CN104039355A - 使用互补性寡核苷酸连接子进行的靶向纳米颗粒的远程组装 - Google Patents
使用互补性寡核苷酸连接子进行的靶向纳米颗粒的远程组装 Download PDFInfo
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Abstract
本发明提供了靶向递送组合物和其用于治疗和诊断受试者疾病状态的方法。靶向递送组合物的组分通过寡核苷酸之间的双链体形成而合并在一起。
Description
相关申请的交叉参考
本申请要求2011年9月30日提交的美国临时申请61/541,797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
癌症为一类可影响所有年龄的人群的疾病。因此,存在很大的努力以提供可治疗或诊断患者癌症的疗法。近期已讨论体内靶向递送纳米颗粒作为药物递送和诊断成像技术的新途径。不幸的是,制备可有效治疗或诊断癌症的基于纳米颗粒的产品仍存在障碍。因此,需要可治疗或诊断癌症新的靶向递送方法且提供促进患者个体化护理的方式。
发明概述
本发明提供靶向递送组合物以及它们用于治疗和诊断受试者的疾病状态如癌性病症的方法。
在本发明的一方面中,所述靶向递送组合物可包括含有治疗剂、诊断剂或其组合的纳米颗粒、具有下式的衍生联接组分:A-(L1)x-C1,和具有下式的靶向组分:C2-(L2)y-T,各自如下文所详述。在另一方面中,所述靶向递送组合物可包含具有下式的诊断性或治疗性组分:DT-(L1)x-C1,和具有下式的靶向组分:C2-(L2)y-T,各自如下文所详述。
该靶向递送组合物和制备和使用该组合物的方法对药物递送和诊断成像领域提供了多种独特的方面。例如,在加入靶向组分形成最终组件前,可通过多种方法将所述靶向递送组合物的一些组分(例如,纳米颗粒和联接组分)组装在一起。本文所述的双链体(duplex)形成技术可提供这些优势。在一些情况中,这些优势也可用于提供更个体化的治疗和/或诊断受试者病症的方法,例如所述靶向递送组合物可促进个体化医疗方法进步。
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解释了本发明示例性实施方案的靶向递送组合物的结构。
图2解释了本发明示例性实施方案的交联反应。
发明详述
I.定义
如本文所用,术语“靶向递送组合物”大体指的是可用于治疗和/或诊断受试者疾病状态的组合物。在一些实施方案中,本发明的靶向递送组合物可包括“靶向治疗性或靶向诊断性递送组合物”,其可包含如本文所述的纳米颗粒、衍生的联接组分和靶向组分。在其它实施方案中,本发明的靶向递送组合物可包含诊断性或治疗性组分和靶向组分。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“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、氧化铁等。脂质可包括脂肪、蜡类、甾醇类、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、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靶向递送组合物结合中的用途,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“联接组分”指的是具有式A-(L1)x-C1的衍生联接组分的A部分,如本文进一步所述。本发明的联接组分可(共价地或非共价地)连接至纳米颗粒。在一些实施方案中,联接组分可共价地与包含表面或内部区域的纳米颗粒的任何部分键接。可使用本领域公知的连接化学(包括但不限于本文进一步所述的那些)实现共价连接。在其它实施方案中,非共价相互作用可包括亲和力相互作用、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中,其中在一些实施方案所述纳米颗粒为脂质体。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。
如本文所用,术语“衍生的”指的是经修饰或制备以适于特定目的的分子的衍生形式。例如,本发明的衍生联接组分可具有式A-(L1)-C1,使得联接组分经亲水性、非免疫原性、水溶性连接基团(其可再共价连接至寡核苷酸,例如C1)衍生化。
如本文所用,术语“靶向组分”指的是具有式C2-(L2)y-T的靶向递送组合物的组分,如本文进一步所述。在一些实施方案中,本发明的靶向组分可与特异性靶点例如癌细胞上的靶点、表位、组织位点或受体位点结合。
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“亲水性、非免疫原性、水溶性连接基团”指的是连接组分的一部分至该相同组分的另一部分的分子。所述连接基团在本文有进一步描述并包括L1和L2。
如本文所用,术语“寡核苷酸”通常指的是可包括多于一个核苷酸的任何核苷酸链的核苷酸链。例如,寡核苷酸可包括8至20个核酸的短核苷酸序列。在一些实施方案中,寡核苷酸的长度范围可为约2至约100个核酸、约2至约50个核酸、约8至约50个核酸、约8至约40个核酸、约10至约30个核酸,或约20至约30个核酸。例如,寡核苷酸可包括中性碱基(例如,腺嘌呤、鸟嘌呤、胸腺嘧啶、尿嘧啶和胞嘧啶)。在一些实施方案中,所述寡核苷酸序列可为天然或非天然的。在一些实施方案中,寡核苷酸可形成双链体且可以是DNA或RNA。
如本文所用,术语“寡核苷酸模拟物”指的是可模拟DNA或RNA的分子。寡核苷酸模拟物可包括人工或非天然模拟物,如肽核酸(PNA)和其它硫代磷酸酯类似物。在一些实施方案中,所述寡核苷酸模拟物可一起(例如PNA/PNA)或与寡核苷酸(例如,PNA/DNA或PNA/RNA)形成双链体。在一些实施方案中,可使用通用和/或经修饰的碱基。
如本文所用,术语“连接部分”指的是能够典型地通过共价连接将两个或两个以上寡核苷酸连接在一起的化学基团。例如,在本发明的一些实施方案中,核苷酸对可在一些条件如光致交联,或者碱或酸催化的交联下交联在一起。两个或两个以上寡核苷酸间交联的方法是公知的,且例如在Webb,ThomasR.,Matteucci,Mark D.,Nucleic Acids Research(1986)14(19),7661-7674中有所描述。
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“系连至(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,联接组分可系连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,联接组分可系连至纳米颗粒的表面,延伸至该表面之外。
如本文所用,术语“用于共价连接的官能团”指的是可用于将第一分子共价连接至第二分子上的另一官能团(或所述第一分子上的另一位点)的第一分子的部分。官能团是本领域公知的,并且包括但不限于氨基、羟基、羧酸、酰胺、叠氮化物、α-卤代酮、α,β-不饱和酮、炔烃、二烯、烯胺、马来酰亚胺基、巯基等。
如本文所用,术语“脂质”指的是脂质分子,其可包括脂肪、蜡类、甾醇类、胆固醇、胆固醇衍生物、脂溶性维生素、甘油一酯、甘油二酯、磷脂类、鞘脂类、糖脂类、阳离子或阴离子脂质、衍生脂质等。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。在一些实施方案中,所述脂质可作为单层或双层包被纳米颗粒的表面。
