联接组分可包括允许与纳米颗粒非共价相互作用的一个基团,但也考虑到多个基团。例如,多个离子电荷可用于产生联接组分和纳米颗粒之间的足够的非共价相互作用。在替代性实施方案中,该联接组分可包括多种脂质,使得该多种脂质与脂质体双层膜或涂覆在纳米颗粒上的双层或单层互相作用。在某些实施方案中,可改变周围的溶液条件以破坏非共价相互作用,从而将联接组分从纳米颗粒分离。
如本文进一步所述,一些本发明的化合物可包括R1、R2和/或R3作为联接组分。在一些实施方案中,所述联接组分可包括饱和或不饱和的C10-C24烷基、取代的饱和或不饱和的C10-C24烷基或胆固醇。在一些例示性实施方案中,可选择所述联接组分以促进所述联接组分与脂质双层的结合。例如,可选择烷基的长度、双键的位置和几何构型和/或烷基的取代以提供与脂质双层所需水平的掺合从而通过其它组分例如靶向剂和/或隐形剂的展示来修饰脂质体的表面性质。
在其它实施方案中,可通过连接基团L1、L2和/或L3将所述膦酸酯化合物直接连接至纳米颗粒。在这些实施方案中,R1、R2和/或R3可为纳米颗粒。
连接基团
连接基团是本发明膦酸酯化合物的另一特征。本领域的普通技术人员能够理解多种连接基团是本领域已知的,且可在例如以下参考文献中找到:Hermanson,G.T.,Bioconjugate Techniques,2nd Ed.,Academic Press,Inc.(2008)。本发明的连接基团可用于向所述化合物提供额外的性质,如提供化合物的不同部分之间的间距。该间距可用于例如克服由纳米颗粒引起的位阻问题,例如当与纳米颗粒有一定距离的靶向剂可结合靶点时。在一些实施方案中,连接基团可用于改变所述化合物的物理性质。
在一些实施方案中,本发明的膦酸酯化合物包括L1、L2和L3,其可各自独立地为连接基团或键。在一些实施方案中,L1、L2和L3可各自独立地选自亲水性、非免疫原性水溶性连接基团。本发明的亲水性、非免疫原性水溶性连接基团可包括但不限于,聚乙二醇、聚丙二醇、聚乙烯醇、聚羧酸酯、多糖和葡聚糖。本领域的普通技术人员应当理解可为一些应用(如上文所讨论的间距因素)选择连接基团的长度和/或化学性质。
在其它实施方案中,所述连接基团可为,例如C1-30亚烷基连接基团或相似的杂亚烷基连接基团(碳链被1至10个选自O、N和S的杂原子中断的亚烷基连接基团)。或者,在一些实施方案中,所述连接基团可包括芳基部分如亚苯基环或杂芳基对应物。在一些实施方案中,所述连接基团可包括上文对联接组分所列的官能团。所述官能团(例如,羧基)可用于将另一种试剂(例如,隐形剂或靶向剂)连接至所述膦酸酯化合物。根据公知的连接化学的广泛范围,本领域的普通技术人员应当理解连接基团用于连接本文所述的试剂(例如,隐形剂)的众多方法。
在一些实施方案中,本发明的化合物还可包括连接骨架,其可例如连接本文进一步所述的膦酸酯化合物。本发明的连接骨架由L4表示且可包括亚烷基、亚芳基或其组合。所述连接骨架可包括亚烷基连接骨架或相似的杂亚烷基连接骨架(碳链被1至10个选自O、N和S的杂原子间断的亚烷基连接基团)。所述连接骨架还可包括亚芳基连接骨架(例如,亚苯基)或相似的杂亚芳基连接骨架(至少一个芳环中的碳被选自O、N和S的杂原子替代的亚芳基连接骨架)。在一些实施方案中,L4可任选包括取代的亚烷基、取代的亚芳基或其组合。例如,所述亚烷基和/或亚芳基可被烷基、胺、腈和羧酸取代。
隐形剂
在一些实施方案中,所述膦酸酯化合物可包括至少一种隐形剂。例如,在一些实施方案中,R1、R2和R3可独立地选自隐形剂。隐形剂可防止纳米颗粒彼此粘附和防止纳米颗粒粘附至血液细胞或血管壁。在一些实施方案中,当纳米颗粒被给予至受试者时,隐形纳米颗粒,例如隐形脂质体,可降低免疫原性和/或反应原性。隐形剂还可增加纳米颗粒在受试者内的血液循环时间。在一些实施方案中,纳米颗粒可包括隐形剂,从而,例如使得所述纳米颗粒部分地或全部地由隐形剂组成或所述纳米颗粒被隐形剂包被。用于本发明的隐形剂可包括本领域所公知的那些。适宜的隐形剂可包括但不限于树枝状聚合物、聚环氧烷烃、聚乙二醇、聚乙烯醇、聚羧酸酯、多糖和/或羟基烷基淀粉。隐形剂可通过共价和/或非共价连接(如上文关于联接组分所述)连接至本文所述的膦酸酯化合物。例如,在一些实施方案中,所述隐形剂对本文所述的膦酸酯化合物的连接可涉及隐形剂上的端官能团(例如,氨基)与具有官能团(例如羧基)末端的连接基团之间的反应。
在一些实施方案中,隐形剂可包括聚环氧烷烃,如“聚乙二醇”(其是本领域所公知的),并且通常指的是环氧乙烷的低聚物或聚合物。聚乙二醇(PEG)可以是直链或支链的,其中支链PEG分子可具有从中央核发散的额外的PEG分子和/或可将多个PEG分子接枝至聚合物主链。如本领域所理解的,聚乙二醇可以分子量分布(其可用于鉴定PEG的类型)的形式产生。例如,PEG500通过具有平均分子量为~500g/mol的PEG分子的分布鉴定,其根据本领域公知的方法测量。或者,PEG可以下式表示:H-[O-(CH2)2]n-OH,其中n为聚合物中存在的单体的数目(例如,n的范围可为1至200)。例如,对于PEG100的分布可包括n等于2的PEG聚合物。在另一种情况中,PEG1000可包括n等于24的PEG分子。或者,PEG5000可包括n等于114的PEG分子。在一些实施方案中,PEG可以甲基代替-OH作为末端,如上所示。
在一些实施方案中,PEG可包括低或高分子量PEG,例如PEG100、PEG500、PEG1000、PEG2000、PEG3400、PEG5000、PEG10000或PEG20000。在一些实施方案中,PEG范围可为PEG100至PEG10000,或PEG1000至PEG10000,或PEG1000至PEG5000。在一些实施方案中,所述隐形剂可为PEG500、PEG1000、PEG2000或PEG5000。在一些实施方案中,PEG可以胺、甲基醚、醇或羧酸为末端。在一些实施方案中,所述隐形剂可包括至少两个PEG分子,其各自经连接基团连接在一起。连接基团可包括上文所述的那些,例如酰胺键。在一些实施方案中,纳米颗粒如脂质体的双层中存在足以使所述纳米颗粒“隐形”的量的PEG化的脂质,其中隐形纳米颗粒显示降低的免疫原性。
治疗性试剂
在一些实施方案中,本发明的化合物可包括治疗性试剂、诊断性试剂或其组合。在一些实施方案中,所述治疗性和/或诊断性试剂可直接与本发明的膦酸酯化合物结合。例如,所述治疗性和/或诊断性试剂可共价连接至所述膦酸酯化合物。在其它实施方案中,所述治疗性试剂和/或诊断性试剂可存在于与本发明的膦酸酯化合物结合的纳米颗粒中、表面或周围。在一些实施方案中,所述治疗性试剂和/或诊断性试剂可嵌入、包封于或系连于所述纳米颗粒。在一些实施方案中,所述纳米颗粒为脂质体且所述诊断性和/或治疗性试剂包封于所述脂质体中。
用于本发明的治疗性试剂可包括任何治疗受试者中病状的试剂。通常,可使用本领域已知的任何治疗性试剂,包括但不限于美国药典(U.S.P);Goodman and Gilman’s The Pharmacological Basis of Therapeutics,10th Ed.,McGraw Hill,2001;Katzung,Ed.,Basic and Clinical Pharmacology,McGraw-Hill/Appleton&Lange,8th ed.,September21,2000;Physician’s DeskReference(Thomson Publishing;and/or The Merck Manual of Diagnosis andTherapy,18th ed.,2006,Beers and Berkow,Eds.,Merck Publishing Group;或在动物的情况下,The Merck Veterinary Manual,9th ed.,Kahn Ed.,MerckPublishing Group,2005中所列的试剂,其全部引入本文作为参考。
治疗剂可根据预期治疗的疾病的类型而选择。例如,某些类型的癌症或肿瘤,如癌、肉瘤、白血病、淋巴瘤、骨髓瘤,和中枢神经系统癌症以及实体瘤和混合肿瘤,可包括给药相同或可能不同的治疗剂。在某些实施方案中,可递送治疗剂以治疗或影响受试者的癌性病症,且其可包括化学治疗剂,如烷化剂、抗代谢物、蒽环类抗生素、生物碱、拓扑异构酶抑制剂,和其它抗癌剂。在一些实施方案中,该试剂可包括反义试剂、microRNA、siRNA和/或shRNA剂。
