CN103491870B - 官能化磁性纳米颗粒及在淀粉样沉积物和神经原纤维缠结成像中用途 - Google Patents
官能化磁性纳米颗粒及在淀粉样沉积物和神经原纤维缠结成像中用途 Download PDFInfo
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Abstract
本公开提供包含结合至β‑淀粉样沉积物和/或NFT(PHF)的官能团的官能化磁性纳米颗粒(MNP)。本公开提供包含官能化MNP的组合物以及使用所述官能化MNP对β‑淀粉样沉积物和/或NFT(PHF)成像的方法。
Description
交叉引用
本申请要求于2011年4月21日提交的美国临时专利申请No.61/477,958,所述申请通过引用整体并入本文。
背景
纳米颗粒是直径尺寸范围通常为小至一纳米到大至几百纳米的非常小的颗粒。纳米颗粒的小尺寸允许其被开发以用来生产各种产品诸如染料和颜料;美化或功能涂层;用于生物探索、医疗成像和治疗学的工具;磁性记录媒介;量子点;以及甚至均匀且纳米尺寸的半导体。
淀粉样沉积物和神经原纤维缠结(NFT,也称为成对螺旋丝,PHF)是包括阿尔茨海默氏病(AD)的各种疾病的标志。在本领域中需要对患有或疑似患有AD的活个体脑中的淀粉样沉积物和NFT成像的方法。
文献
美国专利No.6,548,264和6,767,635;Berry和Curtis(2003)J.Phys.D:AppliedPhysics36:R198-R206;Pankhurst等(2003)J.Phys.D:Applied Physics36:R167-R181;Dousset等(1999)Am.J.Neuroradiol.20:223-227;Dunning等(2004)J.Neurosci.24:9799-9810;Dousset等(1999)Magnetic Resonance in Medicine41:329-333;Moghimi等(2001)Pharmacol.Rev.53:283-318;Puchtler等(1962)J.Histochem.Cytochem.10:35;Klunk等(2004)Annals Neurol.55:306;美国专利No.7,270,800;美国专利No.6,274,119;Agdeppa等(2003)Neurosci.117:723;美国专利No.5,411,730;美国专利No.6,534,039;美国专利公布No.2008/0206146;WO2006/102377;Lee等(2003)J.Neuroimaging13:199。
发明概述
本公开提供包含结合β-淀粉样沉积物和/或NFT(PHF)的官能团的官能化磁性纳米颗粒(MNP)。本公开提供包含官能化MNP的组合物和使用官能化MNP对β-淀粉样沉积物和/或NFT(PHF)成像的方法。
附图简述
图1A和1B示出未治疗大鼠脑的磁共振(MR)图像。
图2A和2B示出阿尔茨海默氏病的大鼠模型的脑MR图像。
图3A和3B示出为阿尔茨海默氏病的大鼠模型的第二只大鼠的脑MR图像。
图4A-C示出AD大鼠模型的脑的代表性MR图像。
图5A-D使用MRI示出大鼠AD模型的脑中的扩散斑块的存在。对大鼠AD模型施用DNP-MNP。
图6A和6B示出AD的转基因大鼠模型的DAB增强的Perl染色。
图7示出缀合2-(1-{6-[(2-羟乙基)(甲基)氨基]-2-萘基}亚乙基)丙二腈(HODDNP)至磁性纳米颗粒的方法。
图8示出缀合(4’-氨基苯基)-6-羟基苯并噻唑(PIB-2)至磁性纳米颗粒的方法。
定义
如本文所使用,术语“纳米颗粒”是指直径在约1至1000nm之间的颗粒。类似地,术语“纳米颗粒群(nanoparticles)”是指平均直径为约1至1000nm之间的多个颗粒。
提及的纳米颗粒的“尺寸”是指纳米颗粒的最大直的尺寸的长度。例如,完全球状纳米颗粒的尺寸是它的直径。
如本文所使用,与“官能片段”和“官能配基”可互换使用的术语“官能团”是指赋予具有化学基团的制品(如纳米颗粒)特定功能的化学基团。例如,官能团可包括己知结合特定分子的物质诸如抗体、低聚核苷酸、生物素,或链酶亲和素;或诸如胺、羧酸酯等的小分子基团。
如本文所使用,“受试者”或“个体”或“患者”指需要诊断、预后或治疗的任何受试者,并通常指根据所发明来实践的诊断方法、预后方法或治疗方法的接受者。受试者可以是任何哺乳动物,如人、非人灵长类动物、家养牲畜、实验室受试者(如与β-淀粉样沉积物和/或NFT相关的疾病的非人动物模型;如啮齿类诸如大鼠)或宠物。
如本文所使用,术语“治疗(treatment)、”“治疗(treating)”等指获得期望的药理和/或生理效应。在完全或部分防止疾病或其症状方面,所述效应可以是预防性的,和/或在部分或完全治愈疾病和/或由该疾病引起的不利影响方面,所述效应可以是治疗性的。如本文所使用,“治疗”包括在哺乳动物特别在人中的疾病的任何治疗,并包括:(a)防止疾病或疾病的症状在可对疾病易感但还未被诊断为患有该疾病(如包括可与原发性疾病相关或由原发性疾病引起的疾病)的受试者中发生;(b)抑制疾病,即阻止其发展;和(c)减轻疾病,即引起疾病的消退。
在进一步描述本发明前,应理解此发明不限于描述的特定实施方案,因此当然可以发生变化。还应当理解,本文所用的术语只是为了描述特定实施方案,并非旨在进行限制,因为本发明的范围将仅由所附权利要求书来限定。
如果提供了值的范围,则应当理解,介于该范围上限与下限之间的每个居间值(直至下限单位的十分之一,除非上下文另有明确指出)且该所述范围内的任何其他所述值或居间值均涵盖在所发明内。这些较小范围的上限和下限可独立地被包括在所述较小范围内且也涵盖在所发明中,受所述范围内任何具体排除的限值的约束。如果所述范围包括限值的一个或两个,则排除这些所包括的限值一者或两者的范围也包括在所发明内。
除非另有定义,否则本文所用的所有技术和科学术语具有与此发明所属领域的普通技术人员通常所理解相同的含义。尽管在实践或测试本发明中也可使用与本文描述的那些方法和材料相似或相等的任何方法和材料,但是现在描述优选的方法和材料。本文提及的所有公布以引用方式并入以公开和描述与引用的公布相关的方法和/或材料。
