CN1747747B - 作为穿过血脑屏障的载体的抑酶肽及类似物 - Google Patents
作为穿过血脑屏障的载体的抑酶肽及类似物 Download PDFInfo
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Abstract
本发明涉及药物传递领域中的改进。更特别地,本发明涉及一种非-侵入性和柔性的方法和载体,该方法和载体用于运送化合物或药物穿过个体的血脑屏障。特别地,本发明涉及将与之相连接的药剂运送穿过血脑屏障的载体,其中,载体在与药剂相连接后能够穿透血脑屏障并由此将药剂运送穿过血脑屏障。
Description
技术领域
本发明涉及药物传递领域的改进。更特别地,本发明涉及用于将化合物或药物运送穿过个体的血脑屏障的非-侵入性和柔性的方法与载体。
发明背景
在脑病理学新疗法的开发中,血脑屏障(BBB)被认为是潜在使用治疗中枢神经***(CNS)疾病的药物的主要障碍。1998年CNS药物的全球市场为$330亿美金,为心血管药物全球市场的大致一半,既便在美国,CNS障碍患者也几乎是心血管疾病患者人数的两倍。这种不平衡的原因是超过98%潜在的CNS药物不能穿过血脑屏障。此外,全球超过99%的CNS药物的开发仅仅涉及CNS药物发现,仅有不到1%的开发涉及CNS药物的传递。这个比例可以证明为什么对主要的神经学疾病诸如脑瘤、阿耳茨海默氏病和中风没有有效的治疗现行可使用。
通过两个屏障***保护脑抵抗潜在毒性物质,这两个屏障***是:血脑屏障(BBB)和血脑脊液屏障(BCSFB)。BBB被认为是摄取血清配体的主要途径,因为其表面积比BCSFB的大大约5000倍。脑内皮,它构成BBB,表示抗CNS多种疾病的潜在药物使用的主要障碍。作为一般规则,只有小于约500道尔顿的亲脂性分子能够穿过BBB,即从血液至脑。然而,用于治疗CNS疾病的在动物研究中显示有希望的效果的很多药物的尺寸相当地更大。由此,因为脑毛细管内皮壁对所述药物几乎没有渗透性,肽和蛋白质治疗剂通常被排除从血液运送到脑。脑毛细管内皮细胞(BCECs)被紧密连接所密封,与其它器官的毛细管相比,几乎没有开口和细胞内的囊泡。BCECs被细胞外基质、星形胶质细胞、外膜细胞和小神经胶质细胞所包围。内皮细胞和星形胶质细胞足突和毛细管的基底膜的紧密结合,对于形成和维持BBB的性质(它允许严格控制血-脑交换)是重要的。
至今还没有有效的可用于脑的药物传递方法。研究中的将肽和蛋白药物传递到脑的方法可以分为三种主要策略。首先,侵入性的方法包括通过手术方法直接脑室内给予药物,以及通过颈动脉内输注高摩尔渗透压的溶液短暂破坏BBB。其次,药理学-基础的策略表现为通过增加肽或蛋白的脂溶性来促使其穿过BBB。第三,生理学-基础的策略利用BBB的各种载体机制,这是最近几年被表征的。在此方法中,药物连接在蛋白质载体上,其表现如同在BBB上的受体-靶向的传递介质。此方法非常特异,并且表现出高功效,对具有不定靶标的临床适应症具有非常的柔性。在本发明中,研究最后一种方法。
人们非常希望在药物传递领域提供改进。
人们还非常希望提供一种非-侵入性的且柔性的方法和载体,该方法和载体用于运送化合物或药物穿过个体的BBB。
发明概述
本发明的一个目的是提供一项药物传递领域的改进。
本发明的另一个目的是提供一种非-侵入性的且灵活的方法和载体,该方法和载体用于运送化合物或药物穿过个体的血脑屏障。
根据本发明的一项实施方案,其中提供了一种用于运送药剂穿过患者血脑屏障的方法,该方法包括以下步骤:向患者给予一种化合物,该化合物含有与抑酶肽、抑酶肽的药学可接受的盐、抑酶肽片段或抑酶肽片段的药学可接受的盐相连接的所述药剂。
根据本发明进一步的一项实施方案,其中提供提供了抑酶肽、抑酶肽的药学可接受的盐、抑酶肽片段或抑酶肽片段的药学可接受的盐在运送与之相连接的化合物穿过患者血脑屏障中的用途。
根据本发明的另一项实施方案,其中提供了抑酶肽、抑酶肽的药学可接受的盐、抑酶肽片段或抑酶肽片段的药学可接受的盐在制备用于穿过患者血脑屏障治疗神经学疾病的药物中的用途。
根据本发明的还另一个实施方案,其中提供提供了抑酶肽、抑酶肽的药学可接受的盐、抑酶肽片段或抑酶肽片段的药学可接受的盐在制备穿过患者血脑屏障治疗中枢神经系障碍的药物中的用途。
根据本发明的另一项实施方案,其中提供了一种式为R-L-M的化合物或其药学可接受的盐,其中R是抑酶肽或其片段,L是一种连接体或一条键,且M是选自小分子药物、蛋白、肽和酶的药剂或药物。
根据本发明的另一项实施方案,其中提供了一种治疗患者神经学疾病的方法,该方法包括向患者给予一种药物,该药物含有抑酶肽、抑酶肽的药学可接受的盐、抑酶肽片段或抑酶肽片段的药学可接受的盐,以及一种适于治疗该疾病的化合物,所述化合物连接在抑酶肽上。
根据本发明进一步的一项实施方案,其中提供提供了一种治疗患者中枢神经***障碍的方法,该方法包括向患者给予一种药物,该药物含有抑酶肽、抑酶肽的药学可接受的盐、抑酶肽片段或抑酶肽片段的药学可接受的盐,以及一种适于治疗该疾病的化合物,所述化合物连接在抑酶肽上。
根据本发明的一项实施方案,其中提供提供了一种用于运送与之相连接的药剂穿过血脑屏障的载体,其中所述载体在与药剂相连接后能够穿过血脑屏障,并由此将药剂运送穿过血脑屏障。
在本发明的一项优选的实施方案中,所述运送不会影响血脑屏障的完整性。
在本发明的一项优选的实施方案中,载体选自抑酶肽、抑酶肽的功能性衍生物、血管肽1(Angio-pepl)和血管肽1的功能性衍生物。
在本发明的一项优选的实施方案中,药剂选自由药品、药物、蛋白、肽、酶、抗生素、抗癌药剂、中枢神经***水平上活性的分子、放射显影剂、抗体、细胞毒素、可检测标记和抗血管生成化合物组成的组。
在本发明的一项优选的实施方案中,抗癌剂是紫杉醇。
在本发明的一项优选的实施方案中,可测标记选自放射性标记、绿色荧光蛋白、组氨酸标签(histag)蛋白和β-半乳糖苷酶。
在本发明的一项优选的实施方案中,药剂的最大分子量为160,000道尔顿。