在一些实施方案中,治疗剂可包括抗癌剂或细胞毒素剂,包括但不限于阿瓦斯丁、多柔比星、顺铂、奥沙利铂、卡铂、5-氟尿嘧啶、吉西他滨或紫杉烷,如紫杉醇和多西紫杉醇。另外的抗癌剂可包括但不限于20-epi-1,25-二羟基维生素D3,4-甘薯苦醇、5-乙炔基尿嘧啶、9-二氢紫杉醇、阿比特龙、阿西维辛、阿柔比星、盐酸阿考达唑、阿克罗宁、酰基富烯(acylfulvene)、腺环戊醇、阿多来新、阿地白介素、all-tk拮抗剂、六甲蜜胺、氨莫司汀、安波霉素、醋酸阿美蒽醌、艾美多(amidox)、氨磷汀、氨鲁米特、氨基乙酰丙酸、氨柔比星、安吖啶、阿那格雷、阿那曲唑、穿心莲内酯、血管发生抑制剂、拮抗剂D、拮抗剂G、安雷利克斯、安曲霉素、抗背侧化形态形成蛋白-1(anti-dorsalizing morphogenetic protein-1)、抗雌激素药、抗瘤酮、反义寡核苷酸、阿非迪霉素甘氨酸盐、凋亡基因调节剂、凋亡调节剂、脱嘌呤核酸、ARA-CDP-DL-PTBA、精氨酸脱氨基酶、门冬酰胺酶、曲林菌素、奥沙那宁(asulacrine)、阿他美坦、阿莫司汀、海洋环肽1、海洋环肽2、海洋环肽3、阿扎胞苷、阿扎司琼、阿扎毒素、重氮酪氨酸、阿扎替派、阿佐霉素、浆果赤霉素III衍生物、班兰诺(balanol)、巴马司他、苯并二氢卟酚、苯佐替派、苯甲酰基十字孢碱、β内酰胺衍生物、β-阿立辛(beta-alethine)、贝拉霉素B(betaclamycin B)、桦木酸、BFGF抑制剂、比卡鲁胺、比生群、盐酸比生群、双吖丙啶基精胺、双奈法德、甲碘酸双奈法德、双曲群A(bistratene A)、比折来新、博来霉素、硫酸博来霉素、BRC/ABL拮抗剂、breflate、布喹那钠、溴匹立明、布度钛、白消安、丁硫氨酸亚矾胺、放线菌素C、卡泊三醇、卡弗他丁C、卡普睾酮、喜树碱衍生物、金丝雀痘IL-2(canarypox IL-2)、卡培他滨、卡醋胺、卡贝替姆、卡铂、甲酰胺-氨基-三唑、羧基酰胺基三唑、carestM3、卡莫司汀、cam700、软骨衍生的抑制剂(cartilage derived inhibitor)、盐酸卡柔比星、卡折来新、酪蛋白激酶抑制剂、澳粟精胺、杀菌肽B、西地芬戈、西曲瑞克、苯丁酸氮芥、绿素类、氯喹喔啉磺酰胺、西卡前列素、西罗霉素、顺铂、顺-卟啉、克拉屈滨、氯米芬类似物、克霉唑、克里霉素(collismycin)A、克里霉素B、考布他汀A4、考布他汀类似物、conagenin、crambescidin816、克立那托、甲磺酸克立那托、念珠藻素8、念珠藻素A衍生物、curacin A、环戊蒽醌、环磷酰胺、cycloplatam、cypemycin、阿糖胞苷、阿糖胞苷烷磷酯(cytarabine ocfosfate)、溶细胞因子、磷酸己烷雌酚、达卡巴嗪、达昔单抗、放线菌素D、盐酸柔红霉素、地西他滨、脱氢膜海鞘素B(dehydrodidemnin B)、地洛瑞林、右异环磷酰胺、右奥马铂(dexormaplatin)、右雷佐生、右维拉帕米、地扎呱宁、甲磺酸地扎呱宁、地吖醌、代代宁B、didox、二乙基去甲精胺、二氢-5-氮胞苷、dioxamycin、二苯基螺莫司汀、多西紫杉醇、二十二烷醇、多拉司琼、去氧氟尿苷、多柔比星、盐酸多柔比星、屈洛昔芬、柠檬酸屈洛昔芬、丙酸屈他雄酮、屈大麻酚、达佐霉素、duocarmycinSA、依布硒、依考莫司汀、依达曲沙、依地福新、依决洛单抗、依氟鸟氨酸、盐酸依氟鸟氨酸、榄香烯、依沙芦星、乙嘧替氟、恩洛铂、恩普氨酯、依匹哌啶、表柔比星、盐酸表柔比星、爱普列特、厄布洛唑、红细胞基因治疗载体体系、盐酸依索比星、雌莫司汀、雌莫司汀类似物、雌莫司汀磷酸酯钠、雌激素激动剂、雌激素拮抗剂、依他硝唑、依托泊苷、磷酸依托泊苷、氯苯乙嘧胺、依西美坦、法倔唑、盐酸法倔唑、法扎拉滨、芬维A胺、非格司亭、非那雄胺、夫拉平度、氟卓斯汀、氟尿苷、fluasterone、氟达拉滨、磷酸氟达拉滨、fluorodaunorunicin盐酸盐、氟尿嘧啶、fluorocitabine、福酚美克、福美坦、磷喹酮、福司曲星、福司曲星钠、福莫司汀、钆替沙林、硝酸镓、加洛他滨、加尼瑞克、明胶酶抑制剂、吉西他滨、盐酸吉西他滨、谷胱甘肽抑制剂、hepsulfam、heregulin、六亚甲基双乙酰胺、羟基脲、金丝桃素、伊班膦酸、伊达比星、盐酸伊达比星、吲哚昔酚、伊决孟酮、异环磷酰胺、ilmofosine、伊洛马司他、咪唑并吖啶酮、咪喹莫特、免疫刺激剂肽、胰岛素样生长因子-1受体抑制剂、干扰素激动剂、干扰素α-2A、干扰素α-2B、干扰素α-N1、干扰素α-N3、干扰素β-IA、干扰素γ-IB、干扰素、白介素、碘苄胍、碘阿霉素、异丙铂、伊立替康、盐酸伊立替康、伊罗普拉、伊索拉定、isobengazole、isohomohalicondrin B、伊他司琼、jasplakinolide、kahalalide F、lamellarin-Ntriacetate、兰瑞肽、醋酸兰瑞肽、leinamycin、来格司亭、硫酸蘑菇多糖、leptolstatin、来曲唑、白血病抑制因子、白细胞α干扰素、醋酸亮丙瑞林、亮丙瑞林/雌激素/孕酮、亮丙瑞林、左旋咪唑、利阿唑、盐酸利阿唑、线性多胺类似物、亲脂二糖肽、亲脂铂化合物、lissoclinamide7、洛铂、胍乙基磷酸丝氨酸、洛美曲索、洛美曲索钠、洛莫司汀、氯尼达明、洛索蒽醌、盐酸洛索蒽醌、洛伐他汀、洛索立宾、勒托替康、lutetium texaphyrin、lysofylline、裂解肽、美坦新、mannostatin A、马立马司他、马索罗酚、maspin、基质溶解因子抑制剂、基质金属蛋白酶抑制剂、美登素、氮芥盐酸盐、乙酸甲地孕酮、醋酸美仑孕酮、美法仑、美诺立尔、merbarone、疏基嘌呤、美替瑞林、蛋氨酸酶、甲氨蝶呤、甲氨蝶呤钠、甲氧氯普胺、氯苯氨啶、美妥替哌、微藻蛋白激酶C抑制剂、MIF抑制剂、米非司酮、米替福新、米立司亭、错配双链RNA、米丁度胺、米托卡星、丝裂红素、米托洁林、米托胍腙、二溴卫矛醇、米托马星、丝裂霉素、丝裂霉素类似物、米托萘胺、米托司培、米托坦、迈托毒素成纤维细胞生长因子-皂草素、米托蒽醌、盐酸米托蒽醌、莫法罗汀、莫拉司亭、单克隆抗体、人绒毛膜促性腺激素、单磷酰脂质A/分支杆菌细胞壁SK、莫哌达醇、多重抗药性基因抑制剂、基于多重肿瘤抑制因子1的治疗、芥子抗癌剂、印度洋海绵(mycaperoxide)B、分枝杆菌细胞壁提取物、麦考酚酸、myriaporone、正乙酰基地那林、那法瑞林、nagrestip、纳洛酮/喷他佐辛、napavin、萘萜二醇、那托司亭、奈达铂、奈莫柔比星、奈立膦酸、中性肽链内切酶、尼鲁米特、nisamycin、一氧化氮调节剂、硝基氧抗氧化剂(nitroxideantioxidant)、nitrullyn、诺考达唑、诺拉霉素、n-取代的苯甲酰胺、06-苄基鸟嘌呤、奥曲肽、okicenone、寡核苷酸、奥那司酮、昂丹司琼、oracin、口腔细胞因子诱导剂、奥马铂、奥沙特隆、奥沙利铂、oxaunomycin、奥昔舒仑、紫杉醇、紫杉醇类似物、紫杉醇衍生物、palauamine、棕榈酰基根霉素、帕米磷酸、人参炔三醇、帕诺米芬、parabactin、帕折普汀、培门冬酶、培得星、培利霉素、戊氮芥、戊聚硫钠、喷司他丁、pentrozole、硫酸培洛霉素、全氟溴烷、培磷酰胺、紫苏醇、phenazinomycin、乙酸苯酯、磷酸酶抑制剂、溶链菌素、盐酸毛果云香碱、哌泊溴烷、哌泊舒凡、吡柔比星、吡曲克辛、盐酸吡罗蒽醌、placetin A、placetin B、纤溶酶原激活物抑制剂、铂络合物、铂化合物、铂-三胺络合物、普卡霉素、普洛美坦、卟吩姆钠、泊非霉素、泼尼莫司汀、盐酸丙卡巴肼、丙基双吖啶酮、前列腺素J2、前列腺癌抗雄激素、蛋白酶体抑制剂、基于蛋白质A的免疫调节剂、蛋白质激酶C抑制剂、蛋白质酪氨酸磷酸酶抑制剂、嘌呤核苷磷酸化酶抑制剂、嘌呤霉素、嘌呤霉素盐酸盐、红紫素、吡唑呋喃菌素、吡唑并吖啶、吡哆醛化血红蛋白聚氧乙烯缀合物、RAF拮抗剂、雷替曲塞、雷莫司琼、RAS法呢基蛋白质转移酶抑制剂、RAS抑制剂、RAS-GAP抑制剂、脱甲基瑞替普汀、铼RE186依替膦酸盐、根霉素、利波腺苷、核酶、RII维甲酰胺(retinamide)、RNAi、罗谷亚胺、罗希吐碱、罗莫肽、罗喹美克、rubiginone B1、ruboxyl、沙芬戈、盐酸沙芬戈、saintopin、sarcnu、sarcophytol A、沙格司亭、SDI1模拟物、司莫司汀、老化衍生的抑制剂1、正义寡核苷酸、信号转导抑制剂、信号转导调节剂、辛曲秦、单链抗原结合蛋白质、sizofuran、索布佐生、硼卡钠、苯基乙酸钠、solverol、生长调节素结合蛋白质、索纳明、磷乙酰天冬氨酸钠、膦门冬酸、司帕霉素、spicamycin D、盐酸螺旋锗、螺莫司汀、螺铂、脾脏五肽、海绵抑制素1、角鲨胺、干细胞抑制剂、干细胞分裂抑制剂、stipiamide、链黑菌素、链佐星、基质分解素抑制剂、sulfinosine、磺氯苯脲、强效血管活性肠肽拮抗剂、suradista、苏拉明、苦马豆碱、合成糖胺聚糖、他利霉素、他莫司汀、他莫昔芬甲碘化物、牛磺莫司汀、他扎罗汀、替可加兰钠、替加氟、tellurapyrylium、端粒酶抑制剂、替洛蒽醌盐酸盐、替莫泊芬、替莫唑胺、替尼泊苷、替罗昔隆、睾内酪、四氯十氧化物、tetrazomine、thaliblastine、沙利度胺、硫咪嘌呤、噻可拉林、硫鸟嘌呤、塞替派、血小板生成素、血小板生成素模拟物、胸腺法新、胸腺喷丁受体激动剂、胸腺曲南、甲状腺刺激激素、噻唑羧胺核苷、本紫红素乙酯锡、替拉扎明、二氯环戊二烯钛、盐酸拓扑替康、topsentin、托瑞米芬、柠檬酸托瑞米芬、全能干细胞因子、翻译抑制剂、醋酸曲托龙、维甲酸、三乙酰基尿苷、曲西立滨、磷酸曲西立滨、三甲曲沙、葡萄糖醛酸三甲曲沙、曲普瑞林、托烷司琼、盐酸妥布氯唑、妥罗雄脲、酪氨酸激酶抑制剂、酪氨酸磷酸化抑制剂、UBC抑制剂、乌苯美司、尿嘧啶芥子、乌瑞替派、泌尿生殖窦衍生的生长抑制因子、尿激酶受体拮抗剂、伐普肽、variolin B、维拉雷琐、藜芦明、verdins、维替泊芬、硫酸长春碱、硫酸长春新碱、长春地辛、硫酸长春地辛、硫酸长春匹定、硫酸长春甘酯、硫酸长春罗新、长春瑞滨、酒石酸长春瑞滨、硫酸长春罗定、vinxaltine、硫酸长春利定、vitaxin、伏氯唑、扎诺特隆、折尼铂、亚苄维C、净司他丁、净司他丁斯酯,或盐酸佐柔比星。
