CN102316902A - 基于谷胱甘肽的药物递送系统 - Google Patents
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Abstract
本发明涉及化合物的靶向药物递送方法,所述化合物包括化学剂、(多)肽和基于核酸的药物(如DNA疫苗、反义寡核苷酸、核酶、催化性DNA(DNA核酶)或RNA分子、siRNA或编码其的质粒)。而且,本发明涉及向细胞、组织和器官中的血管外和细胞内靶位点,特别是向中枢神经系统(CNS)中的靶位点靶向药物递送化合物,进入和穿过血脑屏障的方法,该方法通过靶向存在于这些细胞、组织和器官上的谷胱甘肽转运蛋白而实现。此外,化合物或其药学可接受的载体缀合至基于谷胱甘肽的配体,所述配体促进特异性结合这些谷胱甘肽转运蛋白和被这些谷胱甘肽转运蛋白内化。
Description
技术领域
本发明涉及靶向药物递送领域。本发明涉及任选地包含于载体或纳米容器(nanocontainer)中的活性药物成分的缀合物,所述活性药物成分或者载体或纳米容器与介导特异性结合、胞吞作用或转胞吞作用的谷胱甘肽转运蛋白的配体连接。这些缀合物优选用于治疗或预防基于脑的疾病状况的方法中。
背景技术
为了适当发挥功能,神经元需要受到紧密调控的细胞外环境。通过调养称为星形胶质细胞(或星形胶质)的脑细胞,这种明确的重要微环境在局部受到维护。为了有效处理血液组成和脑细胞外空间之间相当大且易变的差异,中枢神经系统(CNS)受到多种血-CNS屏障的保护而不受基本血液循环的伤害,即血脑屏障、血脑脊液(CSF)屏障、软膜血管(pial vessel)-CSF屏障、室管膜和胶质界膜,还有血视网膜屏障、血神经屏障、血脊髓屏障。血脑屏障(BBB)被认为是最重要的血-CNS屏障,因为与其他血-CNS屏障相比,其覆盖的表面积大1000倍。BBB的特征在于覆盖CNS中毛细血管的独特的紧密内皮细胞层。此外,在这些内皮细胞中,通过在毛细血管上伸出“胶质足(glialfoot)”,星形胶质细胞是BBB特性的主要诱导物。
特别地,BBB调节离子(Na+、K+、Ca2+)、水、养分、代谢物、神经递质(谷氨酸、色氨酸)、血浆蛋白(白蛋白、纤维蛋白原、免疫球蛋白)、来自免疫系统的细胞以及异生素(药物)进出脑的运输。与外周毛细血管相比,脑中的毛细血管内皮具有独特的性质。其具有狭窄的紧密连接、无孔、低胞饮活性以及连续的基膜。狭窄的紧密连接导致1500-2000Ohm.cm2的高电阻。另外,内皮细胞具有排斥带负电化合物的表面负电荷。它们具有许多分解化合物的线粒体和酶以及将养分和其他化合物主动运输到脑内外的各种选择性转运系统。通常,BBB被认为是保护脑稳态的器官。然而,BBB也因此限制了异生素(如药物和诊断剂)向脑的递送,这使得脑病症的经典药物治疗(即靶向神经元)复杂化。因此,期望经由内源BBB转运系统将药物选择性靶向脑。
另外,对于到达其细胞内靶标的一些药物类型,需要将它们跨亲脂细胞膜递送到亲水细胞质中。这种亲脂到亲水转运要求成为设计和递送许多此类药物的挑战。以非磷酸化形式给予药物可以改善药物的细胞进入,因为细胞膜不易渗透磷酸化的药物。随后,可以通过胸腺嘧啶核苷激酶将药物磷酸化成其活性形成。然而,所有机体组织都非特异性地发生药物吸收。另一缺陷是,为了实现药物的稳态血浆水平,需要花费高达4周的剂量给药。例如,一些治疗要求每日给予高剂量(800-1200mg/天),持续24-48周。这对于非慢性疾病状况的治疗而言太晚。另一缺陷是,此类治疗通常受到毒性的限制。总之,对于许多治疗和疗法,需要在合适的时间段将有效量的药物递送到期望的位点,同时降低副作用。可能最大的挑战是将药物(及时)递送到受生理屏障保护的位点,如CNS、视网膜、胎盘以及睾丸。
市场上还没有靶向特异性吸收受体的CNS药物。实际上,用于治疗神经病症(如中风、偏头痛和MS)的大部分市售药物针对脑外靶标(如脑血管系统或免疫系统)。与小分子不同,生物制药药物不大可能是增强其跨血脑屏障渗透性的化学修饰的候选者。与直接和局部定向注射、鞘内输注和甚至血脑屏障的(药理)破坏一样,此类化合物目前还依赖对患者的侵入和伤害技术。由于这些技术的严重神经后果,这些技术仅在所选的威胁生命的疾病中得到许可。此外,在递送药物遍及大体积的人脑时,局部给药是无效的。因此,亟需创新的CNS药物递送技术。
谷胱甘肽(GSH)是内源抗氧化剂。如果其在血清中的浓度不足,则可能会发生一些神经疾病,如慢性疲劳综合征(CFS)。在1994年,Berislav V.Zlokovic宣称,GSH通过诸如GSH转运蛋白的特殊途径到达并穿过豚鼠的BBB而不分解(1994,Biochem.Biophys.Res.Commun.201:402-408)。在1995年,Berislav V.Zlokovic断言GSH以毫摩尔浓度存在于脑、星形胶质细胞和内皮细胞中(1995,Pharm.Res.12:1395-1406)。在1995年,RamKannan宣称,GSH吸收依赖于Na+浓度(1995,Invest.Ophthalmol.Vis.Sci.36:1785-1792)。如果Na+浓度低,则脑内皮细胞的GSH吸收可能受到抑制。他还指出,位于BBB腔侧(luminal side)的Na依赖性GSH转运蛋白管理GSH吸收,而位于BBB腔侧的Na非依赖性GSH转运蛋白管理GSH的流出(1996,J.Biol.Chem.271:9754-9758)。另外,Kannan利用小鼠和豚鼠的脑构建了大鼠肝小管GSH转运蛋白(RcGSHT)系统来分析cDNA片段5、7和11。结果表明,片段7代表Na依赖性GSH转运蛋白,片段5和11代表Na非依赖性GSH转运蛋白。在1999年,Ram Kannan构建了刺激BBB环境的小鼠脑内皮细胞系(MBEC-4)模型(1999,J.Neurochem.73:390-399)。该模型证实,Na依赖性GSH转运蛋白位于MBEC-4细胞的腔侧。在2000年,RamKannan断言,GSH经由Na依赖性GSH转运蛋白穿过BBB进入人脑血管内皮细胞(HCBC),而Na依赖性GSH转运蛋白存在于HCEC的腔细胞膜中(2000,Brain.Res.852:374-382)。在2003年,Zhao Zhiyang提供了通过氨磺酰共价键与谷胱甘肽s-转移酶(GST)/谷胱甘肽(GSH)键合的抗癌前药,来在US2003109555所述的氨磺酰键断裂后靶向并治疗特定癌细胞。这种修饰能够保护药物的氨基,增加其溶解性并改变其在体内的吸收和分布。在2005年,Ae-June Wang et al.在美国专利第7,446,096号中公开了一项发明,其提供了包含载体或接枝于载体上的活性化合物和谷胱甘肽或谷胱甘肽衍生物的递送系统。该发明还提供了包含这样的部分的化合物,该部分包含维生素E衍生物或磷脂衍生物、与其键合的聚乙二醇(PEG)或聚乙二醇衍生物,以及与聚乙二醇或PEG衍生物键合的谷胱甘肽(GSH)或谷胱甘肽衍生物。在2008年,Pieter Gaillard在美国专利申请第60/907,176号中公开了抗病毒化疗剂和其他抗病毒剂的(CNS)靶向递送,其在体外和体内利用GSH-PEG脂质体。那一年之后,Swati More和Robert Vince发表了利用体外方法设计、合成和生物学评价作为抗帕金森前药组分的谷胱甘肽拟肽类(peptidomimetics)的论文(More,2008,J.Med.Chem.51:4581-4588)。
然而,这些公开并没有提供药物和化合物之间的特定相关组合的充分细节,其对特定CNS和相关病症的诊断和/或(预防)治疗具有特殊用途。因此本发明的目的是提供安全有效且通用的方法,以用于利用谷胱甘肽转运受体运送负荷如小分子、肽、蛋白和含有药物和基因的纳米容器(如脂质体)穿过细胞膜并穿过血组织屏障,如特别是CNS药物靶向的血脑屏障。令人惊讶的是,除了上文所述的公开以外,我们确定谷胱甘肽和谷胱甘肽衍生物与肽、蛋白(如酶和抗体)、其他小分子和阳离子聚合物DNA复合物(polyplex)通过直接偶联或利用间隔分子连接的缀合在将上述物质特异性靶向谷胱甘肽转运受体中是有效的。
发明概述
定义
本文所用术语“寡核苷酸”和“多核苷酸”包括天然或修饰的单体或连接物的线性寡聚体和聚合物,所述天然或修饰的单体或连接物包括脱氧核糖核苷、核糖核苷、其α-异头形式、聚酰胺核酸等,并能通过单体与单体相互作用(如核苷与核苷)的常规模式与靶多核苷酸特异性结合,如Watson-Crick型碱基配对、Hoogsteen或反向Hoogsteen型碱基配对等。通常,单体通过磷酸二酯键或其类似物连接以形成大小为诸如3-4个的若干单体单元到数百个单体单元的寡核苷酸。只要寡核苷酸以诸如″ATGCCTG″的字母序列表示,都应当理解除非另有说明,核苷酸从左到右为5′->3′的顺序,且″A″表示脱氧腺苷,″C″表示脱氧胞苷,″G″表示脱氧鸟苷以及″T″表示胸腺嘧啶核苷。磷酸二酯键的类似物包括硫代磷酸酯、二硫代磷酸酯、硒代磷酸酯(phosphoroselenoate)、二硒代磷酸酯(phosphorodiselenoate)、phosphoroanilothioate、phosphoranilidate、氨基磷酸酯、N3′→P5′氨基磷酸酯等。多核苷酸基本上可以为任何长度,通常为约10个核苷酸到约1x109个核苷酸或更大。如本文所用,“寡核苷酸”定义为长度为4-100个核苷酸的多核苷酸。因此,寡核苷酸是多核苷酸的子集。
本文所用的术语“特异性结合”表示可测量地不同于非特异性相互作用的结合。特异性结合可以通过以下方式测定,例如与对照分子(配体)的结合相比测定分子(配体)的结合,所述对照分子通常是不具有亲和活性的类似结构的分子,如缺少特异性亲和序列的类似大小的肽。如果配体对受体具有比对照配体可测量地高的亲和力,则存在特异性结合。结合的特异性可以通过例如与已知与靶标结合的对照配体的竞争来测定。本文所用的术语“特异性结合”包括低和高亲和力特异性结合。特异性结合可以通过例如Kd为至少约10-4M.E.g.的低亲和力靶向剂来展示,如果受体具有多个配体结合位点,则具有低亲和力的配体可用于靶向微血管内皮。特异性结合也可以通过高亲和力配体来展示,如Kd为至少约10-7M、至少约10-8M、至少约10-9M、至少约10-10M的配体,或者Kd可以为至少约10-11M或10-12M或更大的配体。低亲和力和高亲和力靶向配体都可用于并入本发明的缀合物中。
发明详述
本发明基于称为受体介导的胞吞作用的安全内源(非毒性)转运机制,以用于运送治疗性部分如大蛋白以及含有药物和基因的脂质体即封装于脂质体中的药物和基因,穿过细胞膜或穿过诸如血脑屏障的血组织屏障来进行例如所述治疗部分的脑递送。一系列有效且公知的内化受体存在于用于此用途的细胞和血脑屏障中。这些受体包括但不限于硫胺转运蛋白、α(2,3)-唾液酸糖蛋白受体、运铁蛋白受体、清道夫受体、LDL受体、LRP1B、LRP2、DTR、胰岛素受体、IGF受体、瘦蛋白受体、6-磷酸甘露糖受体。然而,本发明涉及一种更安全且更有效的方式,其通过靶向脑中毛细血管上的谷胱甘肽内源内化吸收(转运)受体,将药物特异性递送至细胞并穿过血脑屏障或者特异性增强药物递送至细胞并穿过血脑屏障,而无需修饰或破坏神经保护性血脑屏障的正常功能。
在第一方面,本发明涉及一种缀合物,其包含:a)谷胱甘肽转运蛋白的配体;和b)诊断或治疗剂和包含所述诊断或治疗剂的药学可接受的纳米容器中的至少一种;其中a)中的配体优选缀合至b)中的诊断或治疗剂和纳米容器中的至少一种。
“缀合物”在本文中定义为由偶联在一起的两个实体组成。优选地,两个实体通过以下方式缀合:非特异性或特异性蛋白-蛋白相互作用;共价键合;非共价键合;配位化学键合;化学合成,直接或经由(不)可切割间隔物、接头(linker)或纳米容器的组分;或通过重组技术。在本发明中,第一实体可以是诊断和/或治疗剂或者包含所述诊断和/或治疗剂的药学可接受的纳米容器,而第二实体是靶细胞上的谷胱甘肽转运蛋白的配体。下文进一步定义了用于本发明缀合物的合适诊断和/或治疗剂、用于此类诊断和/或治疗剂的药学可接受的纳米容器以及合适的谷胱甘肽转运蛋白的配体。
治疗或诊断剂
本发明的缀合物包含至少一种诊断或治疗剂。并入本发明缀合物的优选诊断或治疗剂为小分子化学剂。本文的化学剂应理解为定义明确的化学分子,通常是较小的非聚合分子(如小于2kDa),其至少部分是有机的,通常通过化学合成获得并且不包含寡核苷酸或多核苷酸。可以衍生小分子药物部分的所关注药物化合物或者诊断或治疗剂还列于:Goodman &Gilman′s,The Pharmacological Basis of Therapeutics(9th Ed)(Goodman et al.eds)(McGraw-Hill)(1996);和1999 Physician′s Desk Reference(1998)。可衍生药物部分的所关注的其他具体药物和化合物包括但不限于:
中枢神经系统抑制剂(depressant):全身麻醉药(巴比妥酸盐、苯二氮类、类固醇、环己酮衍生物以及混和药剂(miscellaneous agent))、镇静催眠药(苯二氮类、巴比妥酸盐、哌啶二酮和三酮、喹唑啉衍生物、氨基甲酸酯、醛和衍生物、酰胺、无环酰脲、苯并氮杂和相关药物、吩噻嗪等)、中枢随意肌张力修饰药物(抗惊厥药,如乙内酰脲、巴比妥酸盐、噁唑烷二酮、琥珀酰亚胺、酰基酰脲(acylureide)、戊二酰亚胺、苯二氮类、仲醇和叔醇、二苯并氮杂衍生物、丙戊酸和衍生物、GABA类似物等)、镇痛药(吗啡和衍生物、东罂粟碱衍生物、吗啡喃衍生物、苯基哌啶、2,6-甲烷-3-苯并氮杂环辛烯(2,6-methane-3-benzazocaine)衍生物、二苯基丙胺和电子等排物、水杨酸盐、对氨基苯酚衍生物、5-吡唑啉酮衍生物、芳基乙酸衍生物、芬那酯和电子等排物、纳曲酮、甲基纳曲酮等)以及止吐药(抗胆碱能药、抗组胺剂、抗多巴胺剂等),以下美国专利所所公开的镇痛药:5292,736,5,688,825,5,554,789,5,455,230,5,292,736,5,298,522,5,216,165,5,438,064,5,204,365,5,017,578,4,906,655,4,906,655,4,994,450,4,749,792,4,980,365,4,794,110,4,670,541,4,737,493,4,622,326,4,536,512,4,719,231,4,533,671,4,552,866,4,539,312,4,569,942,4,681,879,4,511,724,4,556,672,4,721,712,4,474,806,4,595,686,4,440,779,4,434,175,4,608,374,4,395,402,4,400,534,4,374,139,4,361,583,4,252,816,4,251,530,5,874,459,5,688,825,5,554,789,5,455,230,5,438,064,5,298,522,5,216,165,5,204,365,5,030,639,5,017,578,5,008,264,4,994,450,4,980,365,4,906,655,4,847,290,4,844,907,4,794,110,4,791,129,4,774,256,4,749,792,4,737,493,4,721,712,4,719,231,4,681,879,4,670,541,4,667,039,4,658,037,4,634,708,4,623,648,4,622,326,4,608,374,4,595,686,4,594,188,4,569,942,4,556,672,4,552,866,4,539,312,4,536,512,4,533,671,4,511,724,4,440,779,4,434,175,4,400,534,4,395,402,4,391,827,4,374,139,4,361,583,4,322,420,4,306,097,4,252,816,4,251,530,4,244,955,4,232,018,4,209,520,4,164,514,4,147,872,4,133,819,4,124,713,4,117,012,4,064,272,4,022,836,3,966,944;