在本发明的一项优选的实施方案中,通过受体-介导的胞转或吸附-介导的胞转而实现所述运送。
在本发明的一项优选的实施方案中,药剂用于治疗神经学疾病。
在本发明的一项优选的实施方案中,神经学疾病选自由脑瘤、脑转移瘤、精神***症、癫痫、阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病、中风以及血脑屏障相关的机能障碍组成的组。
在本发明的一项优选的实施方案中,血脑屏障相关的机能障碍疾病是肥胖。
在本发明的一项优选的实施方案中,运送导致药剂传递至个体的中枢神经***(CNS)。
在本发明的一项优选的实施方案中,药剂在运送穿过血脑屏障之后,可从载体中释放出来。
在本发明的一项优选的实施方案中,药剂在运送穿过血脑屏障之后,从载体中被释放出来。
在本发明的一项优选的实施方案中,本发明提供了一种用于将药剂运送穿过血脑屏障的药物组合物,该组合物含有与药学可接受的赋形剂结合的本发明实施方案的载体。
根据本发明的另一项实施方案,其中提供了一种用于治疗神经学疾病的药物组合物,该组合物含有与药学可接受的赋形剂结合的本发明实施方案的载体。
根据本发明的另一项实施方案,其中提供了一种用于将药剂运送到个体CNS的药物组合物,该组合物含有与药学可接受的赋形剂结合的本发明实施方案的载体。
根据本发明的另一项实施方案,其中提供了一种用于将药剂运送穿过血脑屏障的缀合物,该缀合物包含:(a)载体;和(b)连接到载体上的药剂,其中,所述缀合物能够穿过血脑屏障并由此将药剂运送穿过血脑屏障。
根据本发明的另一项实施方案,其中提供了一种用于将药剂运送穿过血脑屏障的药物组合物,该组合物含有与药学可接受的赋形剂结合的本发明实施方案的缀合物。
根据本发明的一项实施方案,其中提供提供了一种用于治疗神经学疾病的药物组合物,该组合物含有与药学可接受的赋形剂结合的本发明实施方案的缀合物。
根据本发明的另一项实施方案,其中提供了一种用于将药剂运送到个体CNS的药物组合物,该组合物含有与药学可接受的赋形剂结合的本发明实施方案的缀合物。
根据本发明的另一项实施方案,其中提供了一种载体在制备用于将药剂运送穿过血脑屏障的药物中的用途,所述载体用于运送与之相连的药剂穿过血脑屏障。
根据本发明的另一项实施方案,其中提供了一种用于运送药剂穿过血脑屏障的药物组合物,该组合物中含有与药学可接受的赋形剂结合的按照本发明实施方案中定义的制备的药物。
根据本发明的另一项实施方案,其中提供了一种载体在制备用于治疗个体神经学疾病的药物中的用途,所述载体用于运送与之相连接的药剂穿过血脑屏障。
根据本发明的另一项实施方案,其中提供了一种用于治疗神经学疾病的药物组合物,所述组合物含有与药物可接受的赋形剂结合的按照本发明实施方案中定义的制备的药物。
根据本发明的另一项实施方案,其中提供了一种载体在制备用于治疗个体中枢神经***障碍的药物中的用途,所述载体用于运送与之相连的药剂穿过血脑屏障。
根据本发明的另一项实施方案,其中提供了一种用于治疗中枢神经***障碍的药物组合物,所述组合物含有与药物可接受的赋形剂结合的按照本发明实施方式中定义的所制备的药物。
根据本发明的另一项实施方案,其中提供了式R-L-M的缀合物或其药学可接受的盐,其中的R是一种在与L-M连接后能穿过血脑屏障的载体,从而可以将M运送穿过血脑屏障,L是一种连接体或者化学键,M是选自由药品、药物、蛋白、肽、酶、抗生素、抗癌剂、中枢神经***水平上活性的分子、放射显影剂、抗体、细胞毒素、可检测标记和抗血管生成化合物组成的组。
根据本发明的另一项实施方案,其中提供了本发明实施方案的缀合物在运送与之相连接的药剂穿过血脑屏障中的用途。
根据本发明的另一项实施方案,其中提供了本发明实施方案的缀合物在治疗个体中神经学疾病中的用途。
根据本发明的另一项实施方案,其中提供了本发明实施方案的缀合物在治疗个体中枢神经***障碍中的用途。
根据本发明的另一项实施方案,其中提供了一种运送药剂穿过血脑屏障的方法,该方法包括向个体给予本发明实施方案的药物组合物的步骤。
在本发明一项优选的方法中,药物组合物通过动脉内、鼻内、腹膜内、静脉内、肌内、皮下、透皮或口服给予个体。
根据本发明的另一项实施方案,其中提供了一种治疗个体中神经学疾病的方法,该方法包括向需要它的个体给予治疗有效量的本发明实施方案的药物组合物。
根据本发明的另一项实施方案,其中提供了一种治疗个体中枢神经***障碍的方法,该方法包括向需要它的个体给予治疗有效量的本发明实施方案的药物组合物。
为了本发明目的,对以下术语作如下定义。
术语“载体”指的是能够穿过血脑屏障,并且能够与另一种化合物或药剂相连接或缀合,并由此能够运送另一种化合物或药剂穿过血脑屏障的化合物或分子。例如,此种载体可以与脑内皮细胞上存在的受体相结合,并由此通过胞转被运送穿过血脑屏障。优选地,载体是获得很高的透内皮运送水平,对血脑屏障的完整性没有任何影响的蛋白质或分子。载体可以是,但是不限于蛋白、肽或肽模拟物,并可以是自然产生或通过化学合成或重组基因技术(基因工程)得到的。
术语“载体-药剂缀合物”指的是载体和另一种化合物或药剂的缀合物。缀合可以是化学性质的,例如用键;或者是基因性质的,例如通过重组基因技术,诸如以与例如绿色荧光蛋白,β-半乳糖苷酶或组氨酸标签蛋白的融合蛋白形式。
词语“小分子药物”指的是分子量等于或小于1000g/mol的药物。
术语“治疗”等等指的是获得了希望的药理学和/或生理学效果,例如,抑制了癌细胞的生长,癌细胞死亡或改善了神经学疾病或病况。所述效果从完全或部分预防疾病或其症状来说可以是预防性的,和/或从完全或部分治愈疾病和/或疾病导致的不良作用来说可以是治疗性的。此处的“治疗”涵盖了哺乳动物,特别是人的疾病的任何治疗,包括:(a)在容易患病但是尚未诊断出患病的个体中防止疾病或病况的发生(例如,预防癌症);(b)抑制疾病(例如,阻止疾病发展);或者,(c)缓解疾病(例如,减轻与疾病相关的症状)。此文所用的“治疗”涵盖了任何向个体给予药物物质或化合物以治疗、治愈、缓解、改善、减轻或抑制个体中的病况,其包括但不限于向个体给予载体-药剂缀合物。