在一些实施方案中,该治疗剂可为药物混合物的部分,其包括给药两种或更多种治疗剂。例如,可给药具有顺铂和奥沙利铂两者的脂质体。此外,该治疗剂可在免疫刺激性佐剂之前、之后或同时递送,所述佐剂如铝凝胶或盐佐剂(例如,磷酸铝或氢氧化铝)、磷酸钙、内毒素、Toll样受体佐剂等。
本发明的治疗剂也可包括用于治疗应用的放射性核素。例如,Auger电子的发射体,如111In,可与螯合剂,如二乙烯三胺五乙酸(DTPA)或1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)结合,且包含在用于治疗的靶向递送组合物(如脂质体)中。其它合适的放射性核素和/或放射性核素-螯合剂组合可包括但不限于β放射性核素(177Lu、153Sm、88/90Y)与DOTA、64Cu-TETA、188/186Re(CO)3-IDA;188/186Re(CO)三胺(环状或线状)、188/186Re(CO)3–Enpy2和188/186Re(CO)3-DTPA。
如上所述,用于本发明的治疗剂可以多种方式与纳米颗粒结合,如嵌入、包封入或束缚至纳米颗粒。治疗剂的负载可通过本领域已知的多种方式实现,例如以下文献中公开的:de Villiers,M.M.等人,Eds.,Nanotechnology in DrugDelivery,Springer(2009);Gregoriadis,G.,Ed.,LiposomeTechnology:Entrapment of drugs and other materials into liposomes,CRC Press(2006)。在一组实施方案中,一种或多种治疗剂可负载至脂质体中。脂质体的负载可通过例如主动或被动方式进行。例如,治疗剂可在溶液中脂质体的自组装过程中包含在其中,使得治疗剂包囊在脂质体中。在某些实施方案中,该治疗剂也可嵌入脂质体双层或多层脂质体的多层中。在替代性实施方案中,该治疗剂可主动负载至脂质体中。例如,该脂质体可暴露于条件,如电穿孔,其中使双层膜对包含治疗剂的溶液可渗透,从而使得治疗剂进入脂质体的内部体积。
诊断性试剂
用于本发明的诊断性试剂可包括本领域已知的任何诊断性试剂,例如以下文献所提供的:Armstrong et al.,Diagnostic Imaging,5th Ed.,BlackwellPublishing(2004);Torchilin,V.P.,Ed.,Targeted Delivery of Imaging Agents,CRC Press(1995);Vallabhajosula,S.,Molecular Imaging:Radiopharmaceuticalsfor PET and SPECT,Springer(2009)。在一些实施方案中,R1、R2和R3可独立地选择为诊断性试剂。诊断剂可通过多种方式检测,包括提供和/或增强可检测信号的试剂,该信号包括,但不限于,γ-发射、放射性、回声、光学、萤光、吸收、磁性或断层摄影信号。用于成像诊断剂的技术可包括,但不限于,单光子发射计算体层摄影术(SPECT)、磁共振成像(MRI)、光学成像、正电子发射断层摄影术(PET)、计算机断层摄影术(CT)、X-射线成像、γ射线成像等。
在一些实施方案中,诊断剂可包括螯合剂,该螯合剂例如结合至金属离子以用于多种诊断成像技术。示例性螯合剂包括但不限于乙二胺四乙酸(EDTA)、[4-(1,4,8,11-四氮杂环十四烷-1-基)甲基]苯甲酸(CPTA)、环己烷二胺四乙酸(CDTA)、乙二醇双(2-氨基乙基醚)四乙酸(EGTA)、二乙烯三胺五乙酸(DTPA)、柠檬酸、羟基乙基乙二胺三乙酸(HEDTA)、亚氨基二乙酸(IDA)、三亚乙基四胺六乙酸(TTHA)、1,4,7,10-四氮杂环十二烷-1,4,7,10-四(亚甲基膦酸)(DOTP)、1,4,8,11-四氮杂环十二烷-1,4,8,11-四乙酸(TETA)、1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA),及其衍生物。
放射性同位素可掺入本文所述的一些诊断剂中,且可包括发射γ射线、正电子、β和α颗粒和X-射线的放射性核素。合适的放射性核素包括但不限于225Ac、72As、211At、11B、128Ba、212Bi、75Br、77Br、14C、109Cd、62Cu、64Cu、67Cu、18F、67Ga、68Ga、3H、123I、125I、130I、131I、111In、177Lu、13N、15O、32P、33P、212Pb、103Pd、186Re、188Re、47Sc、153Sm、89Sr、99mTc、88Y和90Y。在某些实施方案中,放射性试剂可包括111In-DTPA、99mTc(CO)3-DTPA、99mTc(CO)3-ENPy2、62/64/67Cu-TETA、99mTc(CO)3-IDA、和99mTc(CO)3三胺(环状或线状)。在其它实施方案中,该试剂可包括DOTA及其具有111In、177Lu、153Sm、88/90Y、62/64/67Cu、或67/68Ga的多种类似物。在一些实施方案中,该脂质体可被放射标记,例如,通过掺入连接至螯合剂的脂质,如DTPA-脂质,如以下文献提供:Phillips等人,Wiley Interdisciplinary Reviews:Nanomedicineand Nanobiotechnology,1(1):69-83(2008);Torchilin,V.P.&Weissig,V.,Eds.Liposomes2nd Ed.:Oxford Univ.Press(2003);Elbayoumi,T.A.&Torchilin,V.P.,Eur.J.Nucl.Med.Mol.Imaging33:1196–(2006);Mougin-Degraef,M.等人,Int’l J.Pharmaceutics344:110-117(2007)。
在其它实施方案中,该诊断剂可包括光学试剂如荧光剂、磷光试剂、化学发光试剂等。多种试剂(例如染料、探针、标记或指示剂)是本领域已知的且可在本发明使用。(参见,例如,Invitrogen,The Handbook—A Guide toFluorescent Probes and Labeling Technologies,Tenth Edition(2005))。荧光剂可包括多种有机和/或无机小分子或多种荧光蛋白质及其衍生物。例如,荧光剂可包括但不限于花青、酞菁、卟啉、靛青、罗丹明、吩嗪、苯基呫吨、吩噻嗪、吩硒嗪、荧光素、苯并卟啉、方酸菁、二吡咯并嘧啶酮、并四苯(tetracenes)、喹啉、吡嗪、咕啉、克酮酸(croconiums)、吖啶酮、菲啶、罗丹明、吖啶、蒽醌、chalcogenopyrylium类似物、二氢卟酚、萘酞菁、甲川染料(methine dyes)、吲哚染料(indolenium dyes)、偶氮化合物、甘菊蓝、氮杂甘菊蓝、三苯基甲烷染料、吲哚、苯并吲哚、吲哚碳菁、苯并吲哚碳菁,和具有4,4-二氟-4-硼-3a,4a-二氮杂-s-二环戊二烯并苯的通用结构的BODIPYTM衍生物,和/或任意这些的缀合物和/或衍生物。可使用的其它试剂包括,但不限于,例如,荧光素、荧光素-多天冬氨酸缀合物、荧光素-多谷氨酸缀合物、荧光素-多精氨酸缀合物、靛青绿、靛青-十二天冬氨酸缀合物、靛青-多天冬氨酸缀合物、异舒泛蓝、吲哚二磺酸盐(indole disulfonates)、苯并吲哚二磺酸盐、二(乙基羧基甲基)靛青、二(戊基羧基甲基)靛青、多羟基吲哚磺酸盐、多羟基苯并吲哚磺酸盐、刚性杂原子吲哚磺酸盐、靛青双丙酸、靛青双己酸、3,6-二氰基-2,5-[(N,N,N’,N’-四(羧基甲基)氨基]吡嗪、3,6-[(N,N,N’,N’-四(2-羟基乙基)氨基]吡嗪-2,5-二羧酸、3,6-二(N-氮杂环丁烷子基(azatedino))吡嗪-2,5-二羧酸、3,6-二(N-吗啉代)吡嗪-2,5-二羧酸、3,6-二(N-哌嗪子基)吡嗪-2,5-二羧酸、3,6-二(N-硫吗啉代)吡嗪-2,5-二羧酸、3,6-二(N-硫吗啉代)吡嗪-2,5-二羧酸S-氧化物、2,5-二氰基-3,6-二(N-硫吗啉代)吡嗪S,S-二氧化物、吲哚碳菁四磺酸盐(indocarbocyaninetetrasulfonate)、氯吲哚碳菁,和3,6-二氨基吡嗪-2,5-二羧酸。
本领域技术人员将理解使用的具体光学试剂可取决于用于激发的波长、皮肤组织下面的深度,和本领域通常众所周知的其它因素。例如,光学试剂的最佳的吸收或激发最大量可根据使用的试剂的而改变,但通常,本发明的光学试剂将吸收以下光或被以下光激发:电磁波谱的紫外(UV)、可见或红外(IR)范围的光。对于成像,在近红外吸收和发射的染料(~700-900nm,例如,靛青)是优选的。对于使用内窥镜方法的局部可视化,在可见范围吸收的任何染料是合适的。
在一些实施方案中,本发明的方法中使用的非电离辐射的波长范围可为约350nm至约1200nm。在一个示例性实施方案中,该荧光剂可被波长在电磁波谱的可见部分的蓝色范围的光激发(约430nm至约500nm)且以在电磁波谱的可见部分的绿色范围的波长(约520nm至约565nm)发射。例如,荧光素染料可被波长约488nm的光激发且具有约520nm的发射波长。作为另一实例,3,6-二氨基吡嗪-2,5-二羧酸可被波长约470nm的光激发且在波长约532nm发荧光。在另一实施方案中,光学试剂的激发和发射波长可落在电磁波谱的近红外范围。例如,靛青染料,如靛青绿,可被波长约780nm的光激发且具有约830nm发射波长。