如本文所用,术语“适体”指的是结合至具体靶点的核酸或肽分子。DNA或RNA适体可包括但不限于天然或非天然的短寡核苷酸序列并且可使用体外选择方法如SELEX(指数式富集配体系统进化)选择。SELEX在例如美国专利5,270,163和5,475,096中有所描述,其引入本文作为参考。其它的选择方法可进一步包括MonoLexTM技术(AptaRes AG的单轮适体分离操作;描述于例如美国专利公开20090269752中)、体内选择方法或其组合。用于本发明的适配体可经设计以结合多种靶点,包括但不限于MUC-1、EGFR、Claudin4、MUC-4、CXCR4、CCR7、FOL1R、生长抑素受体4、Erb-B2(成红细胞白血病癌基因同系物2)受体、CD44受体、VEGF受体-2激酶和核仁素。
如本文所用,术语“优先结合对”指的是通常以特定方式彼此结合的分子(例如寡核苷酸或寡核苷酸模拟物)成的对。在一些实施方案中,优先结合对可包括一个相对于其它例如第二个寡核苷酸成员而言优先与单个或多个DNA序列结合的寡核苷酸成员。对于给定的寡核苷酸,存在对不同DNA序列的广泛的差别亲和力,其范围从非序列特异性(无可检测的优先)至序列优先至绝对的序列特异性(即,在所有可能的序列中仅识别单一序列)。结合对的优先性质可以多种方式如通过解链温度或两个结合对成员间的互补性描述。在一些方案中,所述优先结合对包括C1和C2,如本文所进一步描述。
如本文所用,术语“互补的”指的是寡核苷酸链之间碱基配对的量。在一些实施方案中,两个寡核苷酸之间互补性的量可以百分数表示。例如,如果沿第一和第二寡核苷酸链的每个相邻的核苷酸之间均形成碱基配对,则所述第一寡核苷酸链与第二寡核苷酸链完全互补(即100%互补)。在一些实施方案中,全长或部分长度的寡核苷酸链与另一寡核苷酸链是互补的(例如,完全互补)。互补的寡核苷酸链可以是不同长度或相同长度的。在一些实施方案中,本发明的寡核苷酸可以至少70%互补。例如,70%互补的两个寡核苷酸长度可为例如10个核苷酸,其中所述寡核苷酸的7个核苷酸形成碱基对,3个核苷酸不形成碱基对。在其它实施方案中,所述寡核苷酸可以大于80%互补,或大于90%互补,或大于95%互补。当为了最大对应性(maximumcorrespondence)比较和比对时,术语“百分比同一性”也可用于相同或具有规定百分比的相同核苷酸或氨基酸残基的两个或多个核酸或多肽序列的情况中。为测定百分比同一性,比对所述序列以达到最佳的比较目的(例如,可在第一氨基酸序列或核酸序列中引入空位以达到与第二氨基酸或核酸序列最佳比对)。然后比较相应氨基酸位置或核苷酸位置的氨基酸残基或核苷酸。当第一序列的位置被与第二序列中对应位置相同的氨基酸残基或核苷酸占据时,则所述分子在该位置完全相同。两个序列之间的百分比同一性是所述序列共有的相同位置的数目的函数(即,%同一性=相同位置的数/总位置数(例如,重叠位置)x100)。
如本文所用,术语“足以形成双链体的条件”指的是允许寡核苷酸杂交的条件。可通过选择适当的杂交条件来完成一个寡核苷酸和另一个寡核苷酸的杂交。在一些实施方案中,杂交条件可包括足以在寡核苷酸或寡核苷酸模拟物之间形成双链体的条件。例如,通常选择寡核苷酸:寡核苷酸杂交体的稳定性以与试验和洗涤条件相容从而仅在特定寡核苷酸之间形成稳定的、可检测的杂交体。一种或多种不同测定参数的处理决定具体杂交试验的确切的敏感性和特异性。更具体地,DNA、RNA、PNA或DNA、RNA和PNA的组合的互补碱基之间的杂交可在多种条件下发生,这些条件的温度、盐浓度、静电强度、缓冲组合物等可变。应用这些条件和方法的实例在例如Tijssen,Hybridization with Nucleic Acid Probes,Vol.24,Elsevier Science(1993)中有所描述。通常杂交发生在约0℃至约70℃,历时约1分钟至约1小时,取决于待杂交的序列的性质和其长度。然而,公认地,杂交可在数秒或数小时中发生,取决于额反应的条件。
如本文所用,术语“非天然的”指的是不天然存在于自然中的序列或分子。非天然序列可用于提供仅在2个优先结合对之间的特异性结合,以不与存在于测试样品或接受治疗的受试者中的其它天然存在的寡核苷酸序列结合。
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、口服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
本发明提供了靶向递送组合物和其用于治疗和诊断受试者疾病状态的方法。公开的组合物和方法相比现有方法提供了多种有益特征。例如,本发明的靶向递送组合物和方法可用于个体化医疗方法,其可治疗和/或诊断受试者疾病状态。例如,所述靶向递送组合物的组分之间的双链体连接提供了独特的优势,该优势使得在限定如何组装所述靶向递送组合物中具有额外的自由。
III.靶向递送组合物
A.包含纳米颗粒的靶向递送组合物
在一方面中,本发明的靶向递送组合物可包括靶向治疗性或诊断性递送组合物,其包含(a)包含治疗剂或诊断剂或其组合的纳米颗粒;(b)具有下式的衍生联接组分:A-(L1)x-C1;和(c)具有下式的靶向组分:C2-(L2)y-T,其中A为联接组分;L1和L2各自为亲水性、非免疫原性、水溶性连接基团;C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;T为靶向剂;且下标x和y各自独立地为0或1,但x和y至少一个不为0;其中所述衍生联接组分的A部分与所述纳米颗粒连接。
图1解释了本发明示例性实施方案的靶向递送组合物的一般结构。所提供的脂质体的部分显示脂质双层膜。衍生的联接组分可由脂质联接组分A(其为1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺(DSPE))组成。所述脂质联接组分可共价连接至聚乙二醇(PEG)连接子,该连接子可共价连接至DNA单链(C1)。靶向组分可由与C1互补并共价连接至PEG连接子(其进一步共价连接至靶向剂)的DNA单链(C2)组成。靶向递送组合物可由衍生的联接组分组成,其中脂质端与脂质体的脂质双层结合,并且所述靶向剂的的单链DNA,C2,与所述衍生的联接组分的单链DNA,C1杂交。
纳米颗粒
多种纳米颗粒可用于构建靶向递送组合物。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50nm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、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、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,靶向递送组合物如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。在一项实施方案中,脂质体可由约50.6mol%HSPC、约44.3mol%胆固醇和约5.1mol%DSPE-PEG2000构成。
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)6656–6665(1997));Wooley,K.L.,Chem.Eur.J.,3(9):1397-1399(1997);Wooley,K.L.,J.Poly.Sci.:Part A:PolymerChem.,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、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))。氧化铁颗粒或量子点也可使用且是本领域熟知的(van Vlerken,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。