术语“癌症”指的是任何细胞恶性,其独有特征在于正常控制的丧失(导致无调节的生长),分化的缺少以及侵入局部组织和迁移的能力。癌症可在任何器官的任何组织中发生。更特别地,癌症意指包括,但不限于脑的癌。
术语“给予”和“给药”指的是传递的方式,其包括但不限于动脉内、鼻内、腹膜内、静脉内、肌内、皮下、透皮或口服。优选的是口服。每日剂量可以分成适宜形式的一份、两份或更多份剂量,以在整个时间段以一次、两次或更多次给药。
术语“治疗有效”指的是足以实质上改善某些与疾病或医学病况相关的症状的一定量的化合物。例如,在癌症或精神病况或神经学或CNS疾病的治疗中,减少、预防、延缓、抑制或阻止任何疾病或病况的症状的药剂或化合物将是治疗有效的。治疗有效量的药剂或化合物并不需要治愈疾病或病况,但将对疾病或病况提供治疗,以便延缓、阻断、预防疾病或病况的发生,或者,缓解疾病或病况的症状,或者改变疾病或病况的期限或者,例如不太严重,或者加速个体的恢复。
本发明的载体和载体-药剂缀合物可与常规治疗方法和/或疗法相结合使用,或者可与常规治疗方法和/或疗法分开使用。
当本发明载体-药剂缀合物与用其他药剂的疗法联合使用时,它们可以顺序或同时给予个体。可替代地,如本申请所述,本发明药物组合物可以由与药学可接收的赋形剂以及另一种本领域公知的治疗或预防剂结合的本发明载体-药剂缀合物的组合组成。
将理解,对于任何特定个体的特定“有效量”将取决于多种因素,所述因素包括:使用的特定药剂的活性、个体的年龄、体重、一般健康、性别和/或饮食、给药时间、给药途径、***速率、药物结合以及经受预防或治疗的特定疾病的严重程度。
药学可接收的酸加成盐可以通过本领域公知的方法制备。
如本文所使用的,“药学可接受的载体”包括任何以及所有的溶剂(诸如磷酸盐缓冲盐水缓冲剂、水、盐水)、分散介质、包衣剂、抗细菌剂以及抗真菌剂、等渗剂和吸收延迟剂等等。这类介质和药剂用于药学活性物质的用途是本领域非常公知的。任何的常规介质或药剂在治疗组合物中的使用都被想到,除了其与活性成分不相容。也可将补加的活性成分掺入到组合物中。
术语“功能性衍生物”指的是本发明的载体或药剂或载体-药剂缀合物或它们的盐的“化学衍生物”、“片段”或“变体”生物学活性序列或部分。载体功能性衍生物能够与另一种化合物或药剂相连接或缀合,并穿过血脑屏障,从而能够将其它的化合物或药剂转运穿过血脑屏障。
术语“化学衍生物”指的是本发明的载体、药剂或载体-药剂缀合物,其含有附加的化学部分,该化学部分不是载体、药剂或载体-药剂缀合物的一部分。共价修饰也包括在本发明的范围之内。化学衍生物可以通过直接的化学合成,使用本领域公知的方法方便制备。这类修饰可以是,例如,通过将靶氨基酸残基与能够与经选择的侧链或末端残基发生反应的有机衍生化剂进行反应,导入到蛋白或肽载体、药剂或载体-药剂缀合物中。载体化学衍生物能够穿过血脑屏障并能与另一种化合物或药剂相连接或缀合,并由此将另一种化合物或药剂运送穿过血脑屏障。在一项优选的实施方案中,获得了非常高水平的穿过血脑屏障的透内皮运送,对血脑屏障的完整性不产生任何影响。
术语“片段”指的是载体、药剂或载体-药剂缀合物的任何碎片或部分。蛋白或肽的片段,例如,可以是构成整个蛋白或肽的氨基酸的亚型。载体片段能与另一种化合物或药剂相连接或发生缀合并穿过血脑屏障,并由此能够将另一种化合物或药剂运送穿过血脑屏障。
术语“变体”指的是与本发明载体、药剂或载体-药剂缀合物或他们的任何片段的任一结构实质上类似的载体、药剂或载体-药剂缀合物。载体变体能与另一种化合物或药剂相连接或发生缀合并穿过血脑屏障,并由此将另一种化合物或药剂运送穿过血脑屏障。设想到了变体蛋白、肽、肽模拟物和本发明载体的化学结构。
术语“抑酶肽片段”指的是仍然能将化合物运送穿过BBB的抑酶肽的部分。这样的片段可含有至少12个氨基酸,优选至少25个氨基酸,更优选至少35个氨基酸。Hussain,M.,Strickland,D.K.,Bakillah,A.,在The mammalian low-density lipoprotein receptorfamily.(Anno.Rev.Nutr.1999,19,141-172)一文中进行了测定有效的与megalin相互作用的抑酶肽的最小序列的研究。例如,抑酶肽与Megalin受体相互作用的最小序列被确定为CRAKRNNFKSA(序列号NO:1)。因此,意味着含有该最小序列的片段也包括在该术语中。
术语“药剂”无差别地指的是药物或化合物,诸如治疗剂或化合物、标记、示踪物或显影化合物。
术语“治疗剂”或“药剂”指的是用于治疗疾病、身体或精神病况、创伤或感染的症状的药剂和/或药物和/或药品,包括但不限于抗生素、抗癌剂、抗血管生成药物和中枢神经***水平上活性的分子,例如紫杉醇,可以通过静脉给药以治疗脑癌。
术语“患者”或“治疗的个体”指的是任何接受某种医学治疗的患者或个体,包括为了检测、追踪、标记或显影某种病况,诸如肿瘤,被进行载体-药剂或化合物缀合物的给药。优选地,患者或治疗的个体是哺乳动物,更优选的是人类。
术语“病况”指的是任何对或在个体中造成疼痛、不舒服、恶心、疾病或残疾(精神或身体上的)的状况,包括神经学疾病、损伤、感染、或慢性或急性疼痛。可以用本发明治疗的神经学疾病包括但不限于脑瘤、脑转移瘤、精神***症,癫痫,阿尔茨海默氏病,帕金森氏病,亨廷顿舞蹈病和中风。
附图简要说明
图1是显示抑酶肽(●)、p97(◆)和血浆铜蓝蛋白(■)穿过牛脑毛细管内皮细胞(BBCECs)的胞转试验的结果图;
图2是显示抑酶肽(●)和转铁蛋白(o)穿过牛脑毛细管内皮细胞(BBCECs)的胞转试验的结果团;
图3是说明在血脑屏障模型中,抑酶肽的胞转能力高于转铁蛋白的条形图;
图4是SDS-PAGE分析,它说明了抑酶肽完整性不受其穿过BBECE单层的胞转的影响;
图5是以时间的函数形式表达的[14C]-蔗糖的清除率的图。在含有和不含250nM抑酶肽的情况下测定蔗糖的清除率;
图6是显示牛脑毛细管内皮细胞(BBCECs)的蔗糖渗透性测试的结果图。