在其它实施方案中,该诊断剂可包括但不限于本领域通常已知的磁共振(MR)和X-射线造影剂,包括,例如,基于碘的X-射线造影剂、超顺磁氧化铁(SPIO)、钆或锰的复合物,等。(参见,例如,Armstrong等人,DiagnosticImaging,5th Ed.,Blackwell Publishing(2004))。在一些实施方案中,诊断剂可包括磁共振(MR)显像剂。示例性磁共振试剂包括但不限于顺磁剂、超顺磁剂,等。示例性顺磁剂可包括但不限于钆喷酸、钆特酸、钆双胺、钆、钆特醇、锰福地吡、钆弗塞胺、柠檬酸铁铵、钆贝酸、钆布醇或钆塞酸。超顺磁剂可包括但不限于超顺磁氧化铁以及氧化铁和氧化亚铁复合物(Ferristene)。在某些实施方案中,该诊断剂可包括X-射线造影剂,例如,在以下文献提供:H.S Thomsen,R.N.Muller and R.F.Mattrey,Eds.,Trends in Contrast Media,(Berlin:Springer-Verlag,1999);P.Dawson,D.Cosgrove and R.Grainger,Eds.,Textbook of Contrast Media(ISIS Medical Media1999);Torchilin,V.P.,Curr.Pharm.Biotech.1:183-215(2000);Bogdanov,A.A.等人,Adv.Drug Del.Rev.37:279-293(1999);Sachse,A.等人,Investigative Radiology32(1):44-50(1997)。X-射线造影剂的实例包括包括,但不限于,碘帕醇、碘美普尔、碘海醇、碘喷托、碘普胺、碘西胺、碘佛醇、碘曲仑、碘酞硫、碘克沙醇、碘西醇、碘葡糖酰胺、碘葡苯胺、iogulamide、碘沙考、碘昔兰、碘帕醇、甲泛葡胺、碘比醇和碘美醇。在某些实施方案中,该X-射线造影剂可包括碘帕醇、碘美普尔、碘普胺、碘海醇、碘喷托、碘佛醇、碘比醇、碘克沙醇、碘曲仑和碘美醇。
类似于上述治疗剂,该诊断剂可以多种方式与纳米颗粒结合,包括例如嵌入、包封入或束缚至纳米颗粒。类似的,诊断剂的负载可通过本领域已知的多种方式进行,例如以下文献公开的:de Villiers,M.M.等人,Eds.,Nanotechnology in Drug Delivery,Springer(2009);Gregoriadis,G.,Ed.,Liposome Technology:Entrapment of drugs and other materials into Liposomes,CRC Press(2006)。
靶向剂
在一些实施方案中,本发明的膦酸酯化合物还可包括至少一种靶向剂。例如,在一些实施方案中,R1、R2和R3可独立地选择为靶向剂。通常,本发明的靶向剂可与任何感兴趣的靶点(如与器官、组织、细胞、细胞外基质和细胞内区域有关的靶点)结合。在某些实施方案中,靶点可与具体疾病状态,如癌性病症相关。或者,靶向剂可靶向一种或多种具体类型的细胞,例如,该细胞可具有指示细胞、组织和/或受试者的具体疾病和/或具体状态的靶点。在一些实施方案中,靶向剂可特异于仅一个靶点,如受体。合适的靶点可包括但不限于核酸,如DNA、RNA,或其修饰的衍生物。合适的靶点也可包括但不限于蛋白质,如细胞外蛋白质、受体、细胞表面受体、肿瘤-标记、跨膜蛋白质、酶,或抗体。合适的靶点可包括碳水化合物,如可例如存在于细胞的表面的单糖、二糖或多糖。在某些实施方案中,合适的靶点可包括粘蛋白如MUC-1和MUC-4、生长因子受体如EGFR、Claudin4、核仁磷蛋白如核仁素、趋化因子受体如CCR7、受体如生长抑素受体4、Erb-B2(成红细胞白血病致癌基因同源物2)受体、CD44受体,和VEGF受体-2激酶。
在某些实施方案中,靶向剂可包括靶标配体的小分子模拟物(例如,肽的模拟的配体)、靶标配体(例如,包含RGD肽的肽或叶酸酰胺),或对具体靶点特异的抗体或抗体片段。在一些实施方案中,靶向剂可进一步包括叶酸衍生物、B-12衍生物、整联蛋白RGD肽、NGR衍生物、生长抑素衍生物或结合至生长抑素受体的肽,例如,奥曲肽和octreotate等。
本发明的靶向剂还可包括适体。适体可被设计为与感兴趣的靶点关联或结合。适体可由以下构成,例如,DNA、RNA和/或肽,且适体的某些方面是本领域众所周知的。(参见例如,Klussman,S.,Ed.,The Aptamer Handbook,Wiley-VCH(2006);Nissenbaum,E.T.,Trends in Biotech.26(8):442-449(2008))。在本发明中,合适的适体可为线性或环状且可包括具有少于约150个碱基的寡核苷酸(即,少于约150的聚体)。适体的长度范围可为约100至约150个碱基或约80至约120个碱基。在某些实施方案中,适体的范围可为约12至约40个碱基,约12至约25个碱基,约18至约30个碱基,或约15至约50个碱基。可开发所述适体与适宜的靶点一起使用,所述靶点在疾病状态下存在或表达,且包括但不限于本文所记录的靶点。
IV.制备膦酸酯化合物和关联组分的方法
可以多种方式生产所述膦酸酯化合物。在一方面中,本发明包括制备膦酸酯化合物的方法,所述方法包括:将具有下式的H-膦酸酯化合物:
和具有下式的炔烃化合物混合:
在催化剂存在下形成具有下式的膦酸酯化合物:
其中标识为的键为单键或双键;L1、L2和L3各自为连接基团;R1、R2和R3各自独立地选自联接组分、靶向剂、诊断性试剂和隐形剂;且R4为选自H和-P(=O)(OL1-R1)(OL2-R2)的一员,其中当R4不为H时,所述表示为的键为单键。
如本文所提供的,所述涉及H-膦酸酯化合物和炔烃化合物的反应可用于生产很多种化合物,所述化合物可包括联接组分、靶向剂、诊断性试剂、治疗性试剂、隐形剂或其组合。此外,当一种起始物料(例如炔烃化合物)连接至纳米颗粒时,可将制备这些化合物的方法与纳米颗粒组合以合成所述化合物。
本领域的普通技术人员应当理解多种合成方法可用于生产本发明的膦酸酯化合物。例如,如图1所述,炔烃化合物可分别连接至脂质体并与H-膦酸酯化合物组合以在所述脂质体的表面上合成膦酸酯化合物,从而呈现例如靶向剂和/或隐形剂。如图1所示,炔烃化合物连接至具有R3(联接组分)的脂质体。随后与例如两种H-膦酸酯化合物的反应可生成图1中所示呈现组件,其中两种靶向剂(R1)和两种诊断性试剂(R2)呈现于脂质体表面。
或者,如实例图2所述,H-膦酸酯化合物可连接至纳米颗粒,然后与炔烃化合物结合以在纳米颗粒的表面上生成本发明的膦酸酯化合物。例如,如图2所示,R1和R2可以是连接脂质体脂质双层的联接组分。然后将所制备的具有H-膦酸酯化合物的脂质体与炔烃化合物(其,例如包括靶向剂)结合。在随后的氢膦酸酯化反应后,所述靶向剂可呈现于所述脂质体的表面,从而将所述脂质体转变成靶向脂质体。图2的锚固组件分别通过允许两种和四种联接组分嵌入脂质双层中提供额外的稳定性。如上文所详述,可独立地选择连接L1、L2和L3作为连接基团或键以允许所需的间距或特定应用所需的其它特性。
尽管氢膦酸酯化反应为在纳米颗粒上生成本发明的膦酸酯化合物提供了若干优势,但可使用其它方法制备所述化合物。例如,可将H-膦酸酯化合物和炔烃化合物一起反应以形成本发明的膦酸酯化合物。随后,可将所述膦酸酯化合物连接至纳米颗粒。在一些实施方案中,可通过以下方法将膦酸酯化合物掺合至脂质体中:首先使用标准方法(例如,挤压法)生成脂质体,随后将所述膦酸酯化合物连接至所述脂质体。在其它实施方案中,可在脂质体形成过程中将膦酸酯化合物掺合至所述脂质体双层中,例如将膦酸酯化合物和脂质组分一起干燥,然后将混合物重悬于水性溶液中以形成膦酸酯化合物与双层结合的脂质体。
使用其它合成顺序生成所述膦酸酯化合物也在考虑之中。例如,如图1所示,可将包括R3和L3的炔烃化合物与不含R1和R2的H-膦酸酯反应。在此类实施方案中,L1可为连接基团(其包括与R1和/或R2结合的官能团),R1和/或R2可包括例如靶向剂、隐形剂或诊断性试剂。因此,可将R1和/或R2与L1的官能团反应以生成最终的膦酸酯化合物。本领域的普通技术人员应当理解存在若干种其它可能的合成顺序以生成本发明的膦酸酯化合物。例如,L3可具有在H-膦酸酯化合物与炔烃化合物反应后可与R3反应的官能团。在一些实施方案中,R1和R2可以是相同的,且因此,例如,若R1和R2为靶向剂,则L1和L2可各自含有可与所述靶向剂反应生成本发明的膦酸酯化合物的官能团。
本发明还提供了包括连接骨架的化合物,所述连接骨架可例如连接本文进一步所述的H-膦酸酯化合物。本文进一步所述的连接骨架由L4表示且可包括亚烷基、亚芳基或其组合。
在一方面中,本发明包括制备膦酸酯化合物的方法,所述方法包括:将具有下式的H-膦酸酯化合物:
和具有下式的炔烃化合物混合:
在催化剂存在下形成具有下式的膦酸酯化合物:
其中L1和L2各自为键或连接基团;R1和R2各自独立地选自纳米颗粒、联接组分、靶向剂、诊断性试剂和隐形剂;且L4选自亚芳基、亚烷基或其组合。在一些实施方案中,所述H-膦酸酯化合物和所述炔烃化合物分别以2:1的摩尔比结合。