中枢神经系统刺激剂:兴奋剂(呼吸刺激剂、惊厥刺激剂、精神运动刺激剂)、麻醉剂拮抗剂(吗啡衍生物、东罂粟碱衍生物、2,6-甲烷-3-苯并噁嗪衍生物、吗啡喃衍生物)、促智药物、氟马西尼;
精神药物(psychopharmacological):抗焦虑镇静药(苯二氮类、丙二醇氨基甲酸酯)、抗精神病药(吩噻嗪衍生物、硫黄嘌呤衍生物、其他三环化合物、丁酰苯衍生物和电子等排物、二苯基丁胺衍生物、取代的苯甲酰胺、芳基哌嗪衍生物、吲哚衍生物等)、抗抑郁药(三环化合物、MAO抑制剂等),以下美国专利所公开的精神药物:5,192,799,5,036,070,4,778,800,4,753,951,4,590,180,4,690,930,4,645,773,4,427,694,4,424,202,4,440,781,5,686,482,5,478,828,5,461,062,5,387,593,5,387,586,5,256,664,5,192,799,5,120,733,5,036,070,4,977,167,4,904,663,4,788,188,4,778,800,4,753,951,4,690,930,4,645,773,4,631,285,4,617,314,4,613,600,4,590,180,4,560,684,4,548,938,4,529,727,4,459,306,4,443,451,4,440,781,4,427,694,4,424,202,4,397,853,4,358,451,4,324,787,4,314,081,4,313,896,4,294,828,4,277,476,4,267,328,4,264,499,4,231,930,4,194,009,4,188,388,4,148,796,4,128,717,4,062,858,4,031,226,4,020,072,4,018,895,4,018,779,4,013,672,3,994,898,3,968,125,3,939,152,3,928,356,3,880,834,3,668,210;
呼吸道药物:中枢性镇咳药(阿片生物碱及其衍生物);
外周神经系统药物:局部麻醉药(酯衍生物、酰胺衍生物);
在突触连接位点或神经效应器连接位点起作用的药物:胆碱能剂、胆碱能阻断剂、神经肌肉阻断剂、肾上腺素能剂、抗肾上腺素能剂、以下美国专利所公开的胆碱能剂:5,219,872,5,219,873,5,073,560,5,073,560,5,346,911,5,424,301,5,073,560,5,219,872,4,900,748,4,786,648,4,798,841,4,782,071,4,710,508,5,482,938,5,464,842,5,378,723,5,346,911,5,318,978,5,219,873,5,219,872,5,084,281,5,073,560,5,002,955,4,988,710,4,900,748,4,798,841,4,786,648,4,782,071,4,745,123,4,710,508;以下美国专利所公开的肾上腺素能剂:5,091,528,5,091,528,4,835,157,5,708,015,5,594,027,5,580,892,5,576,332,5,510,376,5,482,961,5,334,601,5,202,347,5,135,926,5,116,867,5,091,528,5,017,618,4,835,157,4,829,086,4,579,867,4,568,679,4,469,690,4,395,559,4,381,309,4,363,808,4,343,800,4,329,289,4,314,943,4,311,708,4,304,721,4,296,117,4,285,873,4,281,189,4,278,608,4,247,710,4,145,550,4,145,425,4,139,535,4,082,843,4,011,32I,4,001,421,3,982,010,3,940,407,3,852,468,3,832,470;
平滑肌活性药物(active drug):解痉药(抗胆碱能药、向肌肉性解痉药)、血管舒张剂、平滑肌刺激剂;
组胺剂和抗组胺剂:组胺及其衍生物(倍他唑)、抗组胺剂(H1-拮抗剂、H2-拮抗剂)、组胺代谢药,以下美国专利所公开的组胺剂和抗组胺剂:5,874,479,5,863,938,5,856,364,5,770,612,5,702,688,5,674,912,5,663,208,5,658,957,5,652,274,5,648,380,5,646,190,5,641,814,5,633,285,5,614,561,5,602,183,4,923,892,4,782,058,4,393,210,4,180,583,3,965,257,3,946,022,3,931,197;
心血管药物:强心药(植物提取物、丁烯羟酸内酯、pentadienolid、来自格木属(erythrophleum)物种的生物碱、离子载体、肾上腺素能受体刺激剂等)、抗心律不齐药、抗高血压剂、降血脂剂(氯贝酸衍生物、烟酸衍生物、激素和类似物、抗生素、水杨酸和衍生物)、抗静脉曲张药、止血剂,以下美国专利所公开的心血管药物:4,966,967,5,661,129,5,552,411,5,332,737,5,389,675,5,198,449,5,079,247,4,966,967,4,874,760,4,954,526,5,051,423,4,888,335,4,853,391,4,906,634,4,775,757,4,727,072,4,542,160,4,522,949,4,524,151,4,525,479,4,474,804,4,520,026,4,520,026,5,869,478,5,859,239,5,837,702,5,807,889,5,731,322,5,726,171,5,723,457,5,705,523,5,696,111,5,691,332,5,679,672,5,661,129,5,654,294,5,646,276,5,637,586,5,631,251,5,612,370,5,612,323,5,574,037,5,563,170,5,552,411,5,552,397,5,547,966,5,482,925,5,457,118,5,414,017,5,414,013,5,401,758,5,393,771,5,362,902,5,332,737,5,310,731,5,260,444,5,223,516,5,217,958,5,208,245,5,202,330,5,198,449,5,189,036,5,185,362,5,140,031,5,128,349,5,116,861,5,079,247,5,070,099,5,061,813,5,055,466,5,051,423,5,036,065,5,026,712,5,011,931,5,006,542,4,981,843,4,977,144,4,971,984,4,966,967,4,959,383,4,954,526,4,952,692,4,939,137,4,906,634,4,889,866,4,888,335,4,883,872,4,883,811,4,847,379,4,835,157,4,824,831,4,780,538,4,775,757,4,774,239,4,771,047,4,769,371,4,767,756,4,762,837,4,753,946,4,752,616,4,749,715,4,738,978,4,735,962,4,734,426,4,734,425,4,734,424,4,730,052,4,727,072,4,721,796,4,707,550,4,704,382,4,703,120,4,681,970,4,681,882,4,670,560,4,670,453,4,668,787,4,663,337,4,663,336,4,661,506,4,656,267,4,656,185,4,654,357,4,654,356,4,654,355,4,654,335,4,652,578,4,652,576,4,650,874,4,650,797,4,649,139,4,647,585,4,647,573,4,647,565,4,647,561,4,645,836,4,639,461,4,638,012,4,638,011,4,632,931,4,631,283,4,628,095,4,626,548,4,614,825,4,611,007,4,611,006,4,611,005,4,609,671,4,608,386,4,607,049,4,607,048,4,595,692,4,593,042,4,593,029,4,591,603,4,588,743,4,588,742,4,588,741,4,582,854,4,575,512,4,568,762,4,560,698,4,556,739,4,556,675,4,555,571,4,555,570,4,555,523,4,550,120,4,542,160,4,542,157,4,542,156,4,542,155,4,542,151,4,537,981,4,537,904,4,536,514,4,536,513,4,533,673,4,526,901,4,526,900,4,525,479,4,524,151,4,522,949,4,521,539,4,520,026,4,517,188,4,482,562,4,474,804,4,474,803,4,472,411,4,466,979,4,463,015,4,456,617,4,456,616,4,456,615,4,418,076,4,416,896,4,252,815,4,220,594,4,190,587,4,177,280,4,164,586,4,151,297,4,145,443,4,143,054,4,123,550,4,083,968,4,076,834,4,064,259,4,064,258,4,064,257,4,058,620,4,001,421,3,993,639,3,991,057,3,982,010,3,980,652,3,968,117,3,959,296,3,951,950,3,933,834,3,925,369,3,923,818,3,898,210,3,897,442,3,897,441,3,886,157,3,883,540,3,873,715,3,867,383,3,873,715,3,867,383,3,691,216,3,624,126;
胃肠道药物:助消化药(健胃药、利胆药)、抗溃疡药、止泻剂;
类固醇剂(steroidal agent):氢化可的松(皮质醇)、醋酸可的松、泼尼松、泼尼松龙、甲泼尼龙或醋酸甲泼尼龙或半琥珀酸甲泼尼龙、地塞米松、倍他米松、曲安西龙、倍氯米松、醋酸氟氢可的松或半琥珀酸氟氢可的松、醋酸脱氧皮质酮(DOCA)或半琥珀酸脱氧皮质酮、醛甾酮,包括以下美国专利所公开的:5,863,538,5,855,907,5,855,866,5,780,592,5,776,427,5,651,987,5,346,887,5,256,408,5,252,319,5,209,926,4,996,335,4,927,807,4,910,192,4,710,495,4,049,805,4,004,005,3,670,079,3,608,076,5,892,028,5,888,995,5,883,087,5,880,115,5,869,475,5,866,558,5,861,390,5,861,388,5,854,235,5,837,698,5,834,452,5,830,886,5,792,758,5,792,757,5,763,361,5,744,462,5,741,787,5,741,786,5,733,899,5,731,345,5,723,638,5,721,226,5,712,264,5,712,263,5,710,144,5,707,984,5,705,494,5,700,793,5,698,720,5,698,545,5,696,106,5,677,293,5,674,861,5,661,141,5,656,621,5,646,136,5,637,691,5,616,574,5,614,514,5,604,215,5,604,213,5,599,807,5,585,482,5,565,588,5,563,259,5,563,131,5,561,124,5,556,845,5,547,949,5,536,714,5,527,806,5,506,354,5,506,221,5,494,907,5,491,136,5,478,956,5,426,179,5,422,262,5,391,776,5,382,661,5,380,841,5,380,840,5,380,839,5,373,095,5,371,078,5,352,809,5,344,827,5,344,826,5,338,837,5,336,686,5,292,906,5,292,878,5,281,587,5,272,140,5,244,886,5,236,912,5,232,915,5,219,879,5,218,109,5,215,972,5,212,166,5,206,415,5,194,602,5,166,201,5,166,055,5,126,488,5,116,829,5,108,996,5,099,037,5,096,892,5,093,502,5,086,047,5,084,450,5,082,835,5,081,114,5,053,404,5,041,433,5,041,432,5,034,548,5,032,586,5,026,882,4,996,335,4,975,537,4,970,205,4,954,446,4,950,428,4,946,834,4,937,237,4,921,846,4,920,099,4,910,226,4,900,725,4,892,867,4,888,336,4,885,280,4,882,322,4,882,319,4,882,315,4,874,855,4,868,167,4,865,767,4,861,875,4,861,765,4,861,763,4,847,014,4,774,236,4,753,932,4,711,856,4,710,495,4,701,450,4,701,449,4,689,410,4,680,290,4,670,551,4,664,850,4,659,516,4,647,410,4,634,695,4,634,693,4,588,530,4,567,000,4,560,557,4,558,041,4,552,871,4,552,868,4,541,956,4,519,946,4,515,787,4,512,986,4,502,989,4,495,102;
