CN101155549A - 官能化磁性纳米颗粒及其使用方法 - Google Patents
官能化磁性纳米颗粒及其使用方法 Download PDFInfo
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- CN101155549A CN101155549A CNA2006800086773A CN200680008677A CN101155549A CN 101155549 A CN101155549 A CN 101155549A CN A2006800086773 A CNA2006800086773 A CN A2006800086773A CN 200680008677 A CN200680008677 A CN 200680008677A CN 101155549 A CN101155549 A CN 101155549A
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Abstract
本发明提供包含一个官能团的官能化磁性纳米颗粒,官能化磁性纳米颗粒显示对一个组织,包括脑组织、骨,和血管组织的不同结合力。本发明更进一步地提供了组合物,包括包含了主题官能化磁性纳米颗粒的药物组合物。本发明更进一步地提供涉及使用主题官能化磁性纳米颗粒的诊断和研究方法。本发明更进一步地提供一个磁共振图象(MRI)-可见的药物传输***;以及合成它的方法。MRI-可见的药物传输***在使用MRI确定药物的分布上,以及组织特异性药物的传输上有应用。
Description
对照
本申请要求2005年3月21日提交的申请号60/664,046的美国临时专利的优先权,该文献以引用的方式全文***本文。
发明的领域
本发明涉及磁性纳米颗粒的领域,及其在组织成像,例如,磁共振成像,中的应用。
发明的背景
纳米颗粒是直径尺寸通常从一nm到几百nm的颗粒。纳米颗粒的小尺寸使之能用来生产各种各样的产品譬如染料和颜料;美化或功能涂层;作为为生物探索、医疗成像,和治疗学的工具;用作磁性录音媒介;量子打点;甚至均匀一致和纳米尺寸的半导体。
已提出将磁性纳米颗粒用于各种生物医学的目的,包括磁共振成像,恶性细胞的高温治疗,和药物传输。在成像上一个主要挑战是在患病的组织和正常组织之间进行区别的能力。本发明用于这种需求,并提供相关有利条件。
文献
美国专利6,548,264,6,767,635;
Berry and Curtis(2003)J.Phys.D:Applied Physics 36:R198-R206;
Pankhurst et al.(2003)J Phys.D:Applied Physics 36:R167-R181;
Dousset et al.(1999)Am.J.Neuroradiol.20:223-227;
Dunning et al.(2004)J Neurosci.24:9799-9810;
Dousset et al.(1999)Magnetic Resonance in Medicine 41:329-333;
Moghimi et al.(2001)Pharmacol.Rev.53:283-318.
发明概述
本发明提供包含一种含有官能团的官能化磁性纳米颗粒,所述官能化磁性纳米颗粒显示对组织(包括脑组织、骨,和血管组织)的不同结合力。本发明更进一步地提供各种组合物(包括药物组合物),该组合物包括本发明官能化磁性纳米颗粒。本发明更进一步地提供诊断和研究方法,它包括使用本发明官能化磁性纳米颗粒。本发明更进一步地提供一种磁共振图象(MRI)-可见的药物传输***;以及合成它的方法。所述MRI-可见的药物传输***可用于使用MRI确定药物的分布,以及组织特异性药物的传输。
附图的简要描述
图1概要地描述了一种本发明官能化磁性纳米颗粒的具体实施方式。
图2A-D描述了经红藻氨酸治疗的大鼠大脑的磁共振照片
注射AMT-磁性纳米颗粒后零小时(图2A);
注射AMT-磁性纳米颗粒后6个小时(图2B);
注射非官能化磁性纳米颗粒后零小时(图2C);
注射非官能化磁性纳米颗粒后6小时(图2D)。
图3A-D描述在一个人的血清白蛋白基质内AMT-磁性纳米颗粒微粒的透射电子显微照片。
图4A和4B描述聚(氰基丙烯酸丁酯)-磁性纳米颗粒的TEM照片。
定义
本文中,术语“纳米颗粒”是指一种直径在大约1到1000nm之间的微粒。同样,由术语“纳米颗粒群”是指直径在大约1到1000nm之间的许多微粒。
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,一个完全球状纳米颗粒的尺寸是它的直径。
在本文中,短语“特异性结合”是指一个分子识别并附着在样品中特定的第二个分子上,但基本未识别并附着在样品中的其它分子上。例如,“特异性结合”一个预选抗原的抗体是这样一个抗体,它以大于大约10-7M的结合引力结合该抗原,例如,至少以大约10-7M,或至少大约10-8M,或至少大约10-9M,或大于10-9M结合引力结合。
本文中,术语“官能团”与“官能片段”和“官能配基”可互换使用,是指一种化学基团,它能使带有该化学基团的制品(例如,纳米颗粒)具有特殊功能。例如,官能团可包括如已知用来结合特定分子的物质,如抗体、低聚核苷酸、生物素,或抗生物素蛋白链菌素;或例如胺、羧酸酯等小分子基团。
本温中,术语“主体”或“个体”或“病人”是指需要诊断,病情预测,或治疗的任何主体,并且通常是指接受本发明诊断方法、病情预测方法,或治疗方法的接受者。所述主体可以是任一种脊椎动物,但典型地是哺乳动物。如果是哺乳动物,则在许多具体实施方式中所述主体是人,但也可能是一个家养的家畜、实验室主体,或宠物。
本文中,术语“治疗”或相似的词是指获得一个期望的药物和/或生理学效果。该效果可以是预防性的,用以完全地或部份地防止疾病或其症状,和/或可以是治疗性的,用以部份地或完全地治疗疾病和/或疾病的有害影响。本文中术语“治疗”包括哺乳动物,特别是人,疾病的任一种治疗,它包括:(a)防止主体发生疾病或疾病症状,该主体可以是具有该疾病的倾向,但未被确诊(例如,包括与一种主要疾病有关的或者由其造成的疾病);(b)抑止疾病,例如,阻止它的发展;(c)缓解疾病,例如,导致疾病的消退。
在进一步描述本发明之前,应理解本发明不限于描述的具体实施方式,因为所述具体实施方式当然是变化的。还应理解本文的术语仅仅是为描述具体的实施方式,并非为了限定,因为本发明的范围只受所附的权利要求书的限制。
当提供一个数值范围时,除非上下文清楚地另有规定,否则应理解本发明该范围包括在该范围上限和下限之间的各个中间值(精确至所述下限单位的十分之一)以及该范围内用其它方式表示的或中间的值。。这些更小范围的上限和下限各自包括在该更小范围之中,并且也包括在本发明范围内,除非明确排除所述范围以外的数值。当所述范围包括一个或两个端值时,不包括该一个或两个端值的范围也在本发明范围内。
除非另有定义,否则所有在此所用的技术的和科学的术语与本领域普通技术人员通常理解的含义相同。虽然在实践或试验本发明时可使用与本文所述相似或等同的方法和材料,但是优选的方式和材料是本文所述的方法和材料。在此提到的所有出版物均以引用的方法***本文,以便通过引用的出版物描述所述方法和/或材料。
必须注意在本文和所附权利要求书中,除非上下文清楚地规定了其它方式,否则单数形式的“一种”、“和”和“所述”均包括多个指示物。因此,例如,“一种官能化磁性纳米颗粒”包括多个这种纳米颗粒,并且“所述药物”包括一种或更多种药物和本领域普通技术人员所知的等价物,等等。还应该注意,撰写的权利要求可不包括任选的元素。因此,它是使用排他的术语(例如:“单独的”、”仅仅”等)与引用的权利要求要素或者使用“否定式”限制的前提基础。
本文提到的出版物仅仅涉及本申请的申请日之前它们所公开的内容。这并不意味着承认本发明不能通过在先发明而获得早于该出版物的权利。进一步地,出版物所提供的出版日期可能不同于其真实的出版日,这需要单独地予以确认。。
发明的详述
本发明提供一种官能化磁性纳米颗粒,该磁性纳米颗粒共轭有一种官能片段,所述官能化磁性纳米颗粒对特定组织(例如脑组织、骨,和血管组织)显示出的不同结合力。本发明更进一步地提供一种包含本发明官能化磁性纳米颗粒的组合物。本发明更进一步地提供使用本发明官能化磁性纳米颗粒的诊断,预诊,治疗,和研究方法。本发明更进一步地提供一种磁共振图象(MRI)-可见的药物传输***;以及合成它的方法。所述MRI-可见的药物传输***可用于使用MRI确定药物的分布,以及组织特异性药物的传输上。
官能化磁性纳米颗粒
本发明提供一种官能化磁性纳米颗粒,它共轭有一种官能片段,所述官能化磁性纳米颗粒对特定组织(例如脑组织、骨,和血管组织)显示出不同结合力。本发明官能化磁性纳米颗粒可用于各种诊断,预诊,治疗,和研究用途。
磁性纳米颗粒
本发明纳米颗粒的平均尺寸一般在从大约1nm到大约1000nm的范围,例如,从大约1nm到大约10nm,从大约10nm到大约50nm,从大约50nm到大约100nm,从大约100nm到大约250nm,从大约250nm到大约500nm,从大约500nm到大约750nm,或从大约750nm对大约1000nm。在一些具体实施方式中平均直径的范围从大约10nm至大约1000nm,例如,从大约10nm到大约20nm,从大约20nm到大约40nm,从大约40nm到大约60nm,从大约60nm到大约80nm,从大约80nm到大约100nm,从大约100nm到大约200nm,从大约200nm到大约400nm,从大约400nm到大约600nm,从大约600nm到大约800nm,或从大约800nm到大约1000nm。