必须注意除非上下文另外清楚地指明,否则如本文和在所附权利要求中使用的,单数形式“一个、”“一种、”和“该”包括复数的指示物。因此,例如,提及的“官能化磁性纳米颗粒”包括多个此类官能化磁性纳米颗粒而提及的“HODDNP部分”包括提及的本领域技术人员已知的一种或多种HODDNP部分及其等同物等。进一步指出,撰写权利要求可排除任何可选元素。因此,该陈述意图用作与权利要求要素的描述联合使用此类排他性术语“单独地、”“仅仅”等或使用“否定”限制的在先基础。
应了解为清楚起见,在单独实施方案的上下文中描述的所发明的某些特征也可在单个实施方案中组合提供。相反地,还可分开地或以任何适合的子组合(sub-combination)的方式提供所发明的各种特征,为简便起见所述特征被描述于单个实施方案的上下文中。关于所发明的实施方案的所有组合被明确地包括在本发明中并公开于本文中,就如同每个和每一个组合被个别地且明确地公开。此外,各种实施方案的所有子组合及其元素也被明确地包括在本发明中并在本文公开,就如同每个和每一个此类子组合中个别地和清楚地在本文公开。
本文所论述的公布仅针对它们在本申请提交日之前的公开内容而提供。不得将本文任何条款视为允许本发明未经授权依靠现有发明先于此公开内容。进一步地,所提供的公布日可不同于实际的公开日(所述日期可能需要独立地进行确认)。
详述
本公开提供适合用于对患有或疑似患有β-淀粉样沉积物和/或NFT的活个体的脑组织成像的官能化磁性纳米颗粒(MNP)。主题官能化MNP区分具有淀粉样沉积物和/或神经原纤维缠结(NFT,已知为成对螺旋丝PHF)的神经组织与正常神经组织。主题官能化MNP可用于在疾病例如唐氏综合征或阿尔茨海默病(AD)中检测和定量淀粉样沉积物和/或NFT。
主题官能化MNP可用于检测和定量患有与β-淀粉样沉积物和/或NFT存在有关或者由其引起的疾病的活的哺乳动物如人、非人动物或非人动物模型的脑中的淀粉样沉积物和/或NFT。向活的哺乳动物施用包含主题MNP官能化的药物组合物。存在于脑中的任何β-淀粉样沉积物(如聚集的β-淀粉样诸如可与神经原纤维缠结相关)可使用磁共振成像(MRI)或任何其他适当的成像方法来可视化。
官能部分
可连接至磁性纳米颗粒的官能团(部分)包括提供用于结合至β-淀粉样肽的聚集体和/或NFT的官能团。提供用于结合至β-淀粉样肽的聚集体和/或NFT且可被连接至磁性纳米颗粒的适合的官能团包括2-(1-{6-[(2-羟乙基)(甲基)氨基]-2-萘基}亚乙基)丙二腈(HODDNP)及其类似物和衍生物。提供用于结合至β-淀粉样肽的聚集体且连接至磁性纳米颗粒的适合的官能团包括(4’-氨基苯基)-6-羟基苯并噻唑(PIB-2)及其类似物和衍生物。
可将HODDNP通过HODDNP分子中的许多连接位点的任何一个缀合至MNP。HODDNP具有下式:
例如,经由HODDNP的羟基部分可将HODDNP缀合至MNP。作为一个非限制性实例,HODDNP-缀合的MNP可通过适当的连接子经由HODDNP的羟基部分通过共价连接HODDNP至环氧-MNP来制备。可将HODDNP直接地或通过适当的连接子通过分子或其修饰物、前体、衍生物或变体的任何氮或碳的部分共价或非共价地键合至MNP。
通过在PIB-2分子中许多连接位点的任何一个,可将PIB-2缀合至MNP。PIB-2具有下式:
例如,可经由PIB-2的氨基氮将PIB-2缀合至MNP。作为一个非限制性实例,PIB-2-缀合的MNP可通过适当的连接子经由PIB-2的氨基氮通过共价连接PIB-2至环氧-MNP来制备。同样,经由PIB-2的酚氧,可将PIB-2缀合至MNP。作为一个非限制性实例,PIB-2-缀合的MNP可通过适当的连接子经由PIB-2的酚氧通过共价连接PIB-2至环氧-MNP来制备。
可将PIB-2直接地或通过适当的连接子通过分子的或其修饰物、衍生物或变体的任何氢、氧、硫或碳部分共价或非共价地键合至MNP。
可被偶联至MNP的其它适合的官能部分包括但不限于,
1)W-372(7-甲氧基-2(6-氟吡啶-3-基)咪唑并[2,1-b]-8-吡啶并噻唑)
2)Bay-94-9172(ZK6013443;{4-[2-(4-{2-2[2-(2-氟-乙氧基)-乙氧基]-乙氧基}-苯基)-乙烯基]-苯基}-甲基-胺))
3)BF-227(2-(2-[2-二甲基氨基噻唑-5-基]乙烯基)-6-(2-[氟]乙氧基)苯并噁唑)
4)SB-13(4-N-甲基氨基-4'-羟基芪)
5)AV-45((E)-4-(2-(6-(2-(2-(2-(氟乙氧基)乙氧基)乙氧基)吡啶-3-基)乙烯基)-N-甲基苯胺)
6)AZD-2184(2-[6-(甲基氨基)吡啶-3-基]-1,3-苯并噻唑-6-醇)
7)PK11195(1-(2-氯苯基)-N-甲基-N-(1-甲基丙基)-3-异喹啉-甲酰胺)
8)DAA1106(N-(2-苯氧基-5-氟苯基)-N-(2,5-二甲氧基苄基)乙酰胺)
9)DED(N,N-二乙基二乙烯基三胺)
或其衍生物或类似物。
在任何上述的官能部分中,氟基团可被氧替代。例如,可将适合的官能部分经由官能部分的羟基部分缀合至MNP。作为一个非限制性实例,官能部分-缀合的MNP可通过适当的连接子经由官能部分的羧基部分直接或通过共价连接官能部分至环氧-MNP来制备。例如,可被偶联至MNP的其它适合的官能部分包括但不限于,
1)W-372-2
2)Bay-94-9172-2
3)BF-227-2
4)AV-45-2
5)PK11195-2
6)DAA1106-2
或其衍生物或类似物。
在任何上述任何官能部分,氟基团可被氨基团替代。例如,可将包含氨基团的官能部分经由官能部分的氨基团直接或经由连接子缀合至MNP。作为一个非限制性实例,官能部分-缀合的MNP可通过适当的连接子经由官能部分的氨基团通过共价连接官能部分至环氧-MNP来制备。例如,可被偶联至MNP的其它适合的官能部分包括但不限于,
1)W-372-3
2)Bay-94-9172-3
3)BF-227-3
4)AV-45-3
5)PK11195-3
6)DAA1106-3
或其衍生物或类似物。