细胞生长抑制剂或抗肿瘤剂:抗代谢药:叶酸(氨基蝶呤、甲氨喋呤、培美曲塞、雷替曲塞)、嘌呤(克拉屈滨、氯法拉滨、氟达拉滨、巯嘌呤、喷司他丁、硫鸟嘌呤)、嘧啶(阿糖胞苷、地西他滨、氟尿嘧啶/卡培他滨、氟尿苷、吉西他滨、依诺他滨、沙帕他滨);烷化剂/烷化剂样:氮芥(苯丁酸氮芥、氮芥(Chlormethine)、环磷酰胺、异环磷酰胺、美法仑、苯达莫司汀、曲磷胺、乌拉莫司汀)、亚硝基脲(卡莫司汀、福莫司汀、洛莫司汀、尼莫司汀、泼尼莫司汀、雷莫司汀、司莫司汀、链佐星)、铂(烷化剂样)(卡铂、顺铂、奈达铂、奥沙利铂、四硝酸三铂、沙铂)、烷基磺酸酯(白消安、甘露舒凡、曲奥舒凡)、肼(丙卡巴肼)、三氮烯(达卡巴嗪、替莫唑胺)、吖丙啶(卡波醌、塞替派、三亚胺醌、三亚乙基蜜胺);纺锤体毒素/有丝分裂抑制剂:紫杉烷(多西他赛、拉罗他赛、奥他赛、紫杉醇、替司他赛)和长春花生物碱(长春碱、长春新碱、长春氟宁、长春地辛、长春瑞滨)、伊沙匹隆;细胞毒素/抗肿瘤抗生素:蒽环霉素(阿柔比星、柔红霉素、多柔比星、表柔比星、伊达比星、氨柔比星、吡柔比星、戊柔比星、佐柔比星)、蒽二酮(anthracenedione)(米托蒽醌、匹蒽醌)、链霉菌(Streptomyces)(放线菌素、博来霉素、丝裂霉素、普卡霉素)、羟基脲;拓扑异构酶抑制剂:喜树(Camptotheca)(喜树碱、托泊替康、伊立替康、卢比替康、贝洛替康)、鬼臼(Podophyllum)(依托泊苷、替尼泊苷);酪氨酸激酶抑制剂:阿昔替尼、波舒替尼、西地尼布、达沙替尼、厄洛替尼、吉非替尼、伊马替尼、拉帕替尼、来妥替尼、来那替尼、尼洛替尼、司马沙尼、索拉非尼、舒尼替尼、凡德他尼;细胞周期蛋白依赖性激酶抑制剂:阿伏西地、塞利西利;光敏剂:氨基酮戊酸/氨基酮戊酸甲酯、乙法昔罗、卟啉衍生物(卟吩姆钠、他拉泊芬、替莫泊芬、维替泊芬);其他:六甲蜜胺、安吖啶、贝沙罗汀、雌莫司汀、伊罗夫文、曲贝替定、融合蛋白(阿柏西普)、地尼白介素-毒素连接物、类视黄醇(阿利维A酸、维甲酸)、阿那格雷、三氧化二砷、天冬酰胺酶/培门冬酶、阿曲生坦、硼替佐米、卡莫氟、塞来考昔、秋水仙胺、伊利司莫、依沙芦星、依托格鲁、氯尼达明、硫蒽酮、马索罗酚、二溴甘露醇、米托胍腙、米托坦、奥利美生、替加氟、睾内酯、噻唑呋林、替匹法尼、伏林司他;以及以下美国专利所公开的细胞生长抑制剂或抗肿瘤剂:5,880,161,5,877,206,5,786,344,5,760,041,5,753,668,5,698,529,5,684,004,5,665,715,5,654,484,5,624,924,5,618,813,5,610,292,5,597,831,5,530,026,5,525,633,5,525,606,5,512,678,5,508,277,5,463,181,5,409,893,5,358,952,5,318,965,5,223,503,5,214,068,5,196,424,5,109,024,5,106,996,5,101,072,5,077,404,5,071,848,5,066,493,5,019,390,4,996,229,4,996,206,4,970,318,4,968,800,4,962,114,4,927,828,4,892,887,4,889,859,4,886,790,4,882,334,4,882,333,4,871,746,4,863,955,4,849,563,4,845,216,4,833,145,4,824,955,4,785,085,4,684,747,4,618,685,4,611,066,4,550,187,4,550,186,4,544,501,4,541,956,4,532,327,4,490,540,4,399,283,4,391,982,4,383,994,4,294,763,4,283,394,4,246,411,4,214,089,4,150,231,4,147,798,4,056,673,4,029,661,4,012,448;
抗感染剂:杀外寄生虫药(氯化烃、除虫菊酯、加硫化合物)、驱肠虫剂、抗原生动物剂、抗疟剂、抗阿米巴剂、抗利什曼原虫药、抗毛滴虫剂、抗锥体虫剂、氨磺酰、抗分支杆菌药、抗病毒化疗剂和美国专利申请第60/907,176号所公开的其他抗病毒剂;
抗生素:氨基糖苷类,如阿米卡星、安普霉素、阿贝卡星、班贝霉素、布替罗星、地贝卡星、双氢链霉素、福提霉素、庆大霉素、异帕米星、卡那霉素、小诺米星、新霉素、乙基西梭霉素、巴龙霉素、核糖霉素、西索米星、大观霉素、链霉素、妥布霉素、丙大观霉素;酰胺醇类(amphenicols),如叠氮氯霉素、氯霉素、氟苯尼考以及甲砜霉素(theimaphenicol);安莎霉素类,如利福米特、利福平、利福霉素、利福喷汀、利福昔明;β-内酰胺类,如碳头孢烯、碳青霉烯、头孢菌素、头霉素、单环内酰胺、氧头孢烯(oxaphem)、青霉素;林可胺类抗生素,如克林霉素、林可霉素;大环内酯,如克拉霉素、地红霉素、红霉素等;多肽,如安福霉素、杆菌肽、卷曲霉素等;四环素,如阿哌环素、金霉素、氯莫环素等;合成抗菌剂,如2,4二氨基嘧啶、硝基呋喃类、喹诺酮类及其类似物、氨磺酰、砜;
抗真菌剂:多烯,如两性霉素B、克念菌素、制皮菌素、菲律宾菌素、制霉色基素、曲古霉素、哈霉素、鲁斯霉素、美帕曲星、那他霉素、制霉菌素、培西洛星、表霉素;合成抗真菌剂,如烯丙胺,如布替萘芬、萘替芬、特比萘芬;咪唑,如联苯苄唑、布康唑、氯登妥因、氯米达唑等;硫代氨基甲酸酯,如托西拉酯、三唑,如氟康唑、伊曲康唑、特康唑;
驱肠虫剂:槟榔碱、绵马素、绵马酚、双氯芬、恩贝酸、苦苏素、萘、氯硝柳胺、石榴碱、奎纳克林、阿兰内酯、阿莫卡嗪、硝硫氰胺、驱蛔素、酚乙铵(bephenium)、双硫氰苯、四氯化碳、香芹酚、环苯达唑、乙胺嗪等;
抗疟剂:醋氨苯砜、阿莫地喹、蒿乙醚、蒿甲醚、青蒿素、青蒿琥酯、阿托伐醌、贝比碱、黄连素、印度当药(chirata)、氯胍、氯喹、氯丙胍、金鸡纳、金鸡尼丁、辛可宁、环氯胍、龙胆苦苷、卤泛群、羟氯喹、盐酸甲氟喹、3-甲基醋氨苯胂(3-methylarsacetin)、帕马喹、甲氧胺喹(plasmocid)、伯氨喹、乙胺嘧啶、奎纳克林、奎宁、奎宁、喹西特、奎宁、砷酸氢二钠;
抗微生物剂:如以下美国专利所公开的:5,902,594,5,874,476,5,874,436,5,859,027,5,856,320,5,854,242,5,811,091,5,786,350,5,783,177,5,773,469,5,762,919,5,753,715,5,741,526,5,709,870,5,707,990,5,696,117,5,684,042,5,683,709,5,656,591,5,643,971,5,643,950,5,610,196,5,608,056,5,604,262,5,595,742,5,576,341,5,554,373,5,541,233,5,534,546,5,534,508,5,514,715,5,508,417,5,464,832,5,428,073,5,428,016,5,424,396,5,399,553,5,391,544,5,385,902,5,359,066,5,356,803,5,354,862,5,346,913,5,302,592,5,288,693,5,266,567,5,254,685,5,252,745,5,209,930,5,196,441,5,190,961,5,175,160,5,157,051,5,096,700,5,093,342,5,089,251,5,073,570,5,061,702,5,037,809,5,036,077,5,010,109,4,970,226,4,916,156,4,888,434,4,870,093,4,855,318,4,784,991,4,746,504,4,686,221,4,599,228,4,552,882,4,492,700,4,489,098,4,489,085,4,487,776,4,479,953,4,477,448,4,474,807,4,470,994,4,370,484,4,337,199,4,311,709,4,308,283,4,304,910,4,260,634,4,233,311,4,215,131,4,166,122,4,141,981,4,130,664,4,089,977,4,089,900,4,069,341,4,055,655,4,049,665,4,044,139,4,002,775,3,991,201,3,966,968,3,954,868,3,936,393,3,917,476,3,915,889,3,867,548,3,865,748,3,867,548,3,865,748,3,783,160,3,764,676,3,764,677;
抗炎剂:如以下美国专利所公开的:5,872,109,5,837,735,5,827,837,5,821,250,5,814,648,5,780,026,5,776,946,5,760,002,5,750,543,5,741,798,5,739,279,5,733,939,5,723,481,5,716,967,5,688,949,5,686,488,5,686,471,5,686,434,5,684,204,5,684,041,5,684,031,5,684,002,5,677,318,5,674,891,5,672,620,5,665,752,5,656,661,5,635,516,5,631,283,5,622,948,5,618,835,5,607,959,5,593,980,5,593,960,5,580,888,5,552,424,5,552,422,5,516,764,5,510,361,5,508,026,5,500,417,5,498,405,5,494,927,5,476,876,5,472,973,5,470,885,5,470,842,5,464,856,5,464,849,5,462,952,5,459,151,5,451,686,5,444,043,5,436,265,5,432,181,5,393,756,5,380,738,5,376,670,5,360,811,5,354,768,5,348,957,5,347,029,5,340,815,5,338,753,5,324,648,5,319,099,5,318,971,5,312,821,5,302,597,5,298,633,5,298,522,5,298,498,5,290,800,5,290,788,5,284,949,5,280,045,5,270,319,5,266,562,5,256,680,5,250,700,5,250,552,5,248,682,5,244,917,5,240,929,5,234,939,5,234,937,5,232,939,5,225,571,5,225,418,5,220,025,5,212,189,5,212,172,5,208,250,5,204,365,5,202,350,5,196,431,5,191,084,5,187,175,5,185,326,5,183,906,5,177,079,5,171,864,5,169,963,5,155,122,5,143,929,5,143,928,5,143,927,5,124,455,5,124,347,5,114,958,5,112,846,5,104,656,5,098,613,5,095,037,5,095,019,5,086,064,5,081,261,5,081,147,5,081,126,5,075,330,5,066,668,5,059,602,5,043,457,5,037,835,5,037,811,5,036,088,5,013,850,5,013,751,5,013,736,5,006,542,4,992,448,4,992,447,4,988,733,4,988,728,4,981,865,4,962,119,4,959,378,4,954,519,4,945,099,4,942,236,4,931,457,4,927,835,4,912,248,4,910,192,4,904,786,4,904,685,4,904,674,4,904,671,4,897,397,4,895,953,4,891,370,4,870,210,4,859,686,4,857,644,4,853,392,4,851,412,4,847,303,4,847,290,4,845,242,4,835,166,4,826,990,4,803,216,4,801,598,4,791,129,4,788,205,4,778,818,4,775,679,4,772,703,4,767,776,4,764,525,4,760,051,4,748,153,4,725,616,4,721,712,4,713,393,4,708,966,4,695,571,4,686,235,4,686,224,4,680,298,4,678,802,4,652,564,4,644,005,4,632,923,4,629,793,4,614,741,4,599,360,4,596,828,4,595,694,4,595,686,4,594,357,4,585,755,4,579,866,4,578,390,4,569,942,4,567,201,4,563,476,4,559,348,4,558,067,4,556,672,4,556,669,4,539,326,4,537,903,4,536,503,4,518,608,4,514,415,4,512,990,4,501,755,4,495,197,4,493,839,4,465,687,4,440,779,4,440,763,4,435,420,4,412,995,4,400,534,4,355,034,4,335,141,4,322,420,4,275,064,4,244,963,4,235,908,4,234,593,4,226,887,4,201,778,4,181,720,4,173,650,4,173,634,4,145,444,4,128,664,4,125,612,4,124,726,4,124,707,4,117,135,4,027,031,4,024,284,4,021,553,4,021,550,4,018,923,4,012,527,4,011,326,3,998,970,3,998,954,3,993,763,3,991,212,3,984,405,3,978,227,3,978,219,3,978,202,3,975,543,3,968,224,3,959,368,3,949,082,3,949,081,3,947,475,3,936,450,3,934,018,3,930,005,3,857,955,3,856,962,3,821,377,3,821,401,3,789,121,3,789,123,3,726,978,3,694,471,3,691,214,3,678,169,3,624,216;