衍生联接组分
在一些实施方案中,本发明的靶向递送组合物也可包含具有下式的衍生联接组分:A-(L1)x-C1。所述联接组分A可用于将所述衍生联接组分连接至纳米颗粒。所述联接组分可连接至纳米颗粒的任何位置,如所述纳米颗粒的表面上。所述联接组分可通过多种方式包括共价和/或非共价连接与所述纳米颗粒连接。如下文所进一步详述,所述衍生联接组分也可包含连接基团L1和优先结合对的成员C1。
在某些实施方案中,该联接组分A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机理;(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):2004–2021(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、代表性列表。
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。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。
连接基团
连接基为本发明的靶向递送组合物的另一特征。本领域技术人员可理解多种连接基是本领域已知的且可在,例如,以下文献中发现: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组合物提供额外的性质,如提供组分的不同部分之间的间距。例如,所述联接组分可与优先结合对的成员(例如C1)间隔一定距离。该间距可用于例如促进优先结合对成员之间的结合。或者,例如当靶向剂结合靶点时,额外的间隔可用于克服由纳米颗粒引起的立体位阻问题。在一些实施方案中,连接基团可用于改变所述靶向递送组合物的物理性质,如修饰组分的亲水性或疏水性。
在一组实施方案中,所述衍生联接组分和靶向组分可分别包含亲水性、非免疫原性、水溶性连接基团,如L1和L2。对于衍生联接组分,亲水性、非免疫原性、水溶性连接基团将联接组分A连接至优先结合对的成员例如C1。对于靶向组分,亲水性、非免疫原性、水溶性连接基团将靶向剂连接至优先结合对的成员例如C2。所述亲水性、非免疫原性、水溶性连接基团可包括但不限于,聚亚烷基二醇、聚乙二醇、聚丙二醇、聚乙烯醇、聚羧酸酯、多糖和葡聚糖。潜在的连接基团的列表在美国申请20090149643中有进一步描述。在一些实施方案中,聚乙二醇(PEG)连接基团可包括环氧乙烷的寡聚物或多聚物。本发明涵盖本领域公知的PEG和其衍生物的使用。例如,聚乙二醇连接基团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。聚乙二醇连接基团可以被衍生化。聚乙二醇连接基团可以具有低或高分子量,且可包括例如PEG500、PEG2000、PEG3400、PEG5000、PEG10000或PEG20000,其中数字例如500指示平均分子重量。在一些实施方案中,所述PEG连接基团可包括多分散和/或单分散PEG。
衍生联接组分或靶向组分中存在的亲水性、非免疫原性、水溶性连接基团如L1和L2的数目可分别由下标x和y指示。在本发明中,多种组合可用于所述连接基团。在一些实施方案中,下标x和y可各自独立地为0或1。在其它实施方案中,x和y至少一个不为0。在其它实施方案中,x可为0且y可为1。
隐形剂
在一些实施方案中,本发明的靶向递送组合物可包括至少一种隐形剂。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
本发明的靶向治疗性或诊断性组合物中所用的纳米颗粒包括治疗性试剂、诊断性试剂或其组合。所述治疗性试剂和/或诊断性试剂可存在于纳米颗粒中、表面或周围的任何地方。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用于治疗受试者中病症的试剂。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,11th ed.,McGraw Hill,2005;Katzung,Ed.,Basic and Clinical Pharmacology,McGraw-Hill/Appleton&Lange,11th ed.,September21,2009;Physician’s DeskReference,PDR Network,64th ed.2010;The Merck Manual of Diagnosis andTherapy,Merck,18th ed.,2006;或在动物的情况下,The Merck VeterinaryManual,10th ed.,Kahn Ed.,Merck,2010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和/或siRNA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辅料之前、之后或同时递送,所述辅料如铝凝胶或盐辅料(例如,磷酸铝或氢氧化铝)、磷酸钙、内毒素、Toll样受体辅料等。
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、包封入或系连至纳米颗粒。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)。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.Imaging33:1196–1205(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-(NIRD)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造影剂,包括,例如,超顺磁氧化铁(SPIO)、钆或锰的复合物,等。(参见,例如,Armstrong等人,Diagnostic Imaging,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、包封入或系连至纳米颗粒。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)。
优先结合对
如本文提供,本发明的优先结合对包括通常以特定方式彼此结合的分子(例如寡核苷酸或寡核苷酸模拟物)成的对。在一些实施方案中,优先结合对可包括一个相对于其它例如第二个寡核苷酸成员而言优先与单个或多个DNA序列结合的寡核苷酸成员。对于给定的寡核苷酸,存在对不同DNA序列的广泛的差别亲和力,其范围从非序列特异性(无可检测的优先)至序列优先至绝对的序列特异性(即,在所有可能的序列中仅识别单一序列)。在本发明中,C1和C2是优先结合对的成员。在一些例示性实施方案中,C1可以是具有第二成员C2的优先结合对的一员,从而C1和C2可以是寡核苷酸或寡核苷酸模拟物。在一些实施方案中,C1和C2可包括互相杂交但不与受试者中存在的任何核苷酸序列杂交的核苷酸序列。在一些实施方案中,C1和C2可作为本发明的靶向递送组合物的部分给药至受试者,从而使得C1和/或C2与该受试者中存在的另一分子之间无竞争性结合。在一些实施方案中,寡核苷酸序列可以是自然界不存在的序列,即非天然序列。
优选结合成员,如C1和C2,可包括宽范围长度的寡核苷酸和/或寡核苷酸模拟物。例如,寡核苷酸和/或寡核苷酸模拟物的长度范围可为2至100单位。在一些实施方案中,寡核苷酸的长度范围可为约2至约个100核酸、约2至约50个核酸、约8至约50个核酸、约8至约40个核酸、约10至约30个核酸,或约20至约30个核酸。