纳米颗粒可以是简单的分子团聚物或它们可构造至二层或更多层不同物质中层。例如,合适使用由磁铁矿或磁赤铁矿组成的简单纳米颗粒。参见,例如,磁性微 球的科学和临床应用,U.Hafeli,W.Schutt,J.Teller,和M.Zborowski(eds.)Plenum Press,New York,1997;以及Tiefenauer等.,生物配合化学.4:347,1993。更复杂的纳米颗粒可由一种物质构成的核和由其它物质构成的一个或更多个壳制成。术语“磁性纳米颗粒”包括顺磁性纳米颗粒、反磁性纳米颗粒,和铁磁纳米颗粒。
本发明纳米颗粒的典型的核材料是通用组成为MeOxFe2O3的铁氧体,其中Me是一种二价金属譬如Co,Mn或Fe。其它适合的材料是γ-Fe2O3、纯金属Co,Fe,Ni,和金属化合物譬如碳化物和氮化物。核材料一般是MRI可见的试剂。核心材料通常是被包被的。适当的涂层包括,但不限于,葡聚糖、白蛋白、淀粉、硅,及其类似物。
许多不同类型的小颗粒(纳米颗粒或微米大小的微粒)可从不同的供应商市售购得,所述供应商包括:Bangs实验室(Fisher,Ind.);Promega(Madison,Wis.);Dynal Inc.(Lake Success,N.Y.);Advanced Magnetics Inc.(Surrey,U.K.);CPGInc.(Lincoln Park,N.J.);Cortex Biochem(San Leandro,Calif.);EuropeanInstitute of Science(Lund,Sweden);Ferrofluidics Corp.(Nashua,N.H.);FeRxInc.;(San Diego,Calif);Immunicon Corp.;(Hunting don Valley,Pa.);Magnetically Delivered Therapeutics Inc.(San Diego,Calif);Miltenyi BiotecGmbH(USA);Microcaps GmbH(Rostock,Germany);Poly Microspheres Inc.(Indianapolis,Ind.);Scigen Ltd.(Kent,U.K.);SeradynInc.;(Indianapolis,Ind.);和Spherotech Inc.(Libertyville,111.)。这些微粒的大多数使用常规技术制备,譬如研磨和碾碎,乳液聚合,嵌段共聚,和微乳化。
业已报道了制造氧化硅纳米颗粒的方法。该方法包括微晶核团聚(Philipseetal,Langmuir,10:92,1994);用***的氧化硅增强超顺磁性聚合物纳米颗粒(Gruttner,Cand J Teller,Journal of Magnetismand MagneticMaterials,194:8,1999);和微波介导的自集合(Correa-Duarteetal.,Langmuir,14:6430,1998)。
本发明纳米颗粒核是磁性的,它可包括选自磁铁矿、磁赤铁矿和硫复铁矿的金属。可使用磁性材料譬如磁铁矿、磁赤铁矿,和硫复铁矿作为核的一部分来制造磁性纳米颗粒。通过改变这种磁核的整体大小和形状,该磁性颗粒可具有顺磁性或稳定的单磁区(从磁场中取出后保留稳定的磁性的微粒)。核的大小决定一种磁性纳米颗粒是否是顺磁性的或单磁区的。因而,相对同样大小的顺磁性微粒一般有小于50到80nm的核。当颗粒的大小在这个范围上限之上时,为了使内部磁性能量减到最小,微粒的磁性会***成具有不同磁性矢量的磁区。
在一些具体实施方式中,所述核包括一种颜料,它可以是无机盐譬如高锰酸钾、重铬酸钾、硫酸镍、氯化钴、三氯化铁(III),或硝酸铜。同样,所述核可包括一种染料譬如Ru/Bpy、Eu/Bpy,或类似物;或一种金属譬如Ag和Cd。
在一些具体实施方式中,本发明改性的纳米颗粒包括一个核和一个包围核心的氧化硅壳。所述官能团共轭结合在所述氧化硅壳上,例如,如美国专利6,548,264所述。众多已知的用于将官能团附着在氧化硅上的方法适用于本发明。参见,例如,RalphK.Her,氧化硅化学:可溶性、聚合、胶体和表面特性,和生物化学,Wiley-Interscience,NY,1979;Van Der Voort,P.和Vansant,E.F.,液相色谱 和相关技术学报,19:2723-2752,1996;和固定的酶,抗原、抗体,和肽:制备和特性 描述,Howard H.Weetall(ed.),M.Dekker,NY,1975。将官能团加至氧化硅涂覆的纳米颗粒上的典型方法包括用硅烷化试剂处理所述纳米颗粒,使之与纳米颗粒的氧化硅表面反应并将化学基团结合在该表面上。所述化学基团本身可以是一个官能团,或者它可以是用于结合官能团的基体。
例如,在一个例举性的方法中,如上述制备用氧化硅包覆的纳米颗粒并且微粒表面用三甲基甲硅烷基丙基-二亚乙基三胺(DETA)(一种硅烷化试剂,用于将伯胺基团附着在氧化硅表面上)硅烷化,。随后抗体或其它蛋白质能用溴化氰(CNBR)法共价地结合在硅烷化的表面上。作为一个例子,可如下实施采用CNBR的结合:将氧化硅包覆的纳米颗粒悬浮在2M碳酸钠缓冲液中,所述氧化硅包覆的纳米颗粒预先用DETA硅烷化;和对该混合物进行超声处理以形成微粒的悬浮液。随后向该颗粒悬浮液中加入CNBR溶液(例如,2gCNBR/1ml乙腈),在用中性缓冲液(例如,PBS,pH8)洗涤纳米颗粒后,将抗体溶液被加入到该激活的纳米颗粒悬浮液中,使抗体与纳米颗粒发生结合。还可向包被抗体的纳米颗粒加入氨基乙酸溶液以封闭(block)任何残余的未反应的位点。
在一些具体实施方式中,磁性纳米颗粒是包覆了葡聚糖的。磁性纳米颗粒用任一已知的方式制造。例如,磁性铁葡聚糖微粒是通过混合10ml50%(w/w)水性葡聚糖T-40(Pharmacia)与等体积的含有1.51gFeCl3-6H2O和0.64gFeCl2-4H2O水溶液而制备的。边搅拌边滴加7.5%(v/v)NH4OH,将混合物滴定至pH10-11,所述NH4OH用水浴加热到60-65℃15分钟。随后用一台低速临床离心机在600xg每次离心5分钟共离心三次,去除聚集物。铁磁性的铁-葡聚糖微粒用Sephacryl-300采用凝胶过滤色谱法从未结合的葡聚糖中分离出来。5ml反应混合物被施加至一个2.5x33cm色谱柱上并且用0.1M醋酸钠和0.15MNaCl在pH6.5洗脱。纯化了的铁磁性铁-葡聚糖微粒被收集在空容器中,用干重法测定浓度为7-10mg/ml。参见Molday和Mackenzie(1982)JournalofImmunologicalMethods52:353-367.同样见于(Xianqiao(2003)China Particuology VoL l,No.2,76-79)。
在一些具体实施方式中,本发明官能化磁性纳米颗粒具有通式:M-(L)-Z,在L和Z之间的连接点位具有共价结合的官能团,其中M代表磁性核微粒,L代表任选的连接基团,Z代表一个官能团。在其它具体实施方式中,本发明官能化磁性纳米颗粒具有通式:M-S-(L)-Z,在S和L以及L和Z之间的连接点位具有共价结合的官能团,其中M代表磁性核微粒,S代表一个生物相容的固定在M上的基体(substrate),M代表磁性核微粒,L代表任选的连接基团,Z代表官能团。官能团包括用于连接特定组织或细胞的片段;包括用于穿透(cross)BBB、治疗药剂的片段;及其类似物。
在一些具体实施方式中,本发明官能化磁性纳米颗粒包括附着在同一核微粒上的二个或更多不同的官能团。例如,在一些具体实施方式中,本发明官能化磁性纳米颗粒具有通式M-(L)-Z1Z2,或M-S-(L)-Z1Z2,其中Z1和Z2是不同的官能团。在一些具体实施方式中,例如,Z1是组织特意性结合片段而Z2是治疗剂。在其它具体实施方式中,例如,Z1是一个细胞特意性结合片段而Z2是治疗剂。在其它具体实施方式中,例如,Z1是用于穿越BBB的片段而Z2是一个治疗剂。在其它具体实施方式中,例如,Z1是提供穿越BBB的片段而Z2是一个组织特意性结合片段。在其它具体实施方式中,例如,Z1是用于与患病的组织结合的片段而Z2是一个治疗剂。在一些具体实施方式中,本发明官能化磁性纳米颗粒包括至少一个第三官能片段Z3。
如上所述所述磁性核微粒由磁铁矿,磁赤铁矿,通用分子式为MeOxFe2O3的铁氧体组成,其中Me是一种二价金属譬如钴,锰,铁,或者由钴,铁,镍,碳化铁,或氮化铁组成。如果存在基体S的话,则该基体S由化合物譬如多聚糖或低聚糖或其衍生物形成,譬如葡聚糖,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,譬如白蛋白,肽,合成聚合物,譬如聚乙二醇,聚乙烯基吡咯烷酮,聚乙烯亚胺,聚甲基丙烯酸盐,双官能羧酸和其衍生物,譬如巯基丁二酸或羟基羧酸。
连接基团L是由一种化合物(譬如多和二羧酸,聚羟基羧酸,二胺,氨基酸,肽,蛋白质,油脂,脂蛋白,糖蛋白,凝集素,低聚糖,多聚糖,低聚核苷酸和其烷基化的衍生物,和核酸(DNA,RNA,PNA)及其烷基化的衍生物反应形成的,该化合物以单链或双链(double-strandedform)的形式存在,该化合物包括至少二个相同或不同的官能团。