纳米颗粒
如本文所提供的,本发明包括可通过本领域公知的多种方式生成的纳米颗粒的用途,并且制备此类纳米颗粒的方法可取决于所需的特定纳米颗粒。本领域可用的任何测量技术可用于测定靶向递送组合物和纳米颗粒的性质。例如,技术如动态光散射、X-射线光电子显微术、粉末X-射线衍射、扫描电子显微术(SEM)、透射电子显微术(TEM)和原子力显微镜法(AFM)可用于确定纳米颗粒和/或靶向递送组合物的平均尺寸和分散度。
本发明使用的脂质体可使用本领域通常众所周知的多种技术制备。(参见,例如,Williams,A.P.,Liposomes:A Practical Approach,2nd Edition,OxfordUniv.Press(2003);Lasic,D.D.,Liposomes in Gene Delivery,CRC Press LLC(1997))。例如,脂质体可通过但不限于以下技术制备,如挤压、搅拌、超声处理、反相蒸发(reverse phase evaporation)、水溶液中自组装(self-assembly inaqueous solution)、基于电极的形成技术(electrode-based formation techniques)、微流体导向的形成技术(microfluidic directed formation techniques),等。在某些实施方案中,该方法可用于制备多层和/或单层的脂质体,其可包括大单层脂质体(LUV)和/或小单层脂质体(SUV)。类似于溶液中脂质体的自组装,胶束可使用本领域通常众所周知的技术制备,使得当溶于足以形成胶束的溶液条件时两亲型分子将形成胶束。脂质涂覆的泡囊和脂蛋白也可使用本领域已知的方法构造(参见,例如,Farook,U.,J.R.Soc.Interface,6(32):271-277(2009);Lacko等人,Lipoprotein Nanoparticles as Delivery Vehicles forAnti-Cancer Agents in Nanotechnology for Cancer Therapy,CRC Press(2007))。
制备可用于本发明的聚合物纳米颗粒的方法是本领域公知的(参见,例如Sigmund,W.et al.,Eds.,Particulate Systems in Nano-and Biotechnologies,CRCPress LLC(2009);Karnik et al.,Nano Lett.,8(9):2906-2912(2008))。例如,可使用本领域已知的合成方法制备嵌段共聚物从而使得所述嵌段共聚物可在溶液中自组装以形成聚合物泡囊和/或嵌段共聚物胶束。类脂囊泡是本领域已知的,且可使用多种技术和组合物制备(Baillie A.J.et al.,J.Pharm.Pharmacol.,38:502-505(1988))。可使用本领域已知的任何方法(如共沉淀、热分解和微乳化)构建磁性和/或金属颗粒。(也参见Nagarajan,R.&Hatton,T.A.,Eds.,Nanoparticles Synthesis,Stabilization,Passivation,and Functionalization,OxfordUniv.Press(2008))。可使用本领域公知的多种技术(如Turkevich方法、Brust方法、Perraut方法或超声波分解法)制备金颗粒和其衍生物(也参见Grzelczaket al.,Chem.Soc.Rev.,37:1783-1791(2008))。在一些实施方案中,所述联接组分可通过硫金束缚化学(sulfur-gold tethering chemistry)连接。可使用本领域已知的任何方法(如胶体合成技术)合成量子点或半导体纳米晶体。通常,量子点可由多种材料如半导体材料(包括硒化镉、硫化镉、砷化铟、磷化铟等)组成。
其它关联组分
如本文所述,本发明的膦酸酯化合物可包括组分如靶向剂、隐形剂、诊断性试剂、治疗性试剂和联接组分。本领域的普通技术人员应当理解可用于生成各种组分的标准的、公知的技术。例如,靶向剂、隐形剂、诊断性试剂、治疗性试剂可通过共价和/或非共价连接(如上文关于联接组分所述)连接至本文所述的膦酸酯化合物。
关于靶向剂,对于一些实施方案而言,所述靶向剂可包括适体。可使用本领域已知的技术鉴别特定靶点的适体,如但不限于体外选择方法,如SELEXTM(指数富集的配体系统进化技术)或MonoLexTM技术(用于AptaResAG的单轮适体分离程序)、体内选择方法,或其组合。(参见,例如Ellington,A.D.&Szostak,J.W.,Nature346(6287):818-22;Bock et al.,Nature355(6360):564-6(1992))。在一些实施方案中,上述提及的方法可用于鉴别特定的DNA或RNA序列,所述序列可用于结合感兴趣的特定靶点,如本文所公开的。一旦已经识别了特定适体的序列,则可以本领域已知的多种方法(如亚磷酰胺合成法)构建所述适体。对于肽适体,可使用多种鉴别和制备技术(参见,例如Colas,P.,J.Biol.7:2(2008);Woodman,R.et al.,J.Mol.Biol.352(5):1118-33(2005)。
可通过多种方式将适体连接至H-膦酸酯化合物和炔烃化合物。例如,H-膦酸酯化合物和炔烃化合物上的连接基团L1、L2或L3可与所述适体的3'或5'端反应。在替代实施方案中,可通过将核酸一次一个添加至所述H-膦酸酯化合物和所述炔烃化合物上的连接基团L1、L2或L3来连续合成所述适体。
V.给予靶向递送组合物的方法
本发明还包括包含膦酸酯化合物的靶向递送组合物。在一方面中,本发明包括包含本文所述的膦酸酯化合物的靶向递送组合物,其中R1和R2中的至少一个为靶向剂且R3为纳米颗粒或连接至纳米颗粒的联接组分。如上文所详述,所述联接组分可以若干种方式连接纳米颗粒,例如,所述联接组分可以为与脂质体双层结合的脂质。
本发明的靶向递送组合物和方法可用于治疗和/或诊断任何与受试者有关的疾病、病症和/或病状。在一项实施方案中,本发明的方法包括用于治疗和诊断受试者癌性病状的方法,其包括向所述受试者给予包含本发明的膦酸酯化合物和纳米颗粒的靶向递送组合物,其中所述组合物还包含足以治疗或诊断所述病状的治疗性或诊断性试剂。在一些实施方案中,所述癌性病状可包括充分表达(例如,在细胞表面上或脉管系统中)可被本发明的靶向递送组合物的靶向剂靶向的受体的癌症。
在另一项实施方案中,本发明的方法包括测定受试者对靶向治疗性治疗适用性的方法,其包括向所述受试者给予包含本文所述的纳米颗粒和膦酸酯化合物的靶向递送组合物,其中所述膦酸酯化合物或纳米颗粒包含诊断性试剂,并使所述受试者成像以检测所述诊断性试剂。
给药
在一些实施方案中,本发明可包括靶向递送组合物和生理学上(即,药学上)可接受的载体。如本文所述,术语"载体"是指通常的用作药物如治疗剂的稀释剂或媒介物的惰性物质。该术语也包括赋予组合物粘聚性的通常的惰性物质。通常,生理学上可接受的载体以液体形式存在。液体载体的实例包括生理盐水、磷酸盐缓冲液、生理缓冲盐水(135-150mM NaCl)、水、缓冲水溶液、0.4%盐水、0.3%甘氨酸、糖蛋白以提供增强的稳定性(例如,白蛋白、脂蛋白、球蛋白等),等。因为生理学上可接受的载体部分通过给予的具体组合物以及通过用于给予组合物的具体方法而决定,因此有很多种本发明的药物组合物的合适制剂(参见,例如,Remington's Pharmaceutical Sciences,17thed.,1989)。
本发明的组合物可通过常规、众所周知的灭菌技术灭菌或可在无菌条件下制备。水溶液可被包装使用或在无菌条件过滤且冻干,该冻干制剂在给药前与无菌水溶液合并。该组合物可按需要包含药物可接受的辅助物质以接近生理条件,如pH调节和缓冲剂、张度调节剂、湿润剂,等,例如,乙酸钠、乳酸钠、氯化钠、氯化钾、氯化钙、脱水山梨醇单月桂酸酯和三乙醇胺油酸盐。可包含糖以稳定该组合物,如用于冻干的靶向递送组合物的稳定剂。
所选择的靶向递送组合物,当单独或与其它合适的组分组合时,可制备成气溶胶制剂(即,它们可被"雾化")以通过吸入给药。气溶胶制剂可置于加压可接受的推进剂中,如二氯二氟甲烷、丙烷、氮气,等。
用于直肠给药的合适的制剂包括,例如,栓剂,其包含有效量的包装的靶向递送组合物以及栓剂基质。合适的栓剂基质包括天然或合成的甘油三酯或烷属烃。此外,也可使用明胶直肠胶囊,其包含选择的靶向递送组合物与基质的组合,基质包括,例如,液体甘油三酯、聚乙二醇,和烷属烃。
适合肠胃外给药的制剂,例如,通过关节内(关节中)、静脉内、肌内、瘤内、皮内、腹腔内、和皮下途径,包括水性和非水性、等渗无菌注射溶液,其可包含抗氧化剂、缓冲剂、抑菌剂和使得制剂与预期接受者的血液等渗的溶质,和水性和非水性无菌悬浮液,其可包括助悬剂、增溶剂、增稠剂、稳定剂和防腐剂。注射溶液和悬浮液也可由无菌粉末、颗粒和片剂制备。在本发明的实践中,组合物可通过,例如,静脉内输注、局部、向腹膜内、膀胱内或鞘内给药。肠胃外给药和静脉内给药是优选给药方法。靶向递送组合物的制剂可存在于单元剂量或多剂量密封容器,如安瓿和小瓶中。