图7是以时间的函数形式表达的[14C]-蔗糖的清除率的图,该图说明抑酶肽不影响血脑屏障完整性。在含有和不含5μM抑酶肽的情况下测定蔗糖的清除率;
图8是说明[125I]-抑酶肽在人和大鼠毛细管中的蓄积条形图。
图9是说明在人和大鼠毛细管中抑酶肽摄取的时间过程图。
图10是说明抑酶肽-生物素缀合物和抑酶肽具有相同的胞转能力的条形图;
图11是说明抑酶肽和抑酶肽-生物素缀合物胞转是温度-依赖型和构象依赖型的;
图12A和12B是一组说明温度和加热对BBCEC细胞中的(A)抑酶肽和(B)抑酶肽-生物素缀合物胞转的影响的图;
图13是说明在存在抑酶肽-生物素缀合物的情况下,链霉抗生物素胞转的增加的条形图;
图14是说明LRP拮抗剂、受体-相关蛋白(RAP)抑制抑酶肽胞转的条形图;
图15是说明原位脑灌流试验中抑酶肽摄取的条形图;
图16说明了一种合成的抑酶肽序列;
图17说明了抑酶肽和三种具有相似域的人类蛋白质之间的序列比较;
图18是说明转铁蛋白、抑酶肽和血管肽1的原位脑灌流的条形图;
图19是说明血管肽1与抑酶肽比较的胞转图;以及
图20是血管肽1穿过体外血脑屏障模型的胞转图。
优选实施方式的详述
本发明涉及新的运送药剂、药物或其它分子至脑和/或中枢神经***(CNS)的载体。该载体允许与所述载体连接或偶联(缀合)并且它们本身不能穿过血脑屏障的药剂、药物或其它分子通过,以被运送穿过血脑屏障。载体-缀合物可以是载体-治疗剂缀合物。这样的缀合物可以呈组合物形式,诸如药物组合物,用于治疗疾病或病况。本发明基于抑酶肽以非常有效的方式与脑毛细管内皮壁相结合并穿过脑毛细管内皮壁的发现而作出。在本领域中已知抑酶肽是有效抑制各种丝氨酸蛋白酶包括胰蛋白酶、糜蛋白酶、激肽释放酶和胃蛋白酶的碱性多肽。抑酶肽的透内皮运送比其它蛋白质包括转铁蛋白或血浆铜蓝蛋白高约10-50倍。这种高通过速率不是由破坏血脑屏障完整性而导致的,因为蔗糖的透性系数并没有受到抑酶肽的影响。
这种方法是多用途的,因为它允许具有非常多样的治疗靶点的小以及大分子的缀合。
根据本发明,运送药剂穿过血脑屏障的方法包括向个体给予一种药剂,该药剂含有与载体诸如抑酶肽或其功能性衍生物相连接的活性成分或药物物质。
根据本发明,化合物可以动脉内、鼻内、腹膜内、静脉内、肌内、皮下、透皮或口服给予患者。药剂优选的是抗血管生成药物。药剂可能具有最大分子量160,000道尔顿。优选地,药剂是一种标记或药物,诸如小分子药物、蛋白、肽或酶。药物优选适于治疗患者的神经学疾病或中枢神经***障碍。药物可以是细胞毒药物,标记物可以是可检测的标记,诸如放射性标记、绿色荧光蛋白、组氨酸标签蛋白或β-半乳糖苷酶。所述药剂优选被传递进入患者的中枢神经***内。
根据本发明还另一项优选的实施方案,本发明的用途、方法、化合物、药剂、药物或药剂不改变患者血脑屏障的完整性。
根据本发明进一步的一项优选实施方案,抑酶肽可以连接到药剂或化合物上,用以将药剂或化合物运送穿过患者血脑屏障,所述药剂和化合物适于治疗神经学疾病或治疗中枢神经***障碍。
本发明的载体或其功能性衍生物或它们的混合物可以与可检测的标记相连接或用它进行标记,可检测的标记诸如放射显影剂,诸如发射辐射的那些,用于检测疾病或病况,例如,通过使用放射显影剂-抗体-载体缀合物而实施,其中的抗体与疾病或病况特异性抗原相结合。除了抗体之外的在本领域公知并且使用的其它结合分子也被本发明想到。可替代地,本发明的载体或其功能性衍生物或者它们的混合物可以与治疗剂相连接,以治疗疾病或病况,或者可以与它们的混合相连接,或者用它们的混合物标记。在允许药剂运送穿过血脑屏障的条件下,通过向个体给予一种本发明的载体-药剂缀合物,完成治疗。
本发明治疗剂可以是让细胞杀灭的药品、药物、发出辐射的物质、细胞毒素(例如,化疗剂)和/或它们的生物活性片段,和/或它们的混合物,或者它可以是治疗、治愈、缓解、改善、减小或抑制所治疗个体的疾病或病况的药剂。治疗剂可以是合成产物或者是真菌、细菌或其它微生物诸如支原体、病毒等等,动物,诸如爬行动物,或者植物来源的产物。治疗剂和/或它们的生物活性片段可以是酶活性物质和/或它们的片段,或者可通过抑制或阻断重要和/或必需的细胞路径,或者通过与重要和/或必需的天然存在的组分竞争而起作用。
本发明中使用的发射辐射的放射显影剂(可检测的放射标记)示例性的为铟-111、锝(technitium-99),或低剂量的碘-131。
用于本发明的可检测的标记可以是放射标记、荧光标记、核磁共振活性标记、发光标记、发色团标记、用于PET扫描仪的发射正电子的同位素、化学发光标记或者酶标记。荧光标记包括但不限于绿色荧光蛋白(GFP)、荧光素和若丹明。化学发光标记包括但不限于,萤光素酶和β-半乳糖苷酶。酶标记包括但不限于,过氧化物酶和磷酸酶。组氨酸标签也可以是可检测标记。
设想到,药剂在穿过血脑屏障之后可以从载体中释放出来,例如通过载体和药剂之间化学键的酶裂解或断裂。随后释放药剂可以在不存在载体的情况下发挥其预期的能力。
通过参考以下的实施例将更容易地理解本发明,给出所述实施例以举例说明本发明,而不是限制本发明的范围。
试验部分
适宜载体的确定
证明体内特征的可重现血脑屏障体外模型已被用于筛选试验以及药物向脑运送的机理性研究。这种有效的血脑屏障体外模型是由CELLIALTMTechnologies公司开发的,其对于可靠评估不同载体到达脑的能力是最重要的。该模型由牛脑毛细管内皮细胞和大鼠神经胶质细胞的共培养物组成。它代表了脑内皮包括紧密连接的超微结构特征,缺乏膜孔、缺乏透内皮通道、对亲水性分子的低渗透性以及高电阻。进而,该模型在宽范围的被测试分子的体外和体内分析之间显示了好的相关系数。迄今为止,所有获得的数据显示,这种BBB模型通过再现某些体内存在的细胞环境的复杂性而紧密地模拟了体内状况,同时保留了与组织培养物相关的试验优点。由此,很多研究已证实所述细胞共培养物是BBB最可重现的体外模型之一。