本发明官能化磁性纳米颗粒能穿透血脑障壁。例如,本发明官能化磁性纳米颗粒可包括一种或多种聚合物,该聚合物附着在纳米颗粒上、位于纳米颗粒制剂中、或者涂覆纳米颗粒。促进穿越血脑屏障的适当的聚合物包括,但不限于,表面活性剂譬如聚山梨醇酯(如吐温_20,40,60和80);泊洛沙姆(poloxamers)譬如Pluronic_F68;及其类似物。在一些具体实施方式中,本发明官能化磁性纳米颗粒涂覆有聚山梨醇酯,例如,吐温_80(它是聚氧乙烯-80-山梨糖醇酐单油酸酯),吐温_40(它是聚氧乙烯山梨糖醇酐单棕榈酸酯);吐温_60(它是聚氧乙烯山梨糖醇酐单硬酯酸酯);吐温_20(是聚氧乙烯-20-山梨糖醇酐单月桂酸酯);聚氧乙烯-20-山梨糖醇酐单棕榈酸酯;聚氧乙烯20山梨糖醇酐单硬酯酸酯;聚氧乙烯20山梨糖醇酐单油酸酯;等。水溶性的聚合物也是适用的,它包括,例如:聚醚,如聚环氧烷譬如聚乙二醇(“PEG”),聚环氧乙烷(“PEO”),聚环氧乙烷共聚聚环氧丙烷(“PPO”),环氧丙烷的嵌段共聚物或无规共聚物,和聚乙烯醇(“PVA”);聚乙烯基吡咯烷酮(“PVP”);聚氨基酸;葡聚糖,和蛋白质譬如白蛋白。嵌段共聚物也是适用的,例如,聚环氧乙烷-聚环氧丙烷-聚环氧乙烷(PEO-PPO-PEO)三嵌段共聚物(例如,Pluronic_F68);及其类似物;参见,例如,美国授权专利6,923,986。各种出版物讨论了穿越血脑屏障的其它方法,包括,e.g.,Chenetal.(2004)Curr.DrugDelivery 1:361-376。
在一些具体实施方式中,本发明官能化磁性纳米颗粒包括一种或更多种用于逃避网状内皮组织***(RES)的药剂。用于逃避RES的药剂包括,但不限制于,嵌段共聚物非离子表面活性剂譬如泊洛沙姆,譬如泊洛沙姆508,泊洛沙姆908,泊洛沙姆1508,等。在一些具体实施方式中,本发明官能化磁性纳米颗粒包括大约1%的泊洛沙姆。
纳米颗粒也可以通过利用存在于血脑障壁(BBB)中的特殊的传输通道穿越血脑屏障(BBB)。作为一个非限制的例子,将α-甲基色氨酸附着于纳米颗粒可使色氨酸通道被这些微粒所接受并协助穿越BBB释放。其它机理是在或不在存在于BBB的通道的协助下的细胞摄入效果(transcytosis)和血球渗出。
可通过神经外科技术将本发明官能化磁性纳米颗粒释放至中枢神经***(CNS)。在重症患者的情况下,譬如事故受害者或那些遭受各种各样痴呆的病人,尽管伴随风险,外科干预仍是有保障的。例如,可将本发明官能化磁性纳米颗粒通过直接物理手段(譬如心室内或胸内注射)介入CNS。心室内注射可借助一支心室内的导管进行,该导管例如附着有一个储存槽,譬如脑室(Ommaya)储存槽。介入方法也可通过再充电或生物可分解的设备提供。其它方法是用能够增加血脑屏障渗透性的物质破坏血脑屏障。例子包括在动脉中注入扩散性很差的物质譬如甘露醇,增加脑血管渗透性的药物,如足叶乙甙,或血管作用剂例如白三烯。参见NeuweltandRappoport(1984)Fed.Proc.43:214-219;Babaetal.(1991)J.Cereb.Blood FlowMetab.11:638-643;和Gennuso et al.(1993)Cancer Invest.11:638-643。
进一步,需要将本发明官能化磁性纳米颗粒给药至需要诊断或治疗的局部区域;这可以通过例如,在手术期间局部注入,通过注射,通过导管,或通过植入管(所述的植入管是多孔,非多孔的,或是凝胶状材料,包括膜,譬如硅橡胶膜,或纤维)。
本发明官能化磁性纳米颗粒也可通过使用包括化学改性这样的药物学技术来传输,从而使本发明官能化磁性纳米颗粒穿透血脑屏障。可对本发明官能化磁性纳米颗粒进行改性以增加纳米颗粒的憎水性,降低纳米颗粒的净电荷或分子量,或者对纳米颗粒进行改性,以使其能与通常能穿越血脑屏障的药剂相似。参见Levin(1980)J.Med.Chem。23:682-684;Pardridge(1991)在:对大脑的肽类药物的传输;和Kostis等(1994)J.Clin.Pharmacol.34:989-996。
将本发明官能化磁性纳米颗粒封闭在一个疏水环境(譬如脂质体)里也有助于将药物传输至CNS。例如WO91/04014描述了一种脂质体传输***,药物被包封在脂质体之内,该脂质体中加有通常要传输穿透血脑屏障的分子。
另一种配制本发明官能化磁性纳米颗粒以穿过血脑屏障的方法是将本发明官能化磁性纳米颗粒包封在环糊精里。可使用能通过血脑屏障的任何适当的环糊精,包括但不限于,α-环糊精,β-环糊精及其衍生物。参见,美国专利5,017,566,5,002,935和4,983,586。这样的组合物也可如美国专利5,153,179所述包括丙三醇衍生物。
在一些具体实施方式中,本发明官能化磁性纳米颗粒能进入大脑的细胞,例如,横渡细胞膜并进入细胞的细胞质。进入大脑细胞的机理包括,例如,借助或不借助膜管道的细胞摄入(transcytosis)和血球渗出。
治疗药剂
在一些具体实施方式中,本发明官能化磁性纳米颗粒进一步包括一种或更多种的治疗药剂,用于传输至组织(例如,用于有目标地传输至一个具体组织,譬如患病的脑组织、一个患病的血管组织,或一个患病的骨组)。治疗药剂的本质将部分地取决于要治疗的状态和病理学。例如,当失调是癫痫症时,适当的治疗药剂包括,但不限于抗惊厥药物。当失调是脑瘤,适当的治疗药剂包括,但不限于,抗肿瘤药。那当失调是血管组织或骨组织的一个炎症时,适当的治疗药包括,但不限于,抗炎药。
适当的治疗药剂包括,但不限于,作用于突触神经和神经效应器的连接位点的药物;总体的和局部的镇痛药和麻醉剂譬如阿片类镇痛药和抑制剂;***和镇静剂;用来精神失常的治疗的药物譬如抑郁,精神***症;抗癫痫药和抗惊厥剂;亨廷顿病、衰老和阿尔茨海默氏病;神经保护药剂(譬如兴奋性氨基酸拮抗剂和亲神经的因子)和神经再生药剂;营养因子譬如大脑产生的神经营养因子、纤毛神经营养因子,或神经生长因子;用于CNS精神创伤或打击的治疗的药物;对成瘾和滥用毒品的治疗的药物;内分泌物和抗炎药物;用于寄生传染和微生物疾病的化学治疗剂;免疫抑制的药剂和抗癌药物;激素和激素拮抗剂;重金属和重金属拮抗剂;非金属毒性药剂的拮抗剂;对癌症治疗的抑制细胞生长的药剂;放射治疗免疫活性和免疫反应性药剂;和一系列其它药剂譬如递质(transmitters)和它们的各自受体激动剂和抑制剂、它们的各自前体或代谢产物;抗生素,镇痉药,抗组胺剂,止吐剂,止恶心药,***,“正义”和”反义”低聚核苷酸、脑血管扩张药、精神调理药物、抗狂躁药、血管扩张剂和收缩剂、抗高血压药、偏头痛治疗剂、***、升糖或降糖药剂、矿物或营养药剂、减肥药物、合成代谢和抗过敏剂。
一系列适当的治疗药剂在Gilmanetal.(1990)“Goodmanand Gilman’s-ThePharmacological Basis of Therapeutics”,Pergamon Press,NewYork,中被描述,并且包括以下药剂:
乙酰胆碱和合成的胆碱酯类、天然的拟胆碱生物碱和它们的合成的类似物、胆硷酯抑制剂药剂、神经节的***、颠茄碱、东莨菪碱和相关的抗蕈毒碱型乙酰胆碱受体药物,儿茶酚胺和拟交感神经效果的药物,譬如肾上腺素、降肾上腺素和多巴胺、肾上腺素能的受体激动剂、肾上腺素能的受体拮抗剂、递质譬如GABA,氨基乙酸、谷氨酸、乙酰胆碱、多巴胺、5-羟色胺,和组胺,神经激动肽;镇痛药和麻醉剂譬如阿片镇痛药和拮抗剂;预先麻醉和麻醉的药物譬如苯二氮平类、巴比土酸盐、抗组胺、酚噻嗪类和丁基苯酚;阿片类;止吐药;抗副交感神经的药物譬如颠茄碱、东莨菪碱或格隆溴铵;***;氯荃衍生物;氯乙基戊烯炔醇;导眠能;甲乙哌酮;安宁片;三聚乙醛;双琉醒;***、芬太尼和纳洛酮;中枢兴奋性止咳药;精神病学的药物譬如酚噻嗪类、硫杂蒽类和其它杂环化合物(例如,halperiodol);三环的抗抑郁剂譬如去甲丙咪嗪和丙咪嗪;非典型抗抑郁剂(例如,氟西汀和曲唑酮),单胺氧化酶抑制剂譬如异卡波肼;锂盐;抗焦虑药譬如利眠宁和苯甲二氮卓;抗癫痫药包括乙内醢尿、抗惊厥的巴比土酸盐、iminostibine(譬如痛可宁),琥珀酰亚胺、丙戊酸、噁唑烷双酮类和苯二氮卓类;抗帕金森药物譬如L-DOPA/CARBIDOPA、D2和D3受体激动剂和拮抗剂、阿朴***、金刚烷胺、麦角灵、司来吉兰、罗匹尼罗、甲磺酸溴隐亭和抗副交感神经的药剂;抗痉挛药剂譬如贝可芬,苯甲二氮卓和丹曲洛林;神经保护药剂,譬如兴奋氨基酸拮抗剂,神经营养因子和脑源的神经营养因子、纤毛神经营养因子,或神经成长因子;神经营养因子(NT)3(NT3);NT4和NT5;神经节苷酯;神经再生药物;用于成瘾和滥用毒品治疗的药物包括阿片拮抗剂和抗抑郁剂;内分泌和抗发炎药物譬如组胺、缓激肽、胰激肽和他们的各自激动剂和桔抗剂;寄生传染和微生物疾病的化学治疗剂;抗癌药物包括烷基化的药剂(即,亚硝基脲)及抗代谢物;氮芥、乙基烯胺和甲基三聚氰胺;烷基硫磺酸盐;叶酸类似物;嘧啶类似物,嘌呤类似物,长春碱;和抗生素。
官能片段
各种各样的官能团(片段)可附着在磁性纳米颗粒上。适合附着在磁性纳米颗粒上的官能团直接地或间接地、各不相同地或有选择性地结合在具体的预先选定的脑组织、血管组织,或骨组织结合上。如上所述,在一些具体实施方式中,官能团是治疗药剂。
术语“各不相同地结合”或“有选择性地结合”在具体的组织(例如,脑组织、一个血管组织,或骨组织)上是指官能化磁性纳米颗粒以这样的方式结合至第一组织上,即与第一脑组织,血管组织,或骨组织的结合可区别于与第二脑组织,血管组织,或骨组织的结合。例如,在一些具体实施方式中,本发明官能化磁性纳米颗粒以这样的方式与第一脑组织结合,即其与第一脑组织的结合可以区别于与第二脑组织的结合。在其它具体实施方式中,本发明官能化磁性纳米颗粒以这样的方式与第一血管组织结合,即它与第一血管组织的结合可与第二血管组织的结合相区别。在其它具体实施方式中,本发明官能化磁性纳米颗粒以这样的方式与第一骨组织相结合,即它与第一骨组织的结合可以与第二骨组织的结合相区别。