该药物制剂优选以单位剂型形式。以该形式,制剂细分为包含合适的量的活性成分的单位剂量,例如,靶向递送组合物。该单位剂型可为包装的制剂,包含离散量的制剂的包装。如果需要的话,该组合也可包含其它相容的治疗剂。
在治疗癌症的治疗用途中,本发明的药物组合物中使用的包含治疗和/或诊断剂的靶向递送组合物可以初始剂量为每日约0.001mg/kg至约1000mg/kg给药。可使用日剂量范围约0.01mg/kg至约500mg/kg,或约0.1mg/kg至约200mg/kg,或约1mg/kg至约100mg/kg,或约10mg/kg至约50mg/kg。然而,该剂量可根据患者的需求、治疗病症的严重性和使用的靶向递送组合物而改变。例如,剂量可考虑具体患者中诊断的癌症的类型和阶段而凭经验地确定。给药于患者的剂量,在本发明的上下文,应足以随时间在患者中实现有益治疗响应。剂量大小也将通过在具体患者中伴随给药具体靶向递送组合物的任何不利副作用的存在、性质和程度而确定。对具体情形的适当剂量的确定是医生技能范围内的。通常,治疗起始于较小剂量,其小于靶向递送组合物的最佳剂量。之后,剂量通过小增量增加直到达到情况下的最佳效果。为方便起见,总日剂量可分开且在一天过程中分部分给药,如果需要的话。
在一些实施方案中,本发明的靶向递送组合物可用于诊断疾病、障碍和/或病症。在一些实施方案中,该靶向递送组合物可用于诊断受试者的癌性病症,如肺癌、乳腺癌、胰腺癌、前列腺癌、子宫颈癌、卵巢癌、结肠癌、肝癌、食管癌,等。在一些实施方案中,诊断疾病状态的方法可包括使用靶向递送组合物以物理检测和/或定位受试者体内的肿瘤。例如,肿瘤可与充分表达(例如,在细胞表面或在脉管系统中)被本发明的靶向递送组合物的靶向剂靶向的受体的癌症相关。在一些实施方案中,该靶向递送组合物也可用于诊断癌症之外的疾病,如增殖性疾病、心血管疾病、胃肠疾病、泌尿生殖疾病、神经病、肌骨病、血液疾病、炎性疾病、自身免疫性疾病、类风湿性关节炎等。
如本文所述,本发明的靶向递送组合物可包括具有本质上可检测性质的诊断剂。在检测受试者中的诊断剂中,该靶向递送组合物,或部分为靶向递送组合物的一群颗粒,可给药于受试者。该受试者然后可使用用于成像诊断剂的技术成像,如单光子发射计算机断层摄影术(SPECT)、磁共振成像(MRI)、光学成像、正电子发射断层摄影术(PET)、计算机断层摄影术(CT)、X-射线成像、γ射线成像,等。任何本文所述的成像技术可与其它成像技术结合使用。在一些实施方案中,将用于成像的放射性同位素掺入颗粒使得在受试者体内示踪该靶向递送组合物。例如,靶向递送组合物的生物分布和/或消除可被测量且任选用于改变患者的治疗。例如,可能需要或多或少的靶向递送组合物以优化患者的治疗和/或诊断。
靶向递送
在某些实施方案中,本发明的靶向递送组合物可递送至受试者以通过靶向的方式释放治疗剂或诊断剂。例如,靶向递送组合物可递送至受试者中的靶点,然后嵌入、包封入或束缚至靶向递送组合物(如至纳米颗粒)的治疗剂,可基于靶点附近的溶液条件而递送。溶液条件,如pH、盐浓度等,可引起治疗剂经较短或较长时间释放至靶点附近的区域。或者,酶可裂解该源自靶向递送组合物的治疗剂或诊断剂以引发释放。在一些实施方案中,该靶向递送组合物可通过内吞作用递送至细胞内部区域且可能随后在细胞的内部的功能区隔(如溶酶体)降解。本领域技术人员将理解治疗剂或诊断剂的靶向递送可使用本领域通常已知的多种方法进行。
试剂盒
本发明还提供用于将靶向递送组合物给药至受试者以治疗和/或诊断疾病状态的试剂盒。该试剂盒通常包括两种或更多种治疗和/或诊断疾病状态所需的组分,如癌性病症所需的组分。该组分可包括本发明的靶向递送组合物、试剂、容器和/或装置。在一些实施方案中,试剂盒中的容器可包含靶向递送组合物,该组合物包含在使用前被放射标记的放射性药物。该试剂盒可进一步包括给药靶向递送组合物所需的任何反应组分或缓冲液。而且,该靶向递送组合物可为冻干形式且然后在给药前重构。
在某些实施方案中,本发明试剂盒可包括包装组件,其可包括一种或多种用于治疗和/或诊断患者疾病状态的组分。例如,包装组件可包括容纳至少一种如本文所述的靶向递送组合物的容器。单独的容器可包含可在给药至患者前与靶向递送组合物混合的其它赋形剂或试剂。在一些实施方案中,医师可根据具体患者所需的治疗或诊断选择和匹配某些组分和/或包装组件。
应理解本文所述的实施方案仅是解释性目的,基于其的各种变化或修饰都对本领域技术人员进行了暗示,且包含在本申请的精神和范围以及所附权利要求的范围内。本文引用的所有公开、专利和专利申请以其整体在此引入作为参考用于所有目的。
VI.实施例
实施例1
辛-1-烯-2基膦酸双十八烷基酯的制备
图3显示了制备辛-1-烯-2基膦酸双十八烷基酯的一般反应流程。在具有搅拌棒的卷曲顶部微波瓶中将四(三苯基膦)钯(0)(0.10g,0.09mmol)、双十八烷基膦酸酯(1.56g,2.66mmol)、THF(6mL)和1-辛炔(0.30g,2.69mmol)在110℃经微波辐射(Biotage Initiator)90分钟。通过31P NMR(CDCL3)检查浅棕色的反应混合物并确定该反应完成。蒸发反应混合物并通过正相快速色谱(40g硅胶柱)和己烷-乙酸乙酯梯度(0%至10%乙酸乙酯,历时15min,48mL/min流速,ELSD检测)纯化粗产物以得到产物辛-1-烯-2-基膦酸双十八烷基酯(1.61g,86.7%,90%外向异构体A和10%E-异构体B)。外向异构体A的1H、13C和31P NMR光谱显示峰与预期的结构一致。m/z697.6571-697.6711(接近外向异构体A的[M+H]+离子的范围)的提取离子液相色谱显示峰在约11.80和11.90分钟处。外向异构体A的质谱显示[M+H]+和[2M+H]+离子的峰分别在697.6627m/z和1394.3190m/z处。其它NMR、液相色谱和质谱数据与预期结构一致。
实施例2
5-(双(十八烷基氧基)磷酰基)己-5-烯酸的制备。
图4显示了制备5-(双(十八烷基氧基)磷酰基)己-5-烯酸的一般反应流程。在具有搅拌棒的卷曲顶部微波瓶中将四(三苯基膦)钯(0)(0.11g,0.09mmol)、氢膦酸双十八烷基酯(1.55g,2.64mmol)、THF(6mL)和5-己炔酸(0.30g,2.69mmol)在110℃经微波辐射(Biotage Initiator)90分钟。通过31P NMR(CDCL3)检查黄色的反应混合物并确定该反应完成。蒸发反应混合物并通过正相快速色谱(40g硅胶柱)和己烷-乙酸乙酯梯度(0%至100%乙酸乙酯,历时10min,48mL/min流速,ELSD检测)纯化粗产物以得到产物5-(双(十八烷基氧基)磷酰基)己-5-烯酸(0.98g,52.8%,96%外向异构体C和4%E-异构体D)。外向异构体C的1H、13C和31P NMR光谱显示峰与预期的结构一致。m/z699.5980-699.6120(接近外向异构体C的[M+H]+离子的范围)的提取离子液相色谱显示峰在约11.14和11.20分钟处。外向异构体C的质谱显示[M+H]+和[2M+H]+离子的峰分别在699.6050m/z和1398.2035m/z处。其它NMR、液相色谱和质谱数据与预期结构一致。
实施例3
5-(双(十八烷基氧基)磷酰基)己-5-烯酸的与PEG1000-NH2(-胺)的偶联
图5显示将5-(双(十八烷基氧基)磷酰基)己-5-烯酸与PEG1000-NH2偶联的一般反应流程。将含-胺(102.0mg,0.09mmol)、5-(双(十八烷基氧基)磷酰基)己-5-烯酸(64.4mg,0.09mmol)、三乙胺(13.3mg,0.13mmol)、DMF(2mL)和CHCL3(1mL)的25mL圆底烧瓶在氩气氛下在室温搅拌30分钟。将TBTU(35.7mg,0.11mmol)添加至反应混合物溶液并在室温继续搅拌16h。通过旋转蒸发除去挥发物并通过正相快速色谱(4g硅胶柱)和氯仿-甲醇梯度(0%至10%甲醇,历时10分钟,10mL/min流速,ELSD检测)纯化粗产物以得到产物(75-氧代-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-二十四氧杂-74-氮杂八十碳-79-烯-79-基)膦酸双十八烷基酯(58.1mg,35.0%)。高分辨质谱与预期的反应产物一致:(正离子模式)对于C91H182NO28P:理论值1769.2659,实测值1769.2690。类似地,1H和31P NMR谱与预期的结构一致:31P NMR(202.3MHz,CDCL3)δ(ppm):19.3和1H NMR(500MHz,CDCL3)δ(ppm)显示多个一致的峰。
实施例4
5-(双(十八烷基氧基)磷酰基)己-5-烯酸叔丁酯(D)的制备
如图6所示,5-(双(十八烷基氧基)磷酰基)己-5-烯酸叔丁酯(D,MW755.2)可在实施例2所提供的基本上相同的条件和操作下制备,除了使用5-己炔酸叔丁酯代替5-己炔酸外。
实施例5
5,7-双(双(十八烷基氧基)磷酰基))庚酸叔丁酯(E)的制备