在任何上述任何官能部分,氟基团可被硫醇基团替代。例如,可将包括硫醇基团的官能部分经由官能部分的硫醇基团直接或经由连接子缀合至MNP。作为一个非限制性实例,官能部分-缀合的MNP可经由官能部分的硫醇基团通过适当的连接子经由官能部分的共价连接至环氧-MNP来制备。例如,可被偶联至MNP的其它适合的官能部分包括但不限于,
1)W-372-4
2)Bay-94-9172-4
3)BF-227-4
4)AV-45-4
5)PK11195-4
6)DAA1106-4
或其衍生物或类似物。
在上述任何官能基团中,烷基基团可被羟基烷基替代。例如,可将适合的官能部分直接或通过连接子经由适合的官能部分的羟基部分缀合至MNP。作为一个非限制性实例,官能部分-缀合的MNP可经由官能部分的羧基部分通过适当的连接子通过共价连接官能部分至环氧-MNP来制备。例如,可被偶联至MNP的其它适合的官能部分包括但不限于,
1)SB-13-5
2)AZD-2184-5
3)DED-5
或其衍生物或类似物。
在上述任何官能基团,烷基基团可被硫烷基替代。例如,可将适合的官能部分经由适合的官能部分的硫醇部分缀合至MNP。作为一个非限制性实例,官能部分-缀合的MNP可通过适当的连接子经由官能部分的硫醇部分通过共价连接官能部分至环氧-MNP来制备。例如,可被偶联至MNP的其它适合的官能部分包括但不限于,
1)SB-13-6
2)AZD-2184-6
3)DED-6
或其衍生物或类似物。
主题官能化MNP的官能部分可具有对β-淀粉样肽(如聚集的β-淀粉样肽)和/或NFT的亲和力。例如,该官能部分可具有对β-淀粉样肽(如聚集的β-淀粉样肽)和/或NFT约10-6M、10-7M、10-8M或大于10-8M的亲和力。
主题官能化MNP可包括放射性标记,如官能部分可包括放射性标记。可选地,主题官能化MNP不包括放射性标记,如官能部分不包括放射性标记,并且官能化MNP的其他组分不包括放射性标记。
主题官能化MNP可穿过血脑屏障。主题官能化MNP提供在受影响的组织(如具有β-淀粉样沉积物和/或NFT的脑组织)T2、T2*、和T1时间的对比以使得组织对MRI可见。
主题官能化MNP具有相对长的半衰期(如t1/2为约2小时至约14天;如约2小时至约4小时、约4小时至约8小时、约8小时至约16小时、约16小时至约24小时、约24小时至约2天、约2天至约4天、约4天天至约7天或约7天至约2周)。
磁性纳米颗粒
主题纳米颗粒的平均尺寸范围通常为1nm至约1000nm,如约1nm至约10nm、约10nm至约50nm、约50nm至约100nm、约100nm至约250nm、约250nm至约500nm、约500nm至约750nm或约750nm至约1000nm。在一些实施方案中平均直径范围是约10nm至约1000nm,如约10nm至约20nm、约20nm至约40nm、约40nm至约60nm、约60nm至约80nm、约80nm至约100nm、从约100nm至约200nm、约200nm至约400nm、约400nm至约600nm、约600nm至约800nm或约800nm至约1000nm。
纳米颗粒可以是分子的简单聚集体或它们可被构造成两层或多层不同的物质。例如,由磁铁矿或磁赤铁矿组成的简单的纳米颗粒适合使用。参见,例如Scientific andClinical Applications of Magnetic Microspheres,U.Hafeli,W.Schutt,J.Teller和M.Zborowski(编辑)Plenum Press,New York,1997;和Tiefenauer等人,BioconjugateChem.4:347,1993.更复杂的纳米颗粒可由从一种物质制备的核心和从另一种物质制备的一种或多种壳组成。术语“磁性纳米颗粒”包括顺磁性纳米颗粒、逆磁性纳米颗粒和铁磁性纳米颗粒。
根据所发明,纳米颗粒的示例性核心材料是通常组合物MeOxFe2O3铁氧体,其中Me是二价金属诸如Co、Mn或Fe。其他适合的材料是γ-Fe2O3、纯金属Co、Fe、Ni和金属化合物诸如碳化物和氮化物。核心材料通常是MRI可见的试剂。核心材料通常被涂覆。适合的涂层包括但不限于葡聚糖、白蛋白、淀粉、硅等。
许多不同类型的小颗粒(纳米颗粒或微米尺寸颗粒)可商购自如下几个不同制造商,所述制造商包括:Bangs Laboratories(Fishers,Ind.);Promega(Madison,Wis.);Dynal Inc.(Lake Success,N.Y.);Advanced Magnetics Inc.(Surrey,U.K.);CPG Inc.(Lincoln Park,N.J.);Cortex Biochem(San Leandro,Calif.);European Institute ofScience(Lund,Sweden);Ferrofluidics Corp.(Nashua,N.H.);FeRx Inc.;(San Diego,Calif.);Immunicon Corp.;(Huntingdon Valley,Pa.);Magnetically DeliveredTherapeutics Inc.(San Diego,Calif.);Miltenyi Biotec GmbH(USA);Microcaps GmbH(Rostock,Germany);PolyMicrospheres Inc.(Indianapolis,Ind.);Scigen Ltd.(Kent,U.K.);Seradyn Inc.;(Indianapolis,Ind.);和Spherotech Inc.(Libertyville,Ill.)。这些颗粒的大部分是使用诸如研磨和碾碎、乳化聚合、嵌段共聚和微乳化的常规技术制备的。
二氧化硅纳米颗粒的制备方法也已有报道。所述方法包括微晶核聚集(Philipse等,Langmuir,10:92,1994);用插入的二氧化硅增强的超顺磁性聚合物纳米颗粒(Gruttner,C和J Teller,Journal of Magnetism and Magnetic Materials194:8,1999);和微波介导的自组装(Correa-Duarte等,Langmuir,14:6430,1998)。