举一个例子,在一些具体实施方式中本发明官能化磁性纳米颗粒与第一脑组织相结合的亲和力是与第二脑组织相结合的亲合力的大约至少20%,大约至少30%,大约至少40%,大约至少50%,大约至少70%,大约至少90%,大约至少2倍,大约至少2.5倍,大约至少3倍,大约至少4倍,大约至少5倍,大约至少10倍,或大约至少50倍,或更高。作为另一个例子,在一些具体实施方式中,本发明官能化磁性纳米颗粒与第一血管组织相结合的亲和力是与第二血管组织相结合的亲合力的大约至少20%,大约至少30%,大约至少40%,大约至少50%,大约至少70%,大约至少90%,大约至少2倍,大约至少2.5倍,大约至少3倍,大约至少4倍,大约至少5倍,大约至少10倍,或大约至少50倍,或更高。举一个例子,在一些具体实施方式中,本发明官能化磁性纳米颗粒与第一骨组织相结合的亲和力是与第二骨组织相结合的亲合力的大约至少20%,大约至少30%,大约至少40%,大约至少50%,大约至少70%,大约至少90%,大约至少2倍,大约至少2.5倍,大约至少3倍,大约至少4倍,大约至少5倍,大约至少10倍,或大约至少50倍,或更高。
在一些具体实施方式中,所述第一脑组织是患病的脑组织;所述第二脑组织是正常非患病的脑组织。在其它具体实施方式,所述第一脑组织是正常(非患病的)脑组织;所述第二个组织是患病的脑组织。在其它具体实施方式中,所述第一脑组织是第一组织类型的第一非患病的脑组织;所述第二脑组织是第二种组织类型的第二非患病的脑组织。在其它具体实施方式中,所述第一脑组织是在受到外在或内部刺激物刺激以后的脑组织;所述第二脑组织是在受到外在或内部刺激物刺激以后的同一个脑组织。
在一些具体实施方式中,所述第一血管组织是一个患病的血管组织;所述第二个血管组织是一个正常的非患病的血管组织。在其它具体实施方式中,所述第一血管组织是一个正常(非患病的)血管组织;所述第二个组织是一个患病的血管组织。患病的血管组织包括,例如,发炎的血管组织,例如,炎症反应发生在血管组织或者血管组织附近。在其它具体实施方式中,第一血管组织是由于任意外部或内部原因受危害之前的一个血管组织;第二个血管组织是由于任意外部或内部原因受危害之后的同一血管组织。受危害的血管组织是患病的或以任意方式受干扰的血管组织,从而它至少有一个生理参量与正常血管组织不同。发炎的血管组织是受危害的血管组织的例子。
在一些具体实施方式中,第一骨组织是一个患病的骨组织;第二个骨组织是一个正常的非患病的骨组织。在其它具体实施方式中,第一骨组织是一个正常(非患病的)骨组织;第二骨组织是一个患病的骨组织。患病的骨组织包括,例如,发炎的骨组织,例如,炎症反应发生在骨组织或者骨组织附近(例如,在发炎的骨中骨破坏引起再吸收的失常譬如骨关节炎、类风湿病的关节炎、糖尿病,及类似疾病)。在其它具体实施方式中,第一骨组织是由于任意外部或内部原因受危害之前的一个骨组织;第二个骨组织是由于任意外部或内部原因受危害之后的同一骨组织。受危害的骨组织是患病的或以任何方式受干扰的骨组织,从而它至少有一个生理参量与正常骨组织不同。
在一些具体实施方式中,官能片段是一个对患病的脑组织比对非患病的正常脑组织有更大的亲合力的片段。在其它具体实施方式中,官能片段是一个对正常脑组织比对患病的脑组织有更大亲合力的片段。在一些具体实施方式中,官能片段是一个对第一非患病的脑组织比对第二非患病的脑组织有更大亲合力的片段。在其它具体实施方式中,所述官能片段是一个对在受到外在或内部刺激物刺激以后的第一脑组织比在受到外在或内部刺激物刺激以前的同一脑组织具有更大的亲合力的片段。
在一些具体实施方式中,官能片段是一个对患病的血管组织比对非患病的正常血管组织有更大的亲合力的片段。在其它具体实施方式中,官能片段是一个对正常血管组织比对患病血管组织有更大的亲合力的片段。在其它具体实施方式中,官能片段是一个对由于任意外部或内部原因受危害之后的第一血管组织比对由于任意外部或内部原因受危害之前同一血管组织有更大的亲合力的片段。
在一些具体实施方式中,官能片段是一个对患病骨组织比对非患病的正常骨组织具有更大亲合力的片段。在其它具体实施方式中,官能片段是一个对正常骨组织比对患病骨组织有更大的亲合力的片段。在其它具体实施方式中,官能片段是一个对由于任意外部或内部原因受危害之后的第一骨组织比对由于任意外部或内部原因受危害之前同一骨组织有更大的亲合力的片段。
合适的官能团包括,但不限于,与存在于脑,血管,或骨组织的中的抗原决定基特异性结合的抗体;与存在于脑,血管,或骨组织细胞的质膜上的受体特异性结合的配基,与存在于脑,血管,或骨组织细胞的细胞质上的受体特异性结合的配基,与存在于脑组织,或脑,血管,或骨组织的细胞上的成分特异性结合的受体或受体片断,及其类似物。例举性的非限制性官能团包括抗体;神经传送体(例如,GABA,谷氨酸、NMDA、***制剂、***制剂类似物、5-羟色胺、5HTlA,MPPA,等等);细胞活素(例如,白介素,譬如IL-I至IL-16,IFN-γ,IFN-α,IFN-β);受体拮抗剂;及类似物。当官能团是抗体时,适当的抗体包括抗体整体(例如,IgG),抗体片断,譬如Fv,F(ab’)2和Fab,虚拟抗体,及类似物。
患病的组织(例如脑组织、血管组织,或骨组织)可以用本发明官能化磁性纳米颗粒成像。患病的脑组织可以成像的神经学疾病和失常包括,但不限于,脑瘤;多发性硬化症(MS);德维克病(德维克综合症或视神经脊髓炎);HIV(HIV)传染;华勒变性;癫痫症;帕金森氏病;亨廷顿病;肌萎缩侧索硬化症(ALD);阿尔茨海默病(AD);费特-雅各布氏病(CJD);药物依赖失调,例如,对抗抑郁剂的依赖、抗焦虑药化合物、***化合物,或其它对神经起显著效果的化合物;精神失常譬如双极心情失常、精神***症,及类似症状;等。
可以用本发明官能化磁性纳米颗粒成像的血管疾病和失调包括,但不限于,通过血管手术由于再接合或移植引起的炎症和/或再狭窄,或由于疾病(譬如糖尿病)引起的周边或中央血管***炎症疾病。
可以用本发明官能化磁性纳米颗粒成像的骨疾病和改变包括,但不限于,由于糖尿病或化学制品或药物,以及源自骨组织的整形疾病或移动骨组织引起的炎症反应。
在一些具体实施方式中,官能片段是以更高或更低的亲合力与在脑中的癫痫组织相结合的片段。这种官能片段的非限制性的例子有:
1)葡萄糖或葡萄糖衍生物譬如氟去氧葡萄糖(fludeoxyglucose),与正常的非癫痫的组织相比,葡萄糖被癫痫的组织有差别地摄取了;
2)N-甲基-D-天门冬氨酸(NMDA),根据在细胞上的NMDA受体的增量或减少,NMDA与癫痫组织细胞的受体有差别地结合,;
3)α-甲基色氨酸,α-甲基色氨酸在儿童的难处理的带有结节硬化的癫痫中被癫痫结节选择性地摄取;
4)细胞因子譬如肿瘤坏死因子(TNF),和白介素譬如IL-1,IL-6,和IL-10,在癫痫组织上的IL-1受体、IL-6受体,或IL-10受体的表达增加,会导致与IL-I结合的磁性纳米颗粒或IL-6共轭的磁性纳米颗粒更多;
5)γ-氨基丁酸(GABA),GABAA(GABAA-α 1-6,GABAA-β 1-3,GABAA-γ 2,GABAA-δ,和GABAA-ε)受体的水平,通过显著改变在齿状回和海马趾构成的其它部份的受体亚基的表达,发生神经退行性导致的受体丢失,显示GABAA受体生理和药理的改变;
6)***制剂或阿片譬如阿芬太尼,丁丙诺啡,甲氧基芬太尼,可待因,双氢可待因,二丙诺啡,埃托啡,芬太尼,***,氢可酮,氢***酮,LAAM,左啡诺,***,美撒痛,***,纳洛酮,纳曲酮,β-羟基-3-甲基芬太尼,羟考酮,羟***酮,丙氧吩,瑞芬太尼,舒芬太尼,痛立定、曲马多,及其类似物;
7)5-羟色胺,例如,5-羟色胺1A(5HTlA),和其它5-羟色胺受体竞争剂;
8)3-甲基磷酸亚基丙酸(MPPA);
9)苯(并)二氮类,譬如氟吗西尼,氯羟去甲安定,苯甲二氮卓,阿普***,溴替***,利眠宁,服利宁,氯硝西泮,氯拉卓酸,地莫西泮,舒乐安定,氟西泮,哈拉西泮,咪唑安定,硝西泮,去甲西泮,去甲羟基安定,普拉西泮,夸西泮,羟基安定,和***仑;
10)谷氨酸;和
11)乙酰胆碱和其它乙酰胆碱受体竞争剂。
在一些具体实施方式中,所述官能片段是对多巴胺神经末梢有差别地结合的片段(例如,D2和D3激动剂和拮抗剂)。***识别位点定位在多巴胺转运器上,其转运器自身定位在多巴胺神经末梢。因此结合在这些点位上的药物的潜在用途包括:(i)作为神经退行性失常的成像探针;和(ii)作为多巴胺转运器/***结合位点的成像探针。与多巴胺神经末梢特异性结合的合适的官能片段包括N-卤代烯丙基去甲茛菪烷衍生物,譬如Iodoaltropane。参见,例如,美国专利5,853,696以这样衍生物为例。用N-卤代烯丙基去甲茛菪烷衍生物官能化的官能化磁性纳米颗粒适用于与多巴胺神经末梢有关联的神经退行性失常的成像,这样的失常包括帕金森病。
适当的官能片段包括对阿尔茨海默病(AD)相关联的病变脑组织的差异性结合的片段。适当的官能片段包括与β-淀粉样斑块差异性结合的片段,与神经原纤维缠结(NFT)差异性结合的片段;与CCRl受体差异性结合的片段(参见,例如,在美国专利6,676,926中描述的化合物)等。适当的官能片段包括,但不限于,在美国专利6,274,119中描述的化合物;β-淀粉样蛋白的抗体,NFT的一个构成的抗体,及其类似物。
适当的官能片段包括对脑瘤差异性结合的片段,例如,差异性结合在脑瘤细胞的表面表达的抗原决定部位上。脑瘤标志包括神经胶质瘤、星形细胞瘤的标志,及其类似物。参见,例如,Luetal.(2001)Proc.Natl.Acad.ScI USA 98:10851;Boonetal.(2004)BMC Cancer 4(1):39。
适当的官能片段包括与受多发性硬化症影响的脑组织差异性结合的片段,包括表达在单核细胞和/或CD4+T细胞的表面的片段,所述细胞调节了MS的病理学,而且可在脑或其它被MS影响的CNS组织附近找到。