免疫抑制剂:如以下美国专利所公开的:4,450,159,4,450,159,5,905,085,5,883,119,5,880,280,5,877,184,5,874,594,5,843,452,5,817,672,5,817,661,5,817,660,5,801,193,5,776,974,5,763,478,5,739,169,5,723,466,5,719,176,5,696,156,5,695,753,5,693,648,5,693,645,5,691,346,5,686,469,5,686,424,5,679,705,5,679,640,5,670,504,5,665,774,5,665,772,5,648,376,5,639,455,5,633,277,5,624,930,5,622,970,5,605,903,5,604,229,5,574,041,5,565,560,5,550,233,5,545,734,5,540,931,5,532,248,5,527,820,5,516,797,5,514,688,5,512,687,5,506,233,5,506,228,5,494,895,5,484,788,5,470,857,5,464,615,5,432,183,5,431,896,5,385,918,5,349,061,5,344,925,5,330,993,5,308,837,5,290,783,5,290,772,5,284,877,5,284,840,5,273,979,5,262,533,5,260,300,5,252,732,5,250,678,5,247,076,5,244,896,5,238,689,5,219,884,5,208,241,5,208,228,5,202,332,5,192,773,5,189,042,5,169,851,5,162,334,5,151,413,5,149,701,5,147,877,5,143,918,5,138,051,5,093,338,5,091,389,5,068,323,5,068,247,5,064,835,5,061,728,5,055,290,4,981,792,4,810,692,4,410,696,4,346,096,4,342,769,4,317,825,4,256,766,4,180,588,4,000,275,3,759,921;
亚氨基糖:脱氧野尻霉素或脱氧野尻霉素衍生物,如正丙基脱氧野尻霉素、正丁基脱氧野尻霉素、正丁基脱氧半乳糖野尻霉素、正戊基脱氧野尻霉素、正庚基脱氧野尻霉素、正戊酰脱氧野尻霉素、N-(5-金刚烷-1-基甲氧基)戊基)-脱氧野尻霉素、N-(5-胆甾烯氧基戊基)-脱氧野尻霉素(N-(5-cholesteroxypentyl)-deoxynojirimycin)、N-(4-金刚烷甲酰氧基羧基-1-氧)-脱氧野尻霉素(N-(4-adamantanemethanylcarboxy-1-oxo)-deoxynojirimycin)、N-(4-金刚烷基羧基-1-氧)-脱氧野尻霉素、N-(4-菲基羧基-1-氧)-脱氧野尻霉素(N-(4-phenantrylcarboxy-1-oxo)-deoxynojirimycin)、N-(4-胆甾烯基羧基-1-氧)-脱氧野尻霉素或N-(4-β-胆甾烷基羧基-1-氧)-脱氧野尻霉素;
神经酰胺类似物:D-苏型-1-苯基-2-棕榈酰氨基-3-吡咯烷-1-丙醇(P4)或P4衍生物,如D-苏型-4′-羟基-1-苯基-2-棕榈酰氨基-3-吡咯烷-1-丙醇(4′-羟基-P4)、D-苏型-1-(3′,4′-三亚甲二氧基)苯基-2-棕榈酰氨基-3-吡咯烷-1-丙醇(三亚甲二氧基(trimethylenedioxy)-P4)、D-苏型-1-(3′,4′-亚甲二氧基)苯基-2-棕榈酰氨基-3-吡咯烷-1-丙醇(亚甲二氧基-P4)和D-苏型-1-(3′,4′-亚乙二氧基)苯基-2-棕榈酰氨基-3-吡咯烷-1-丙醇(亚乙二氧基-P4或D-t-et-P4);
在本发明缀合物的可选实施方案中,所述诊断或治疗剂是包含肽或多肽(蛋白)的诊断或治疗剂,所述肽或多肽(蛋白)如生长因子、细胞因子、酶、抗体、抗体片段等。药物部分所衍生的具体所关注(多)肽药物和化合物包括但不限于:
血液和造血系统药物:抗贫血药、凝血药(止血剂、抗凝血剂、抗血栓药、溶栓剂、血液蛋白及其组分)、血红蛋白;
细胞因子:Intron或α-干扰素;ProleukinIL-2或阿地白介素、干扰素-α、干扰素-β(Avonex或干扰素β-1a;Betaseron/Betaferon或干扰素β-1b;Rebif或干扰素β-1a)、干扰素-γ、白介素1(IL-1)、白介素2(IL-2)、白介素3(IL-3)、白介素4(IL-4)、白介素5(IL-5)、白介素6(IL-6)、TNF、粒细胞巨噬细胞集落刺激因子(GM-CSF:Leukine或沙格司亭)、粒细胞集落刺激因子(G-CSF:Neupogen或非格司亭)、巨噬细胞集落刺激因子(M-CSF)、血小板衍生生长因子(PDGF);
酶:Cerezyme或葡糖脑苷脂酶;AldurazymeTM或拉罗尼酶;AryplaseTM或芳基硫酸酯酶B;I2S或艾杜糖硫酸酯酶;α-L-艾杜糖醛酸苷酶;N-乙酰半乳糖胺4-硫酸酯酶;苯酶(phenylase);天冬氨酰氨基葡糖苷酶;酸性脂酶;半胱氨酸转运蛋白;Lamp-2;α-半乳糖苷酶A;酸性神经酰胺酶;α-L-岩藻糖苷酶;ss-氨基己糖苷酶A;GM2-激活蛋白缺陷(GM2-activatordeficiency);α-D-甘露糖苷酶;ss-D-甘露糖苷酶;芳基硫酸酯酶A;皂化蛋白B;神经氨酸苷酶;α-N-乙酰氨基葡糖苷酶磷酸转移酶;磷酸转移酶7-亚基;类肝素-N-硫酸酯酶;a-N-乙酰氨基葡糖苷酶;乙酰辅酶A:N-乙酰转移酶;N-乙酰葡糖胺6-硫酸酯酶;半乳糖6-硫酸酯酶;0-半乳糖苷酶;透明质酸氨基葡糖苷酶(hyaluronoglucosaminidase);多种硫酸酯酶;棕榈酰蛋白硫酯酶;三肽基肽酶I;酸性鞘磷脂酶;胆固醇运输;组织蛋白酶K;α-半乳糖苷酶B;唾液酸转运蛋白SOD或Cu/Zn过氧化物歧化酶;脑啡肽酶(Neprilysin);
(有机磷酸酯)解毒剂或清除剂:硫氰酸酶、对硫磷水解酶;磷酸三酯酶;丁酰胆碱酯酶;有机磷酸酐酶(organophosphorus acid anhydrolase);或非多肽清除剂样喷替酸或二亚乙基三胺五乙酸(DTPA);肟;
脑作用激素(brain-acting hormone)和神经递质:生长抑素、缩宫素、加压素、咖啡因、VIP、促肾上腺皮质素(ACTH)、缩胆囊肽(CCK)、P物质、蛙皮素、胃动素、肠高血糖素、胰高血糖素、胰高血糖素-样肽(GLP-1)、瘦蛋白;
神经肽及其衍生物:肽YY(PYY)、神经肽Y(NPY)、胰多肽(PP)、神经激肽A、神经激肽B、内啡肽、脑啡肽、met-脑啡肽(Tyr-Gly-Gly-Phe-Met)、亮啡肽类似物、洛哌丁胺、内吗啡肽-1和2、神经降压素、神经调节肽K、神经调节肽L、降钙素相关肽(CGRP)、内皮素、ANP(“心钠肽”)、BNP(“脑钠肽”)、CNP(“C型利钠肽”)和PACAP(“垂体腺苷酸环化酶激活肽”)、TAPP(H-Tyr-D-Ala-Phe-Phe-NH2)、senktide(具有修饰的序列DFFGLM:Asp-1=琥珀酰-Asp,Phe-3=Me-Phe,Met-6=C-末端酰胺);
神经营养因子:NGF或神经生长因子;BDNF或脑源性神经营养因子;NT3或神经营养蛋白-3;NT4或神经营养蛋白-4;NT5或神经营养蛋白-5;RDGF或视网膜衍生生长因子;CNTF或睫状神经营养因子;活化素;bFGF或碱性成纤维细胞生长因子;aFGF或酸性成纤维细胞生长因子;GDNF或胶质细胞系衍生神经营养因子或神经胚活素(neublastin)或青蒿琥酯(artemin)或enovin、presephin、神经生长因子(neurturin);CTGF或结缔组织生长因子;EGF或上皮生长因子);红细胞生成素(EPO)(Procrit/Eprex或红细胞生成素α;Epogen或红细胞生成素;NeoRecormon或红细胞生成素β;Aranesp或达贝泊汀α);生长激素或促生长素(HumatropeProtropin/NutropinSerostimSaizen);抗-NogoA Mab(IN-1);Nogo-A、B或C拮抗剂,或Nogo66抑制剂(NEP1-40);Lingo-1;FGL肽(pGlu-Val-Tyr-Val-Val-Ala-Glu-Asn-Gln-Gln-Gly-Lys-Ser-Lys-Ala或EVYVVAENQQGKSKA);NAP(Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln,单氨基酸字母代码,NAPVSIPQ);ADNF-9(Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala,SALLRSIPA);
抗体或其功能性(表位结合)片段:3F8、阿巴伏单抗(Abagovomab)、阿巴西普(Orencia)、阿昔单抗(ReoPro)、ACZ885(卡那单抗(canakinumab))、阿达木单抗(Humira)、阿德木单抗、阿柏西普(Aflibercept)、阿夫土珠(Afutuzumab)、Alacizumab pegol、阿仑珠单抗(Campath)、阿妥莫单抗、阿非莫单抗、麻安莫单抗、安芦珠单抗(Anrukinzumab)(IMA-638)、阿泊珠单抗、阿西莫单抗、阿塞珠单抗、Atlizumab、阿托木单抗、巴匹珠单抗、巴利昔单抗(舒莱)、巴土昔单抗、贝妥莫单抗(LymphoScan)、贝拉西普、贝利木单抗(LymphoStat-B)、柏替莫单抗、贝索单抗、贝伐珠单抗(阿瓦斯丁)、比西单抗溴烯比妥、比伐单抗-DM1、Blinatumomab、卡那单抗、美坎珠单抗、卡罗单抗喷地肽(Prostascint),卡妥索单抗(Removab)、西利珠单抗、培舍珠单抗(Cimzia)、西妥昔单抗(爱必妥)、Citatuzumab bogatox、西妥木单抗(Cixutumumab)、Claretuzumab tetraxetan、克立昔单抗、Clivatuzumabtetraxetan、CNTO 148(戈利木单抗)、CNTO 1275(优特克单抗(ustekinumab))、西他土珠(Conatumumab)、达西珠单抗(Dacetuzumab)、达昔单抗或达克珠单抗(赛尼哌)、地舒单抗、地莫单抗、阿托度单抗、Dorlixizumab、Drimakinzumab、依美昔单抗、依库珠单抗(Soliris)、埃巴单抗、依决洛单抗(单抗17-1A)、依法珠单抗(Raptiva)、依夫单抗(Mycograb)、艾西莫单抗、培戈赖莫单抗、西依匹莫单抗(Epitumomab cituxetan)、依帕珠单抗、厄立珠珠单抗(Erlizumab)、厄马索单抗(Rexomun)、依那西普(恩利)、埃达珠单抗(Etaracizumab)、艾韦单抗、法索单抗(NeutroSpec)、法拉莫单抗、非维珠单抗、Figitumumab、芳妥珠单抗(HuZAF)、夫瑞韦如(Foravirumab)、加利昔单抗、Gantenerumab、Gavilimomab、吉妥珠单抗奥佐米星(Mylotarg)、Ginakinzumab、戈利木单抗、戈利昔单抗、Ibalizumab、替伊莫单抗(Zevalin)、伊戈伏单抗、英西单抗、英利昔单抗(Remicade)、伊诺莫单抗、伊珠单抗奥佐米星、伊匹木单抗、伊妥木单抗、Ixutumumab、凯利昔单抗、拉贝珠单抗、来马索单抗(Lemalesomab)、Lebrilizumab、乐地单抗、来沙木单抗、利韦单抗、林妥珠单抗、鲁卡木单抗(Lucatumumab)、鲁昔单抗、马帕木单抗、马司莫单抗、马妥珠单抗、美泊利单抗(Bosatria)、美替木单抗、Milatuzumab、明瑞莫单抗、米妥莫单抗、莫罗木单抗、莫他珠单抗(Numax)、莫罗单抗、MYO-029(司他芦单抗)、他那可单抗、他那莫单抗(Naptumomabestafenatox)、那他珠单抗(Tysabri)、奈巴库单抗、奈瑞莫单抗、尼妥珠单抗(BIOMAbEGFR)、巯诺莫单抗(Verluma)、奥瑞珠单抗、奥度莫单抗、奥法木单抗、奥马珠单抗(Xolair)、奥戈伏单抗(OvaRex)、奥昔珠单抗(Otelixizumab)、帕昔单抗、帕利珠单抗(Synagis)、Pamtuzumab tetraxetan、帕尼单抗(Vectibix)、帕考珠单抗、Pemtumomab(Theragyn)、培妥珠单抗(Omnitarg)、培克珠单抗、平妥单抗(Pintumomab)、普立昔单抗、普立木单抗、PRO 140、瑞非韦鲁(Rafivirumab)、雷莫芦单抗(Ramucirumab)、雷珠单抗(Lucentis)、雷昔库单抗、瑞加韦单抗、瑞利珠单抗、利洛西普(Arcalyst)、Rintalizumab、利妥昔单抗(MabThera,Rituxan)、Robatumumab、罗维珠单抗、鲁利单抗、沙妥莫单抗、司韦单抗、西罗珠单抗、西利珠单抗、Sonepcizumab、松妥珠单抗、司他芦单抗、Stolanezumab、硫索单抗(LeukoScan)、替他珠单抗(Tacatuzumab tetraxetan)、他度珠单抗、他利珠单抗、他尼珠单抗(Tanezumab)、帕他普莫单抗(Taplitumomab paptox)、替非珠单抗(金息斯)、阿替莫单抗、Tenatumomab、替奈昔单抗、替利珠单抗(Teplizumab)、TGN1412、替西木单抗(tremelimumab)、替加珠单抗(Tigatuzumab)、TNX-355(ibalizumab)、TNX-650、TNX-901(他利珠单抗)、托珠单抗(Actemra)、托利珠单抗、托西莫单抗(Bexxar)、曲妥珠单抗(赫赛汀)、Tremelimumab、西莫白介素单抗、妥韦单抗、乌珠单抗、优特克单抗(Ustekinumab)、伐利昔单抗、维多珠单抗(Vedolizumab)、维妥珠单抗(Veltuzumab)、维帕莫单抗、Vimakinzumab、维西珠单抗(Visilizumab)(Nuvion)、伏洛昔单抗、Vontakinzumab、伏妥莫单抗(HumaSPECT)、扎芦木单抗、扎木单抗(Zanolimumab)(HuMax-CD4)、齐拉木单抗(Ziralimumab)、阿佐莫单抗。
在本发明缀合物的可选实施方案中,所述诊断或治疗剂是包含寡核苷酸或多核苷酸的诊断或治疗剂。包含寡核苷酸或多核苷酸的诊断或治疗剂可以是DNA疫苗、反义寡核苷酸、核酶、催化性DNA(DNA核酶)或RNA分子、siRNA或编码其的表达构建体中的任一种。DNA疫苗在本文中应理解为表示包含编码特定抗原的序列的核酸构建体,在将所述构建体引入要用DNA疫苗接种的宿主有机体的细胞中时,其能表达所述抗原。
所有上述专利公开的内容,在此通过援引加入本文。
配体
本发明缀合物中的第二实体是谷胱甘肽转运蛋白的配体。优选地,谷胱甘肽转运蛋白介导以下作用中的至少一种:配体和包含所述配体的缀合物特异性结合、胞吞和转胞吞进入和/或通过表达所述转运蛋白的靶细胞。转运蛋白或受体介导的递送是近几年发展的一种可能的靶向药物递送技术。其具有向表达与药物或药物载体缀合的配体的受体/转运蛋白的细胞高特异性递送的潜在优势。通过使用转运蛋白/受体介导的递送,可以大大增强低分子量以及多肽和基于核酸的治疗或诊断剂和包含这些诊断或治疗剂的纳米容器向细胞和组织的特异性靶向。