主题纳米颗粒核心是磁性的且可包括选自由磁铁矿、磁赤铁矿和硫复铁矿组成的组的金属。磁性纳米颗粒可使用作为核心的一部分的磁性材料(诸如磁铁矿、磁赤铁矿和硫复铁矿)来制备。通过改变此类磁性核心的总尺寸和形状,它们可被制备为超顺磁性的或为稳定的单域(从磁场中取出后仍保持稳定的磁矩的颗粒)。核心尺寸涉及磁性纳米粒子是否为超顺磁性的或单磁区的。因此,相对等量纲的超顺磁性核心颗粒通常具有尺寸小于50-80nm的核心。当颗粒尺寸超过此上限时,颗粒的磁化强度被分成具有不同磁化矢量的不同区域以最小化内部磁能。
在一些实施方案中,核心包括可以是无机盐诸如高锰酸钾、重铬酸钾、硫酸镍、氯化钴、三氯化铁(III)或硝酸铜的颜料。类似地,核心可包括染料诸如Ru/Bpy、Eu/Bpy等;或金属诸如Ag和Cd。
在一些实施方案中,主题修饰的纳米颗粒包含核心和包裹所述核心的二氧化硅壳例如,如美国专利No.6,548,264所描述,将官能团缀合至二氧化硅壳。用于将官能团连接至二氧化硅的许多已知方法可适用于本发明。参见,如Ralph K.Iler,The Chemistry ofSilica:Solubility,Polymerization,Colloid and Surface Properties,andBiochemistry,Wiley-Interscience,NY,1979;VanDerVoort,P.和Vansant,E.F.,Journalof Liquid Chromatography and Related Technologies,19:2723-2752,1996;以及Immobilized Enzymes.Antigens,Antibodies,and Peptides:Preparation andCharacterization,Howard H.Weetall(编辑),M.Dekker,NY,1975。用于将官能团加至涂覆有二氧化硅的纳米颗粒的典型方法包括用与纳米颗粒的二氧化硅表面反应并将化学基团偶联至所述二氧化硅表面上的硅烷化剂来处理纳米颗粒。该化学基团本身可以是官能团,或者它可以用作可将所述官能团偶联其上的底物。
例如,在示例性方法中,如上所述制备涂覆有二氧化硅的纳米颗粒并使用三甲基甲硅烷基丙基-二亚乙基三胺(DETA)(其为将伯胺基团连接至二氧化硅表面的硅烷化剂)对颗粒的表面进行硅烷化。然后使用溴化氰(CNBR)法,可将官能团共价偶联至硅烷化的表面。作为一个实例,CNBR介导的偶联可通过将预先用DETA硅烷化的涂覆有二氧化硅的纳米颗粒悬浮在2M碳酸钠缓冲液中并进行超声处理混合物以产生颗粒悬浮液来获得。然后将CNBR的溶液(如2g CNBR/1ml乙腈)加入到颗粒悬浮液中以活化纳米微粒。用中性缓冲液(如PBS,pH8)洗涤纳米颗粒后,加入抗体溶液至活化的纳米颗粒悬液中,导致抗体能够键合至纳米微粒上。也可加入甘氨酸溶液至涂覆有抗体的纳米颗粒以封闭任何残留的未反应位点。
在一些实施例中,磁性纳米颗粒被葡聚糖涂覆。使用任何已知方法制备磁性纳米颗粒。例如,磁性铁-葡聚糖颗粒是通过将等体积的含有1.51g FeCl3-6H2O和0.64g FeCl2-4H2O的水溶液与10ml50%(w/w)水性葡聚糖T-40(Pharmacia)混合来制备的。在搅拌的同时,通过逐滴加入被加热(在水浴中15分钟)至60-65℃的7.5%(v/v)NH4OH,将混合物滴定至pH10-11。然后通过低速临床离心机在3个循环的离心(600x g5分钟)来除去聚集体。通过Sephacryl S-300上的凝胶过滤层析从未键合的葡聚糖中分离出铁磁性的铁-葡聚糖颗粒。然后将5ml反应混合物施加至2.5×33cm的柱并在pH6.5下用0.1M乙酸钠和0.15M NaCl洗脱。在空隙体积中收集的纯化的铁磁性的铁-葡聚糖颗粒将具有7-10mg/ml的浓度,如干重分析所测定。Molday和Mackenzie(1982)Journal of Immunological Methods52:353-367.也参见(Xianqiao(2003)China Particuology第1卷,第2期,76-79)。所得的磁性纳米颗粒可基于尺寸和或通过具有适当的磁场强度的高梯度磁场分离时的磁性特征而被分离。
在一些实施方案中,涂覆的纳米颗粒可包含环氧基团。图8和9阐述了包含环氧基团的涂覆的纳米颗粒的实例。对于涂覆有二氧化硅的纳米颗粒,二氧化硅涂层可包含环氧基团。例如,可使用环氧硅烷。对于涂覆有葡聚糖的纳米颗粒,葡聚糖涂层可包含环氧基团。例如,环氧修饰的葡聚糖可通过葡聚糖与具有环氧基团的试剂反应来制备。例如,葡聚糖的羟基基团可反应以形成包含环氧基团的甲硅烷基化的葡聚糖。
涂层可具有以下厚度(如从核心磁性颗粒的外表面到涂层的内表面的平均距离):约1nm至约500nm,如约1nm至约5nm、约5nm至约10nm、约10nm至约15nm、约15nm至约20nm、约20nm至约25nm、约25nm至约30nm、约30nm至约40nm、约40nm至约50nm、约50nm至约60nm、约60nm至约70nm、约70nm至约80nm、约80nm至约90nm、约90nm至约100nm、约100nm至约125nm、约125nm至约150nm、约150nm至约175nm、约175nm至约200nm、约200nm至约225nm、约225nm至约250nm、约250nm至约275nm、约275nm至约300nm。
涂层的厚度与磁性核心颗粒的直径的比率为约1:1至约1:1000,如约1:1至约1:1.5、约1:1.5至约1:2、约1:2至约1:2.5、约1:2.5至约1:5、约1:5至约1:10、约1:10至约1:25、约1:25至约1:50、约1:50至约1:100、约1:100至约1:250、约1:250至约1:500、约1:500至约1:750或约1:750至约1:1000。
在一些实施方案中,主题官能化磁性纳米颗粒具有式:M-(L)-Z,L和Z之间的连接位点具有共价键合的官能团,其中M代表磁性核心颗粒,L代表任选的连接基团,且Z代表官能团。在其他的实施方案中,主题官能化磁性纳米颗粒具有下式:M-S-(L)-Z,S和L以及L和Z之间的连接位点具有共价键合的官能团,其中M代表磁性核心颗粒,其中S代表固定到M的生物相容性基物,其中M代表磁性核心颗粒,L代表任选的连接基团,且Z代表官能团。官能团包括提供用于结合β-淀粉样肽(如聚集的β-淀粉样肽)和/或NFT的部分;提供穿过BBB的部分;治疗剂;等。