合适的官能片段包括,与受外在或内部刺激之前的脑组织相比,与受外在或内部刺激以后的同样脑组织差异性结合的片段。这种官能片段包括与受体(例如,细胞表面受体)结合的抗体,所述受体在受外在或内部刺激以后上调(up-regulated);包括结合在受体上的受体配基,所述受体在外在或内部刺激以后上调;包括结合在受体(例如,细胞表面受体)上的抗体,所述受体在外在或内部刺激以后下调;包括结合在受体上的受体配基,所述受体在外在或内部刺激以后下调;及类似情况。外在和内部刺激包括,但不限制于,电子刺激;药物,例如,对神经起显著效果的化合物,抑制剂(阿片样物质、合成麻醉剂譬如甲氧基芬太尼,巴比土酸盐、格鲁米特、甲乙哌酮、氯乙基戊烯炔醇、***,酒精);抗焦虑药(氟吗西尼、苯甲二氮卓、利眠宁、阿普***、去甲羟基安定,羟基安定);***(安非他明、脱氧麻黄碱,***);和迷幻剂(LSD,酶斯卡灵,佩约特仙人掌,***;及类似物;声;热;光;想法;压力;及类似物。
组合物
本发明还提供组合物(包括药物组合物),它包括本发明官能化磁性纳米颗粒。含有本发明官能化磁性纳米颗粒的组合物还包括一种或多种下列组分:盐;缓冲液;pH调节试剂;非离子洗涤剂;蛋白酶抑制剂;核酸酶抑制剂;及类似物。
含有本发明官能化磁性纳米颗粒的药物组合物包括一种或更多种药学上可接受的载体。本文中术语“药学上可接受的载体”包括任何材料,当与组合物的活性成分结合时,它能使该成分保留生物活性并且不会导致主体的免疫***或其它生理功能的失常反应。例子包括,但不限于,任何标准的药物载体譬如磷酸盐缓冲生理盐水,水、乳化液譬如油/水乳状液,和各种各样的类型湿药剂。用于气雾剂或肠外给药的例举性稀释剂有磷酸盐缓冲的生理盐水或普通的(0.9%)生理盐水。包含这种载体的组合物是由公知的常规方法配制的(参见,例如,雷明顿制药科学,43章,第14版.,Mack出版Col,EastonPA18042,美国)。药学上可接受的赋形剂详细地描述在各种出版物里,包括,例如,A.Gennaro(2000)“雷明顿:药房,“科学和实践;第20编辑,Lippincott,威廉斯,&Wilkins;Remington’s配药科学、第14位Ed.或晚版,Mack出版Col,EastonPA18042,美国;配药剂量表和药物传输***(1999)H.C。Ansel等,eds.,7编辑,Lippincott,威廉斯,&Wilkins;并且配药赋形剂(2000)A.H.Kibbe手册等,eds.,3编辑。美国制药协会。
本发明官能化磁性纳米颗粒可以通过溶解,悬浮或乳化在水性或非水性的溶剂(譬如植物油或其它相似的油,合成的脂肪酸甘油酯、高级脂肪酸酯或丙二醇)中配制成注射用制剂;并且如果需要,可加入常规添加剂譬如增溶剂、等渗剂、悬浮剂、乳化剂、稳定剂和防腐剂。
穿越血脑屏障的官能化磁性纳米颗粒的制造方法
本发明还提供能穿越血脑屏障(BBB)的本发明官能化磁性纳米颗粒的制造方法。该方法一般包括将官能团直接地或通过连接剂附着在磁性纳米颗粒上。在一些具体实施方式,磁性纳米颗粒涂覆有一层层,官能团或连接剂共价地或非共价地附着在该层上。能穿越BBB的官能化磁性纳米颗粒可用几个方式中的任一个制备。
在一些具体实施方式中,官能化磁性纳米颗粒进一步包括附着在该官能化磁性纳米颗粒上的载脂蛋白(例如,apoA,apoB,或apoE)。载脂蛋白用于与BBB的内皮细胞结合,因而使官能化磁性纳米颗粒能穿越BBB。
在一些具体实施方式中,还通过将人血清白蛋白和/或载脂蛋白附着在官能化磁性纳米颗粒上对官能化磁性纳米颗粒进行进一步加工。人血清白蛋白(HSA)通过乙酰基,通过氨基,通过聚(乙二醇)(PEG)连接剂,或通过硫醇键被共价地或非共价地(例如,通过离子的相互作用)结合在官能化磁性纳米颗粒上。载脂蛋白或它的一个功能片段共价地或非共价地附着在人血清白蛋白上。参见,例如,Muller和Keck((2004)J Nanosci.Nano technol.4:471);和Kreuter等((2002)J 靶向药物,10:317)。载脂蛋白的氨基酸序列在本领域是公知的;例如,apoE多肽的氨基酸序列可在,GenBankAxxession Nos.AAD02505;和AAB59397中找到。
如下所述,在一些具体实施方式中官能化的磁性纳米颗粒被包封在人血清白蛋白基质中。
在其它具体实施方式中,官能化磁性纳米颗粒还包括通过吐温80附在官能化磁性纳米颗粒上的载脂蛋白。在一些具体实施方式中,通过将吐温80共价或非共价地附着在官能化磁性纳米颗粒上对该官能化磁性纳米颗粒进行进一步加工。在一些具体实施方式中,通过乙酰基,通过氨基,通过PEG连接剂,或通过硫醇键将吐温80直接地附着在包被层上。载脂蛋白被共价地或非共价地附在吐温80上。
在其它具体实施方式中,官能化磁性纳米颗粒同聚(丁基氰基丙烯酸酯)(PBCA)微粒结合(例如,吸附,共价连接,非共价连接)在一起,例如,官能化磁性纳米颗粒被吸附在PBCA微粒的表面上。在其它具体实施方式中,官能化磁性纳米颗粒包括共价地或非共价地附着在官能化磁性纳米颗粒上的吐温80;并且还包括聚(氰基丙烯酸丁酯)。
结合入微生物
在一些具体实施方式中,官能化磁性纳米颗粒或非官能化磁性纳米颗粒被结合入微生物,例如,细菌或病毒。含有官能化或非官能化磁性纳米颗粒的微生物适用于在体内观察(成像)这种微生物的位置和/或运动。
MRI可见的药物传输***
本发明提供一个磁共振成像(MRT)-可看见的药物传输***;以及其合成方法。本发明MRI-可见的药物传输***,如上所述,含有官能化磁性纳米颗粒,所述官能化磁性纳米颗粒包含至少一种药物(例如,一种治疗药剂)。在一些具体实施方式中,本发明MRI-可见的药物传输***适用于确定一种药物在身体中的分布。在其它具体实施方式中,本发明MRI-可见的药物传输***适用于组织特异性药物传输。例如,当本发明官能化磁性纳米颗粒不仅包括组织特异性结合片段还包括一个治疗药剂时,所述官能化磁性纳米颗粒是一个组织特异性的药物传输***。在一些具体实施方式中,本发明药物传输***适于穿越BBB,例如,药物传输***包括用于穿越BBB的一个或更多个元素。
作为一个非限制性的例子,第一官能团用来与一个在脑中的癫痫组织结合;第二个官能团是癫痫症的一种治疗药剂。癫痫症的一种治疗药剂包括,但不限于,地仑丁(硫酸二苯乙内酰脲);立痛定(卡巴咪嗪);抗癫灵(2-丙基戊酸钠);柴朗丁(乙琥胺);利福全(氯硝西泮);服利宁(clobazepam);及类似物。
实用性
本发明还提供本发明官能化磁性纳米颗粒具有实用性的各种用途,包括研究应用,诊断应用,以及治疗应用。
诊断方法
本发明提供用于识别或检测特异性的脑组织的诊断方法。该方法一般包括对个体给药本发明官能化磁性纳米颗粒;并且对官能化磁性纳米颗粒所结合的脑区域成像。通常,将一种包含本发明官能化磁性纳米颗粒的液体药物组合物被注射入个体(例如,静脉内注射);并用成像技术检测该官能化磁性纳米颗粒。在许多具体实施方式中,所述成像是磁共振成像。本发明方法允许对一个活的主体的特定脑组织成像。本发明方法允许对脑内的患病组织进行检测,也为医师提供一个监测患者为疾病所接受治疗的进展的方式。
本发明诊断方法对诊断一种神经学疾病的出现和/或为监测个体对为一种神经学疾病或失常进行的治疗的反应是有用的,疾病包括,但不限于,脑瘤;多发性硬化症(MS);癫痫症;帕金森病;亨廷顿病;肌肉萎缩侧向硬化症(ALD);德维克病;阿尔茨海默氏病(AD);费特-雅各布氏病(CJD);大脑皮层发育异常;Rasmussen脑炎;药物依赖失调;例如,对抗抑郁剂的依赖、抗焦虑药化合物、***化合物,或其它对神经起显著效果的化合物;精神失常譬如双极心情失常、精神***症,及类似症状;等。
本发明提供识别血管组织再狭窄危险的方法。该方法一般包括对个体给予本发明官能化磁性纳米颗粒;并对官能化磁性纳米颗粒所结合的血管组织成像。在一些具体实施方式中,血管组织是用,与正常血管组织相比,带有与发炎的血管组织特异性结合的官能团的官能化磁性纳米颗粒成像的。在一些具体实施方式中,所述官能团是一种炎症细胞因子,或与该炎症细胞因子相结合的一个片段(例如,它的抗体或抗原的片段)。适当的细胞因子包括IL-I至IL-16,和TNF-α。
另外,用未共轭磁性纳米颗粒载带的免疫学活性细胞结合在血管组织表面,并可在本发明方法中用来识别血管组织,例如,患病的血管组织。适当的细胞包括单核细胞,T细胞(例如,CD4+T细胞),及其类似物。
本发明也提供用于检测在个体中患病的骨组织的方法。该方法一般包括对个体给予本发明官能化磁性纳米颗粒;并且对官能化磁性纳米颗粒所结合的骨组织成像。在一些具体实施方式中,骨组织是用带有能与患病的骨组织特异性结合的官能团的官能化磁性纳米颗粒成像的。在一些具体实施方式中,所述官能团是一种炎症细胞因子,或与该炎症细胞因子相结合的一个片段(例如,它的抗体或抗原的片段)。适当的细胞因子包括IL-I至IL-16,和TNF-α。
另外,用未共轭磁性纳米颗粒载带的免疫学活性细胞结合在骨组织表面上,并可在本发明方法中用来识别骨组织,例如,患病的骨组织。适当的细胞包括单核细胞,T细胞(即,CD4+T细胞),及其类似物。
本发明更进一步提供用于检测个体患病的血管或骨组织(例如,由炎症影响的血管组织或由炎症影响的骨组织)的方法。该方法一包括对个体给予未官能化的磁性纳米颗粒,使所述磁性纳米颗粒与发炎的血管组织或发炎的骨组织结合;使用成像技术譬如MRI为患病的血管或骨组织成像。
研究应用
本发明提供使用本发明官能化磁性纳米颗粒的研究应用。将本发明官能化磁性纳米颗粒注射入主体,并由成像检测官能化磁性纳米颗粒。研究应用包括检验一个指定的测试试剂在一种特殊疾病的效果。研究应用更进一步包括测试在正常和患病的脑组织的各种各样的外部和内部刺激的效果。研究应用更进一步包括测试在正常和患病的血管或骨组织各种各样的危害因素(外在或内部)的效果。