通常,C1和C2可分别包括形成双链体的寡核苷酸,该双链体在接受治疗或诊断的受试者中在适于该靶向递送组合物递送和转运的条件下是稳定的。结合对的优先性质可以多种方式如通过解链温度或两个结合对成员间的互补性描述。公知的是单链寡核苷酸在与具有互补序列的单链寡核苷酸接触后可容易地形成双链DNA。在一些实施方案中,C1和C2可分别包括互补的寡核苷酸序列,其可大于约95%互补,大于约90%互补,大于约85%互补,大于约80%互补,大于约75%互补,大于约70%互补,大于约60%互补或大于约50%互补。在一些实施方案中,C1或C2可较对方更长或者具有相同长度。C1也可与C2的一部分互补,或者反之。例如,C1可与C2的一部分至少60%互补,至少70%互补,至少80%互补,或至少90%互补,或者反之。在一项实施方案中,C1和C2的长度可为40个核酸,且C1和C2在约8至约30个核酸长度的部分至少70%互补。在另一项实施方案中,C1和C2可包括具有12-25个核酸并大于90%互补的寡核苷酸。
预测两个序列之间的双链DNA稳定性和解链温度的方法是公知的(在例如Breslauer,K.J.等人,Proc.Natl.Acad.Sci.USA,83,3746-3750(1986),Owczarzy R.等人,Biopolymers44,217-239(1997);Sugimoto N.等人,Biochemistry34,11211-11216(1995);Owczarzy R.等人,Biochemistry43,3537-3554(2004)中有所描述)。因此,可以以使得所述两个成员在一些情况中可预定的一些条件下优先彼此结合的方式构建C1和C2的序列。在一些实施方案中,本发明所使用的优先结合对涵盖解链温度大于所治疗的受试者体温的序列。在一些实施方案中,解链温度可大于至少约37℃,大约至少约38℃,大于至少约39℃,大于至少约40℃,大于至少约41℃。在其它实施方案中,优先结合对的解链温度范围可为约37℃至约41℃,约40℃至约50℃,或者约40℃至约60℃。在其它实施方案中,优先结合对可预设具有大于受试者体温至少1℃、至少2℃、至少3℃、至少4℃、至少5℃、至少10℃或者至少20℃的解链温度。本领域的技术人员将理解可预测具体序列具有一定的解链温度,特定用于本发明的具体用途。
优先结合对的成员也可包括能够优先结合彼此的寡核苷酸模拟物。在一些实施方案中,所述寡核苷酸模拟物可一起(例如PNA/PNA)或与寡核苷酸(例如,PNA/DNA或PNA/RNA)形成双链体。在一些实施方案中,所述寡核苷酸模拟物和/或寡核苷酸可通过非沃森-克里克氢键规则的相互作用杂交,且可在溶液中形成稳定的双链体。(参见,例如Egholm等人,Nature365:566-568(1993))。
在另一项实施方案中,靶向递送组合物可经修饰变得更稳固。例如,在优先结合对的成员如C1和C2杂交后,DNA、RNA和/或PNA的两条互补链可通过本领域已知的多种方法进一步交联。(参见,例如Webb,Thomas R.,Matteucci,Mark D.,Nucleic Acids Research(1986)14(19),7661-7674)。本领域的普通技术人员将理解可使用多种交联剂并可采用多种化学法,例如光致交联或者化学交联。此外,多种连接部分可以数种方式连接至所述寡核苷酸,如共价连接至寡核苷酸和/或在所述寡核苷酸的合成过程中连接至寡核苷酸。在一些实施方案中,可通过掺合至少一个能够在寡核苷酸链间形成共价交联的连接部分增加双链体的稳定性。例如,如图2所示,在一条寡核苷酸链中的3-脱氧尿苷(例如,优先结合对的一个成员如C1)可位于序列中从而其可与互补核苷酸序列中存在的鸟嘌呤(G)(优先结合对的另一成员如C2)的对面杂交。从而交联导致形成共价交联的双链体对。
靶向组分
本发明的靶向递送组合物还包括具有式C2-(L2)y-T的靶向组分。连接基团L2和优先结合对成员C2如上文所详述。下标y通常为0或1。
本发明的靶向递送组合物还包括T,一种靶向剂。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。
B.包含直接连接至连接基团的诊断剂和/或治疗剂的靶向递送组合物
在另一方面中,本发明提供靶向递送组合物,其中诊断性和/或治疗性试剂直接连接至连接基团。在一项实施方案中,本发明的靶向递送组合物包括以下靶向递送组合物,其包含:(a)具有式DT-(L1)x-C1的诊断性或治疗性组分;(b)具有式C2-(L2)y-T的靶向组分,其中DT为治疗剂、诊断剂或其组合;L1和L2各自为亲水性、非免疫原性、水溶性连接基团;C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;T为靶向剂;且下标x和y各自独立地为0或1,但x和y至少一个不为0。
在另一项实施方案中,本发明提供靶向治疗性或诊断性递送组合物,其包含:(a)纳米颗粒;(b)具有下式的衍生联接组分:A-(L1)x-C1;和(c)具有下式的诊断性或治疗性组分:C2-(L2)y-DT,其中A为联接组分;L1和L2各自为亲水性、非免疫原性、水溶性连接基团;C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;DT为治疗剂、诊断剂或其组合;且下标x和y各自独立地为0或1,但x和y至少一个不为0;其中所述衍生联接组分的A部分与所述纳米颗粒连接。
通常,本领域的普通技术人员将理解所述靶向递送组合物的选择实施方案(包括如上所述的纳米颗粒)可类似地应用于本文所公开的靶向递送组合物的实施方案,其中诊断性和/或治疗性试剂直接连接至连接基团。将所述诊断性和/或治疗性试剂连接至所述连接基团的方法是本领域公知的,且通常为上文详述的共价连接。本领域的普通技术人员将理解官能团和/或双功能连接子(各自如上文所详述)可用于将例如DT连接至连接基团(L1或L2)。此外,DT可包括任何上文所述的治疗性和/或诊断性试剂并向受试者直接提供所述治疗性和/或诊断性试剂而无需纳米颗粒。类似地,所述靶向组分可与上文所述的用于基于纳米颗粒的靶向递送组合物的靶向组分相同。优先结合对的成员如C1和C2也与上文所述的与包含纳米颗粒的靶向递送组合物相关的那些成员相同。
C.靶向递送组合物的单独组分
在另一方面中,本发明提供本文所公开的靶向递送组合物的单独组分。具体地,本发明包含具有下式的衍生联接组分:A-(L1)-C1,其中A为联接组分;L1为亲水性、非免疫原性、水溶性连接基团;且C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物。
在另一方面中,本发明包含具有下式的靶向组分:C2-(L2)-T,其中L2为亲水性、非免疫原性、水溶性连接基团;且C2为具有第二成员C1的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;且T为靶向剂。
在另一方面中,本发明包含具有下式的诊断性或治疗性组分:(DT)-(L1)-C1,其中DT为治疗剂、诊断剂或其组合;L1为亲水性、非免疫原性、水溶性连接基团;且C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物。
本领域的普通技术人员将理解所述靶向递送组合物的各组分类似地包括上文所述的具体实施方案的各组分。
IV.制备靶向递送组合物和组分的方法
A.包含纳米颗粒的靶向递送组合物