在一实施方案中,本发明缀合物中的配体是谷胱甘肽转运蛋白的配体,所述谷胱甘肽转运蛋白表达于血组织屏障的内皮细胞上,所述血组织屏障包括例如血睾丸屏障和血-CNS屏障,如血脑屏障、血脑脊液(CSF)屏障、软膜血管-CSF屏障、室管膜和胶质界膜、血视网膜屏障、血神经屏障以及血脊髓屏障。优选的配体是谷胱甘肽转运蛋白的配体,所述谷胱甘肽转运蛋白表达于血脑屏障和/或脑实质细胞(神经元和神经胶质)的内皮细胞上。这类配体的使用会允许这类靶向的诊断或治疗剂向中枢神经系统(CNS)的特异性递送或特异性增强的递送以用于治疗脑疾病。受体介导的靶向可以进一步与非特异性药物递送系统(如蛋白缀合物、PEG化(聚乙二醇化,PEGylation)、纳米颗粒、脂质体等)组合以大大改善药物的药物动力学和生物分布特性,这会显著地使药物特异性地再定向至表达受体的细胞、组织和器官,包括受到如CNS、血脑屏障(BBB)、视网膜和睾丸的特定血组织屏障保护的细胞、组织和器官。
因此,在优选的实施方案中,要并入本发明缀合物的配体是靶细胞上内源谷胱甘肽转运蛋白的配体。配体优选为脊椎动物靶细胞的谷胱甘肽转运蛋白、更优选哺乳动物靶细胞的谷胱甘肽转运蛋白并且最优选人靶细胞的谷胱甘肽转运蛋白的配体。配体优选为特异性结合谷胱甘肽转运蛋白的配体。更优选地,如Kannan et al.(2000,Brain Res.852(2):374-82)所述,配体特异性结合存在于人脑血管内皮细胞中的Na依赖性GSH转运蛋白。配体与转运蛋白的特异性结合优选地如本文上文所定义。在另一实施方案中,配体为被胞吞和/或转胞吞进入和/或通过靶细胞的配体,这可以通过Gaillard et al.(2001,Eur J Pharm Sci.12(3):215-222)所述的BBB细胞培养模型(利用初步分离的牛脑毛细血管内皮细胞(BCEC))或利用如RBE4细胞或MDCK细胞作为靶细胞的类似模型来测定。被胞吞和/或转胞吞进入和/或通过靶细胞的配体在本文中定义为这样的配体,当将所述配体添加至BCEC或MDCK靶细胞后15、30或60分钟或者1、2、4、8或18小时或更少测量时,与选自以下的对照条件相比,所述配体以提高至少5、10、20或50%的速率被胞吞或转胞吞进入或通过所述靶细胞:a)缺少GSH转运蛋白表达的细胞;b)用过量游离GSH预处理的细胞;和c)缺少GSH部分的参照化合物。可选地,GSH转运蛋白靶向的配体的胞吞作用和/或转胞吞作用可以利用例如与其缀合的近红外染料或放射性标记,通过体内生物成像技术测定,这使得与合适对照条件相比(如与缺少GSH部分的参照化合物比较),在给定的时间点(基于目标区(region of interest,ROI)像素定量),配体在CNS区域的保留提高至少10、20或50%。
本发明所用的结合谷胱甘肽转运蛋白的优选配体包括例如选自以下的配体:谷胱甘肽(GSH或γ-谷氨酰半胱氨酰甘氨酸);S-(对溴苄基)谷胱甘肽;γ-(L-γ-氮杂谷氨酰)-S-(对溴苄基)-L-半胱氨酰甘氨酸;S-丁基谷胱甘肽;S-癸基谷胱甘肽;谷胱甘肽还原乙酯;谷胱甘肽磺酸;S-己基谷胱甘肽;S-乳酰谷胱甘肽;S-甲基谷胱甘肽;S-(4-硝基苄基)谷胱甘肽;S-辛基谷胱甘肽;S-丙基谷胱甘肽;正丁酰γ-谷氨酰半胱氨酰甘氨酸(还简写为GSH-C4)或其乙酰、己酰、辛酰或十二酰衍生物(还分别简写为GSH-C2、GSH-C6、GSH-C8和GSH-C12);GSH单异丙酯(还称为N-(N-L-谷氨酰-L-半胱氨酰)甘氨酸1-异丙酯硫酸盐一水合物或YM737);以及美国专利第6,747,009号所公开的式I的GSH衍生物或其药学可接受的盐:
其中Z=CH2且Y=CH2,或Z=O且Y=C,
R1和R2独立地选自H、线性或支化的烷基(1-25C)、芳烷基(6-26C)、环烷基(6-25C)、杂环(6-20C)、醚或聚醚(3-25C)、以及其中R1-R2一起具有2-20C原子,并与式I的剩余部分(remainder)形成大环;
R3选自H和CH3,
R4选自6-8C烷基、苄基、萘基和治疗活性化合物,并且
R5选自H、苯基、CH3和CH2苯基。
在优选的实施方案中,上文通式中的R3为H。在另一优选的实施方案中,上文通式中的R4为苄基。在另一优选的实施方案中,上文通式中的R5为苯基。
在本发明的一优选实施方案中,经由N端氨基酸残基即谷氨酸残基的氨基(amine group)缀合或合成配体。
在本发明的另一优选实施方案中,经由C端氨基酸残基即甘氨酸残基的羧基缀合或合成配体。
在本发明的另一优选实施方案中,经由半胱氨酸部分的巯基(SH)基团缀合或合成配体。
纳米容器
本发明缀合物中的配体可以直接缀合至诊断或治疗剂,或者可选地,配体可以缀合至包含所述诊断或治疗剂的药学可接受的纳米容器。在此类缀合物中,诊断或治疗剂可以例如封装于诸如纳米颗粒、脂质体或纳米凝胶(nanogel)的纳米容器中,由此配体优选地缀合偶联至此类纳米容器。与纳米容器的缀合可以是直接的或经由任何公知的聚合缀合剂,如鞘磷脂、聚乙二醇(PEG)或其他有机聚合物。制备包含靶向(PEG)脂质体的此类药物组合物的细节描述于美国专利第6,372,250号。因此,在优选的实施方案中,本发明的缀合物是这样的缀合物,其中药学可接受的载体包括以下物质中的至少一种:载体蛋白、纳米容器、脂质体、阳离子聚合物DNA复合物系统、阳离子脂质体DNA复合物(lipoplex)系统和聚乙二醇。
在诊断或治疗剂包含多核苷酸或寡核苷酸的本发明缀合物中,药学可接受的载体优选是阳离子脂质体DNA复合物系统,其包含阳离子脂质或两性脂质(如WO2002/066012所详述)中的至少一种;或者是阳离子聚合物DNA复合物系统,其包含聚-L-赖氨酸、聚-L-鸟氨酸、聚乙烯亚胺和聚酰胺胺(polyamidoamine)中的至少一种。存在两类主要的用于细胞内递送基于核酸的抗病毒药物(如DNA疫苗、反义寡核苷酸、核酶、催化性DNA(DNA核酶)或RNA分子、siRNA或编码其的质粒)的非病毒递送系统,包括阳离子脂质体DNA复合物系统(含有DNA的阳离子脂质体)和阳离子聚合物DNA复合物系统(连接至阳离子聚合物的DNA)。在本发明优选的实施方案中,药学可接受的载体是阳离子脂质体DNA复合物系统或阳离子聚合物DNA复合物系统。另外,药学可接受的载体还可以优选地包含蛋白缀合物、聚乙二醇(PEG化)、纳米颗粒或脂质体。阳离子聚合物DNA复合物系统包含阳离子聚合物,如聚-L-赖氨酸(pLL)、聚-L-鸟氨酸(POL)、聚乙烯亚胺(PEI)、聚酰胺胺(PAM)或其与DNA的组合。聚阳离子系统主要通过吸附或液相胞吞作用进入细胞。包括PEI在内的阳离子聚合物能够浓缩(condens)DNA并使膜电势不稳定。而且,已经证实通过PEI阳离子聚合物DNA复合物系统的质粒递送可以通过控制复合物的物理化学和生物学特性来实现。然而,与病毒转导系统相比,转染效率和基因表达受到限制。因为PEI系统可以干扰膜,所以它们也能够引起与聚合物的分子量和核浓度相关的毒性。在这一方面,已经证实线性PEI(22kDa)比支化的PEI(25kDa)毒性更高,并且还如N/P比(与DNA的量有关的聚合物中氮的量)所表示的,与阳离子聚合物DNA复合物系统中所用的PEI的量有关。其他观点认为,线性PEI阳离子聚合物DNA复合物系统表现出改善的细胞成活力和更高的转染效率。最近已经合成了比线性PEI转染特性更好且毒性更低的各种生物可降解PEI衍生物。总的来说,PEI和或许聚阳离子系统的效率通常取决于分子量、整体阳离子电荷和支化程度。当连接至DNA时,其他因素如DNA的量、粒径和ζ电势是重要的特征。此外,当静脉内给药时,带正电荷的聚阳离子系统与带负电荷的血浆蛋白容易地发生相互作用,并且在与靶向它们以被网状内皮系统(RES)清除的血液蛋白结合后发生调理作用。特别地,聚集体(aggregate)的形成导致被吞噬细胞吸收和被毛细血管网络(主要是静脉内给药后的肺)捕获,这导致从血浆空间(compartment)的快速清除和靶组织/器官的较差转染。然而,PEG化可以显著地减少这种情况。此外,靶向/内化配体的应用避免了以大N/P比应用阳离子聚合物DNA复合物系统以及因此的高整体正电荷的需要,并因此可以减少与阳离子聚合物有关的许多问题(如毒性、与血液组分的结合)。裸阳离子脂质体DNA复合物系统也容易被血清组分调理,并且被与阳离子聚合物DNA复合物系统类似的机制如被网状内皮系统(RES)清除。此外,尽管阳离子脂质体DNA复合物系统未甲基化的CpG受到掩护从而防止先天免疫应答,但一旦它们进入基本循环(general circulation),则阳离子脂质体DNA复合物系统可以和阳离子聚合物DNA复合物系统类似地被血液蛋白(C3、IgG、脂蛋白和纤连蛋白)调理,从而在肺和肝中导致炎性反应(受TNF-α、IL-6和IL-12介导)。另外,已经发现了复合物激活和T-、B-、NK-细胞和巨噬细胞的激活,并且它们与阳离子脂质体DNA复合物的注射剂量有关。在减少未甲基化CpG的数量之后,此类相互作用可以通过这些系统的PEG化或通过使用免疫抑制剂(如地塞米松)而受到限制。另外,通过PEG化减少它们的全身清除并增加靶向效率(通过应用选择性/特异性靶向配体)相当大地改善了这些系统的动力学。此外,降低阳离子脂质体DNA复合物系统的大小看起来在其组织分布和细胞吸收中是关键因素,并且增加了它们的转染效率。通常,胃肠外给药后阳离子脂质体DNA复合物和阳离子聚合物DNA复合物系统表达的组织分布和持续与小分子药物一样还主要取决于药物动力学(清除、分布体积)、制剂(大小、电荷、PEG化等)以及剂量治疗方案(大体积丸药、顺序注射、持续输注)。对于剂量治疗方案,令人感兴趣的是注意到阳离子脂质体DNA复合物和质粒DNA的顺序注射导致更高的表达,但也降低细胞因子诱导。此外,向靶组织/器官的递送依赖于血流和组织/器官吸收或通透性以及靶和非靶组织/器官的清除平衡。因此,应基于药物动力学参数设计合适的剂量治疗方案以优化向器官和组织的递送/靶向。另外,这对于细胞内药物动力学应当是协调的。细胞吸收后,阳离子脂质体DNA复合物和阳离子聚合物DNA复合物系统的细胞内药物动力学(分布、除去)是重要的问题。除了受体介导的吸收外,特别是非靶向的PEI系统的内化(经由网格蛋白或胞膜窖依赖性途径)看起来取决于细胞系和PEI-阳离子聚合物DNA复合物类型(线性PEI比支化的PEI)。此类系统经常结束于后期内体,因此它们需要逃避这些细胞器以进入细胞质,最终到达细胞核。诸如阳离子聚合物DNA复合物系统的阳离子系统能够逃避内体/溶酶体,因为根据所谓的“质子海绵介导的逃脱(proton sponge-mediated escape)”理论,它们能够缓冲pH并引起这些细胞器的渗透溶胀。然而,看起来小部分内化的系统逃脱入细胞质,而大部分则停留在内体/溶酶体中并被降解。然而,已经证实融合脂质(fusogenic lipid)或阳离子肽(蜂毒肽(mellitin))并入这些系统能增强它们的内体逃脱。一旦在胞液中,线性质粒可以被核酸酶容易地降解,而环状质粒则稳定的多。因此环状(脱氧)核酸分子是优选的。特别地,钙敏感性核酸酶看起来负责这种降解。最后,质粒必须经由形成水通道的核孔复合物(NPC)通过核膜被转运入细胞核,并且据估计约0.1%的质粒能够从胞液进入细胞核。小于40kDa的分子能够被动穿过NPC,而较大的分子(>60kDa)则需要特异性核定位信号(NLS)来主动转运以通过允许转运高达25-50MDa分子的NPC。实际上,已经证实NLS与质粒的偶联增强了质粒DNA的核聚集和表达。因此,优选地将NLS偶联至用于本发明缀合物的任何表达构建体。
配体与诊断或治疗剂或载体缀合的各种方法在本领域是已知的。这类方法描述于例如Hermanson(1996,Bioconjugate Techniques,AcademicPress)、U.S.6,180,084和U.S.6,264,914,并包括如用于将半抗原连接至载体蛋白的方法,如应用免疫学所常用的(参阅Harlow and Lane,1988,″antibodies:A laboratory manual″,Cold Spring Harbor Laboratory Press,ColdSpring Harbor,NY)。已经认识到,在一些情况下,缀合时配体或者诊断或治疗剂可能失去效力或功能,这取决于例如其中所用的缀合方法或化学基团。然而,鉴于用于缀合的大量方法,本领域技术人员能发现不影响或最小影响要缀合的实体的效力或功能的缀合方法。用于将配体与诊断或治疗剂或者载体缀合的合适方法包括,例如碳二亚胺缀合(Bauminger andWilchek,1980,Meth.Enzymol.70:151-159)。可选地,诊断或治疗剂或者载体能够偶联至Nagy et al.,Proc.Natl.Acad.Sci.USA 93:7269-7273(1996)和Nagy et al.,Proc.Natl.Acad.Sci.USA 95:1794-1799(1998)所述的配体,上述每一篇文献在此通过援引并入。可合适地使用的用于缀合的其他方法是,例如高碘酸钠氧化随后适当反应物的还原性烷基化以及戊二醛交联。当配体以及诊断或治疗剂或者载体都是(多)肽时,可以应用特别有利的缀合方法。在这类情况下,可以将两个实体合成为包含配体以及肽诊断或治疗剂或者载体的氨基酸序列的单个(多)肽链。除了共价键合外,在本发明的缀合物中,诊断或治疗剂或载体也可以通过非特异性或特异性蛋白-蛋白相互作用、非共价键合和/或配位化学键合直接缀合至配体分子,所述缀合可以任选地经由结合至诊断或治疗剂和配体的间隔物(spacer)或接头而实现。
在另一方面,本发明涉及上文所限定的本发明的缀合物,其用于治疗和/或预防CNS病症。根据本发明,本发明的缀合物用于制备用于治疗和/或预防CNS病症的药物。类似地,本发明涉及用于治疗和/或预防CNS病症的方法,其中向有需要的个体给予有效剂量的本发明的缀合物。需要治疗或预防CNS病症的个体可以是脊椎动物、哺乳动物或优选的人。
CNS疾病和相关病症
下列段落提供了在本发明的各种实施方案中可以用包含GSH转运蛋白靶向活性剂的本发明缀合物来治疗和/或预防的CNS和相关疾病状况或相关病症的各种病理描述。
在本发明优选的实施方案中,CNS病理是以下疾病中的一种:神经变性病症如阿尔茨海默病(AD)、帕金森病(PD)、亨廷顿病(HD)、多发性硬化(MS)、肌萎缩性脊髓侧索硬化症(ALS)、脑血管意外(CVA:缺血性脑卒中、脑内出血(ICH)或蛛网膜下出血(SAH))、血管相关痴呆、脑创伤(创伤性脑损伤)、脊椎损伤、酒精中毒,朊病毒疾病:克雅病(CJD)、疯牛病(BSE)。