可使用Phosphorus,Sulfur and Silicon and the Related Elements,83(1-4),77-98:1993中发现的和图6所述的基本上相同的条件将氢膦酸双十八烷基酯与实施例4制得的5-(双(十八烷基氧基)磷酰基)己-5-烯酸叔丁酯(D)反应。因此,使得溶解于THF(30mL)的氢膦酸双十八烷基酯(MW586.95,1.56g,2.66mmol)和氢化钠(95%,FW24.0,2.66mmol,0.064g)在惰性气氛下在室温在搅拌下反应。然后添加含5-(双(十八烷基氧基)磷酰基)己-5-烯酸叔丁酯(MW1356.2,3.65g,2.69mmol)的THF并允许在惰性气氛下反应直至反应结束。可通过TLC、RP-HPLC或31P NMR跟踪反应进程。在反应结束时,可通过蒸发将溶剂除去,且通过正相快速色谱使用适宜的溶剂系统(例如,己烷-乙酸乙酯梯度(ELSD检测))纯化粗产物以得到基本上纯的产物。所述粗产物也可使用反相HPLC(例如,C4,300A,和适宜的溶剂梯度,例如水:异丙醇)来纯化。预期产物的MS为M+H+1357.2,M+Na+1379.2。
实施例6
5,7-双(双(十八烷基氧基)磷酰基)庚酸(G)的制备。
图7概述了叔丁酯(E)转化成酸G。5,7-双(双(十八烷基氧基)磷酰基)庚酸叔丁酯经三氟乙酸(TFA)或含氯化氢的二烷处理直至除去叔丁基酯。可通过TLC或RP-HPLC跟踪反应进程。在真空下除去挥发物并通过RP-HPLC(例如,C4,300A柱使用适当的溶剂梯度,如水:异丙醇,以及使用ELSD检测器)获得预期的酸产物。预期产物的质量为1306.1。
实施例7
5,7-双(双(十八烷基氧基)磷酰基)庚酸与PEG1000–NH2(-胺)的偶联
图8显示了5,7-双(双(十八烷基氧基)磷酰基)庚酸与PEG1000–NH2的一般反应。该反应通过使用实施例3中所述的相似比例和条件进行。预期产物的质量为2370.4,得到的M+H+为2371.4且M+Na+为2394.4。
实施例8
庚烷-1,3-二基双膦酸四(十八烷基)酯(J)的制备
使用基本上在Phosphorus,Sulfur and Silicon and the Related Elements,83(1-4),77-98:1993中发现的条件,可将氢膦酸双十八烷基酯与辛-1-烯-2-基膦酸双十八烷基酯反应以生成庚烷-1,3-二基双膦酸四(十八烷基)酯(J,见图9)。因此,使得溶解于THF(6mL)的氢膦酸双十八烷基酯(MW586.95,1.56g,2.66mmol)和氢化钠(95%,FW24.0,2.66mmol,0.064g)在惰性气氛下在室温在搅拌下反应。或者,氢化钠可被等摩尔的强碱如二异丙基氨基锂或醇钠等代替。然后添加辛-1-烯-2-基膦酸双十八烷基酯(A,MW697.15,1.88g,2.69mmol)并允许在惰性气氛下反应直至反应结束。可通过TLC、HPLC或31PNMR跟踪反应进程。在反应结束时,可通过蒸发将溶剂除去,且通过正相快速色谱使用适宜的溶剂系统(例如,己烷-乙酸乙酯梯度(ELSD检测))纯化粗产物以得到基本上纯的庚烷-1,3-二基双膦酸四(十八烷基)酯。还可使用RP-HPLC(C4,300A,和适宜的溶剂梯度)纯化粗产物。预期产物的质量为1270.1。
实施例9
2,5,8,11,14,17,20,23,26,29-十氧杂三十三碳-31-烯-31-基膦酸双十八烷基酯(M)的制备。
图10显示了制备2,5,8,11,14,17,20,23,26,29-十氧杂三十三碳-31-烯-31-基膦酸双十八烷基酯的一般反应流程。
步骤1.2,5,8,11,14,17,20,23,26,29-十氧杂三十三碳-32-炔(L)的制备。
根据Shen,R.,Shen,X.,Zhang,Z.,Li,Y.,Liu,S.,Liu,H.,Journal of theAmerican Chemical Society(2010),132(25),8627-8634,进行2,5,8,11,14,17,20,23,26,29-十氧杂三十三-31-炔(L)的合成。将圆底烧瓶填充单甲氧基-聚乙二醇350(3.50g,10mmol)于无水THF(50mL)中的溶液。在0℃在频繁排气下向圆底烧瓶的溶液中添加NaH(70%w/w于矿物油中,0.51g,11mmol)。在搅拌30min后,缓慢加入炔丙基溴(80%于甲苯中,1.31g,11mmol),并在0℃搅拌该混合物1小时,然后回流过夜。过滤混悬液,然后通过在减压下蒸发干燥滤液除去挥发物。将粗产物溶解于50mL水中并用二氯甲烷(3×)萃取。干燥该溶液并除去挥发物以得到预期产物。质子NMR(300MHz,CDCL3):2.42(s,1H),3.38(s,3H),4.20(s,2H),3.64(t,32H)。
步骤2.2,5,8,11,14,17,20,23,26,29-十氧杂三十三碳-31-烯-31-基膦酸双十八烷基酯(M)的制备。
在具有搅拌棒的卷曲顶部微波瓶中将四(三苯基膦)钯(0)(0.11g,0.09mmol)、氢膦酸双十八烷基酯(1.55g,2.64mmol)、THF(6mL)和2,5,8,11,14,17,20,23,26,29-十氧杂三十三碳-32-炔(MW466.56,1.26g,2.69mmol)在110℃经微波辐射(Biotage Initiator)90分钟。可通过31P NMR(CDCL3)跟踪反应。当反应结束时,将其冷却并通过蒸发浓缩。通过正相快速色谱(使用适宜的洗脱溶剂例如己烷-乙酸乙酯梯度(ELSD检测))或通过RP-HPLC(C4,300A使用适当的溶剂程序和ELSD检测)纯化粗产物以得到预期的产物2,5,8,11,14,17,20,23,26,29-十氧杂三十三碳-31-烯-31-基膦酸双十八烷基酯。预期产物的质谱为M+H+1054.5。
实施例10
2,5,8,11,14,17,20,23,26,29-十氧杂三十三烷-32,33-二基双膦酸四(十八烷基)酯的制备
图11显示了制备2,5,8,11,14,17,20,23,26,29-十氧杂三十三烷-32,33-二基双膦酸四(十八烷基)酯的一般反应流程。首先,制备2,5,8,11,14,17,20,23,26,29-十氧杂三十三碳-31-烯-31-基膦酸双十八烷基酯(M)。使用基本上在Phosphorus,Sulfur and Silicon and the Related Elements,83(1-4),77-98:1993中找到的条件,可将氢膦酸双十八烷基酯与2,5,8,11,14,17,20,23,26,29-十氧杂三十三碳-31-烯-31-基膦酸双十八烷基酯反应。因此,使得溶解于THF(6mL)的氢膦酸双十八烷基酯(MW586.95,1.56g,2.66mmol)和氢化钠(95%,FW24.0,2.66mmol,0.064g)在惰性气氛下在室温在搅拌下反应。然后添加2,5,8,11,14,17,20,23,26,29-十氧杂三十三碳-31-烯-31-基膦酸双十八烷基酯(MW1053.5,2.83g,2.69mmol)并允许在惰性气氛下反应直至反应结束。可通过TLC、RP-HPLC或31P NMR跟踪反应进程。在反应结束时,可通过蒸发将溶剂除去,且通过正相快速色谱使用适宜的溶剂系统(例如,己烷-乙酸乙酯梯度(ELSD检测))纯化粗产物以得到基本上纯的产物2,5,8,11,14,17,20,23,26,29-十氧杂三十三烷-32,33-二基双膦酸四(十八烷基)酯。所述粗产物也可使用RP-HPLC(例如,C4,300A,和适宜的溶剂梯度,例如水:异丙醇)来纯化。预期产物的MS为M+H+1655.5,M+Na+1677.5。
实施例11
图12显示了制备1,1'-(1,3-亚苯基)双(乙烯-1,1-二基)双膦酸四(十八烷基)酯的一般反应流程。
在具有搅拌棒的卷曲顶部微波瓶中将四(三苯基膦)钯(0)(0.071g,0.06mmol)、双十八烷基膦酸酯(1.06g,1.80mmol)、1,3-二乙炔基苯(0.076g,0.60mmol)和甲苯(1.5mL)的混合物接受微波辐射(Biotage Initiator,100℃,1h)。通过31P NMR(CDCL3)检查黄色反应混合物并确定反应结束。蒸发该反应混合物,并通过正相快速色谱(40g硅胶柱)和己烷-乙酸乙酯梯度(0%至20%乙酸乙酯历时10min,48mL/min流速,ELSD检测)然后以等度洗脱(20%乙酸乙酯,历时10min)纯化粗产物以得到产物1,1'-(1,3-亚苯基)双(乙烯-1,1-二基)双膦酸四(十八烷基)酯(0.22g,9.3%)。1H NMR(500MHz,CDCL3)δ(ppm):0.88(t,12H),1.26-1.31(m,120H),1.59-1.64(m,8H),3.95-4.09(m,8H),6.12-6.22(d,2H),6.32-6.37(d,2H),7.32(t,1H),7.51(d,2H),7.68(s,1H);13CNMR(125.7MHz,CDCL3)δ(ppm):14.09,22.68,25.52,29.15,29.36,29.53,29.59,29.63,29.66,29.67,29.71,29.76,30.38,30.43,31.92,66.32,66.37,126.37,126.42,126.47,127.40,127.44,128.39,131.94,132.01,136.86,136.95,138.70,140.10;31P NMR(202.3MHz,CDCL3)δ(ppm):16.9。
实施例12
3,5-双(1-(双(十八烷基氧基)磷酰基)乙烯基)苯甲酸的制备
化学式:C83H156O8P2,分子量:1344.07