本发明的靶向递送组合物可以多种方式制备。在一方面中,可使用制备靶向治疗性或诊断性递送组合物的方法制备本发明的靶向递送组合物,所述方法包括使具有式A-(L1)x-C1的衍生联接组分,与具有式C2-(L2)y-T的靶向组分接触,其中A为将衍生联接组分连接至纳米颗粒的联接组分;L1和L2各自为亲水性、非免疫原性、水溶性连接基团;C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;T为靶向剂;且下标x和y各自独立地为0或1,但x和y至少一个不为0;其中所述衍生联接组分的A部分在足以将A连接至纳米颗粒的条件下连接至所述纳米颗粒;且随后将所述纳米颗粒-A-(L1)x-C1缀合物与所述靶向组分在足以使C1和C2形成双链体的条件下接触。
通常,本发明的靶向递送组合物可以以一步或任意顺序进行的逐步方式进行组装。例如,可将衍生联接组分连接至包含治疗性和/或诊断性试剂的纳米颗粒。然后可通过优先结合对成员之间的杂交将所述靶向组分添加至所述靶向递送组合物。在一项替代实施方案中,可将所有组分(例如,纳米颗粒、衍生联接组分和靶向组分)混合在一起以在溶液中自组装在一起。在一些实施方案中,所述纳米颗粒可包括脂质体,且可在脂质体形成过程中包入所述衍生联接组分。靶向组分可在脂质体形成后与衍生联接组分一同加入。或者,可在脂质体的自组装过程中包入靶向组分,以在自组装后形成完全的靶向递送组合物。
纳米颗粒
可通过本领域公知的多种方式制备纳米颗粒,并且制备所述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。
本发明靶向递送组合物中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,Oxford Univ.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 in aqueous solution)、基于电极的形成技术(electrode-basedformation techniques)、微流体导向的形成技术(microfluidic directed formationtechniques),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 asDelivery Vehicles for Anti-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。
衍生联接组分
可使用化学合成领域公知的方法制备本发明的衍生联接组分。例如,可在单独的反应合成中从衍生联接组分的其它部分制备所述衍生联接组分的寡核苷酸和/或寡核苷酸模拟物部分(例如C1)。可使用本领域公知的多种方法进行寡核苷酸合成,且其取决于所述寡核苷酸的长度。对于较短的寡核苷酸,例如20至30个核苷酸,可使用亚磷酰胺合成法。对于较长的寡核苷酸,例如5000个核苷酸,可使用常规克隆技术制得所述寡核苷酸,如Smith等人,PNAS,100(26):15440-15445(2003)中所述。本领域所公知的方法可用于分离核苷酸产物。随后,可使用本领域公知的多种连接化学将所述合成的寡核苷酸和/或寡核苷酸模拟物(例如C1)在3'或5'端共价连接至亲水性、非免疫原性、水溶性连接基团,如本文所述。在一些实施方案中,所述寡核苷酸,例如C1,被连接至所述亲水性、非免疫原性、水溶性连接基团的末端。在一个替代方面中,可将A部分或者所述联接组分连接至所述亲水性、非免疫原性、水溶性连接基团(例如,L1),然后可将所述寡核苷酸或寡核苷酸模拟物合成至与所述联接组分相对的连接基团的末端。
在一方面中,可使用本领域已知的常规化学法将所述亲水性、非免疫原性、水溶性连接基团连接至磷脂,如二硬脂酰基磷酸乙醇胺。然后可使用上文所述的技术将优先结合对成员的末端(例如C1表示的寡核苷酸的3'或5'端)连接至聚乙二醇的另一端。在其它实施方案中,可将优先结合对的成员C1直接连接至无亲水性、非免疫原性、水溶性连接基团的联接组分。
靶向组分
可使用上文所述的衍生联接组分的类似方法构建本发明的靶向组分。可使用上文所述的寡核苷酸合成技术单独地合成优先结合对的成员(例如C2)。然后可将所述优先结合对的成员连接至亲水性、非免疫原性、水溶性连接基团(例如L2)的一端。随后或在连接优先结合对成员之前,可将靶向剂连接至所述亲水性、非免疫原性、水溶性连接基团的相反端。在一些实施方案中,可在连接至优先结合对成员或靶向剂之前,使用本领域公知的方法,合成所述亲水性、非免疫原性、水溶性连接基团。
本领域的普通技术人员将理解,可通过多种方法(其取决于靶向剂的特性)将本发明的靶向剂连接至所述亲水性、非免疫原性、水溶性连接基团。例如,如果靶向剂由肽、核苷酸、碳水化合物等构成,反应合成可不同。
在某些实施方案中,该靶向剂可包括适体。具体靶点的适体可使用本领域已知的技术确定,如但不限于,体外选择方法,如SELEX(通过指数式富集配体系统进化),或MonoLexTM技术(用于AptaRes AG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等人.,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.等人,J.Mol.Biol.352(5):1118-33(2005)。类似于上文所述的关于连接优先结合对成员的反应顺序,可将所述靶向组分的亲水性、非免疫原性、水溶性连接基团与所述适体的3'或5'端反应。在一些实施方案中,在优先结合对的成员(例如C2)已与亲水性、非免疫原性、水溶性连接基团的另一端反应后,可将适体连接至亲水性、非免疫原性、水溶性连接基团。在其它实施方案中,可首先连接适体,然后连接优先结合对成员以形成靶向组分。在替代实施方案中,可通过将核酸一次一个添加至所述靶向组分的亲水性、非免疫原性、水溶性连接基团而连续地合成适体。在其它实施方案中,可将优先结合对成员和靶向剂例如适体放置于相同的反应容器中以在一个步骤中形成靶向组分。
B.包含直接连接至连接基团的诊断剂和/或治疗剂的靶向递送组合物
可通过数种方法制备包含直接连接至连接基团的诊断性和/或治疗性试剂的靶向递送组合物。在一方面中,可使用制备靶向递送组合物的方法制备靶向递送组合物,所述方法包括在足以使C1和C2形成双链体的条件下使具有下式的诊断性或治疗性组分:DT-(L1)x-C1;与具有下式的靶向组分接触:C2-(L2)y-T,其中DT为治疗剂、诊断剂或其组合;L1和L2各自为亲水性、非免疫原性、水溶性连接基团;C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;T为靶向剂;且下标x和y各自独立地为0或1,但x和y至少一个不为0。
在另一方面中,可使用制备靶向治疗性或诊断性递送组合物的方法制备本发明的靶向递送组合物,所述方法包括使具有下式的衍生联接组分:A-(L1)x-C1;和具有下式的诊断性或治疗性组分:C2-(L2)y-DT接触,其中A为联接组分;L1和L2各自为亲水性、非免疫原性、水溶性连接基团;C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;DT为治疗剂、诊断剂或其组合,且下标x和y各自独立地为0或1,但x和y至少一个不为0;其中所述衍生联接组分的A部分在足以将A连接至纳米颗粒的条件下连接至所述纳米颗粒;且随后将所述纳米颗粒-A-(L1)x-C1缀合物与所述诊断性或治疗性组分在足以使C1和C2之间形成双链体的条件下接触。应当理解其它步骤顺序可用于制备包含直接连接至连接基团的诊断性和/或治疗性试剂的靶向递送组合物。
诊断性或治疗性组分