在一些实施方案中,主题官能化磁性纳米颗粒包含连接至相同核心颗粒的两个或多个不同的官能团。例如,在一些实施方案中,主题官能化磁性纳米颗粒具有式M-(L)-Z1Z2或M-S-(L)-Z1Z2,其中Z1和Z2是不同的官能团。例如,在一些实施方案中,Z1是结合部分β-淀粉样肽(如聚集的β-淀粉样肽)和/或NFT;且Z2是治疗剂。例如,在其他实施方案中,Z1是提供穿过BBB的部分;且Z2是提供用于结合至β-淀粉样肽(如聚集的β-淀粉样肽)和/或NFT的结合部分。Z1和Z2部分直接地或经由连接子独立地连接至核心颗粒或聚合物。在一些实施方案中,主题官能化磁性纳米颗粒包含至少一个第三官能部分Z3。
磁性核心颗粒由通式MeOxFe2O3的磁铁矿、磁赤铁矿、铁氧体组成,其中Me是二价金属,诸如钴、锰、铁、或钴、铁、镍、碳化铁或氮化铁,如上所述。如果存在,底物S由诸如以下的化合物形成:多糖或寡糖或其衍生物,诸如葡聚糖、羧甲基葡聚糖、淀粉、二醛淀粉、甲壳质、藻酸盐、纤维素、羧甲基纤维素;蛋白质或其衍生物,诸如白蛋白、肽;合成聚合物,诸如聚乙二醇、聚乙烯吡咯烷酮、聚乙烯亚胺、聚甲基丙烯酸酯;双官能羧酸及其衍生物,诸如巯基丁二酸或羟基羧酸。
连接子基团L是由诸如以下的化合物的反应形成:聚二羧酸和二羧酸(poly-anddicarboxylic acid)、多羟基羧酸、二胺、氨基酸、肽、蛋白质、脂质、脂蛋白、糖蛋白、凝集素、寡糖、多糖、寡核苷酸及其烷基化衍生物,以及以单链或双链形式存在的核酸(DNA、RNA、PNA)及其烷基化衍生物,所述化合物包括至少两个相同或不同的官能团。
主题官能化磁性纳米颗粒能够通过血-脑屏障。例如,主题官能化磁性纳米颗粒可包含连接至纳米颗粒上的或在具有或涂覆纳米颗粒的制剂中的一种或多种聚合物。促进穿过血脑屏障的适合的聚合物包括但不限于表面活性剂诸如聚山梨醇酯(如20、40、60和80);泊洛沙姆诸如F68;等。在一些实施方案中,主题官能化磁性纳米颗粒涂覆有聚山梨糖醇酯诸如80(其为聚氧乙烯-80-脱水山梨糖醇单油酸酯)、40(其是聚氧乙烯脱水山梨糖醇单棕榈酸酯);60(其为聚氧乙烯脱水山梨糖醇单硬脂酸酯),20(其为聚氧乙烯-20-脱水山梨糖醇单月桂酸酯);聚氧乙烯20脱水山梨糖醇单棕榈酸酯;聚氧乙烯20脱水山梨糖醇单硬脂酸酯;聚氧乙烯20脱水山梨糖醇单油酸酯等。同样适用的是水溶性聚合物,包括如聚醚,例如聚亚烷基氧化物(polyalkylene oxides),诸如聚乙二醇(“PEG”)、聚环氧乙烷(“PEO”)、聚环氧乙烷共(-co-)聚环氧丙烷(“PPO”)、共-聚环氧乙烷的嵌段或无规共聚物和聚乙烯醇(“PVA”);聚(乙烯基吡咯烷酮)(“PVP”);聚(氨基酸);葡聚糖和蛋白质(诸如白蛋白)。嵌段共聚物是适用的,如聚环氧乙烷-聚环氧丙烷-聚环氧乙烷(PEO-PPO-PEO)三嵌段共聚物(如F68);等;参见如美国专利No.6,923,986。在包括如Chen等(2004)Curr.Drug Delivery1:361-376的各种出版物中讨论了穿过血脑屏障的其它方法。
在一些实施方案中,主题官能化MNP包含一种或多种提供逃避网状内皮系统(RES)的试剂。提供用于逃避RES的试剂包括但不限于嵌段共聚物非离子表面活性剂,诸如泊洛沙姆(诸如泊洛沙姆508、泊洛沙姆908、泊洛沙姆1508)等。在一些实施方案中,主题官能化MNP包含约1%的泊洛沙姆。
也可将纳米颗粒通过利用存在于BBB中的特定的递送通道转移穿过血脑屏障(BBB)。作为一个非限制性实例,将2-脱氧葡萄糖连接至纳米颗粒使得葡萄糖通道易接收这些颗粒并有助于递送穿过BBB。在有或没有存在于血脑屏障中的通道的调节下,其它机制是转胞吞作用(transcytosis)和血细胞渗出。
使用神经外科技术,可将主题官能化磁性纳米颗粒递送至中枢神经系统(CNS)。在病情严重的患者诸如事故受害者或那些患有各种形式痴呆的患者的情况下,批准进行外科手术干预,尽管其伴有风险。例如,可通过直接物理引入至CNS(诸如心室内或鞘内注射)来递送主题官能化磁性纳米颗粒。心室内注射可以借助例如连接到一个储器(如Ommaya储器)的心室内导管。引入的方法也可由可再充电或生物可降解装置提供。另一个途径是通过增加血-脑屏障的渗透性的物质破坏血脑屏障。实例包括动脉内输注扩散能力较差的试剂(诸如甘露醇)、增加脑血管渗透性的药物(诸如依托泊苷)或血管活性剂(诸如白三烯)。Neuwelt和Rappoport(1984)Fed.Proc.43:214-219;Baba等(1991)J.Cereb.Blood FlowMetab.11:638-643;和Gennuso等(1993)Cancer Invest.11:638-643。
进一步地,需要局部施用主题官能化磁性纳米颗粒至需要诊断或治疗的区域;这可通过例如在外科手术期间局部输注获得、通过借助于导管或借助于植入物的注射获得,所述植入物是多孔、非多孔或凝胶状材料,包括膜(诸如硅橡胶膜)或纤维。
主题官能化磁性纳米颗粒也可以通过使用包括化学修饰的药理学技术来递送使得主题官能化磁性纳米颗粒将穿过血脑屏障。主题官能化磁性纳米颗粒可被修饰以增加纳米颗粒的疏水性,降低纳米颗粒的净电荷或分子量,或修饰纳米颗粒,使得它将类似一个正常运输的穿过血脑屏障的颗粒。Levin(1980)J.Med.Chem.23:682-684;Pardridge(1991)见:Peptide Drug Delivery to the Brain;和Kostis等(1994)J.Clin.Pharmacol.34:989-996。
封装主题官能化磁性纳米颗粒于诸如脂质体的疏水环境中也有效地将药物递送至CNS。例如WO91/04014描述一种脂质体递送系统,其中药物被封装在已添加正常运输穿过血脑屏障的分子的脂质体内。