通过使用BBCECs和星形胶质细胞的共培养物建立BBB体外模型。在细胞培养之前,平板***物(Millicell-PC 3.0μM;直径30-mm)的上侧用大鼠尾胶原蛋白涂敷。然后将它们置于六-孔含有星形胶质细胞的微量培养板中,并且将BBCECs置于2mL的共培养基中的过滤器的上侧。此BBCEC培养基每周换三次。在这些条件下,7天之后,分化后的BBCECs形成了汇合的单层。在达到合之后的第5和第7天之间进行试验。测定蔗糖的透性系数以验证内皮的渗透性。
混合星形胶质细胞的原代培养物是从新生大鼠大脑皮层制备的(Dehouck M.P.,Meresse S.,Delorme P.,Fruchart J.C.,Cecchelli,R.An Easier,Reproductible,and Mass-ProductionMethod to Study Blood-Brain Barrier In Vitro.J.Neurochem,54,1798-1801,1990)。简单的说,在除去脑膜之后,轻轻地使脑组织通过82μm尼龙筛网。将星形胶质细胞以在2mL的最佳培养基(DMEM)中的1.2×105细胞/mL浓度置于六-孔微量培养板上,所述培养基补充有10%的热灭活的胎牛血清。每周换两次培养基。
牛脑毛细管内皮细胞(BBCECs)是从Cellial Technologies得到的。在存在DMEM培养基的情况下培养细胞,所述培养基补充有10%(v/v)马血清和10%热灭活的小牛血清、2mM的谷酰胺、50μg/mL的庆大霉素和1ng/mL的碱性成纤维细胞生长因子,每隔一天添加。
为了确定本发明的适合载体,使用BBB体外模型进行测试。如图1中所示,进行了不同蛋白(抑酶肽(●)、p97(◆)和血浆铜蓝蛋白(■))穿过牛脑毛细管内皮细胞(BBCECs的胞转试验。图2和3显示了用抑酶肽(●)和转铁蛋白(o)并使用和图1试验中相同的方法进行的胞转试验的结果。将被BBCECs覆盖的一个***物置入具有2mL的Ringer-Hepes的六-孔微量培养板中,并在37℃下预孵化2小时。将[125I]-抑酶肽、[125I]-p97、[125I]-血浆铜蓝蛋白或[125I]-转铁蛋白(最终浓度250nM)加入到被细胞覆盖的滤器的上侧。在不同的时间,将***物转移到另一个孔中以避免可能的[125I]-蛋白被BBECEs的近(abluminal)侧再胞吞。试验末期,通过TCA沉淀作用,[125I]-蛋白在500μL孔的较低腔室进行测试。所得结果显示,在血脑屏障模型中,抑酶肽比转铁蛋白、p97或血浆铜蓝蛋白具有更高的胞转能力。
抑酶肽、p97和牛全-转铁蛋白使用碘-珠(得自SigmaTM)采用标准操作进行碘化。将牛全-转铁蛋白在0.1M,pH 6.5(PB)的磷酸盐缓冲液中稀释。来自于Synapse Technologies在pH7.0的中和柠檬酸盐中的P97使用这种PB进行透析。每种蛋白使用两颗碘珠。这些珠在WhatmanTM滤器上使用3mL的PB洗涤两次,并在60μL的PB中重新混悬。将得自于Amersham-Pharmacia biotech的125I(1mCi)在室温下加入到珠子的混悬液中,保持5分钟。通过加入100μg(80-100μL)来启动每种蛋白的碘化。在室温下孵化10分钟之后,将上清液应用到预装了5mL交联葡聚糖(得自于Pierce)的脱盐柱上,并且用10mL的PBS洗脱125I-蛋白质。收集0.5mL的级分,并测定每一5μL级分中的放射性。混合与125I-蛋白相应的级分,用pH 7.4的Ringer-Hepes透析。放射标记的效率在0.6-1×108cpm/100μg蛋白之间。
从图1-3中,清楚的是,抑酶肽的胞转能力远远高于其它的测试蛋白。图1-3的数据总结在表1中,其中针对不同的蛋白作了比较。
表1
125I-蛋白(250nM)穿过BBCEC单层的胞转的比较
表2总结了另一项试验,在该试验中对添加的不同蛋白进行了比较。
表2
抑酶肽穿过血脑屏障的效率
鉴于表1和表2,可以看出,关于抑酶肽,与其它的测试蛋白相比,获得了优良的透内皮运送,并且抑酶肽胞转比这些其它蛋白高约10至50-倍。
其穿过BBCEC单层的胞转不影响抑酶肽完整性
将最终浓度为250nM的[125I]-蛋白(0.5-1.5μCi/检测)加入到滤器上侧,滤器中含有或不含有置于6-孔平板中的BBCEC细胞。在每一时间点,将滤器放入6-孔平板的下一个孔中。在试验结束时,在每一孔中取等份试样,置于SDS-PAGE。然后通过放射自显影法测定凝胶。示于图4中的结果,显示其穿越BBCEC单层的胞转不影响抑酶肽完整性。
抑酶肽不影响血脑屏障完整性
通过测定BBB模型中[14C]蔗糖在生长于滤器上(在星形胶质细胞存在的情况下)的BBCEC单层上的渗透性,进行进一步的试验以确定抑酶肽在250nM时对BBB完整性的影响,为了实现该试验,将在***物上生长的脑内皮细胞单层转移到每孔含有2mL的Ringer-Hepes6-孔平板(基底外侧隔室),在37℃下保持2小时。Ringer-Hepes溶液是由150mM NaCl、5.2mM KCl、2.2mM Cal2、0.2mM MgCl2、6mM NaHCO3、5mM Hepes、2.8mM Hepes组成的,pH为7.4。在每一顶室中,培养基被替换为1mL的含有标记了[14C]的蔗糖的Ringer-Hepes。在不同的时间,将***物置于另一个孔中。在37℃下,在不含细胞(□)或具有用BBCEC细胞涂敷的滤器上,在不含有5μM抑酶肽(△)或含有5μM抑酶肽(○)(图6)的情况下测定[14C]蔗糖的通过。所得结果被作图为作为时间(分钟)的函数的蔗糖清除率(μl)。然后确定蔗糖透性系数。透性系数(Pe)计算如下:
1)清除率
其中:[C]A=近示踪物痕量浓度
VA=近腔的体积
[C]L=腔示踪物浓度
2)1/Pe=(1/PSt-1/PSf)/滤器面积(4.2cm2)