可使用本领域公知的方法制备具有式DT-(L1)x-(C1)的诊断性或治疗性组分。在一些实施方案中,可将螯合剂连接至亲水性、非免疫原性、水溶性连接基团,然后可将靶向剂连接至所述连接基团的另一端。然后放射性同位素可与螯合剂络合。然而,本发明包括制备该缀合物的多种步骤顺序。在一些实施方案中,某些步骤可颠倒。例如,可将螯合剂与放射性同位素结合以形成诊断性组分,然后其可使用常规化学法进一步与亲水性、非免疫原性、水溶性连接基团反应。然后,可将优先结合对成员(C1)连接至本文所述的亲水性、非免疫原性、水溶性连接基团。在另一方面中,可将治疗剂连接至亲水性、非免疫原性、水溶性连接基团并且可将优先结合对成员(C1)连接至所述连接基团的相反端,如本文所述。本领域技术人员将理解诊断和/或治疗组分可以不同于以上提供的实例的多种不同方式构造。此外,诊断或治疗组分的制备可取决于使用的具体诊断和/或治疗剂。
IV.给予靶向递送组合物的方法
如本文所述,本发明的靶向递送组合物和方法可用于治疗和/或诊断与受试者相关的任何疾病、障碍和/或病症。在一项实施方案中,本发明的方法包括用于治疗或诊断受试者癌性病症的方法,其包括向所述受试者给予本发明包含纳米颗粒的靶向递送组合物,其中所述治疗性或诊断性试剂足以治疗或诊断所述病症。在一些实施方案中,所述癌性病症可包括充分表达(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处置适应性的方法,其包括向所述受试者给予包含纳米颗粒的靶向递送组合物,其中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。
在另一项实施方案中,本发明的方法包括用于治疗和诊断受试者癌性病症的方法,其包括向所述受试者给予本发明包含直接连接至连接基团的诊断性和/或治疗性试剂的靶向递送组合物,其中所述治疗性或诊断性试剂足以治疗或诊断所述病症。
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处置适应性的方法,其包括向所述受试者给予本发明包含直接连接至连接基团的诊断剂的靶向递送组合物,并使所述受试者成像以检测所述诊断剂。
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、包封入或系连至靶向递送组合物(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,医师可能根据具体患者所需的治疗或诊断混合和匹配某些组分和/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。
实施例
以下实施例描述了如何制备如本文所述的衍生联接组分、诊断性组分和靶向组分的实例实施方案。在实施例中,联接组分包括经由亲水性、非免疫原性、水溶性连接基团偶联至第一寡核苷酸的脂质。此外,诊断性组分以经由连接基团偶联至与所述第一寡核苷酸互补的第二寡核苷酸的荧光剂的形式提供。靶向组分包括连接至寡核苷酸的肽靶向剂以及连接至寡核苷酸的适体靶向剂。在一些实施例中,可将衍生联接组分掺入脂质体中,然后经由优先结合对之间的杂交与诊断性组分或靶向组分结合。本领域的普通技术人员将理解实施例中所述的方法可类似地用于如本文所述的其它衍生联接组分、靶向组分和诊断性或治疗性组分。
实施例1
制备5’-DSPE-PEG(3400)–S-C6H12–VEGF寡核苷酸类似物1
通过以下步骤制备5’-DSPE-PEG(3400)–S-C6H12–VEGF寡核苷酸类似物1:
步骤1:制备VEGF寡核苷酸类似物1
可使用通常可得的固体载体寡核苷酸合成技术从市售的受保护核苷和适当保护的6-羟基己硫醇类似物制备上文直接所示的VEGF寡核苷酸类似物1。随后从载体解离并经反相纯化得到基本上纯形式的5'-VEGF寡核苷酸类似物1(作为3'-游离硫醇)。
步骤2:制备5’-DSPE-PEG(3400)–S-C6H12–VEGF寡核苷酸类似物1
将步骤1的产物与DSPE-PEG3400-马来酰亚胺在适宜的溶剂中反应,制备5’-DSPE-PEG(3400)–S-C6H12–VEGF寡核苷酸类似物1。在使用适宜水:乙腈梯度的反相色谱后,分离得到基本上纯形式的标题化合物VEGF寡核苷酸类似物1—3-(3-(5-羟基戊基硫基(pentlthio))-2,5-二氧代吡咯烷-1-基)丙酰胺基-PEG3400-DSPE缀合物。
实施例2
制备5’-(6–FAM)–VEGF寡核苷酸类似物2
通过以下步骤制备5’-(6–FAM(Fluorescein Amidite))–VEGF寡核苷酸类似物2:
步骤1:制备VEGF寡核苷酸类似物2
可使用通常可得的固体载体寡核苷酸合成技术从市售的受保护核苷和6-氨基己醇制备上文直接所示的VEGF寡核苷酸类似物2。随后从载体解离并经反相纯化得到基本上纯形式的VEGF寡核苷酸类似物2。
步骤2:制备5’-(6–FAM)–VEGF寡核苷酸类似物2
将步骤1的产物与羧基荧光素NHS酯在适宜的溶剂中反应,制备5’-(6–FAM)–VEGF寡核苷酸类似物2。在使用适宜水:乙腈梯度的反相色谱后,分离得到标题化合物5’-(6–FAM)–VEGF寡核苷酸类似物2。
实施例3
制备单室脂质体
脂质体组合物由1,2-二硬脂酰基-sn-甘油-磷酸胆碱单水合物(DSPC):胆固醇(Chol)以55:45摩尔比组成。在圆底烧瓶中将脂质混合物(40mg)溶于氯仿:甲醇(3:1体积/体积)中。在氮气氛下使用旋转蒸发以蒸发有机溶剂,在烧瓶壁上形成薄磷脂膜。通过在室温在全真空下将烧瓶放置于真空烘箱中过夜除去残余溶剂。通过向圆底烧瓶中添加硫酸铵溶液(250mM硫酸铵溶液,1mL)并在60℃(无真空)在Rotovap上旋转烧瓶30分钟或直至所有物料溶解使得到的脂质薄膜水合。通过加入硫酸铵溶液(9mL)稀释所得溶液。使用Lipex不锈钢挤出机挤过800、400和100nm孔径聚碳酸酯滤器挤出多室囊泡。使用光散射实验评估脂质体的平均大小和大小分布,但通常该操作得到标定直径为100nm的脂质体。
实施例4
将5’-DSPE-PEG(3400)–S-C6H12–VEGF寡核苷酸类似物1热插入实施例3制备的脂质体中得到PEG(3400)-S-C6H12–VEGF1脂质体
可使用以下操作将5’-DSPE-PEG(3400)–S-C6H12–VEGF寡核苷酸类似物1插入至实施例3形成的脂质体中。在温和搅拌下将实施例3制备的最终挤出的脂质体溶液加热至65℃。将5’-DSPE-PEG(3400)–S-C6H12–VEGF1(MW9972.0,4.0mg,2.0摩尔百分数)溶于硫酸铵溶液(250mM硫酸铵溶液,1mL)中,并加入至脂质体溶液中。此时,将溶液冷却至55℃,在此温度进行反应,持续至少30分钟。将反应混合物冷却至室温(RT),通过光散射技术测定颗粒大小。
使用PBS作为洗脱剂(2mL级分),将该反应混合物通过Sepharose CL-4B柱(0.05x12in,GE Healthcare,使用PBS预平衡)获得无起始物料的脂质体结合的5’-DSPE-PEG(3400)–S-C6H12–VEGF1。使用高效液相色谱(HPLC)测定所需的脂质体产物并合并类似的级分。
实施例5
通过PEG(3400)-S-C6H12–VEGF寡核苷酸类似物1脂质体捕获5’-(6–FAM)–VEGF寡核苷酸类似物2
在室温在回荡下,向从实施例3得到的含PEG(3400)-S-C6H12–VEGF寡核苷酸类似物1脂质体的PBS(2mL)中加入含5’-(6–FAM)–VEGF寡核苷酸类似物2的PBS溶液(1mg,2x10-7摩尔,于1mL中)。15分钟后,杂交反应应当基本上结束并且通过如实施例4中的Sepharose柱色谱法从未反应的单链DNA起始物料中分离含双链DNA缀合物的脂质体。使用荧光检测通过HPLC分析确认ds-DNA结合的荧光素的存在。
实施例6
制备VEGF寡核苷酸类似物2,N-琥珀酰基-tyr-3-Octreotate