配制穿过血-脑屏障的主题官能化磁性纳米颗粒的另一种方法是封装主题官能化磁性纳米颗粒于环糊精中。可以采用任何穿过血-脑屏障的适合的环糊精,包括但不限于α-环糊精、β-环糊精及其衍生物。一般参见美国专利No.5,017,566、5,002,935和4,983,586。此类组合物也可以包括如美国专利No.5,153,179所讨论的甘油衍生物。
在一些实施方案中,主题官能化磁性纳米颗粒能够进入脑中的细胞,如穿过细胞膜并进入细胞的细胞质。用于进入脑中的细胞的机制包括如在有或没有适当的膜通道调节时的转胞吞作用和血细胞渗出。
治疗剂
除结合β-淀粉样沉积物和或NFT的官能团外,主题官能化MNP可包括治疗剂如适用于治疗AD的治疗剂。适合的治疗剂包括用于治疗AD的试剂,其中此类试剂包括但不限于乙酰胆碱酯酶抑制剂,包括但不仅限于安理申(Aricept)(多奈哌齐(donepezil))、艾斯能(Exelon)(卡巴拉汀(rivastigmine))、美曲膦酯(metrifonate)、拉扎啶(Razadyne)(加兰他敏(galantamine))和他克林(tacrine)(考克尼克斯(Cognex));非类固醇类的抗炎剂包括但不仅限于布洛芬和吲哚美辛;环氧化酶-2(Cox2)抑制剂诸如塞来昔布(Celebrex);单胺氧化酶抑制剂诸如司来吉兰(Selegilene)(咪多吡(Eldepryl)或地普雷尼尔(Deprenyl));和N-甲基D-天冬氨酸(NMDA)拮抗剂诸如钠门达(Namenda)(美金刚(memantine))。
用于治疗AD的另一种适合的另一种治疗剂是减少apoE4结构域相互作用的apoE4“结构校正剂”。减少apoE4结构域相互作用的试剂包括如在美国专利公布No.2006/0073104;和Ye等(2005)Proc.Natl.Acad.Sci.USA102:18700中所描述的试剂。
用于治疗AD的另一种适合的另外的治疗剂是抑制tau聚集的试剂,如在美国专利No.7,605,179所描述的抑制tau聚集的萘醌衍生物。另一种适合的另外的治疗剂是抑制tau磷酸化的试剂,如在美国专利No.7,572,793描述的抑制tau蛋白激酶1的3-取代-4-嘧啶酮衍生物。
组合物
本公开进一步提供组合物,包括包含主题官能化MNP的药物组合物。包含主题官能化磁性纳米颗粒的组合物包括以下的一种或多种:盐、缓冲剂、pH调节剂、非离子型洗涤剂、蛋白酶抑制剂、核酸酶抑制剂等。
包含主题官能化MNP的药物组合物将包含一种或多种药学上可接受的载体。如本文所使用,“药学上可接受载体”包括任何材料,当与组合物的活性成分组合时,所述材料允许成分保持生物活性且不会引起与受试者免疫系统或其它生理功能的破坏性反应。实例包括但不限于任何标准药物载体诸如磷酸盐缓冲盐水溶液、水、乳剂诸如油/水乳剂和各种类型的润湿剂。用于气雾剂或肠胃外给药的示例性稀释剂是磷酸盐缓冲盐水或生理(0.9%)盐水通过熟知的常规方法(参见例如Remington’s Pharmaceutical Sciences,Chapter43,第十四版,Mack Publishing Col,Easton PA18042,USA)配制包含此类载体的组合物。药学上可接受的赋形剂已经在各种公布中充分描述,包括例如A.Gennaro(2000)“Remington:TheScience and Practice of Pharmacy,”第20版,Lippincott,Williams,&Wilkins;Remington’s Pharmaceutical Sciences,第14版或最新版,Mack Publishing Col,EastonPA18042,USA;Pharmaceutical DosageForms and Drug Delivery Systems(1999)H.C.Ansel等,编辑,第7版,Lippincott,Williams,&Wilkins;和Handbook ofPharmaceutical Excipients(2000)A.H.Kibbe等,编辑,第三版Amer.PharmaceuticalAssoc。
通过在水性或非水溶剂诸如植物油或其它类似的油、合成的脂肪酸甘油酯、高级脂族酸或丙二醇的酯中且如果需要与常规添加剂诸如增溶剂、等渗剂、悬浮剂、乳化剂、稳定剂和防腐剂一起溶解、悬浮或乳化,可将主题官能化磁性纳米颗粒配制成注射用制剂。
成像方法
主题官能化MNP可用于检测和定量与β-淀粉样沉积物和/或NFT有关的或者由其引起的疾病的活的哺乳动物如人、非人动物或非人动物模型的脑中的淀粉样沉积物和/或NFT。向活的哺乳动物施用包含主题MNP官能化的药物组合物。存在于脑中的任何β-淀粉样沉积物(如聚集的β-淀粉样诸如可与神经原纤维缠结相关)可使用磁共振成像(MRI)或任何其他适当的成像方法来可视化。因此,本公开提供检测和定量活哺乳动物脑中的淀粉样沉积物和/或NFT的方法。所述方法通常包括对哺乳动物施用诊断有效量的包含主题官能化MNP的药物组合物;和b)经由MRI对脑组织成像。施用的官能化MNP被允许分布至脑组织中且可使用MRI对任何键合至聚集的β-淀粉样肽和/或NFT的官能化MNP成像。与结合的正常对照水平相比,官能化MNP与脑组织结合的增强表明哺乳动物患有阿尔茨海默氏病或者有形成阿尔茨海默氏病的风险。
主题官能化MNP提供受影响的组织(如具有β-淀粉样沉积物的脑组织)T2、T2*、和T1时间的对比以使得组织对MRI可见。即将进行成像的感兴趣区包括如海马、皮层和中脑。
主题官能化MNP可被用于对如用于研究目的阿尔茨海默氏病(AD)的非人动物模型的脑中的β-淀粉样沉积物(如聚集的β-淀粉样蛋白)和/或NFT成像。AD的适合的非人动物模型包括包含人淀粉样前体蛋白(hAPP)突变体转基因的转基因小鼠;包含早老素1或早老素2转基因的转基因小鼠等。参见如等(2004)Mol.Psychiatry9:664;和Ittner(2008)Nature Reviews9:532。
例如可将用于治疗AD的实验药物施用于AD非人动物模型;且主题官能化MNP可用于测定实验药物对非人动物模型的脑中β-淀粉样沉积物和/或NFT的量的影响。
当实施主题成像方法时,可通过各种施用途径的任何一种施用主题官能化MNP于个体,包括肠胃外和肠道途径。适合的施用途径包括如静脉内、口服、直肠、阴道、鼻、眼、鞘内、颅内、肌内等