在试验结尾,在液体闪烁计数器中测定基底外侧隔室中的放射性示踪物的量。如先前所描述的,使用被EC涂敷或不被EC涂敷的滤器计算蔗糖的透性系数(Pe)(Dehouck,M..,P.,Jolliet-Riant,P.,Bree,F.,Fruchart,J.C.,Cecchelli,R.,Tillement,J.P.,J.Neurochem.58:1790-1797,1992)。两项试验的结果分别根据[14C]-蔗糖(μL)以时间(分钟)的函数形式作图(图5和6)。在图5和6中,PSt代表渗透性x共同培养物的滤器的表面积,PSf表示涂敷有胶原蛋白和置于滤器B的底侧上的星形胶质细胞的滤器的渗透性。计算透性系数(Pe),其证实BBB的完整性没有受到抑酶肽的影响(图6中的Pe是从图5计算得到的,表3中的Pe是从图7计算得到的)。
表3
抑酶肽的透性系数证实抑酶肽不影响血脑屏障的完整性
[
125
I]-抑酶肽在人和大鼠毛细管中的蓄积
在37℃下测定蓄积1小时。培育介质含有最终浓度为100nM的抑酶肽的Ringer/Hepes溶液。通过加入冰冷的终止溶液和在真空中通过0.45μM的滤器来停止蓄积。通过在加入培育介质之前加入冰***液来评估抑酶肽和毛细管表面的非特异性结合。从蓄积值中减去该值,以获得真实的蓄积值。本试验结果示于图8中。
人和大鼠毛细血管中抑酶肽摄取的时间过程
在37℃下测定抑酶肽的摄取达可变的时间。培育介质含有最终浓度为100nM的抑酶肽的Ringer/Hepes溶液。在每一时间点,通过加入冰冷终止溶液和并在真空下通过0.45μM的滤器停止蓄积。在每一时间点,通过在加入培育介质之前加入冰***液来评估抑酶肽和毛细管表面的非特异性结合。本试验结果示于图9中。
抑酶肽-生物素缀合物:生物素化步骤
使用水溶性生物素类似物Sulfo-NHS-LC-LC-生物素(Pierce)用于缀合。在不含有机溶剂,并且是中性pH的条件下该类似物与伯胺发生反应。向10mg/ml抑酶肽溶液中加入12-倍过量的生物素类似物。生物素类似物和抑酶肽混合物在4℃下培育2小时。除去未反应的生物素药剂,在具有3500Da切割值的slide-a-lyzer透析盒(Pierce)中进行透析过夜。然后进行生物素的结合的测定,使用与在500nm产生吸收的抗生物素蛋白结合的染料HABA(2-(4′-羟基偶氮苯)-苯甲酸)。此结合可以被游离的生物素或者生物素化的蛋白替换,允许生物素结合的定量。该缀合物获得的比例为每一抑酶肽三个生物素。
抑酶肽-生物素缀合物和抑酶肽具有相同胞转能力
在37℃下评估[125I]-抑酶肽和[125I]-抑酶肽-生物素的胞转。将最终浓度为250nM的[125I]-蛋白(0.5-1.5μCi/检测)加入到用于胞转测定的细胞-覆盖的滤器的上侧。在试验结尾,通过TCA沉淀直接测定[125I]-蛋白细胞的胞转。本试验结果显示于图10中。
抑酶肽和抑酶肽-生物素缀合物胞转是温度-依赖和构象-依赖的
在37℃和4℃下,或者在100℃下煮沸蛋白10分钟以后在37℃下,评估[125I]-抑酶肽和[125I]-抑酶肽-生物素的蓄积。将最终浓度为250nM的[125I]-蛋白(0.5-1.5μCi/检测)加入到用于胞转测定的细胞-覆盖的滤器的上侧。在试验结尾,切去细胞-包裹的滤器,并通过TCA沉淀直接测定[125I]-蛋白细胞的蓄积。本实验的结果示于图11中。
温度和加热对抑酶肽和抑酶肽-生物素缀合物在BBCEC细胞中胞转的影响
在37℃和4℃下,或者在100℃下煮沸蛋白10分钟以后在37℃下,评估[125I]-抑酶肽(图12A)和[125I]-抑酶肽-生物素(图12B)的胞转。将最终浓度为250nM的[125I]-蛋白(0.5-1.5μCi/检测)加入到用于胞转测定的细胞-覆盖的滤器的上侧。在每个时间点,将滤器转移至6-孔平板中的下一个孔。在试验结尾,通过TCA沉淀在多孔的下区室中评估[125I]-蛋白。
在抑酶肽-生物素缀合物存在的情况下,链霉抗生物素胞转的增加
单独或者在抑酶肽-生物素缀合物存在的情况下评估[125I]-链霉抗生物素的胞转。将最终浓度为250nM的[125I]-蛋白(0.5-1.5μCi/检测)加入到用于胞转测定的细胞-覆盖的滤器的上侧。在每个时间点,将滤器转移至6-孔平板中的下一个孔。在试验结尾,通过TCA沉淀在多孔的下区室中评估[125I]-蛋白。本实验的结果示于图13之中。
抑酶肽胞转被LRP拮抗剂、受体-相关蛋白(RAP)的抑制
在37℃下评估蛋白胞转。将最终浓度为250nM的[125I]-抑酸肽(0.5-1.5μCi/检测)加入到细胞-覆盖的含有或不含rap的滤器的上侧。在试验结尾,通过TCA沉淀在多孔的下区室中评估[125I]-抑酶肽。本实验的结果示于图14中。
抑酶肽摄取:原位小鼠脑灌流
手术步骤
使用原位脑灌注方法测定[125I]-抑酶肽对小鼠脑毛细管腔侧的摄取,该方法在我们的实验室中作了适应性修改用于研究小鼠脑中的药物摄取(Dagenais et al.,2000,J.Cer eb.Blood Flow Metab.20(2):381-386)。简单的说,将右颈总动脉***/塞拉嗪(140/8mg/kg腹膜内注射)麻醉的小鼠暴露,在颈总动脉分叉点的水平,枕动脉喙处结扎。然后,用填充有肝素(25U/ml)并安装在26量规针上的聚乙烯管(0.30mmi.d.x0.70mm o.d.)进行颈总动脉喙处插管。将含有灌流液(pH7.4的Krebs/碳酸氢盐缓冲液中的10nM的[125I]-抑酶肽,充气95%O2和5%CO 2)的注射器置于输注泵(Harvard pump PHD 2000;Harvard Apparatus)中,并与导管相连。就在灌流前,通过切断室以消除对侧血流贡献而阻止心脏。脑灌流10分钟,流速为2.5ml/min。灌流10分钟之后,脑再次用Ringer/HEPES溶液(150mM NaCl、5.2mMKCl、2.2mM Cal2、0.2m MMgCl2、6mM NaHCO3、5mM HEPES、2.8mM葡萄糖,pH 7.4)灌流30秒,用以洗去过量的[125I]-抑酶肽。然后处死小鼠终止灌流,在进行毛细管减液之前将右半球在冰上分离出来(Triguero et al.,1990,J Neurochem.54(6):1882-8)。取出匀浆、上清液、小丸和灌流液的等分试样,通过TCA沉淀测定它们[125I]-抑酶肽的含量,并且评估表观分布容积。
BBB转运常数的测定