在本发明的一实施方案中,阿尔茨海默病用基于胆碱脂酶抑制剂的下述靶向的药物或化合物中的一种来治疗:艾斯能(利凡斯得明)、Razadyne ER(加兰他敏)、Debio 9902 SR、NGX267;NMDA拮抗剂:Namenda/Axura/Ebixa(美金刚)、Dimebon(dimebolin)、NP-0361;α-7烟碱乙酰胆碱拮抗剂:ABT-089、AZD-0328、R-4996/MEM-63908、EVP-6124;被动免疫疗法:Gammagard(IVIG)、巴匹珠单抗(AAB-001)、LY2062430、PF-4360365(RN1219)、AAB-002、ACU-5A5、R-1450、ACI-01-Ab7、BAN-2401;γ-分泌酶抑制剂/γ-分泌酶调节剂:弗禄里赞(tarenflurbil;右旋氟比洛芬)、LY-450139、GSI-953、MK-0752;β-分泌酶抑制剂:CTS-21166;抗-TNF:恩利(依那西普)、培舍珠单抗(CDP870,商品名Cimzia)、Remicade(英利昔单抗)或Humira(阿达木单抗);胰岛素相关:文迪雅(罗格列酮)、TTP-488(RAGE抑制剂)、NGX-96992、胰岛素降解酶、Ketasyn(AC-1202)、SRT-501;Tau/GSK3抑制剂:NP031112、Dimebon;凝血级联:PAI-1拮抗剂;金属螯合剂:PBT2;抑制素:立普妥(阿托伐他汀)、舒降之(辛伐他汀);激素:易维持(雷洛昔芬);5-HT/GABA:来考佐坦/来考佐坦SR、PRX-03140、MK-0249、742457(SB-742457);其他抗淀粉样蛋白:ELND005(鲨肌醇(scyllo-inositol);AZD-103)、姜黄素、caprospinol(SP-233);β片层破坏肽(Leu-Pro-Phe-Phe-Asp或LPFFP、Ac-LPFFP-NH2,如美国专利第5,948,763号和第6,462,171号所公开,或Leu-Pro-Tyr-Phe-Asp-酰胺或LPYFDa,如Juhász et al.,2009,J.Alzheimers Dis.16:189-196)所述;或BACE1抑制剂:抗-BACE1抗体或其片段或脑啡肽酶。
在本发明优选的实施方案中,CNS病理是以下疾病中的一种:具有CNS组分的外周病症,如败血性休克、脑转移、肝性脑病、(糖尿病)高血压、糖尿病(微)血管病、昏睡病、惠普尔病(Whipple disease)、杜氏肌营养不良(DMD)、天冬氨酰氨基葡萄糖尿症、胆固醇脂贮积病、酸性脂酶缺乏症(Wolman disease)、胱氨酸过多症、Danon病、法布莱病、法伯脂肪肉芽肿病(Farber lipogranulomatosis)、法勃氏病(Farber disease)、岩藻糖代谢症、I/II型半乳糖唾液酸代谢症、I/II/III型戈谢病(Gaucher disease types I/II/III)、戈谢病(Gaucher disease)、球形细胞脑白质营养不良(globoid cellleucodystrophy)、克拉伯病(Krabbe disease)、II型糖原贮积病、庞帕病(Pompedisease)、1/11/11I型GM1神经节苷脂沉积症、I型GM2神经节苷脂沉积症、泰-萨病、II型GM2神经节苷脂沉积症、山德霍夫氏病(Sandhoff disease)、GM2神经节苷脂沉积症、1/11型α甘露糖苷过多症、甘露糖苷过多症、异染色性脑白质障碍症、I型粘脂贮积症、1/11型唾液酸贮积症11/III型粘脂贮积症1-细胞病、IIIC型粘脂贮积症假胡尔勒氏多种营养不良(pseudo-Hurler polydystrophy)、I型粘多糖代谢病、II型粘多糖代谢病、亨特综合征、IIIA型粘多糖代谢病、山菲利普综合征、IIIB型粘多糖代谢病、IIIC型粘多糖代谢病、IIID型粘多糖代谢病、IVA型粘多糖代谢病、莫尔基奥综合征(Morquio syndrome)、IVB型粘多糖代谢病莫尔基奥综合征、VI型粘多糖代谢病、VII型粘多糖代谢病、Sly综合征、IX型粘多糖代谢病、多种硫酸酯酶缺陷(multiple sulphatase deficiency)、神经元蜡样脂褐质沉积症(neuronal ceroid lipofuscinosis)、CLN1巴登氏病(CLN1 Batten disease)、A/B型尼曼-皮克病(Niemann-Pick disease)、尼曼-皮克病、C1型尼曼-皮克病、C2型尼曼-皮克病、致密性成骨不全、VII型Schindler病(Schindler disease)、Schindler病、唾液酸积贮病以及(先兆)子痫((pre)eclampsia)。
在本发明的另一实施方案中,溶酶体贮积病用基于减少溶酶体贮积病中的溶酶体贮积物质的药物和化合物的下述靶向的药物或化合物中的一种来治疗:所述溶酶体贮积物质如葡糖脑苷脂、鞘磷脂、神经酰胺、GM1-神经节苷脂、GM2-神经节苷脂、红细胞糖苷脂、半乳糖神经酰胺、硫酸皮肤素、硫酸乙酰肝素、硫酸角质素、硫苷脂、粘多糖、唾液酸寡糖、糖蛋白、唾液酸寡糖、糖脂、三聚己糖神经酰胺(globotriaosylceramide)、O-联糖肽、糖原、游离唾液酸、岩藻糖脂(fucoglycolipid)、岩藻糖基寡糖(fucosyloligosaccharide)、甘露糖基寡糖(mannosyloligosaccharide)、天冬氨酰氨基葡糖、胆固醇酯、甘油三酯,以及溶酶体贮积病中的蜡样脂褐质色素如戈谢病(贮积的葡糖脑苷脂):利用使用β-葡糖脑苷脂酶(如伊米苷酶(Genzyme销售的Cerezyme)或velalglucerase(由Shire研发中)、基因激活β-葡糖脑苷脂酶的靶向酶替代疗法,使用用亚氨基糖(如麦格司他(Actelion销售的麦格司他胶囊(Zavesca))=正丁基-脱氧野尻霉素(NB-DNJ)、正丁基-半乳糖-脱氧野尻霉素(NB-DGJ)、N-(5-金刚烷-1-基-甲氧基戊基)-脱氧野尻霉素(AMP-DNJ)、N-(5-金刚烷-1-基-甲氧基-戊基)脱氧野尻霉素(AMP-DNM)的葡糖神经酰胺合酶的底物抑制,或用葡糖神经酰胺类似物(如Genz 112638:d-苏型-亚乙二氧基苯基-2-棕榈酰氨基-3-吡咯烷-丙醇),或用分子伴侣疗法(如酒石酸异荞麦碱(isofagomine tartrate)、AT2101(将由Amicus Therapeutics作为PliceraTM销售,化学名:(3R,4R,5R)-3,4-二羟基-5-羟甲基-哌啶);法布莱病(贮积的三聚己糖神经酰胺),利用使用α-半乳糖苷酶A(如Algalsidase-α(Shire销售的Replagal)、Algalsidase-β(Genzyme销售的法布瑞酶)的靶向酶替代疗法,或使用用亚氨基糖(如麦格司他(Actelion销售的麦格司他胶囊)=正丁基-脱氧野尻霉素(NB-DNJ),正丁基-半乳糖-脱氧野尻霉素(NB-DGJ)、N-(5-金刚烷-1-基-甲氧基戊基)(AMP-DNJ)、AMP-DNM或来自Macrozyme的MZ-21和MZ-31)的葡糖神经酰胺合酶的底物抑制,或用葡糖神经酰胺类似物(如Genz 112638:d-苏型-亚乙二氧基苯基-2-棕榈酰氨基-3-吡咯烷-丙醇),或用分子伴侣疗法(AT1001,盐酸米加司他(待由Amicus Therpeutics作为AmigalTM销售,化学名为3,4,5-哌啶三醇、2-(羟甲基)盐酸盐、(2R,3S,4R,5S)-,(+)-(2R,3S,4R,5S)-2-(羟甲基)哌啶-3,4,5-三醇盐酸盐、1,5-双脱氧-1,5-亚氨基-D-半乳糖醇盐酸盐);MPS I(贺勒-施艾氏症(Hurler-Scheie)、贮积的硫酸皮肤素、硫酸乙酰肝素),利用使用α-L-艾杜糖醛酸苷酶(如拉罗尼酶(由Genzyme/Biomarin销售的阿杜拉酶)的靶向酶替代疗法;MPS II(亨特综合征(Hunter),贮积的硫酸皮肤素、硫酸乙酰肝素),利用使用艾杜糖-2-硫酸酯酶(如艾度硫酸酯酶(由Shire销售的Elaprase)的靶向酶替代疗法;MPS III A(Sanfilippo A,贮积的硫酸乙酰肝素),利用使用乙酰肝素硫酸胺酶(heparan sulfamidase)的靶向酶替代疗法;MPS III B(Sanfilippo B,贮积的硫酸乙酰肝素),利用使用α-N-乙酰葡糖苷酶的靶向酶替代疗法;MPS III C(Sanfilippo C,贮积的硫酸乙酰肝素),利用使用α-氨基葡糖苷N-乙酰转移酶的靶向酶替代疗法;MPS III D(Sanfilippo D,贮积的硫酸乙酰肝素)利用使用N-乙酰葡糖胺-6-硫酸酯硫酸酯酶的靶向酶替代疗法;MPS IV(莫尔基奥综合征(Morquio),贮积的硫酸角质素),利用使用N-乙酰半乳糖胺-6-硫酸酯酶的靶向酶替代疗法;MPS VI(马洛托-拉米氏症(Maroteaux-Lamy),贮积的糖胺聚糖(GAG)),利用使用芳基硫酸酯酶B(如戈硫酯酶(由Biomarin销售的Naglazyme)的靶向酶替代疗法;MPS VII(Sly综合征(Sly),贮积的硫酸皮肤素、硫酸乙酰肝素),利用使用β-葡糖苷酸酶的靶向酶替代疗法;克拉伯病(Krabbe)(贮积的半乳糖神经酰胺),利用使用半乳糖脑苷脂酶的靶向酶替代疗法;A和B型尼曼-皮克病(贮积的鞘磷脂),利用使用酸性鞘磷脂酶(Genzyme研发中)的的靶向酶替代疗法;C型尼曼-皮克病(贮积的鞘磷脂),利用使用麦格司他(Actelion销售的麦格司他胶囊)=正丁基-脱氧野尻霉素(NB-DNJ)或环糊精(特别是羟丙基-β-环糊精)葡糖神经酰胺合酶的靶向底物抑制;异染色性脑白质障碍症(贮积的硫苷脂),利用使用芳基硫酸酯酶A的靶向酶替代疗法;II/III型粘脂贮积症(贮积的唾液酸寡糖、糖蛋白、糖脂),利用使用UDP-N-乙酰葡糖胺或溶酶体酶N-乙酰葡糖胺-1-磷酸转移酶(GNPT)的靶向酶替代疗法;GM1神经节苷脂沉积病(贮积的GM1神经节苷脂),利用使用β-半乳糖苷酶的靶向酶替代疗法;山德霍夫氏病(具有贮积的GM2神经节苷脂的GM2神经节苷脂沉积病),利用使用β-氨基己糖苷酶A的靶向酶替代疗法,或利用亚氨基糖(如麦格司他(由Actelion销售的麦格司他胶囊)=正丁基-脱氧野尻霉素(NB-DNJ))的葡糖神经酰胺合酶的底物抑制;泰-萨病(GM2神经节苷脂),利用使用α-氨基己糖苷酶A的靶向酶替代疗法,或利用亚氨基糖(如麦格司他(由Actelion销售的麦格司他胶囊)=正丁基-脱氧野尻霉素(NB-DNJ))的葡糖神经酰胺合酶的底物抑制。
仍然在本发明的另一优选实施方案中,CNS病理是以下疾病中的一种:神经精神病症,如抑郁症(如通过利用脑靶向的脂质体盐皮质激素受体激动剂如氟氢可的松、脱氧皮质酮或醛固酮修饰,由此减少外周心血管副作用),孤独症,焦虑症,注意力不足多动症(ADHD),成瘾和其他物质相关病症,神经精神性系统性红斑性狼疮,双相情感障碍(bipolar disorder),进食障碍(eating disorder),精神分裂症,和他精神病;或其他CNS病症,如原发性脑瘤、癫痫/癫痫发作、偏头疼和其他头疼(集束性头痛、血管性头痛、紧张性头痛)、发作性睡病、失眠症(和其他睡眠障碍)、慢性疲劳综合征、高原病、肥胖、细菌和病毒性脑炎、细菌和病毒性脑膜炎、AIDS相关痴呆;或血管发生相关病症,如血管瘤、增殖性玻璃体视网膜病变、类风湿性关节炎、克罗恩病、动脉粥样硬化、卵巢过度刺激、牛皮癣、与新血管形成相关的子宫内膜异位、球囊血管成形术后的再狭窄、疤组织过度产生、外周血管疾病、高血压、炎性血管炎、雷诺氏病(Reynaud′s disease)、雷诺氏现象(Reynaud′s phenomenon)、动脉瘤、动脉再狭窄、血栓性静脉炎、淋巴管炎、淋巴水肿、创伤愈合和组织修复、缺血再灌注损伤、心绞痛、心肌梗死、慢性心脏疾病状况、诸如充血性心力衰竭的心力衰竭、年龄相关性黄斑变性以及骨质疏松。
靶向和/或穿过血组织屏障
本发明的另一方面提供了有效量的诊断或治疗剂或者包含诊断或治疗剂的药学可接受的载体向受特定血组织屏障所保护的靶位点靶向药物递送的方法,所述血组织屏障如CNS、血脑屏障(BBB)、视网膜和睾丸,其中a)所述诊断或治疗剂或者药学可接受的载体缀合至配体,由此形成上文所定义的缀合物,所述配体促进特异性结合靶位点的内化GSH吸收受体和被靶位点的内化GSH吸收受体内化;和b)在给予有需要的人约1天至约5天后的时期内,将所述诊断或治疗剂递送至靶位点。在优选的实施方案中,所述方法中的血组织屏障如血脑屏障未受到给予破坏血组织屏障的诊断或治疗剂的破坏。在另一优选的实施方案中,所述时期为约1天至约7天,更优选约1天至约10天,甚至更优选约1天至约14天,最优选约1天至约21天。
下列段落涉及有关通过受体介导的转胞吞作用向特定血组织屏障所保护的靶位点的主动靶向的本发明各种实施方案,所述血组织屏障如CNS、血脑屏障(BBB)、视网膜和睾丸。在本发明优选的实施方案中,介导胞吞作用和转胞吞作用中至少一种的GSH转运蛋白位于脑的毛细血管(腔侧)中。通常,不期望受任何理论的束缚,受体介导的转胞吞作用以3个步骤发生:诊断或治疗剂在腔(血液)侧的受体介导的胞吞作用、通过内皮细胞质的移动以及药物在脑毛细血管内皮的近腔(脑)侧的胞吐作用。在受体-配体内化时形成网格蛋白(chlathrin)包被的囊泡,其直径为约120nm。这些囊泡可以将它们的内容物转运至细胞的另一侧或进入导致蛋白降解的途径。实际上,已经鉴定了至少两种重要的降解蛋白的途径,包括溶酶体和泛素-蛋白酶体途径。因此,为了逃避内体溶酶体(endosomallysosomal)系统,已经应用了确保药物释放入胞液的机制。这些包括应用pH敏感脂质体或阳离子分子。然而,在应用或不应用溶酶体逃避机制的情况下,已经证实向脑递送蛋白是有效的。因此,受体介导的转胞吞作用允许较大药物分子或携带药物的颗粒(如脂质体、聚合物系统、纳米颗粒)向脑的特异性靶向。在优选的实施方案中,GSH转运蛋白介导胞吞作用和转胞吞作用中的至少一种,选择配体和药学可接受的载体以避开诊断或治疗剂在细胞中的溶酶体降解。
基因治疗
本发明的一些方面涉及包含核苷酸序列的表达载体的用途,所述核苷酸序列编码上文所定义的包含寡核苷酸或多核苷酸的诊断或治疗剂,其中所述载体为适合基因治疗的载体。适合基因治疗的载体描述于Anderson1998,Nature 392:25-30;Walther and Stein,2000,Drugs 60:249-71;Kay et al.,2001,Nat.Med.7:33-40;Russell,2000,J.Gen.Virol.81:2573-604;Amadoand Chen,1999,Science 285:674-6;Federico,1999,Curr.Opin.Biotechnol.10:448-53;Vigna and Naldini,2000,J.Gene Med.2:308-16;Marin et al.,1997,Mol.Med.Today 3:396-403;Peng and Russell,1999,Curr.Opin.Biotechnol.10:454-7;Sommerfelt,1999,J.Gen.Virol.80:3049-64;Reiser,2000,GeneTher.7:910-3;以及本文引用的参考文献中。特别合适的基因治疗载体包括腺病毒和腺伴随病毒(AAV)载体。这些载体感染许多分裂和非分裂细胞类型。另外,腺病毒载体能高水平转基因表达。然而,由于进入细胞后腺病毒和AAV载体的游离属性,如上文所述,这些病毒载体最适合仅要求转基因的瞬时表达的治疗应用(Russell,2000,J.Gen.Virol.81:2573-2604)。如Russell(2000,见上文)所综述的,优选的腺病毒载体经修饰以减少宿主应答。