治疗方法
如上所述,在一些实施方案中,主题官能化MNP可包括除结合β-淀粉样沉积物和/或NFT的官能部分(基团)外的治疗剂。此类官能化MNP可用于对AD成像和/或AD的治疗中。
适合的治疗剂包括用于治疗AD的试剂,其中此类试剂包括但不限于乙酰胆碱酯酶抑制剂,包括不但限于安理申(多奈哌齐)、艾斯能(卡巴拉汀)、美曲膦酯和他克林(考克尼克斯);非类固醇类的抗炎剂包括不但限于布洛芬和吲哚美辛;环氧化酶-2(Cox2)抑制剂诸如塞来昔布;和单胺氧化酶抑制剂诸如司来吉兰(咪多吡或地普雷尼尔)。
用于治疗AD的另一种适合的另外的治疗剂是减少apoE4结构域相互作用的“结构校正”的apoE4。减少apoE4结构域相互作用的试剂包括如在美国专利公布No.2006/0073104;和Ye等(2005)Proc.Natl.Acad.Sci.USA102:18700中所描述的试剂。
用于治疗AD的另一种适合的另外的治疗剂是抑制tau聚集的试剂,如在美国专利No.7,605,179所描述的抑制tau聚集的萘醌衍生物。另一种适合的另外的治疗剂是抑制tau磷酸化的试剂,如在美国专利No.7,572,793描述的抑制tau蛋白激酶1的3-取代-4-嘧啶酮衍生物。
当实施主题治疗方法时,可通过各种施用途径的任何一种施用主题官能化MNP,包括肠胃外和肠道途径。适合的施用途径包括如静脉内、口服、直肠、阴道、鼻、眼、鞘内、颅内、肌内等。
实施例
提出以下实施例以便向本领域的普通技术人员提供如何制备和使用本发明的完整公开和描述,而非意图限制本发明人视为其发明的范围,也非意图表示以下实验是进行的全部或仅有的实验。已努力确保关于所用数字(如量、温度等)的准确性,但是应考虑一些实验误差和偏差。除非另外指明,份数为重量份,分子量为重均分子量,温度单位为摄氏度且压力为大气压或接近大气压。可使用标准的缩写,如bp,碱基对;kb,千碱基;pl,皮升;s或sec,秒;min,分钟;h或hr,小时,aa,氨基酸;kb,千碱基;bp,碱基对;nt,核苷酸;i.m.,肌肉内注射;i.p.,腹膜内;s.c.,皮下等。
实施例1:制备官能化MNP
HODDNP-缀合的MNP(“DNP-MNP”)
对未治疗(无AD)大鼠和AD模型大鼠施用HODDNP-缀合的MNP。数据显示于图1-6中。
图1A和1B。显示未治疗(非-AD)大鼠的MR(磁共振)图像(T2,TR6000毫秒(ms)、TE10-120ms,12次回波)。图1A显示代表性切片的基线(对比前)MR图像。图1b显示相同切片的对比后的MR图像。在此首次用于实验随后用DNP-MNP(也被称为“HODDNP-MNP”)注射的动物中,基线(图1A)和对比后(图1B)扫描的测定体积的感兴趣区(ROI)(其中ROI包括海马、皮层、中脑)的定量T2值的比较未示出显著(p>0.05)的对比增强。
表1显示基线扫描中感兴趣区(ROI)(其中ROI包括海马、皮层、中脑)的定量的T2值(“基础T2(ms)”)。表1显示在静脉内(i.v.;尾静脉)注射HODDNP-MNP1.5小时后相同大鼠的相同感兴趣区的定量T2值(“T2后”)。
表1
ROI | 基础T2(ms) | T2后 |
海马 | 55.0±0.2 | 51.3±0.3 |
皮层 | 53.0±0.3 | 48.6±0.2 |
中脑 | 50.7±0.4 | 46.5±0.4 |
图2A和2B显示为AD基因模型(淀粉样-β(Aβ)斑块的三基因模型)的1岁大鼠的MR图像(T2、TR6000ms、TE10-120ms,12次回波)。图2A显示此大鼠中的代表性切片的基线(对比前)MR图像。图2B显示用增强注射后的2.5小时时的相同切片的对比后的MR图像。基线中(图2A)和对比后(图2B)扫描的测定体积的ROI(海马、皮层和中脑)的定量T2值的比较在随后用DNP-MNP注射的所有ROI中显示出显著的(P<0.05)对比增强。最显著的对比增强是海马,其次是皮层。
表2显示基线扫描中的ROI(海马、皮层和中脑)的定量T2值(“基础T2(ms)”)。表2显示了静脉注射(尾静脉)HODDNP-MNP2.5小时后相同大鼠中相同ROI的定量T2值(“T2后”)。
表2
ROI | 基础T2(ms) | T2后 |
海马 | 56.2±0.3 | 48.5±0.3 |
皮层 | 52.4±0.3 | 45.3±0.3 |
中脑 | 49.4±0.4 | 44.1±0.5 |
图3A和图3B显示为AD基因模型((Aβ)斑块的三基因模型)的第二1岁大鼠的MR图像(T2、TR6000ms、TE10-120ms,12次回波)。图3A显示此大鼠中的代表性切片的基线(对比前)MR图像。图3B显示用对照注射后的2.5小时时的相同切片的对比后的MR图像。基线中(图3A)中和对照后(图3B)扫描的测定体积的ROI(海马、皮层和中脑)T2值的比较在随后用DNP-MNP注射的所有ROI中显示出显著的(P<0.05)对比增强。最显著的对比增强是海马,其次是皮层。
表3显示基线扫描中的ROI(海马、皮层和中脑)的定量T2值(“基础T2(ms)”)。表3显示了静脉注射(尾静脉)HODDNP-MNP2.5小时后相同大鼠中相同ROI的定量T2值(“T2后”)。
表3
ROI | 基础T2(ms) | T2后 |
海马 | 65.8±0.4 | 51.8±0.4 |
皮层 | 61.0±0.4 | 48.8±0.3 |
中脑 | 61.0±0.5 | 46.5±0.5 |
图4A-C。AD的转基因大鼠模型的代表性MRI切片在图4A中显示。相应的加框区域(海马)显示于图4B的染色的组织切片中。插图显示在海马中明显的斑块的存在。观察到在所有的脑区域中更多的扩散斑块(图4C)的存在。这些结果确认在与AD有关的β-淀粉样斑块存在下,具有HODDNP-MNP的对比增强发生。
图5A-D。扩散斑块的存在显示于(图5A)海马中。在相邻切片中Perl铁染色显示含有斑块(图5B-D)的区域中DNP-MNP的存在。
图6A和6B。转基因大鼠脑切片的DAB-增强的Perl染色(经由尾静脉的静脉注射DNP-MNP后)显示于图6A中。DNP-MNP穿过BBB且存在于细胞内(箭头)以及细胞外的脑组织中。未治疗对照动物(无对照注射)的DAB增强的Perl染色(图6B)显示无铁染色存在于图6A显示的相同的脑区域(内嗅皮质)中。