简单的说,通过Smith先前所述的(1996,Pharm.Biotechnol.8:285-307)进行计算。将抑酶肽摄取以分布容积(Vd)表达,Vd从如下等式中得到:
Vd=Q*br/C*pf
其中的Q*br是计算得到的每克右脑半球的[125I]-抑酶肽的量,C*pf是灌流液中测定的标记的示踪物浓度。
此试验的结果显示在图15中,该结果显示对抑酶肽的摄取高于转铁蛋白以及与生物素缀合不改变抑酶肽的脑摄取。
鉴于上文所述的测试所获得的结果,抑酶肽对于运送药剂或化合物穿过BBB而言是一种有希望的载体,因为它比其它的蛋白质具有更高的穿过BBCEC单层的胞转,并且不改变血脑屏障的完整性。此外,抑酶肽在胞转期间不被降解,并且抑酶肽与生物素缀合也不影响它的胞转。进而,抑酶肽是多用途并且柔性的载体,因为很多分子诸如诸如小的药物分子、蛋白、肽和酶都可以容易的连接到抑酶肽蛋白上,从而促进它们穿过BBB。可以想见,这些分子可以通过一种连接体而与抑酶肽连接。
还已确定,抑酶肽的脑分布容积高于转铁蛋白。进一步确定的是,胞转是温度敏感和构象依赖的,这暗示LDL-R族受体,有可能是LRP参与抑酶肽胞转。
由此,抑酶肽是一种有效且高效的将药剂通过血脑屏障传递到脑内的载体。
作为脑的药物载体的肽的设计
使用National Center for Biotechnology Information(NCBI)网站上的BLASTTM程序对抑酶肽的N-末端序列(MRPDFCLEPPYTGPCVARIIR)(图16)(序列号NO:2)进行序列比较。此序列比较导致了四条经鉴定的序列。这些经鉴定的序列没有一条与人类蛋白相对应。
同样在NCBI网站上对抑酶肽的C-末端序列(GLCQTFVYGGCRAKRNNFKSAE)(图16)(序列号NO:3)进行序列比较。该序列比较产生了27条经鉴定的序列,其中某些序列与人类蛋白相对应。然后将得分最高的序列与抑酶肽序列(图17)进行比对。从比对中,产生以下血管肽1肽:TFFYGGCRGKRNNFKTEEY(净电荷+2)(序列号NO:4)。
转铁蛋白,抑酶肽和血管肽1的原位脑灌流
测定了[125I]-转铁蛋白、[125I]-抑酶肽和[125I]-血管肽1的脑表观分布容积。灌流小鼠脑10分钟。实施脑毛细管减液以评估脑实质中的表观分布容积。本试验的结果显示在图18中。
与抑酶肽的对比的血管肽1的胞转
将血管肽1的胞转与抑酶肽的比较。如上文所述,测定[125I]-血管肽1和[125I]-抑酶肽从内皮细胞单层的顶点-至-基底外侧的运送。血管肽1和抑酶肽在本试验中所使用的最终浓度为2.5μM。本实验的结果显示于图19中。
血管肽1穿过体外血脑屏障模型的胞转
测定血管肽1从覆盖或者没有覆盖内皮细胞单层的***物的顶点-至-基底外侧的运送。结果以作为时间的函数的血管肽1的清除率来表达。斜率对应于肽单独通过滤器的渗透(Psf)和内皮细胞单层的总渗透性(Pst)。血管肽1的透性系数(Pe)为1.2×10-3cm/分钟。此试验的结果示显于图20中。
血管肽1、抑酶肽、瘦素和转铁蛋白的透性系数使用体外血脑屏障模型确定。如上文所述计算透性系数(Pe)。透性系数的比较显示于表4中。
表4
血管肽1、抑酶肽、瘦素和转铁蛋白的透性系数
上述试验显示,血管肽1的脑渗透高于抑酶肽和转铁蛋白。试验还显示,使用体外血脑屏障模型测定的血管肽1的胞转高于其它的肽类,包括抑酶肽、瘦素和转铁蛋白。
尽管结合特定的实施方案描述了本发明,将理解,它是能够进一步修饰的,并且该申请意在涵盖大体仿效本发明原理的本发明的任何变体、使用或修改,并且包括了那些在本领域公知或常规的实践之内的、具有上文所述的某些特征的、如权利要求中所阐述的范围之内的一些偏离情况。
Claims (21)
1.一种用于将与之相连接的药剂运送穿过血脑屏障的载体,其中所述的载体能在与所述药剂相连接后穿过血脑屏障并由此将所述药剂运送穿过血脑屏障,所述载体是序列为TFFYGGCRGKRNNFKTEEY的血管肽1。
2.式R-L-M的缀合物,或者其药学可接受的盐,用于将M运送穿过血脑屏障,其中R是在和L-M连接后能穿过所述血脑屏障并由此将M运送穿过所述血脑屏障的载体,L是一种连接体或者化学键,M是选自由药品、蛋白、肽、酶、放射显影剂、抗体、细胞毒素和可检测标记组成的组的药剂,所述载体是序列为TFFYGGCRGKRNNFKTEEY的血管肽1。
3.根据权利要求2的缀合物,其中所述的药品选自抗生素、抗癌剂、中枢神经***水平上活性的分子和抗血管生成化合物。
4.根据权利要求2的缀合物,其中所述可检测标记选自由放射性标记、绿色荧光蛋白、组氨酸标签蛋白和β-半乳糖苷酶组成的组。
5.根据权利要求2的缀合物,其中所述药剂的最大分子量为160,000道尔顿。
6.根据权利要求2的缀合物,其中M是适用于治疗神经学疾病的药剂。
7.权利要求6的缀合物,其中所述神经学疾病选自由脑瘤、脑转移瘤、精神***症、癫痫、阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病、中风以及血脑屏障相关的机能障碍疾病组成的组。
8.权利要求7的缀合物,其中所述血脑屏障相关的机能障碍疾病是肥胖。
9.序列号No.:4的肽。
10.一种缀合物,它包含:
a.载体,所述的载体为权利要求9中所定义的肽;以及
b.与所述载体连接的药剂。
11.根据权利要求10的缀合物,其中所述药剂选自由药品、蛋白、肽、酶、放射显影剂、抗体、细胞毒素和可检测标记组成的组。
12.根据权利要求11的缀合物,其中所述的药品选自抗生素、抗癌剂、中枢神经***水平上活性的分子和抗血管生成化合物。
13.根据权利要求12的缀合物,其中所述抗癌剂是紫杉醇。
14.根据权利要求11的缀合物,其中所述可检测标记选自由放射性标记、绿色荧光蛋白、组氨酸标签蛋白和β-半乳糖苷酶组成的组。
15.根据权利要求10的缀合物,其中所述药剂的最大分子量为160,000道尔顿。
16.一种用于将药剂运送到个体的中枢神经***、将药剂运送穿过血脑屏障或治疗神经学疾病的药物组合物,该组合物包含与药学上可接受的赋形剂结合的根据权利要求2~8或10~15任一项的缀合物。