使用以下步骤制备VEGF寡核苷酸类似物2,N-琥珀酰基-tyr-3-Octreotate
步骤1:制备N-琥珀酰基-tyr-3-Octreotate
(2S,3R)-2((4R,7S,10S,13R,16S,19R)-13-((1H-吲哚-3-基)甲基)-10-(4-氨基丁基)-19-((R)-2-(3-羧基丙酰胺基)-3-苯基丙酰胺基)-16-(4-羟基苄基)-7-((R)-1-羟基乙基)-6,9,12,15,18-五氧代-1,2-二硫代-5,8,11,14,17-五氮杂环二十碳烷-4-甲酰胺基)-3-羟基丁酸
使用标准固体载体肽FMOC合成技术在每步使用延长的偶联时间制备如上所示的N-琥珀酰基-tyr-3-Octreotate。在肽合成结束后,除去Cys Acm保护基并使用适当的溶剂系统进行Tl(III)(TFA)3环化。通过TFA除去剩余的保护基并从树脂中解离该肽。反相HPLC(C18)显示基本上纯的所需产物(通过UV和校正MS显示一个峰),并冻干该产物,无需进一步纯化即可使用。
步骤2:制备VEGF寡核苷酸类似物2,N-琥珀酰基-tyr-3-Octreotate
将步骤2的产物与肽偶联剂TBTU在适宜的溶剂中反应并转化成活性酯。可将混合物加入至溶解于相同或相似溶剂中的VEGF寡核苷酸类似物2(实施例2步骤1的产物)中,并反应。通过反相HPLC纯化得到基本上纯的VEGF寡核苷酸类似物2,N-琥珀酰基-tyr-3-Octreotate,其为所需产物。
实施例7
通过PEG(3400)-S-C6H12–VEGF寡核苷酸类似物1脂质体捕获VEGF寡核苷酸类似物2,N-琥珀酰基-tyr-3-Octreotate
除使用VEGF寡核苷酸类似物2,N-琥珀酰基-tyr-3-Octreotate代替5’-(6–FAM)-VEGF寡核苷酸类似物2外,可使用基本上与实施例5相同的量和条件处理含有和显示实施例4的DSPE PEG(3400)VEGF寡核苷酸类似物1缀合物的脂质体。得到含双链体双链VEGF DNA且捕获的tyr-3-Octreotate呈现在表面上的脂质体。
实施例8
使用基本上如实施例6和7中概述的操作,可将包括VEGF寡核苷酸类似物1序列的组分与包括VEGF寡核苷酸类似物2序列的组分杂交。例如,可合成经由连接基团与适体寡核苷酸连接的VEGF寡核苷酸类似物2序列并使用液相色谱纯化技术纯化。所述适体可为基于RNA的适体、基于DNA的适体或基于RNA-DNA组合的适体。然后可通过脂质体以实施例4所述的类似方式捕获纯化的VEGF寡核苷酸类似物2序列-连接基团-适体。
除使用连接至适体寡核苷酸的VEGF寡核苷酸类似物2序列代替5’-(6–FAM)-VEGF寡核苷酸类似物2外,使用基本上如实施例5所概述的操作,在纯化后,得到含双链体双链VEGF DNA且捕获的适体呈现在脂质体表面上的脂质体。
Claims (54)
1.靶向治疗性或诊断性递送组合物,其包含:
(a)纳米颗粒,其包括治疗剂或诊断剂或其组合;
(b)具有下式的衍生联接组分:
A-(L1)x-C1;和
(c)具有下式的靶向组分:
C2-(L2)y-T
其中
A为联接组分;
L1和L2各自为亲水性、非免疫原性、水溶性连接基团;
C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;
T为靶向剂;和
下标x和y各自独立地为0或1,但x和y至少一个不为0;
其中所述衍生联接组分的A部分连接至所述纳米颗粒。
2.权利要求1的递送组合物,其中所述纳米颗粒选自脂质体、胶束、脂蛋白、脂包衣囊泡、嵌段共聚物胶束、聚合物泡囊、类脂囊泡、氧化铁颗粒、二氧化硅颗粒、树枝状聚合物或量子点。
3.权利要求1的递送组合物,其中所述纳米颗粒为选自SUV、LUV和MLV的脂质体。
4.权利要求1的递送组合物,其中所述治疗剂或所述诊断剂嵌入、包封或系连于所述纳米颗粒。
5.权利要求1的递送组合物,其中所述联接组分包含用于共价连接至所述纳米颗粒的官能团。
6.权利要求1的递送组合物,其中所述联接组分为脂质。
7.权利要求6的递送组合物,其中所述脂质为磷脂、糖脂、鞘脂或胆固醇。
8.权利要求6的递送组合物,其中所述衍生联接组分的A部分存在于所述纳米颗粒的脂质双层部分,并且任选地所述纳米颗粒为脂质体。
9.权利要求1的递送组合物,其中L1和L2各自为亲水性、非免疫原性、水溶性连接基团,其独立地选自聚乙二醇、聚丙二醇、聚乙烯醇、聚羧酸酯、多糖和葡聚糖。
10.权利要求1的递送组合物,其中C1和C2是长度为8-50个核酸的寡核苷酸或寡核苷酸模拟物,且C1和C2在8至30个核酸的序列上至少70%互补,且任选地C1或C2的一个经修饰以包含提供C1和C2之间的共价连接的连接部分。
11.权利要求1的递送组合物,其中C1和C2在约40℃至约60℃的解链温度变性。
12.权利要求1的递送组合物,其中C1和C2长度为8至50个核酸且C1和C2至少70%互补。
13.权利要求1的递送组合物,其中T为适体。
14.权利要求1的递送组合物,其中T为靶向存在于选自以下的受体上位点的适体:MUC-1、EGFR、FOL1R、Claudin4、MUC-4、CXCR4、CCR7、生长抑素受体4、Erb-B2(成红细胞白血病癌基因同系物2)受体、CD44受体、VEGF受体-2激酶和核仁素。
15.权利要求1的递送组合物,其中下标x和y各自为1。
16.权利要求1的递送组合物,其中x为0且y为1。
17.权利要求1的递送组合物,其中x为1且y为0。
18.权利要求1的递送组合物,其中所述治疗剂为选自以下的抗癌剂: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。
19.权利要求1的递送组合物,其中所述诊断剂为放射性试剂、荧光剂或造影剂。
20.权利要求1的递送组合物,其中所述诊断剂为选自以下的放射性试剂:111In-DTPA、99mTc(CO)3-DTPA和99mTc(CO)3-ENPy2。
21.权利要求1的递送组合物,其中所述诊断剂为荧光剂。
22.权利要求1的递送组合物,其中所述诊断剂为MR剂或X射线造影剂。
23.靶向递送组合物,其包含:
(a)具有下式的诊断性或治疗性组分:
DT-(L1)x-C1;
(b)具有下式的靶向组分:
C2-(L2)y-T
其中
DT为治疗剂、诊断剂或其组合;
L1和L2各自为亲水性、非免疫原性、水溶性连接基团;
C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;
T为靶向剂;和
下标x和y各自独立地为0或1,但x和y至少一个不为0。
24.权利要求23的递送组合物,其中下标x和y各自为1。
25.权利要求23的递送组合物,其中x为0且y为1。
26.权利要求23的递送组合物,其中x为1且y为0。
27.靶向治疗性或诊断性递送组合物,其包含:
(a)纳米颗粒;
(b)具有下式的衍生联接组分:
A-(L1)x-C1;和
(c)具有下式的诊断性或治疗性组分:
C2-(L2)y-DT
其中
A为联接组分;
L1和L2各自为亲水性、非免疫原性、水溶性连接基团;
C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;
DT为治疗剂、诊断剂或其组合;和
下标x和y各自独立地为0或1,但x和y至少一个不为0;
其中所述衍生联接组分的A部分连接至所述纳米颗粒。
28.具有下式的衍生联接组分:
A-(L1)-C1
其中
A为联接组分;
L1为亲水性、非免疫原性、水溶性连接基团;和
C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物。