可通过使用基本上实施例11的操作,但使用3,5-二乙炔基苯甲酸替代1,3-二乙炔基苯并保留其摩尔比来制备标题化合物。预期产物的m/z为M+H+1345.0。
实施例13
图13显示制备1-环己烯基乙烯基膦酸双十八烷基酯和(E,Z)-(2-(环己-1-烯-1-基)乙烯基)膦酸双十八烷基酯的反应流程。
在具有搅拌棒的卷曲顶部微波瓶中将四(三苯基膦)钯(0)(0.10g,0.09mmol)、双十八烷基膦酸酯(1.50g,2.66mmol)、THF(12mL)和1-乙炔基环己-1-烯(0.27g,2.57mmol)的混合物接受微波辐射(Biotage Initiator,110℃,1.5h)。通过31P NMR(CDCL3)检查浅棕色反应混合物并确定反应结束。蒸发反应混合物并通过正相快速色谱(40g硅胶柱)和己烷-乙酸乙酯梯度(0%至20%乙酸乙酯,历时20min,48mL/min流速,ELSD检测)纯化粗产物,主要得到1-环己烯基乙烯基产物,(1-(环己-1-烯-1-基)乙烯基)膦酸双十八烷基酯(1.14g,64.4%),并得到E和Z-2-环己烯基乙烯基产物的混合物(0.08g)。(1-(环己-1-烯-1-基)乙烯基)膦酸双十八烷基酯的NMR数据:1H NMR(500MHz,CDCL3)δ(ppm):0.88(t,6H),1.26-1.33(m,60H),1.54-1.71(m,8H),2.17(m,4H),3.94-4.05(m,4H),5.81-5.90(d,1H),6.00-6.04(d,1H),6.31(s,1H);13C NMR(125.7MHz,CDCL3)δ(ppm):14.12,21.83,22.70,25.65,25.76,25.95,26.39,29.20,29.38,29.45,29.58,29.61,29.63,29.68,29.72,30.42,30.47,31.94,32.84,63.12,65.93,65.98,126.77,126.84,130.20,130.25,132.46,132.55,139.28,140.62;31P NMR(202.3MHz,CDCL3)δ(ppm):18.9。
Claims (35)
1.下式的化合物:
其中:
标识为的键为单键或双键;
L1、L2和L3各自为键或连接基团;
R1、R2和R3各自独立地选自纳米颗粒、联接组分、靶向剂、诊断剂和隐形剂;且
R4为选自H和-P(=O)(OL1-R1)(OL2-R2)的一员,其中当R4不为H时,所述标识为的键为单键。
2.权利要求1的化合物,其中L1、L2和L3至少一个为亲水性、非免疫原性、水溶性连接基团。
3.权利要求2的化合物,其中所述亲水性、非免疫原性、水溶性连接基团选自聚乙二醇、聚丙二醇、聚乙烯醇、聚羧酸酯、多糖和葡聚糖。
4.权利要求1的化合物,其中所述靶向剂为适体。
5.权利要求1的化合物,其中所述诊断剂为放射性试剂、荧光剂或对比剂。
6.权利要求1的化合物,其中所述隐形剂选自聚乙二醇、树枝状聚合物、聚乙烯醇、聚羧酸酯、多糖和羟基烷基淀粉。
7.权利要求1的化合物,其中R3为选自脂质和胆固醇的联接组分。
8.权利要求1的化合物,其中L1和L2各自为键且R1和R2各自为选自脂质和胆固醇的联接组分。
9.权利要求1的化合物,其中L1和L2各自为键且R1和R2各自为独立地选自饱和或不饱和的C10-24烷基和取代的饱和或不饱和的C10-24烷基的联接组分。
10.权利要求1的化合物,其中R1和R2各自独立地选自靶向剂、诊断剂和隐形剂;R3为纳米颗粒或连接纳米颗粒的联接组分;且R4为H。
11.权利要求1的化合物,其中L3为连接基团,且R3为隐形剂。
12.权利要求11的化合物,其中所述隐形剂选自PEG500、PEG1000、PEG2000和PEG5000。
13.权利要求1的化合物,其具有下式:
其中R1和R2各自为选自饱和或不饱和的C10-24烷基、取代的饱和或不饱和的C10-24烷基和胆固醇的联接组分;且L1和L2各自为键。
14.权利要求13的化合物,其中所述R3为选自PEG500、PEG1000、PEG2000和PEG5000的隐形剂。
15.权利要求13的化合物,其中R3为靶向剂且L3为亲水性、非免疫原性、水溶性连接基团。
16.权利要求13的化合物,其中R3为诊断剂且L3为亲水性、非免疫原性、水溶性连接基团。
17.权利要求13的化合物,其中R3为隐形剂且L3为亲水性、非免疫原性、水溶性连接基团。
18.权利要求1的化合物,其具有下式:
其中R3为选自饱和或不饱和的C10-24烷基、取代的饱和或不饱和的C10-24烷基和胆固醇的联接组分;且R1和R2各自独立地选自靶向剂、诊断剂和隐形剂。
19.制备膦酸酯化合物的方法,所述方法包括:
将具有下式的H-膦酸酯化合物:
和具有下式的炔烃化合物混合:
在催化剂存在下形成具有下式的膦酸酯化合物:
其中
标识为的键为单键或双键;
L1、L2和L3各自为连接基团;且
R1、R2和R3各自独立地选自联接组分、靶向剂、诊断剂和隐形剂;且
R4为选自H和-P(=O)(OL1-R1)(OL2-R2)的一员,其中当R4不为H时,所述标识为的键为单键。
20.权利要求19的方法,其中R3为选自饱和或不饱和的C10-24烷基、取代的饱和或不饱和的C10-24烷基和胆固醇的联接组分。
21.权利要求20的方法,其中R3连接至纳米颗粒。
22.权利要求19的方法,其中R1和R2各自为独立选自饱和或不饱和的C10-24烷基、取代的饱和或不饱和的C10-24烷基和胆固醇的联接组分。
23.权利要求22的方法,其中R1和R2连接至纳米颗粒。
24.下式的化合物:
其中:
L1和L2各自为键或连接基团;
R1和R2各自独立地选自纳米颗粒、联接组分、靶向剂、诊断剂和隐形剂;且
L4为选自亚烷基、亚芳基或其组合的连接骨架。
25.权利要求24的化合物,其中R1和R2各自为选自饱和或不饱和的C10-24烷基、取代的饱和或不饱和的C10-24烷基和胆固醇的联接组分。
26.制备膦酸酯化合物的方法,所述方法包括:将具有下式的H-膦酸酯化合物:
和具有下式的炔烃化合物混合:
在催化剂存在下形成具有下式的膦酸酯化合物:
其中L1和L2各自为键或连接基团;R1和R2各自独立地选自纳米颗粒、联接组分、靶向剂、诊断剂和隐形剂;且L4选自亚芳基、亚烷基或其组合。
27.权利要求26的方法,其中所述H-膦酸酯化合物和所述炔烃化合物分别以2:1的摩尔比混合。
28.靶向递送组合物,其包含权利要求1和24的化合物,其中R1和R2中的至少一个为靶向剂;且R3为纳米颗粒或联接至纳米颗粒的联接组分。
29.权利要求28的靶向递送组合物,其中所述纳米颗粒为脂质体且所述联接组分为与所述脂质体的双层结合的脂质或胆固醇。
30.靶向递送组合物,其包含权利要求1和24的化合物,其中R1和R2各自为连接纳米颗粒的联接组分且R3选自靶向剂、诊断剂和隐形剂。
31.权利要求30的靶向递送组合物,其中所述纳米颗粒为脂质体且所述联接组分为与所述脂质体的双层结合的脂质。
32.治疗或诊断受试者癌性病状的方法,其包括向所述受试者给予权利要求28或30的靶向递送组合物,其中所述组合物包含足以治疗或诊断所述病状的治疗剂或诊断剂。
33.权利要求32的方法,其中所述纳米颗粒为脂质体且所述治疗剂包封于、嵌入或束缚至所述脂质体。
34.权利要求32的方法,其中所述治疗剂为选自以下的抗癌药物:多柔比星、顺铂、奥沙利铂、卡铂、5-氟尿嘧啶、吉西他滨和紫杉烷。
35.测定受试者对靶向治疗性治疗适用性的方法,其包括向所述受试者给予权利要求28或30的靶向递送组合物,其中R1、R2或R3为诊断剂或所述纳米颗粒包含诊断剂,并使所述受试者成像以检测所述诊断剂。
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PCT/US2012/053211 WO2013033450A2 (en) | 2011-08-31 | 2012-08-30 | Remote assembly of targeted nanoparticles using h-phosphonate-ene/-yne hydrophosphonylation reactions |
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WO2019009434A1 (ja) * | 2017-07-06 | 2019-01-10 | 学校法人京都薬科大学 | 薬物送達用高分子ミセル |
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US20130066098A1 (en) | 2013-03-14 |
IL231216A0 (en) | 2014-04-30 |
BR112014004716A2 (pt) | 2017-03-28 |
EP2750711A2 (en) | 2014-07-09 |
US20160060280A1 (en) | 2016-03-03 |
WO2013033450A3 (en) | 2013-09-06 |
KR20140064917A (ko) | 2014-05-28 |
US9216225B2 (en) | 2015-12-22 |
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