筛选方法
研究应用包括用于检验一个指定的测试药剂在一种特殊疾病中的效果的筛选方法。因而,在一些具体实施方式中,本发明提供了鉴别神经失常的候选治疗药剂的方法,该方法包括对患有神经性疾病实验性(非人)动物模型(例如,多发性硬化症、阿尔茨海默氏病、脑瘤,癫痫症,等的实验性动物模型)给药;并且确定该测试药剂对与神经失常相关的神经学特征的效果(如果有的话)。确定测试药剂的效果是通过对非人动物模型给予含有本发明官能化磁性纳米颗粒的组合物实现的,所述官能化磁性纳米颗粒显示出对受神经失常影响或其相关的患病脑组织的特异性结合;并且检测动物大脑中的官能化磁性纳米颗粒。检测通常是通过磁共振成像实现的。
与一种特殊神经失常相联系的神经学特征包括,例如,癫痫损害的大小(对癫痫症而言);由多发性硬化症影响脑区域的大小(对多发性硬化症而言);β淀粉样斑块的大小和/或数量、NFT的大小和/或数量(对阿尔茨海默氏病而言);脑瘤的大小(对脑瘤而言)等。各种各样神经失常的动物模型是现有技术已知的。例如,对于多发性硬化症(MS),实验性自动免疫的脑炎(EAE;文献中也称为实验性过敏脑炎)模型是一种啮齿目动物的多发性硬化症模型。AD的各种各样的老鼠模型是可用的;参见,例如,Buttini等(1999)J Neurosci。19(12):4867-80。
术语“候选药剂”,“诊断剂”,“药剂”“物质”和“化合物”在此可互换使用。候选药剂包含许多化学分类,典型地合成的,半合成,或天然产生的无机或有机分子。候选药剂包括那些在合成的或天然的化合物大数据库中发现的。例如,综合性复合化合物库是商业可得到从Maybridge化学制品公司(Trevillet,Cornwall,英国),ComGenex(南旧金山,加州),和MicroSource(New Milford,CT)。一个罕见化合物库是可得到从Aldrich(Milwaukee,Wis.)得到。另外,以细菌,霉菌,植物和动物萃取物的形式的天然化合物库是可从Pan实验室(Bothell,WA)得到的或是容易生产的。
候选药剂也可以是分子量超过50但小于大约2,500道尔顿的小的有机或无机化合物。候选药剂也可包括与蛋白质,尤其是氢键之间结构相互作用所必要的官能团,并可包括至少一个胺、羰基、羟基或羧基基团,和可包含至少二个功能化学基团。候选药剂也可包括被一个或更多上述官能团取代的碳环或杂环结构和/或芳香或多芳香族的结构。候选药剂也可在生物分子(包括肽、糖类、脂肪酸、类固醇、嘌呤、嘧啶、衍生物、结构类似物或其组合)中被发现。
筛选分析典型地包括空白对照组,适当的对照包括一个有神经失常的实验动物,并且没有治疗或给予测试药剂。
感兴趣的测试药剂是这样一种药剂,它能使神经学特征失常减少至少大约10%,至少大约20%,至少大约25%,至少大约30%,至少大约35%,至少大约40%,至少大约45%,至少大约50%,至少大约55%,至少大约60%,至少大约65%,至少大约70%,至少大约80%,至少大约90%,或更多(与没有测试药剂的空白对照相比较)。
本发明还适用于识别血管吻合的再狭窄造成的各种免疫反应介质,该血管吻合手术施用于需要该外科干预的周边和中央血管的各种外科疾病。通过对引起再狭窄的具体的吻合处进行MRI成像,利用它们与特别标记的磁性纳米颗粒的反应,本发明还适用于识别血管吻合后血管再狭窄的特异性预报物质。
本发明也用于通过MRI识别对由于糖尿病导致的骨的炎症和伤害引起的免疫反应的特殊介质。本发明还用于识别由于糖尿病导致的骨炎症和伤害的特定的预报物,它通过对可能有炎症和受伤的骨组织进行MR成像,利用它们与特别标记的磁性纳米颗粒(MNP)反应。
治疗应用
本发明提供治疗疾病,失常,或情况(condition)的方法,受伤方法一般包括对有需要的个体给予有效量的本发明官能化磁性纳米颗粒。在这些具体实施方式中,所述官能化磁性纳米颗粒包括一个治疗药剂(“药物”)和一个提供组织特异性导向(例如,导向患病组织)的官能片段。
在一些具体实施方式中,将包括本发明官能化磁性纳米颗粒的药物组合物给药给有需要的个体,所述官能化磁性纳米颗粒包括一个治疗药剂。在一些具体实施方式中,将包括本发明官能化磁性纳米颗粒的药物组合物给药给有需要的个体,所述官能化磁性纳米颗粒包含治疗药剂,用药途径是肠外的,例如,静脉注射,肌肉内,皮肤下,瘤内,颅内,瘤周,等。
有效量的本发明官能化磁性纳米颗粒是这样一种量,它至少足以改良疾病、失常,或情况。在一些具体实施方式中,有效量的本发明官能化磁性纳米颗粒是这样一种量,它能使至少一种疾病或失常症状的严重程度和/或影响减少至少大约10%,至少大约20%,至少大约25%,至少大约30%,至少大约40%,至少大约50%,至少大约60%,至少大约70%,至少大约80%,至少大约90%,或更多(与未用官能化磁性纳米颗粒治疗的个体的疾病或失常症状的严重程度和/或影响相比较)。
本发明官能化磁性纳米颗粒有效量取决于各种各样的因子,包括,例如,疾病、失常,或情况的本质;或疾病、失常,或情况的严重性或程度;年龄或其它个体的物理特性;及类似物。有效量包括,例如,从大约102到大约1018个官能化磁性纳米颗粒,例如,从大约102到大约103个官能化磁性纳米颗粒,从大约至大约103至大约104个官能化磁性纳米颗粒,从大约104至大约105个官能化磁性纳米颗粒,从大约105至大约106个官能化磁性纳米颗粒,从大约106至大约107个官能化磁性纳米颗粒,从大约107至大约108个官能化磁性纳米颗粒,从大约108至大约109个官能化磁性纳米颗粒,从大约109官能化磁性纳米颗粒至大约1010个官能化磁性纳米颗粒,从大约1010官能化磁性纳米颗粒至大约1012个官能化磁性纳米颗粒,从大约1012官能化磁性纳米颗粒至大约1014个官能化磁性纳米颗粒,从大约1014官能化磁性纳米颗粒至大约1016个官能化磁性纳米颗粒,或从大约1016官能化磁性纳米颗粒至大约1018个官能化磁性纳米颗粒。
单位剂量官能化磁性纳米颗粒将包含从大约102到大约1018个官能化磁性纳米颗粒,例如,从大约102到大约103个官能化磁性纳米颗粒,从大约103到大约104个官能化磁性纳米颗粒,从大约104到大约105个官能化磁性纳米颗粒,从大约105至大约106个官能化磁性纳米颗粒,从大约106至大约107个官能化磁性纳米颗粒,从大约107至大约108个官能化磁性纳米颗粒,从大约108至大约109个官能化磁性纳米颗粒,从大约109官能化磁性纳米颗粒至大约1010个官能化磁性纳米颗粒,从大约1010官能化磁性纳米颗粒至大约1012个官能化磁性纳米颗粒,从大约1012官能化磁性纳米颗粒至大约1014个官能化磁性纳米颗粒,从大约1014官能化磁性纳米颗粒至大约1016个官能化磁性纳米颗粒,或从大约1016官能化磁性纳米颗粒至大约1018个官能化磁性纳米颗粒。
在一些具体实施方式中,将给药多剂量的官能化磁性纳米颗粒。例如,给予单位剂量官能化磁性纳米颗粒每月一次给药,每月两次给药,每月三次,每隔一个星期(qow),每星期一次(qw),每星期两次(biw),每星期三次(tiw),每星期四次,每星期五次,每星期六次,每隔一天(qod),每日(qd),每日两次(qid),或每日三次(tid)。在一些具体实施方式中,官能化磁性纳米颗粒以任一个适当的频率给药,且给药一段时间范围,从大约一天至大约一个星期,从大约二个星期至大约四个星期,从大约一个月至大约二个月,从大约二个月至大约四个月,从大约四个月至大约六个月,从大约六个月至大约八个月,从大约八个月至大约1年,从大约1年至大约2年,或从大约2年至大约4年,或更久。
需要治疗的个体包括有任何各种各样的失常,包括特殊的脑或CNS失常的个体,例如,有MS的个体,癫痫症,帕金森病,等。需要治疗的个体包括有血管失常的个体,例如,由于糖尿病出现的血管失常;有或在再狭窄危险中的个体;及类似物。
本发明提供了治疗疾病,失常,或情况的方法,该方法一般包括对所需的个体给予有效量本发明官能化磁性纳米颗粒,所述官能化磁性纳米颗粒包括用于磁性纳米颗粒组织特异性导向的官能片段。在一些具体实施方式中,例如,疾病是癫痫症时,官能化磁性纳米颗粒包括用于将磁性纳米颗粒导向癫痫组织的官能片段。所述官能化磁性纳米颗粒给药给患有癫痫症的个体;官能化磁性纳米颗粒结合在癫痫组织上;通过电磁辐射对该组织加热,以消除患病的组织。所述电磁辐射包括,例如,从大约100千赫(千赫)至大约1000千赫的辐射。
实施例
提出以下实施例以便向本领域的普通技术人员完整地揭示和描述怎样使用本发明,并且不意味着限定发明者认可的范围,也不意味着下列试验是全部或者仅有的实验。努力保证用到的相关数字(例如,数量、温度,等。)的准确性,但允许一些实验错误和偏差。除非有别的说明,部分是以重量计的,分子重量是以分子平均重量计,温度是摄氏度,压力是在或接近大气压。也可使用标准简称,例如,bp,碱基对;kb,千对碱基;pi,皮升;s或sec,秒;min,分钟;h或hr,小时;aa,氨基酸;kb,千对碱基;bp,碱基对;nt,核苷;i.m.,肌肉的;i.p.,腹膜内的;s.c,皮下的;及类似表述。
实施例1:官能化磁性纳米颗粒的制备
纳米颗粒的制备
将200毫克人血清白蛋白(HSA)溶解在2.0ml含有磁性纳米颗粒(MNP;例如,磁铁矿微粒)的水里。在持续的搅拌之下滴加0.01M和0.1MNaOH溶液,使溶液的pH上升到8.4。在持续搅拌下滴加8.0ml乙醇使10%HSA溶液脱溶。加入乙醇后,加入235μl 8%的戊二醛溶液。在24h以后,得到的纳米颗粒提供三次离心(16.100g,8分钟)和再分散在水中进行纯化。在超声浴中进行再分散。使用该方法合成得到的HSA-MNP的平均直径大约60nm到大约990nm,依赖于制剂的pH和非共轭或共轭的磁性纳米颗粒的加入。AMT-MNP纳米颗粒平均直径大约20nm,并且其大小范围从大约10nm到大约40nm。