通常,基因治疗载体在它们包含编码待表达的诊断或治疗剂的核苷酸序列的意义上,与上文所述的表达载体一样,由此核苷酸序列可操作地连接至上文所述的合适的调节基因。这类调节序列包含至少一个启动子序列。如本文所用,术语“启动子”指这样的核酸片段,其功能是控制一个或多个基因的表达,位于所述基因的转录起始位点的转录方向的上游,并且在结构上通过存在DNA依赖性RNA聚合酶的结合位点、转录起始位点和任何其他DNA序列而鉴定,所述任何其他DNA序列包括但不限于转录因子结合位点、阻遏物和激活蛋白结合位点以及本领域技术人员已知的作用为直接或间接调节由启动子转录的量的任何其他核苷酸序列。“组成型”启动子是在大多数生理条件和发育条件下都有活性的启动子。“诱导型”启动子是取决于生理条件或发育条件而受到调节的启动子。“组织特异性”启动子是仅在分化的细胞/组织的特定类型中有活性的启动子。用于表达编码来自基因治疗载体的多肽的核苷酸序列的合适启动子包括如巨细胞病毒(CMV)立即早期启动子(cytomegalovirus intermediate early promoter)、病毒长末端重复启动子(LTR),如来自莫洛尼鼠白血病病毒(MMLV)劳氏肉瘤病毒的启动子,或HTLV-1,猿猴病毒40(SV 40)早期启动子和单纯疱疹病毒胸腺嘧啶核苷激酶启动子。
已经描述了数种诱导型启动子系统,它们可以通过给予小有机或无机化合物而诱导。此类诱导型启动子包括受重金属控制的启动子如金属硫蛋白启动子(Brinster et al.1982 Nature 296:39-42;Mayo et al.1982 Cell 29:99-108)、RU-486(孕酮拮抗剂)(Wang et al.1994 Proc.Natl.Acad.Sci.USA91:8180-8184)、类固醇(Mader and White,1993 Proc.Natl.Acad.Sci.USA 90:5603-5607)、四环素(Gossen and Bujard 1992 Proc.Natl.Acad.Sci.USA 89:5547-5551;美国专利第5,464,758号;Furth et al.1994 Proc.Natl.Acad.Sci.USA 91:9302-9306;Howe et al.1995 J.Biol.Chem.270:14168-14174;Resnitzky et al.1994 Mol.Cell.Biol.14:1669-1679;Shockett et al.1995 Proc.Natl.Acad.Sci.USA 92:6522-6526)以及作为VP16激活结构域的基于由tetR多肽组成的多嵌合反式激活剂的tTAER系统和雌激素受体的配体结合结构域(Yee et al.,2002,US 6,432,705)。
基因治疗载体可以任选地包含编码第二或其他蛋白的第二或一个或多个其他核苷酸序列。第二或其他蛋白可以是(选择)标记蛋白,其允许鉴定、选择和/或筛选含有表达构建体的细胞。用于此目的的合适标记蛋白为例如荧光蛋白如绿色GFP,和选择标记基因HSV胸腺嘧啶核苷激酶(用于HAT培养基的选择)、细菌潮霉素B磷酸转移酶(用于潮霉素B的选择)、Tn5氨基糖苷磷酸转移酶(用于G418的选择)以及二氢叶酸还原酶(DHFR)(用于甲氨蝶呤的选择),CD20、低亲和力神经生长因子基因。获得这些标记基因的来源以及它们的使用方法提供于Sambrook and Russel(2001)″MolecularCloning:A Laboratory Manual(3rd edition),Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Press,New York。
可选地,第二或其他核苷酸序列可以编码提供故障安全(fail-safe)机制的蛋白,如果需要,所述故障安全机制允许由转基因细胞治愈个体。此类核苷酸序列经常称为自杀基因,其编码能将前药转化为毒性物质的蛋白,所述毒性物质能杀死表达所述蛋白的转基因细胞。此类自杀基因的合适实例包括如大肠杆菌胞嘧啶脱氨酶基因或来自单纯胞疹病毒、巨细胞病毒和水痘带状疱疹病毒的胸腺嘧啶核苷激酶基因中的一种,在这种情况下,更昔洛韦可以用作在个体中杀死IL-10转基因细胞的前药(参阅例如Clair et al.,1987,Antimicrob.Agents Chemother.31:844-849)。优选地将基因治疗载体配制于如下文所定义的包含合适的药物载体的药物组合物中。
抗体
抗体或抗体片段可以是本发明缀合物或者诊断或治疗剂的组成部分。优选地,抗体或其片段是单克隆抗体(MAb)。利用本领域已知的多种技术包括使用杂交瘤、重组技术和噬菌体展示技术或其组合,可以制备补充组分的MAb。例如,单克隆抗体可以利用杂交瘤技术产生,包括本领域已知和教导的那些技术,例如Harlow et al.,Antibodies:A Laboratory Manual,(Cold Spring Harbor Laboratory Press,2nd ed.1988);Hammerling,et al.,in:Monoclonal Antibodies and T-Cell Hybridomas 563-681(Elsevier,N.Y.,1981)。为了治疗人,抗补体MAb优选地用作嵌合、去免疫化、人源化或人抗体。此类抗体能够减少免疫原性并因此避免人抗小鼠抗体(HAMA)应答。抗体优选为IgG4、IgG2或不增加抗体依赖性细胞毒性(S.M.Canfield and S.L.Morrison,J.Exp.Med.,1991:173:1483-1491)和补体介导的细胞溶解(Y.Xuet al.,J.Biol.Chem.,1994:269:3468-3474;V.L.Pulito et al.,J.Immunol.,1996;156:2840-2850)的其他基因突变的IgG或IgM。嵌合抗体通过本领域公知的重组方法产生,并具有动物可变区和人恒定区。人源化抗体比嵌合抗体具有更大程度的人肽序列。在人源化抗体中,仅负责抗原结合和特异性的互补性决定区(CDR)是动物来源的,并具有对应于动物抗体的氨基酸序列,而基本上该分子的所有剩余部分(除了在某些情况下可变区内的小部分框架区外)是人来源的,并在氨基酸序列上对应于人抗体。参阅L.Riechmannet al.,Nature,1988;332:323-327;G.Winter,美国专利第5,225,539号;C.Queen et al.,U.S.5,530,101。如WO9852976所述,去免疫化的抗体是其中T和B细胞表位已经被去除的抗体。当体内应用时,它们的免疫原性已经减少。人抗体能够通过数种不同的方式制备,包括通过使用人免疫球蛋白表达文库(Stratagene Corp.,La Jolla,California)来产生人抗体的片段(VH、VL、Fv、Fd、Fab或(Fab’)2,以及利用与产生嵌合抗体类似的技术,使用这些片段来构建全人抗体。人抗体也能够用人免疫球蛋白基因组在转基因小鼠中产生。此类小鼠可从Abgenix,Inc.,Fremont,California和Medarex,Inc.,Annandale,New Jersey获得。也可以产生单肽链结合分子,其中重链和轻链Fv区连接。单链抗体(“ScFv”)及其构建方法描述于美国专利第4,946,778号。可选地,可以通过类似的方式构建并表达Fab(M.J.Evans et al.,J.Immunol.Meth.,1995;184:123-138)。可以用于本发明的另一类抗体是重链抗体及其衍生物。此类单链重链抗体天然存在于如骆驼(Camelidae)中,并且它们分离的可变结构域通常称为“VHH结构域”或“纳米抗体(nanobody)”。获得重链抗体和可变结构域的方法特别提供于下列参考文献中:WO 94/04678,WO 95/04079,WO 96/34103,WO 94/25591,WO 99/37681,WO 00/40968,WO 00/43507,WO 00/65057,WO 01/40310,WO 01/44301,EP1134231,WO 02/48193,WO 97/49805,WO 01/21817,WO 03/035694,WO03/054016,WO 03/055527,WO 03/050531,WO 01/90190,WO 03/025020,WO 04/041867,WO 04/041862,WO04/041865,WO 04/041863,WO04/062551。所有完全和部分人抗体的免疫原性比全鼠MAb(或来自其他非人类动物的MAb)小,并且片段和单链抗体的免疫原性也小。因此,所有这些类型的抗体不太可能激发免疫应答或变应性应答。因此,它们比完整动物抗体更适合人的体内给药,特别是当需要重复或长期给药时。另外,大小较小的抗体片段可以有助于改善组织生物利用度,这对于急性疾病指征如肿瘤治疗或一些病毒感染中更好的剂量聚积非常关键。
药物组合物
本发明还涉及一种药物制剂,其包含作为活性成分的本文所定义的缀合物。除了活性成分(缀合物)外,组合物优选地至少包含一种药学可接受的载体(除了缀合物中的载体外)。在一些方法中,缀合物包含从哺乳动物、昆虫或微生物细胞培养物、转基因哺乳动物的奶或其他来源纯化的本发明的多肽或抗体,将其以纯化的形式与药物载体一起作为药物组合物给予。制备包含多肽的药物组合物的方法描述于美国专利第5,789,543号和第6,207,718号。优选的形式取决于给药和治疗应用的预期模式。药物载体可以是适合将多肽、抗体或基因治疗载体递送至患者的任何相容的非毒性物质。无菌水、醇、脂肪、蜡和惰性固体可以用作载体。还可以将药学可接受的佐剂、缓冲剂、分散剂等并入药物组合物中。本发明的缀合物在药物组合物中的浓度可以在大范围变动,即从小于约0.1重量%,通常为至少约1重量%至多达20重量%或更多。对于口服给药,活性成分可以以固体剂型的形式给予,如胶囊剂、片剂、粉剂,或以液体剂型的形式给予,如酏剂、糖浆剂和混悬剂。活性组分可以与非活性成分和粉末状载体一起封装于明胶胶囊中,如葡萄糖、乳糖、蔗糖、甘露醇、淀粉或纤维素衍生物、硬脂酸镁、硬脂酸、糖精钠、滑石、碳酸镁等。可以添加以提供期望的颜色、味道、稳定性、缓冲能力、分散或其他已知期望特征的其他非活性成分的实例为氧化铁红、硅胶、十二烷基硫酸钠、二氧化钛、可食白墨(ediblewhite ink)等。可以用类似的稀释剂制备压制片剂。可以将片剂和胶囊剂制备为缓释产品以在数小时的时间段内提供药物的持续释放。压制片剂可以是糖包衣或薄膜包衣的以掩盖任何不舒服的味道并保护片剂免受空气的危害,或者是肠溶衣的以用于胃肠道内的选择性崩解。用于口服给药的液体剂型可以含有着色剂和调味剂以增加患者的接受性。本发明的缀合物优选地以胃肠外给予。带有胃肠外给药的缀合物的制剂必须是无菌的。在冻干和重构前后,灭菌容易地借助通过无菌滤膜的过滤来完成。给予缀合物的胃肠外途径与已知的方法一致,如通过静脉内、腹膜内、肌肉内、动脉内、病灶内、颅内、鞘内、透皮、鼻、颊、直肠或阴道途径注射或输注。通过输注或通过团注射(bolus injection)来连续给予缀合物。用于静脉内输注的典型组合物经配制含有10-500ml无菌0.9%NaCl或5%葡萄糖,任选地补充20%白蛋白溶液以及所需剂量的缀合物。用于肌肉内注射的典型药物组合物经配制含有例如1-10ml无菌缓冲水和所需剂量的本发明的缀合物。制备胃肠外给药的组合物的方法在本领域是公知的,并且更详细地描述于各种资料中,包括例如Remington′s Pharmaceutical Science (15th ed.,MackPublishing,Easton,PA,1980)(通过援引加入本文用于所有目的)。
对于治疗应用,以足以减少症状严重性和/或预防或停滞症状进一步发展的量向患有病毒感染或相关疾病状况的患者给予药物组合物。足以实现这一目的的量定义为“治疗有效剂量”或“预防有效剂量”。这类有效剂量会取决于疾病状况的严重性和患者的总体健康状况。
在本说明书和权利要求书中,动词“包含”及其变形以其非限制意义使用,表示包括该词后的项目,但不排斥未专门提及的项目。另外,不定冠词“一个(a)”或“一个(an)”所限定的元素不排除存在多于一个该元素的可能性,除非上下文清楚地要求存在一个且仅一个该元素。因此,不定冠词“一个(a)”或“一个(an)”通常表示“至少一个”。
文说明书所引用的所有专利和文献在此通过援引整体加入本文。
仅出于说明目的提供下列实施例而并非意图以任何方式限制本发明的范围。
附图说明
图1表示BCEC中谷胱甘肽-PEG-脂质体(用Rho-PE标记)吸收的代表性图。所表示的是在BCEC单培养模式(A)和BBB共培养模式(B)中,牛毛细血管内皮细胞(BCEC)对GSH靶向的脂质体的吸收。显微图表示1/2hr(小时)(A)和2hr(B)的孵育时间后,BCEC培养物(细胞核复染色为蓝色)对GSH靶向的脂质体(红色)的吸收。BCEC单培养模式(C)和BBB共培养模式(D)与非靶向的脂质体的孵育清楚地表明在细胞内或周围不存在红色信号。
图2表示连续12天每日静脉内团注射的最后一次后3天,谷胱甘肽-PEG-脂质体(以50mg/kg/天剂量给药治疗方案)向仓鼠脑的特异性靶向的图。以上的显微图表示GSH靶向的脂质体的荧光信号主要是血管周的。
实施例
实施例1诊断或治疗剂与受体特异性配体的缀合
作为诊断或治疗剂与GSH缀合的实例,本文公开了GSH与蛋白药物缀合的优选方法。将类似的缀合化学应用于其他本文公开的诊断或治疗剂和其他本文公开的GSH衍生物。为了观察GSH-转运蛋白特异性细胞吸收以及缀合至亲水诊断或治疗剂的GSH的体内药物动力学和生物分布,用亲水荧光染料异硫氰酸荧光素(FITC)或Cy5.5标记GSH。为此,将GSH溶于PBS和NaHCO3 pH 9.0。添加FITC或Cy5.5,并在室温下将溶液避光搅拌1hr。通过柱离心(ZebaTM,Pierce,Rockford,USA)除去过量的FITC或Cy5.5,然后将溶液于4℃下避光保存。
实施例2 GSH-转运蛋白特异性配体与含有封装的诊断或治疗剂的纳米容器的缀合及其药物动力学和药效学