17.权利要求2~8或10~15任一项的缀合物在制备药物中的用途,该药物用于将所述药剂运送到个体的中枢神经***中或将所述药剂运送穿过血脑屏障。
18.权利要求2~8或10~15任一项的缀合物在制备药物中的用途,该药物用于治疗神经学疾病。
19.根据权利要求18的用途,其中所述神经学疾病选自由脑瘤、脑转移瘤、精神***症、癫痫、阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病、中风以及血脑屏障相关的机能障碍疾病组成的组。
20.根据权利要求19的用途,其中所述血脑屏障相关的机能障碍疾病是肥胖。
21.权利要求2~8或10~15任一项的缀合物在制备药物中的用途,该药物用于治疗个体中的中枢神经***障碍。
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BR112014014599A2 (pt) | 2011-12-16 | 2017-06-13 | Massachusetts Inst Technology | polímeros de alfa-aminoamidina e uso dos mesmos |
WO2013120107A1 (en) | 2012-02-09 | 2013-08-15 | University Of Rochester | Methods and compositions for treating a subject to inhibit hearing loss |
EP2819686A4 (en) | 2012-03-02 | 2016-05-25 | Icahn School Med Mount Sinai | PROTHYMOSIN ALPHA VARIANTS AND METHODS OF USE |
SI2833905T1 (en) | 2012-04-04 | 2018-08-31 | Halozyme, Inc. | Combination therapy with hyaluronidase and tumane-directed taxane |
ES2905359T3 (es) | 2012-04-26 | 2022-04-08 | Univ Yale | Moléculas de suministro de fármacos citotóxicos dirigidas al VIH (CDM-H), actividad citotóxica contra el virus de la inmunodeficiencia humana y métodos de uso |
WO2013185235A1 (en) | 2012-06-15 | 2013-12-19 | Angiochem Inc. | Targeted iduronidase compounds |
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DE19953696A1 (de) * | 1999-11-09 | 2001-05-10 | Alexander Cherkasky | Selektive proteolytische Synzyme (SPS) |
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Title |
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权利要求3,图1. |
Also Published As
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SI1583562T1 (sl) | 2011-10-28 |
AU2004203682A1 (en) | 2004-07-22 |
PT1583562E (pt) | 2011-09-19 |
WO2004060403A2 (en) | 2004-07-22 |
CY1111844T1 (el) | 2015-10-07 |
ES2368941T3 (es) | 2011-11-23 |
CN1747747A (zh) | 2006-03-15 |
EP1583562B1 (en) | 2011-06-15 |
WO2004060403A3 (en) | 2004-11-18 |
AU2004203682B2 (en) | 2009-10-01 |
BRPI0406647A (pt) | 2005-12-06 |
US20060182684A1 (en) | 2006-08-17 |
JP4903036B2 (ja) | 2012-03-21 |
AU2004203682A8 (en) | 2009-09-17 |
DK1583562T3 (da) | 2011-09-19 |
MXPA05007322A (es) | 2006-02-17 |
US9221867B2 (en) | 2015-12-29 |
AU2009251223A1 (en) | 2010-01-28 |
EP1583562A2 (en) | 2005-10-12 |
AU2009251223B2 (en) | 2012-02-09 |
EP2260874A1 (en) | 2010-12-15 |
JP2006515363A (ja) | 2006-05-25 |
CN102775472A (zh) | 2012-11-14 |
JP2012031197A (ja) | 2012-02-16 |
CA2516056A1 (en) | 2004-07-22 |
CA2516056C (en) | 2012-05-29 |
ATE512674T1 (de) | 2011-07-15 |
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