经由HODDNP的羟基基团,可将HODDNP共价缀合至环氧-MNP。缀合方法的一个实施例示出于图7。
PIB-2-缀合的MNP
经由PIB-2的氨基氮,可将PIB-2缀合至环氧-MNP。此类方法的实施例示出于图8中。
虽然已参照其特定的实施方案描述了本发明,但是本领域技术人员应当理解在不背离所发明的精神和范围的情况下可以进行各种变化和等效物替代。此外可以进行许多修改以使得特定的情况、材料、材料的组合物、方法、方法步骤或步骤适应本发明的目的、精神和范围。所有此类修改意图在所附权利要求的范围内。
Claims (20)
1.一种药物组合物,其包含:
a)式M-L-Z或M-S-L-Z的官能化磁性纳米颗粒,其中M是磁性核心,S是聚合物,L是连接基团,且Z是结合聚集的β-淀粉样蛋白和/或神经原纤维缠结的官能团,其中所述官能团经由所述连接基团与磁性核心或聚合物S偶联,其中当被引入哺乳动物受试者的血流中时,所述官能化磁性纳米颗粒能够穿过哺乳动物受试者的血-脑屏障,其中所述官能团是2-(1-(6-[(2-羟乙基)(甲基)氨基]-2-萘基}亚乙基)丙二腈;以及
b)药学上可接受的载体。
2.权利要求1所述的药物组合物,其中所述连接基团包含环氧基团。
3.权利要求1所述的药物组合物,其中经由2-(1-(6-[(2-羟乙基)(甲基)氨基]-2-萘基}亚乙基)丙二腈的羟基将所述2-(1-(6-[(2-羟乙基)(甲基)氨基]-2-萘基}亚乙基)丙二腈官能团偶联至所述磁性核心。
4.权利要求1所述的药物组合物,其中所述官能化磁性纳米颗粒进一步包含治疗剂。
5.权利要求1所述的药物组合物,其中将所述官能化磁性纳米颗粒封装在白蛋白基质中。
6.权利要求1所述的药物组合物,其中所述官能化磁性纳米颗粒包含载脂蛋白。
7.权利要求1所述的药物组合物,其中所述官能化磁性纳米颗粒包含聚(氰基丙烯酸丁酯)。
8.权利要求7所述的药物组合物,其中将所述官能化磁性纳米颗粒连接至聚(氰基丙烯酸丁酯)颗粒的表面。
9.权利要求1所述的药物组合物,其中所述官能化磁性纳米颗粒包含表面活性剂。
10.权利要求9所述的药物组合物,其中所述表面活性剂选自聚氧乙烯脱水山梨糖醇单油酸酯、聚氧乙烯脱水山梨糖醇单棕榈酸酯、聚氧乙烯脱水山梨糖醇单硬脂酸酯和聚氧乙烯脱水山梨糖醇单月桂酸酯。
11.权利要求9所述的药物组合物,其中所述表面活性剂是聚环氧乙烷和聚环氧丙烷的嵌段共聚物。
12.权利要求9所述的药物组合物,其中所述官能化磁性纳米颗粒包含泊洛沙姆。
13.权利要求1所述的药物组合物,其中所述聚合物是葡聚糖。
14.权利要求1~13任一项所述的药物组合物在制备药物中的用途,所述药物用于检测活的哺乳动物脑中的阿尔茨海默氏病或对其易感性。
15.权利要求14所述的用途,其中通过静脉注射施用所述药物。
16.权利要求14所述的用途,其中所述活哺乳动物是人。
17.权利要求1~13任一项所述的药物组合物在制备药物中的用途,所述药物用于检测活的哺乳动物脑中的β-淀粉样沉积物和/或神经原纤维缠结。
18.权利要求17所述的用途,其中通过静脉注射施用所述药物。
19.权利要求17所述的用途,其中所述活哺乳动物是人。
20.权利要求17所述的用途,其中所述活哺乳动物是与β-淀粉样沉积物和/或神经原纤维缠结相关的疾病的非人动物模型。
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AU2019203038A1 (en) | 2019-05-23 |
AU2017203920A1 (en) | 2017-06-29 |
US10751428B2 (en) | 2020-08-25 |
JP2014512382A (ja) | 2014-05-22 |
CA3058702A1 (en) | 2012-10-26 |
CN103491870A (zh) | 2014-01-01 |
EP2699157A2 (en) | 2014-02-26 |
CA3058702C (en) | 2023-11-07 |
EP3345545B1 (en) | 2021-10-20 |
KR20140012732A (ko) | 2014-02-03 |
ES2667894T3 (es) | 2018-05-14 |
JP2018154646A (ja) | 2018-10-04 |
EP3345545A1 (en) | 2018-07-11 |
US20190374658A1 (en) | 2019-12-12 |
CA2831331A1 (en) | 2012-10-26 |
WO2012145169A2 (en) | 2012-10-26 |
EP2699157A4 (en) | 2015-02-25 |
JP6353007B2 (ja) | 2018-07-04 |
US20160184461A1 (en) | 2016-06-30 |
US9272055B2 (en) | 2016-03-01 |
JP2017048218A (ja) | 2017-03-09 |
US20140140932A1 (en) | 2014-05-22 |
AU2019203038B2 (en) | 2021-03-25 |
JP6960883B2 (ja) | 2021-11-05 |
WO2012145169A3 (en) | 2013-03-14 |
AU2012245861A1 (en) | 2013-10-17 |
CN106729771A (zh) | 2017-05-31 |
US10232059B2 (en) | 2019-03-19 |
JP6038122B2 (ja) | 2016-12-07 |
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CA2831331C (en) | 2019-10-15 |
AU2017203920B2 (en) | 2019-03-28 |
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