NeutrAvidinTM-改性纳米颗粒的制备
将NeutrAvidinTM结合至纳米颗粒
使用交联剂NHS-PEG3400-Mal(Nektar,汉茨维尔,美国;这里“NHS”是N-羟基琥珀酰亚胺,“Mal”是马来酰亚胺,和“PEG3400”是有3400道而顿平均分子量的聚(乙二醇))活化纯化的纳米颗粒,得到一个巯基活性的微粒***。将500μl容量的交联剂溶液(NHS-PEG3400-Mal,60mg/ml在PBS缓冲液中,pH8.0)加入2.0ml纳米颗粒(NP)分散液(20mg/ml在PBS缓冲液中,pH8.0)。混合物在室温下震摇1h来孵育。之后,将活化的纳米颗粒如上所述离心和再分散进行纯化。
随后,NeutrAvidinTM通过所述的异种双功能交联与活化的HSA-NP共轭。NeutrAvidinTM是非葡萄糖基化的抗生物素蛋白。将一份(10.0毫克)NeutrAvidinTM溶解于1.0ml TEA-缓冲液(pH8.0)并且加入1.2mg 2-亚氨基四氢噻吩(thiolane)(Traut’s试剂)在1.0mlTEA-缓冲液(pH8.0)中的溶液。在室温下经过12小时的孵育后,用尺寸排除色谱法(D-SaItTM脱盐柱)纯化该硫醇盐化的蛋白。为进行共轭,将1ml硫醇盐化的纯化的NeutrAvidinTM溶液加入1ml巯基活化的人血清白蛋白(HSA)纳米颗粒。混合物在室温下经过12小时的振摇后孵育。非反应的硫醇盐化的蛋白NeutrAvidinTM通过在水中使用NP离心法和再分散法而除去。分析离心步骤中的悬浮物通过分光光度计在280nm检测未偶合的NeutrAvidinTM。
NeutrAvidinTM改性纳米颗粒的ApoE表面修饰
ApoE的生物素化
为了使apoE能附着于NeutrAvidinTM改性的纳米颗粒,按照标准蛋白质改性规则用PFP-生物素(Pierce,Rockford,USA)对apoE进行生物素化。PFP生物素是生物素的五氟苯酚酯类。将ApoE以167μg/ml的浓度溶化在pH7.0的PBS中。生物素化蛋白质通过葡聚糖脱盐柱被从低分子重量化合物中分离出来。生物素化过程的效率由如下所述的western探针确定。
生物素化的apoE与NeutrAvidinTM改性的纳米颗粒的结合
将该载带药物的NeutrAvidinTM改性纳米颗粒以20mg/ml的微粒浓度再分散于水中。随后,加入167μg生物素化的apoE(生物素apoE)最终达到10mg/ml NP和80μg/ml apoE的最终浓度。在12小时孵育后,如下所述用免疫浸透法分析纳米颗粒上清液中的未结合的apoE。
纳米颗粒的药物载入
在乙醇/水溶液中用6.6毫克药物孵育大约20mg纯化的NeutrAvidinTM改性的HSA-MNP。在2小时的孵育期后,未结合的药物被离心法和再分散除去。
将apoE通过PEG交联剂共价结合在纳米颗粒上
用交联剂NHS-PEG3400-Mal活化HSA纳米颗粒,以便如上所述获得巯基活化的微粒***。随后,apoE与被活化的HSA纳米颗粒通过异种双官能交联而共轭。不同的apoE衍生物(apoE3,apoE2Argl42Cys,apoESendai)每种各取一份(500μg),分别溶解在1.0ml TEA-缓冲液(pH8.0)中,并且加入50倍摩尔浓度过量的2-亚氨基四氢噻吩(Traut’s试剂)。在室温下,12小时孵育后,硫醇盐化的蛋白被用尺寸排除色谱法(D-SaItTM色谱柱)纯化。为进行共轭,将500μg硫醇盐化和纯化的apoE加入25毫克巯基活化的HSA纳米颗粒中。混合物在室温下震摇孵育12小时。未反应的硫醇盐化的apoE通过离心和将颗粒再分散在乙醇/水(2.6%乙醇v/v)中而除去。
在乙醇/水中用6.6毫克药物孵育大约20毫克纯化的apoE改性HSA纳米颗粒。在2小时孵育后,未结合的药物被离心法除去。载入了药物的apoE-PEG纳米颗粒被再分散于水中。
聚山梨醇酯80包覆的HSA纳米颗粒的制备
通过如上所述通过使NeutrAvidinTM改性的纳米颗粒吸收药物,制备没有apoE但包被聚山梨醇酯80的纳米颗粒(NP)。然后,药物包被的纳米颗粒用吐温80(1%m/v)溶液孵育30分钟和被使用。
组织特异性配基改性HSA-MNP
组织特异性的配基(例如α-甲基色氨酸(AMT),神经传递素等)与在HSA中的游离的氨基酸或羧基基团结合,或通过多碳键(例如PEG)、通过硫醇键或其它附着片段与HSA中的游离的氨基酸或羧基基团结合。
聚(氰基丙烯酸丁酯)-MNP的制备
在连续搅拌下在10ml 0.001M HCl中加入0.1g稳定剂(葡聚糖70,000或Pluronic F68)。制备两种溶液:1)一种溶液是在10ml 0.001M HCl中含有0.1g葡聚糖70,000(Sigma-Aldrich);2)第二种溶液是在10ml 0.001M HCl中含有0.1gPluronic F68(Sigma,Inc.)。制备下述四种制剂:1)在Pluronic F68溶液中加入非官能化磁性纳米颗粒;2)在葡聚糖溶液中加入非官能化磁性纳米颗粒;3)在Pluronic F68溶液中加入官能化磁性纳米颗粒(AMT-MNP);4)在葡聚糖溶液中加入官能化磁性纳米颗粒。在500rpm的搅拌下,100μg氰基丙烯酸酯单体(Sicomet,Sichel-Werke,GmbH)被缓慢加入到每种制剂中,使之恰在液面之下。
维持搅动各种溶液2-2.5小时。在这个期间以后,通过加入990μl 0.1N NaOH中和各种溶液。最后,过滤各种溶液。
开始搅动以后在1分钟和30分钟之间,药物被加入溶液。
有Pluronic F68作稳定剂时,不添加表面活化剂。当葡聚糖用作稳定剂时,添加1毫克聚山梨醇酯80到100ml微粒溶液中。如上所述制备的官能化磁性纳米颗粒的直径的范围从大约80nm到大约350nm;并且zeta电位在-10mV和-50mV之间,例如,大约-30mV。
AMT-官能化磁性纳米颗粒的合成
如下制备用α-甲基色氨酸(AMT)官能化的包覆葡聚糖的磁赤铁矿(γ-Fe2O3)磁性纳米颗粒。
AMT的结构描述如下:
α-甲基色氨酸
葡聚糖聚合物的化学结构一般是:
反应被概要地描述如下:
□-C-Br+H2O→□-C-OH
其中,
□-C代表AMT;并且”D”代表葡聚糖。
AMT通过下述的α-亚甲基基团被结合在磁性纳米颗粒表面。
改性的AMT被描述如下:
其中,X是Hal,SH,NH2,或用于附着的其它基团。
官能化磁性纳米颗粒的TEM成像
图3A-3D描述了在HSA基质中如上所述制得的AMT-MNP的透射电子显微镜(TEM)照片。图3A描述一个HSA-MNP微粒;显示了HSA(空心箭头)和AMT-MNP(箭头)。图3B描述了在HSA基质中的AMT-MNP微粒。图3C描述磁性纳米颗粒的另一种分布;图3D描述了在图3C中黒框区域的放大图,显示了在磁性纳米颗粒的核心中存在磁性微粒(TEM密集的地区,空心箭头)。图4A和4B描述了如上所述制得的PBCA-MNPTEM的显微照片。图4A描述PBCA微粒(空心箭头)并且AMT-MNP(箭头)被吸附在PBCA微粒的表面。图4B是图4A黒框的放大图。在图4B中描述的放大图显示AMT-MNP(箭头)吸附在PBCA微粒表面。
实施例2:官能化磁性纳米颗粒的体内特征
向一个癫痫症的红藻氨酸(KA)模型给予非官能化磁性纳米颗粒和AMT共轭的磁性纳米颗粒。数据显示出,AMT-MNP显示出对癫痫组织的亲合力。
向二只刘易斯大鼠(90天大)的右侧海马状突起区注射1μl KA溶液。注射KA后大鼠立刻开始了癫痫状态。癫痫状态大约在注射KA后48个小时停止。一天注射KA 3次,使用T2序列(TR=6000ms;TE=50ms;切片厚度=1.5毫米;空隙距离=0.25毫米),获得基线MRI。在获得基线MRI后,对第一只大鼠注射(i.v.)AMT-MNP(300μmol/kg)并且对第二只鼠注射了(i.v.)非官能化MNP(300μmol/kg)。在各只大鼠被注射了与MNP之后6个小时重复MRI。
图2A显示了第一只大鼠的基线MRI;图2B显示了在AMT-MNP治疗的大鼠中的位点在CAl(上部箭头)和对侧的齿状回(下部箭头)区域的(阴性)增强。这些变化是用非官能化磁性纳米颗粒治疗的同样制得的大鼠没有的(图2C和2D)。在AMT-MNP-治疗的大鼠中的对侧CAl上和齿状回中的信号变化与急性癫痫症相关的组织变化是一致的。这些数据暗示AMT-MNP对癫痫的组织的亲合力。
图2B也显示了在右边同身侧海马区的KA注射位点的(阴性)增强(白色箭头)区域。图2C展示了非官能化磁性纳米颗粒治疗的大鼠的基线MRI。图2D显示了在右边同身侧海马区的KA注射位点(白色箭头)的(阴性)增强的区域。两只动物的右边海马区的信号变化与是一致的,伴随着在KA注射位点预期的炎症反应。信号的增强被认为是通过由于通过细胞摄入进入了大脑软组织或常驻神经胶质细胞对纳米颗粒的结合而在巨噬细胞内磁靶向颗粒的存在;这些细胞被认为是脑中炎症反应的调节物。
在AMT-MNP-治疗的大鼠的对侧CAl上和齿状回中的信号变化与急性癫痫相关的组织变化是一致的,并且可能与炎症反应无关。在海马区的区域的增强是由于对两只大鼠注射KA的急性炎症反应,而在CAl和齿状回中的信号变化可归因于急性炎症的释放和AMT-共轭的微粒对这些癫痫的组织亲合力。
关于其具体实施方式,本发明已作了描述,它应该为那些本领域的熟练人员所理解,在不离开发明的真实的精神和范围下,可产生各种各样的变化和可替代的等同物。另外,许多改动也能用以适应本发明的宗旨、精神和范围的一个特殊情况,材料,问题,过程,处理步骤的构成或步骤。所有这一类修饰是为了在此附属权利要求的范围之内。