29.权利要求28的衍生联接组分,其中所述联接组分包含用于共价连接至纳米颗粒的官能团。
30.权利要求28的衍生联接组分,其中所述联接组分为脂质。
31.权利要求30的衍生联接组分,其中所述联接组分为磷脂、糖脂、鞘脂或胆固醇。
32.权利要求28的衍生联接组分,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。
33.权利要求28的衍生联接组分,其中C1和C2至少70%互补。
34.权利要求28的衍生联接组分,其中C1和C2长度为8-50个核酸,且C1和C2在8至30个核酸的序列上至少70%互补,且任选地C1或C2的一个经修饰以包含提供C1和C2之间的共价连接的连接部分。
35.权利要求28的衍生联接组分,其中C1和C2具有经选择至少70%互补的非天然序列。
36.权利要求28的衍生联接组分,其中C1和C2至少一个是体外合成的。
37.具有下式的诊断性或治疗性组分:
(DT)-(L1)-C1
其中
DT为治疗剂、诊断剂或其组合;
L1为亲水性、非免疫原性、水溶性连接基团;和
C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物。
38.权利要求37的诊断性或治疗性组分,其中所述诊断剂为放射性试剂、荧光剂或造影剂。
39.权利要求37的诊断性或治疗性组分,其中所述诊断剂为选自以下的放射性试剂:111In-DTPA、99mTc(CO)3-DTPA和99mTc(CO)3-ENPy2。
40.权利要求37的诊断性或治疗性组分,其中所述诊断剂为荧光剂。
41.权利要求37的诊断性或治疗性组分,其中所述诊断剂为MR剂或X射线造影剂。
42.权利要求37的诊断性或治疗性组分,其中所述治疗剂选自: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。
43.具有下式的靶向组分:
C2-(L2)-T
其中
L2为亲水性、非免疫原性、水溶性连接基团;
C2为具有第二成员C1的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;和
T为靶向剂。
44.权利要求43的靶向组分,其中C1和C2至少70%互补。
45.权利要求43的靶向组分,其中T为适体。
46.制备靶向治疗性或诊断性递送组合物的方法,其包括在足以使C1和C2形成双链体的条件下使具有下式的衍生联接组分:
A-(L1)x-C1;
与具有下式的靶向组分接触:
C2-(L2)y-T
其中
A为联接组分;
L1和L2各自为亲水性、非免疫原性、水溶性连接基团;
C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;
T为靶向剂;和
下标x和y各自独立地为0或1,但x和y至少一个不为0;
其中所述衍生联接组分的A部分连接至纳米颗粒。
47.制备靶向递送组合物的方法,其包括在足以使C1和C2形成双链体的条件下使具有下式的诊断性或治疗性组分:
DT-(L1)x-C1;
与具有下式的靶向组分接触:
C2-(L2)y-T
其中
DT为治疗剂、诊断剂或其组合;
L1和L2各自为亲水性、非免疫原性、水溶性连接基团;
C1为具有第二成员C2的优先结合对的一员,其中C1和C2为寡核苷酸或寡核苷酸模拟物;
T为靶向剂;和
下标x和y各自独立地为0或1,但x和y至少一个不为0。
48.治疗或诊断受试者癌性病症的方法,其包括向所述受试者给予权利要求1的靶向递送组合物,其中所述治疗性或诊断性试剂足以治疗或诊断所述病症。
49.权利要求48的方法,其中所述靶向剂为靶向存在于选自以下的受体上位点的适体:MUC-1、EGFR、FOL1R、Claudin4、MUC-4、CXCR4、CCR7、生长抑素受体4、Erb-B2(成红细胞白血病癌基因同系物2)受体、CD44受体、VEGF受体-2激酶和核仁素。
50.权利要求48的方法,其中所述纳米颗粒为包封选自以下的抗癌剂的脂质体: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。
51.权利要求48的方法,其中C1和C2各自为具有12-25个核酸的寡核苷酸并且大于90%互补。
52.测定受试者对靶向治疗性处置适应性的方法,其包括向所述受试者给予权利要求1的靶向递送组合物,其中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。
53.治疗或诊断受试者癌性病症的方法,其包括向所述受试者给予权利要求37的靶向递送组合物,其中所述治疗性或诊断性试剂足以治疗或诊断所述病症。
54.测定受试者对靶向治疗性处置适应性的方法,其包括向所述受试者给予权利要求37的靶向递送组合物,其中所述诊断剂直接连接至连接基团,并使所述受试者成像以检测所述诊断剂。
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US5718915A (en) * | 1994-10-31 | 1998-02-17 | Burstein Laboratories, Inc. | Antiviral liposome having coupled target-binding moiety and hydrolytic enzyme |
US7833992B2 (en) * | 2001-05-18 | 2010-11-16 | Merck Sharpe & Dohme | Conjugates and compositions for cellular delivery |
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- 2012-09-27 US US14/348,522 patent/US20140234217A1/en not_active Abandoned
- 2012-09-27 WO PCT/US2012/057642 patent/WO2013049405A1/en active Application Filing
- 2012-09-27 CN CN201280059038.5A patent/CN104039355A/zh active Pending
- 2012-09-27 EP EP12775096.6A patent/EP2760476A1/en not_active Withdrawn
-
2014
- 2014-03-27 IL IL231767A patent/IL231767A0/en unknown
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Also Published As
Publication number | Publication date |
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EP2760476A1 (en) | 2014-08-06 |
US20140234217A1 (en) | 2014-08-21 |
BR112014007501A2 (pt) | 2017-04-04 |
IL231767A0 (en) | 2014-05-28 |
JP2014528411A (ja) | 2014-10-27 |
CA2850198A1 (en) | 2013-04-04 |
WO2013049405A1 (en) | 2013-04-04 |
KR20140069269A (ko) | 2014-06-09 |
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