作为由GSH-转运蛋白特异性配体包被的含有诊断或治疗剂的纳米容器的实例,本文公开了GSH与药物负载的PEG化(聚乙二醇化,PEGylated)脂质体缀合的优选方法。脂质体由数摩尔比(如2.0∶1.5)的磷脂和胆固醇组成。为了修饰血浆中的转变/加工温度和颗粒稳定性,以与胆固醇(Chol)的不同比例,使用磷脂如1,2-二棕榈酰-sn-甘油-3-磷酸胆碱(DPPC)、二肉豆蔻酰磷脂酰胆碱(DMPC)、氢化的大豆磷脂酰胆碱(HSPC)、大豆磷脂酰胆碱(SPC)、二硬脂酰磷脂酰胆碱(DSPC)或蛋黄磷脂酰胆碱(EYPC),其中混合物中较少的Chol会导致血浆中较不稳定的脂质体。将组分溶于乙醇或异丙醇。含有DSPE-PEG-GSH(0.2-10摩尔%)的胶束是在制备脂质体前利用DSPE-PEG-MAL和还原的谷胱甘肽(在三肽的半胱氨酸部分赋予MAL反应性巯基)的新鲜溶液合成的,并且以不同的摩尔百分比向溶液添加DSPE-mPEG(Mw 2000)(总计高达5-10摩尔%)。可选地,利用对GSH中的氨基具有活性的DSPE-PEG-NHS缀合DSPE-PEG-GSH,或将GSH在N或C端残基直接合成至DSPE-PEG。当需要改变脂质体的电荷时,向混合物添加磷酸十六烷基酯(DP)或DOTAP。另外,可以向混合物添加非离子表面活性剂聚山梨酯80(Tween 80))。还可以使用其他非离子表面活性剂,如Tween 20、Tween 40、Brij76、Brij78或美国专利6,288,040公开的那些表面活性剂(即碳二亚胺、正乙氧基羰基-2-乙氧基-1,2-二氢喹啉、戊二醛(glutardioldehyde)、bromozyane、偏高碘酸盐(Na-盐或K-盐)、甲苯磺酰氯和氯甲酸酯)。在存在或不存在赋形剂或诸如环糊精的增溶剂的情况下,将(脂质)混合物注射到含有亲水诊断或治疗剂的水溶液中。向脂质混合物中添加亲脂诊断或治疗剂,或用预填充例如硫酸铵或乙酸钙的脂质体,利用主动装载方法将亲脂诊断或治疗剂封装(任选地在医院药房中作为制备后过程)。涡旋后,挤压囊泡通过膜或者在乳化器中均质化。可选地,通过在25℃直至60℃下孵育2-24小时(取决于脂质混合物的转变温度和诊断或治疗剂的温度敏感性),在脂质体制备后添加DSPE-PEG-GSH。通过测量粒径(在Malvern Zetasizer中50-200nm)、ζ电势、磷脂含量(利用磷脂B试剂盒或HPLC/UPLC系统)和肽含量(0.2-10摩尔%GSH,基于HPLC/UPLC或Pierce的OPA测定)以及药物装载(loading)来表征脂质体。将该脂质体捕获策略应用于本文公开的诊断或治疗剂,并且将类似的缀合或合成化学应用于其他本文公开的作为靶向配体的GSH衍生物。另外,将类似的脂质体捕获应用于基于核酸的药物,同时,如Gao and Huang,1991,Biochem Biophys ResCommun.179(1):280-5所详述,通过向脂质体添加胆固醇的阳离子衍生物(DC-Chol),或者如WO2002/066012所详述,通过利用两性脂质体进行核酸捕获的额外富集。为了观察受体特异性细胞吸收以及缀合至填充有诊断或治疗剂的脂质体的GSH的体内药物动力学和生物分布,在制备脂质体的过程中向脂质混合物添加1,2-二油酰-sn-甘油-3-磷酸乙醇胺-N-丽丝胺磺酰若丹明B(Rho-PE)。可选地,用放射性示踪分子标记脂质体,或者封装的诊断或治疗剂是荧光分子(如Cy5.5)或具有缀合至诊断或治疗剂的荧光探针(如Cy5.5或FITC)的化合物。
例如,利用乳化器(Emulsiflex-C3),将在50℃下以100mg/ml溶于PBS的利巴韦林封装于溶于2-丙醇中的脂质体,所述脂质体由DPPC(55%)、胆固醇(41%)、若丹明-PE(0.04%)和mPEG-DSPE(4.4%)组成。为了测试GSH分子的量对脂质体外层的影响,通过将GSH-PEG-DSPE胶束后插入预形成的脂质体以代替mPEG-DSPE来制备不同百分比的GSH-PEG-DSPE(0-2%),从而提供0或0.1、0.2、0.5或2%的GSH-PEG脂质体,总PEG含量为5%。以此方式,利巴韦林GSH-PEG脂质体为90nm,并含有10mg/ml利巴韦林(封装效率为8-12%)。用EYPC而不是DPPC,制备类似的利巴韦林GSH-PEG脂质体。在大鼠中单次静脉内注射50mg/kg后,发现在0%PEG脂质体(基于DPPC)中,利巴韦林的全(脂质体封装的)峰血浆水平以3毫摩尔浓度(millimolar)稳定数小时(据估计半衰期为约19小时),而血浆中的游离部分则为约4微摩尔浓度(micromolar)。对于2%GSH-PEG脂质体(基于DPPC),全血浆水平也为约3毫摩尔浓度(据估计半衰期相同),其中游离部分则仅高于2微摩尔浓度。相反,脑组织液中游离利巴韦林水平(可通过脑微量透析测定),对于0%PEG脂质体仅高于120纳摩尔浓度(nanomolar),而对于2%GSH-PEG脂质体则为约600纳摩尔浓度。另外,发现游离利巴韦林所增强的脑递送效果通过降低脂质体上GSH的%而减少:对于0.5%GSH为450纳摩尔浓度,对于0.2%GSH为250纳摩尔浓度,并且对于0.1%GSH为约120纳摩尔浓度,这又与0%相似。这些结果表明,向PEG化脂质体添加GSH增强游离药物以GSH依赖性方式穿过血脑屏障的递送,系数约5倍。相关的是,不同制剂(0-2%GSH)的利巴韦林的全血浆水平的曲线下的面积无显著不同。相反,在基于EYPC的脂质体中,利巴韦林的全(脂质体封装的)血浆水平(再次在大鼠中单次静脉内注射50mg/kg后)据发现仅在1毫摩尔浓度时达到峰值,并快速下降(半衰期为约3小时),在脂质体的外表面上在0和2%的GSH之间未观察到差异。同时,发现利巴韦林的游离部分为约45微摩尔浓度(峰值),并以全血浆水平的相同速率下降,在脂质体的外表面上在0和2%GSH之间也没有差异。这些结果表明,基于DPPC的脂质体具有长循环时间(和缓慢的利巴韦林释放),而基于EYPC的脂质体具有短循环时间(和快速的利巴韦林释放)。
作为另一实例,将PEG化多柔比星脂质体(基于Cealyx/Doxil)修饰为在PEG的顶端含有GSH。为此,于60℃下,将GSH-PEG-DSPE胶束(5%)溶于2mg/mL硫酸铵溶液。向该溶液添加溶于乙醇(于60℃下)的HSPC(55%)和胆固醇(40%),并且通过挤压通过滤器直至获得约100nm的颗粒来制备脂质体。随后,通过透析除去游离的硫酸铵,并添加2mg/mL多柔比星溶液(于60℃下)以允许多柔比星与铵交换并在脂质体核心中沉淀(“主动装载”)。发现在大鼠中单次静脉内注射6mg/kg后,在未修饰的PEG化脂质体(Caelyx/Doxil)中,多柔比星的全(脂质体封装的)峰血浆水平稳定数小时(据估计半衰期为约24小时),而GSH修饰的PEG化脂质体表现出较快的清除,从而导致估计的半衰期为19小时。结果还表明,未修饰的PEG化脂质体所获得的AUC比GSH修饰的PEG化脂质体大约50%,并且Cmax值高约20%。随后,在无胸腺小鼠中评价这些脂质体的效力,其中利用立体定位框架(stereotactic frame)将人成胶质细胞瘤细胞(U87)的悬浮液缓慢注射到脑中。将小鼠分为3个处理组:对照(盐水)、未修饰的PEG化脂质体(Caelyx/Doxil)中的多柔比星以及GSH修饰的PEG化脂质体中的多柔比星。动物接受5mg/kg的i.v.注射,每周2次。处理在植入U87细胞后14天开始。没有观察到处理的副作用(AE),动物没有表现出任何注射相关的不良事件,它们也没有表现出任何神经症状。用GSH修饰的PEG化脂质体中的多柔比星处理与盐水和未修饰的PEG化脂质体相比(2向ANOVA,p<0.001),及时地表现出脑肿瘤生长的强烈显著减少,并且与对照组相比表现出高显著存活益处(与盐水相比增加42%,与未修饰的PEG化脂质体相比增加19%)。相反,在具有皮下植入的人转移性乳腺癌细胞(MDA-MB-231)的裸鼠中,测试相同的处理组(10mg/kg i.v.,每4天),在两种脂质体制剂之间没有观察到处理效力的差异;与媒介物处理相比,两种制剂在减少肿瘤负荷方面是等效的。
仍然作为另一实例,应用上文对多柔比星GSH修饰的PEG化脂质体所述的相同脂质体制备方法来封装甲泼尼龙和脱氧皮质酮的半琥珀酸盐。为此,用乙酸钙溶液代替硫酸铵溶液,从而导致高药物封装效率(>70%)和稳定的制剂。测试这些制剂在CNS疾病状况(例如在多发性硬化或(应激相关)抑郁症的动物模型中)中的增强的效力以及通常与这些类固醇相关的外周副作用(主要是心血管的)的减少。
作为肽诊断或治疗剂的实例,应用上文对多柔比星GSH修饰的PEG化脂质体所述的相同脂质体制备方法来封装β-片层破坏(breaker)肽LPFFP或Ac-LPFFP-NH2。为此,用50-100mg/mL的肽溶液代替硫酸铵溶液,从而导致脂质体水核心中约15%的肽封装效率和稳定的制剂。在涉及β-淀粉样蛋白(amyloid-beta)的CNS疾病状况(例如,在具有增强的噬斑形成的阿尔茨海默病的转基因动物模型中)中测试这些制剂的增强的效力。
作为更敏感的蛋白诊断或治疗剂如抗体、酶和生长因子的实例,优选较低的处理温度。为此,在37℃下,将95-55%EYPC、DMPC或DPPC,以及0-40%胆固醇和1%mPEG-DSPE溶于乙醇,并添加至如曲妥珠单抗、gammaquin、伊米苷酶、艾度硫酸酯酶(elaprase)、GDNF或白蛋白的用Tween80(<0.01%)稳定的蛋白溶液中,并通过挤压通过滤器直至获得约100nm的颗粒来制备脂质体。随后,在制备过程中或就在向个体注射前,于37℃下向预制的脂质体添加4-8%的GSH-PEG-DSPE胶束,保持30分钟至高达2小时。可选地,向脂质溶液添加5%的GSH-PEG-DSPE冻干产物以代替1%的mPEG-DSPE。如果需要,通过透析/渗滤除去游离蛋白,或通过蛋白特异性柱(如ProtG)再捕获游离蛋白。具有40%胆固醇的基于DMPC的脂质体的半衰期在与上文所述的具有40%胆固醇的基于DPPC的脂质体的半衰期相同的范围内。胆固醇的%减少至10%将血浆半衰期(以及因此的IgG释放)缩短至约2小时,其中从制剂中省略胆固醇甚至进一步将半衰期减少至约30分钟。
实施例3 GSH与基于核酸的药物的载体的缀合
作为通过靶向吸收机制的基于核酸的药物的非病毒递送系统的实例,本文公开了PEG化GSH与聚乙烯亚胺(polyethylenimine,PEI)jetPEI等或其片段缀合的优选方法。PEG化的复合物制备如下。将PEI溶于PBS。向此溶液添加聚(乙二醇)-α-马来酰亚胺-ω-NHS(NHS-PEG-VS),并在室温下孵育,同时混合。通过超滤除去过量的NHS-PEG-VS。将PEI-PEG-VS直接用于与还原的GSH的巯基缀合。
实施例4 GSH与蛋白的缀合
作为直接缀合方法的实例,本文公开了GSH与酶、生长因子、单克隆抗体或其片段缀合的优选方法。GSH缀合的蛋白制备如下。优选地用(硫代)-SMCC修饰赖氨酸基团的氨基,从而提供蛋白上的巯基反应性马来酰亚胺基团。随后将该反应性蛋白直接用于与还原的GSH的巯基缀合。
实施例5靶向的诊断或治疗剂的GSH特异性细胞吸收和/或跨细胞转运
通过分析GSH缀合物的特异性吸收来观察GSH缀合物的GSH特异性细胞吸收,并与对照缀合物的吸收水平进行比较。使用来自数个种类和来源的已知(缺少)表达GSH转运蛋白的细胞,包括猪肾上皮细胞(LLC-PK1)、牛脑毛细血管内皮细胞(BCEC)以及犬MDCK细胞。细胞吸收实验:将靶向和非靶向脂质体的200纳摩尔(nmole)等份添加至血脑屏障的体外模型(大鼠星形胶质细胞和牛毛细血管内皮细胞的共培养物),并且添加至BCEC的单培养物中。37℃下的孵育时间范围为1/2-3hr。处理结束时,将盖玻片上的细胞用4%PFA固定,并洗涤,然后用含有DAPI(细胞核复染)的Vectashield封固剂封片于载玻片上。利用NIKON TE2000-E倒置显微镜,用于若丹明、GFP和DAPI的三频带滤波器(triple band filter),通过荧光显微术以20x或60x的放大率评价细胞培养物中脂质体的结局。图1表示在BCEC单培养模式(图版A)和BBB共培养模式(图版B)中,牛毛细血管内皮细胞(BCEC)对GSH靶向脂质体的吸收。显微图表示在1/2hr(A)和2hr(B)的孵育时间后,BCEC培养物(细胞核复染成蓝色)对GSH靶向脂质体(红色Rho-PE)的吸收。用非靶向脂质体孵育清楚地表明,在细胞内或周围缺少红色信号。
实施例6 GSH靶向的诊断或治疗剂的药物动力学和生物分布
在仓鼠中,在12次每日静脉内团注射后,通过分析脂质体中的Rho-PE标记观察GSH靶向脂质体的药物动力学和生物分布,并与非靶向脂质体进行比较。在最后注射后3天,灌注的仓鼠脑中GSH靶向脂质体与对照脂质体相比表现出较高且特异性的积聚,而在分析的其他组织选择(包括心脏、肺、肝、脾和肾)中较少,所述对照脂质体在脑中不(或几乎不)可检测,但在肺、肾和肝组织中的程度相对较高。图2表示最高剂量组的仓鼠脑载玻片代表性图。
Claims (10)
1.一种缀合物,其包含:
a)谷胱甘肽转运蛋白的配体;和
b)i)和ii)的至少一种:
i)诊断或治疗剂;和
ii)包含所述诊断或治疗剂的药学可接受的纳米容器,
其中a)中的配体缀合至b)中的诊断或治疗剂和纳米容器中的至少一种。
2.如权利要求1所述的缀合物,其中所述配体是这样的配体:当将所述配体添加至BCEC或MDCK靶细胞后18小时或更少测量时,其特异性结合所述靶细胞,或者与选自以下的对照条件相比以提高至少10%的速率被胞吞或转胞吞进入或通过所述靶细胞:a)缺少GSH转运蛋白表达的细胞;b)用过量游离GSH预处理的细胞;和c)缺少GSH部分的参照化合物。
3.如权利要求1或2所述的缀合物,其中所述配体选自:谷胱甘肽、S-(对溴苄基)谷胱甘肽、γ-(L-γ-氮杂谷氨酰)-S-(对溴苄基)-L-半胱氨酰甘氨酸、S-丁基谷胱甘肽、S-癸基谷胱甘肽、谷胱甘肽还原乙酯、谷胱甘肽磺酸、S-己基谷胱甘肽、S-乳酰谷胱甘肽、S-甲基谷胱甘肽、S-(4-硝基苄基)谷胱甘肽、S-辛基谷胱甘肽、S-丙基谷胱甘肽、正丁酰γ-谷氨酰半胱氨酰甘氨酸、乙酰γ-谷氨酰半胱氨酰甘氨酸、己酰γ-谷氨酰半胱氨酰甘氨酸、辛酰γ-谷氨酰半胱氨酰甘氨酸、十二酰γ-谷氨酰半胱氨酰甘氨酸、GSH单异丙酯(N-(N-L-谷氨酰-L-半胱氨酰)甘氨酸1-异丙酯硫酸盐一水合物)以及式I的谷胱甘肽衍生物或其药学可接受的盐:
其中Z=CH2且Y=CH2,或Z=O且Y=C,
R1和R2独立地选自H、线性或支化的烷基(1-25C)、芳烷基(6-26C)、环烷基(6-25C)、杂环(6-20C)、醚或聚醚(3-25C)、以及其中R1-R2一起具有2-20C原子,并与式I的剩余部分形成大环;
R3选自H和CH3,
R4选自6-8C烷基、苄基、萘基和治疗活性化合物,并且
R5选自H、苯基、CH3-和CH2-苯基。
4.如权利要求3所述的缀合物,其中在式I的衍生物中,R3为H,R4为苄基,并且R5为苯基。
5.如前述权利要求中任一项所述的缀合物,其中所述诊断或治疗剂为以下诊断或治疗剂中的至少一种:
a.中枢神经系统抑制剂;
b.中枢神经系统刺激剂;
c.精神药物;
d.呼吸道药物;
e.外周神经系统药物;
f.在突触连接位点或神经效应器连接位点起作用的药物;
g.平滑肌活性药物;
h.组胺能剂(histaminergic agent);
i.抗组胺能剂(antihistaminergic agent);
j.心血管药物;
k.血液和造血系统药物;
l.胃肠道药物;
m.类固醇剂;
n.细胞生长抑制剂或抗肿瘤剂;
o.抗感染剂;
p.抗生素剂;
q.抗真菌剂;
r.驱肠虫剂;
s.抗疟剂;
t.抗原生动物剂;
u.抗微生物剂;
v.抗炎剂;
w.免疫抑制剂;
x.细胞因子;
y.酶;
z.亚氨基糖;
aa.神经酰胺类似物;
bb.脑作用激素或神经递质;
cc.神经肽或其衍生物;
dd.神经营养因子;
ee.抗体或其片段;
ff.阿尔茨海默病药物或化合物;
gg.基于核酸的化合物;
hh.显像剂;
ii.(有机磷酸酯)解毒剂。
6.如前述权利要求中任一项所述的缀合物,其中所述药学可接受的纳米容器包括以下物质中的至少一种:
a)载体蛋白;
b)脂质体;
c)阳离子聚合物DNA复合物系统;
d)阳离子脂质体DNA复合物系统;和
e)聚乙二醇。
7.如权利要求6所述的缀合物,其中所述药学可接受的纳米容器是阳离子脂质体DNA复合物系统,其包含阳离子脂质或两性脂质中的至少一种;或者是阳离子聚合物DNA复合物系统,其包含聚-L-赖氨酸、聚-L-鸟氨酸、聚乙烯亚胺和聚酰胺胺中的至少一种。
8.如前述权利要求中任一项所述的缀合物,其用于治疗、预防或诊断CNS病症。
9.如前述权利要求中任一项所述的缀合物在制备用于治疗、预防或诊断CNS病症的药物中的用途。
10.一种治疗、预防或诊断CNS病症的方法,其中所述方法包括向有需要的个体给予有效剂量的如权利要求1-7中任一项所述的缀合物。
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