Claims (35)
1.一种药物组合物,包括:
a)官能化磁性纳米颗粒(MNP),它含有对脑组织有差别亲合力的官能团,当引入哺乳动物主体的血流中,所述官能化磁性纳米颗粒能够穿越所述主体的血脑屏障并能特异性地与脑组织结合;和
b)药学上可接受的载体。
2.权利要求1的组合物,其特征在于所述组织是一个患病的组织。
3.权利要求2的组合物,其特征在于所述患病的组织选自脑瘤,癫痫的损害,与阿尔茨海默氏病相关的斑块,由多发性硬化症影响了的组织,由亨廷顿舞蹈病影响了的组织,由帕金森氏症影响了的组织,和由肌肉萎缩侧向硬化症影响了的组织。
4.权利要求1的组合物,其特征在于所述组织是经受外在或内部刺激的。
5.权利要求1的组合物,其特征在于所述的官能团是特异性结合脑组织内抗原决定基的抗体。
6.权利要求1的组合物,其特征在于所述的官能团是与脑组织细胞内或细胞上的受体特异性结合的配基。
7.权利要求1的组合物,其特征在于所述官能化磁性纳米颗粒进一步包含一个治疗药物。
8.权利要求1的组合物,其特征在于所述官能化磁性纳米颗粒被包封在一个白蛋白基质中。
9.权利要求1的组合物,其特征在于所述官能化磁性纳米颗粒包含一个载脂蛋白。
10.权利要求1的组合物,其特征在于所述官能化磁性纳米颗粒包含聚氰基丙烯酸丁酯(PBCA)。
11.权利要求10的组合物,其特征在于所述官能化磁性纳米颗粒附着在PBCA颗粒的表面。
12.权利要求1的组合物,其特征在于所述官能化磁性纳米颗粒包含表面活化剂。
13.权利要求12的组合物,其特征在于所述表面活化剂选自聚氧乙烯山梨糖醇酐单油酸酯、聚氧乙烯山梨糖醇酐单棕榈酸酯、聚氧乙烯山梨糖醇酐单硬脂酸酯,和聚氧乙烯山梨糖醇酐单月桂酸酯。
14.权利要求12的组合物,其特征在于所述表面活化剂是聚环氧乙烷和聚环氧丙烷的嵌段共聚物。
15.权利要求12的组合物,其特征在于所述官能化磁性纳米颗粒包含泊洛沙姆。
16.一种药物组合物,包括:
a)官能化磁性纳米颗粒,它含有对有再狭窄危险的发炎的血管组织有差别亲合力的官能团,当引入哺乳动物主体的血流中,所述官能化磁性纳米颗粒能够特异性地与发炎的血管组织结合;和
b)药学上可接受的载体。
17.一种药物组合物,包括:
a)官能化磁性纳米颗粒,它含有一个对患病的骨组织有差别亲合力的官能团,当引入哺乳动物主体的血流中,所述官能化磁性纳米颗粒能够特异性地与患病的骨组织结合;和
b)药学上可接受的载体。
18.权利要求17的组合物,其特征在于所述骨组织由于糖尿病、伤害,或其它危害因素导致的骨组织的炎症反应而处于发炎状态。
19.一种药物组合物,包括:
a)官能化磁性纳米颗粒,它带有一个对脑中癫痫病的组织有差别亲合力的官能团,当引入哺乳动物主体的血流中,所述官能化磁性纳米颗粒能够穿越所述主体的血脑屏障并能特异性地与脑癫痫病的组织结合;和
b)药学上可接受的载体。
20.权利要求19的药物组合物,其特征在于所述官能团是葡萄糖。
21.权利要求19的药物组合物,其特征在于所述官能团是N-甲基-D-天门冬氨酸盐。
22.权利要求19的药物组合物,其特征在于所述官能团是α-甲基色氨酸。
23.权利要求19的药物组合物,其特征在于所述官能团是细胞因子。
24.权利要求19的药物组合物,其特征在于所述官能团是γ-氨基丁酸。
25.权利要求19的药物组合物,其特征在于所述官能团是***制剂或阿片化合物。
26.一种诊断大脑疾病的方法,该方法包括:
a)对一个哺乳动物主体给予包含官能化磁性纳米颗粒的组合物,所述官能化磁性纳米颗粒含有对受大脑疾病影响的脑组织有差别亲合力的官能团,当引入哺乳动物主体的血流中,所述官能化磁性纳米颗粒能够穿越所述主体的血脑屏障,
b)检测脑中官能化磁性纳米颗粒。
27.权利要求26的方法,其特征在于所述大脑疾病选自脑瘤、癫痫症、阿尔茨海默氏病、多发性硬化症、亨廷顿舞蹈病、帕金森氏症、肌肉萎缩侧向硬化症、药物成瘾,和精神混乱。
28.权利要求26的方法,其特征在于所述组合物通过静脉注射给药。
29.权利要求26的方法,其特征在于所述所述的检测是磁共振成像。
30.一种检测具有再狭窄危险的血管组织的方法,该方法包括:
a)对一个哺乳动物的主体给予包含官能化磁性纳米颗粒的组合物,所述官能化磁性纳米颗粒含有对发炎的血管组织有差别亲合力的官能团,当引入哺乳动物主体的血流中,所述官能化磁性纳米颗粒能够与发炎的血管组织特异性结合,并且
b)检测血管组织中官能化磁性纳米颗粒。
31.一种检测哺乳动物主体的患病骨组织的方法,所述方法包括:
a)对一个哺乳动物的主体给予包含官能化磁性纳米颗粒的组合物,所述官能化磁性纳米颗粒含有一个对患病的骨组织有差别亲合力的官能团,当引入哺乳动物主体的血流中,所述官能化磁性纳米颗粒能够与患病的骨组织特异性结合,b)检测骨组织中官能化磁性纳米颗粒。
32.一种识别用于治疗大脑疾病的药剂的方法,该方法包括:
对一个患大脑疾病的非人动物模型给予测试药物;并且,
如果有的话,测定测试药物对大脑疾病的神经学特征的效果,
其中所述检测如下执行:
i)对非人动物模型给予包含官能化磁性纳米颗粒的组合物,所述官能化磁性纳米颗粒显示出受神经疾病影响或神经疾病相关的患病的脑组织有差别亲合力;并且
ii)检测在动物的大脑中的官能化磁性纳米颗粒。
33.权利要求32的方法,其特征在于所述所述的检测是磁共振成像。
34.治疗个体疾病的方法,该方法包括:对有需要的个体给予有效量的权利要求1的组合物。
35.权利要求34的方法,其特征在于所述官能化磁性纳米颗粒进一步包含治疗疾病的治疗药物。
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- 2006-03-21 CA CA2923748A patent/CA2923748C/en active Active
- 2006-03-21 KR KR1020077024132A patent/KR101306641B1/ko active IP Right Grant
- 2006-03-21 CA CA2600719A patent/CA2600719C/en active Active
- 2006-03-21 JP JP2008503113A patent/JP5174654B2/ja active Active
- 2006-03-21 AU AU2006227115A patent/AU2006227115B2/en active Active
- 2006-03-21 EP EP06739214A patent/EP1865839A4/en not_active Withdrawn
- 2006-03-21 CN CN2006800086773A patent/CN101155549B/zh active Active
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WO2017143967A1 (zh) * | 2016-02-24 | 2017-08-31 | 首都医科大学宣武医院 | 一种双重修饰聚氰基丙烯酸正丁酯纳米粒、其制备方法及用途 |
US11351125B2 (en) | 2016-02-24 | 2022-06-07 | Xuanwu Hospital Of Capital Medical University | Poly(n-butyl cyanoacrylate) nanoparticle with dual modifications, preparation method and use thereof |
CN111032023A (zh) * | 2017-06-30 | 2020-04-17 | 奥托磁有限责任公司 | 用于靶向递送的磁性纳米颗粒 |
CN111528931A (zh) * | 2019-02-07 | 2020-08-14 | 温伯格医学物理有限公司 | 用于利用磁性粒子对皮肤进行雕塑的***、方法及部件 |
Also Published As
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CN102343098A (zh) | 2012-02-08 |
CN101155549B (zh) | 2011-11-16 |
JP2008533203A (ja) | 2008-08-21 |
US20080206146A1 (en) | 2008-08-28 |
CA2600719C (en) | 2016-06-07 |
EP1865839A4 (en) | 2011-06-29 |
CA2923748A1 (en) | 2006-09-28 |
AU2006227115A1 (en) | 2006-09-28 |
WO2006102377A3 (en) | 2006-11-09 |
CA2923748C (en) | 2017-06-20 |
CA2600719A1 (en) | 2006-09-28 |
AU2006227115B2 (en) | 2012-04-19 |
WO2006102377A2 (en) | 2006-09-28 |
KR20070121788A (ko) | 2007-12-27 |
EP1865839A2 (en) | 2007-12-19 |
JP5174654B2 (ja) | 2013-04-03 |
KR101306641B1 (ko) | 2013-09-12 |
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