CN101284136A - 传输物质穿过血脑屏障的人工低密度脂蛋白载体 - Google Patents
传输物质穿过血脑屏障的人工低密度脂蛋白载体 Download PDFInfo
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- CN101284136A CN101284136A CNA2008100866051A CN200810086605A CN101284136A CN 101284136 A CN101284136 A CN 101284136A CN A2008100866051 A CNA2008100866051 A CN A2008100866051A CN 200810086605 A CN200810086605 A CN 200810086605A CN 101284136 A CN101284136 A CN 101284136A
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Abstract
本发明涉及用于靶向传递治疗剂穿过血脑屏障(BBB)的高效人工低密度脂蛋白(LDL)载体体系。本发明尤其涉及含有三种脂质成分的人工LDL颗粒:磷脂酰胆碱,脂酰胆甾醇酯和至少一种载脂蛋白。本发明进一步涉及能使药物靶向并穿过BBB用于预防和治疗脑疾病的包含人工LDL颗粒的组合物、方法和试剂盒。
Description
本申请为国际申请号为PCT/IB2003/005558,国际申请日为2003年12月2日,中国国家阶段申请号为200380104563.5,名称为“传输物质穿过血脑屏障的人工低密度脂蛋白载体”的发明专利申请的分案申请。
发明的技术领域
本发明涉及人工低密度脂蛋白(LDL)颗粒有效地靶向并传递物质穿过血脑屏障(BBB)的用途。
本发明进一步提供用于预防和治疗各种脑疾病的人工LDL颗粒组合物,方法和试剂盒。
发明背景
血脑屏障(BBB)能有效保护脑免受循环毒素的影响,但是也在诸如阿尔茨酶默病,帕金森氏病和脑癌和脑疾病的药理治疗中产生许多困难。大部分带电分子和大部分超过700道尔顿的分子不能穿过屏障,而较小的分子可在肝中结合。这些因素在脑和中枢神经系统(CNS)疾病如阿尔茨海默病、帕金森氏病、细菌和病毒感染与癌症的药理治疗中产生许多困难。
治疗脑和CNS疾病和障碍的许多治疗剂的亲水性足以阻碍直接传输穿过BBB。而且,这些药物和试剂易于在血液和周围组织中降解,必须增加剂量以达到治疗有效血清浓度。本发明提供的方法是通过将治疗剂封装在人工低密度脂蛋白颗粒(LDL)中,传递治疗剂到BBB。本发明的LDL有助于通过胞吞转运用传输治疗剂穿过BBB。由于大部分太亲水性而无法穿过BBB的药物和治疗剂也太亲水性而无法掺入LDL颗粒中,本发明提供产生治疗剂与LDL组分的共轭物的方法,促使其掺入LDL颗粒中,传输穿过BBB并随后将治疗剂释放在细胞中。
传送药物穿过BBB的先有方法一般包括三种:(1)基于脂质体的方法,其中治疗剂被封装在载体内;(2)基于合成聚合物的方法,其中颗粒是使用合成聚合物形成的,以获得精确限定的尺寸特征;和(3)使载体与药物直接结合,其中治疗剂与载体如胰岛素共价结合。
A.脂质体
脂质体是在水溶液中超声处理磷脂时自发形成的小颗粒,由成形为包围水相环境的中空球的对称脂双层组成。以此作为传输水溶性药物通过细胞膜的方法是有吸引力的,因为磷脂可以在质膜中吸收,能将脂质体的内含物自动释放入细胞液中。该技术更成功的变化包括使用阳离子脂质,能在膜中协同形成纳米孔。阳离子脂质广泛用于细胞培养,在实验培养细胞中引入水溶性物质如DNA分子。
因为脂质体的承载力大,所以对于传输药物穿过BBB是有吸引力的。但是脂质体通常太大而无法有效地通过BBB,本来是不稳定的,其构成的脂质会被血浆中的脂结合蛋白质吸收而逐渐损失。比如,在一些研究中,所用大尺寸脂质体产生给出脑摄取的假像的微型栓塞。在一些研究中,与Polysorbate 80共注射的脂质体作为稳定剂,Polysorbate 80是能破坏BBB的清洁剂。在这些研究中,Polysorbate 80对BBB的破坏作用是任何观察到传输穿过BBB的原因。
因此,脂质体作为传输药物穿过BBB的载体具有变化多端的历史。多次试图将脂质体导向特定细胞目标。使用BBB的靶内源性受体的肽模拟物单克隆抗体(mAb)将加入聚乙二醇的免疫脂质体靶向各种BBB受体,目的是获得受体介导的摄取。但是,这种方法还需要单克隆抗体昂贵的生产、测试成本,和政府的批准。因为mAb通常是在小鼠中产生的,易于降解,引入肽模拟物单克隆抗体不仅面临显著的管理障碍,而且证明难以用于病人环境。
例如,免疫脂质体的构建过程中涉及将单克隆抗体(mAb)共价附着于脂质体表面上。由于这些免疫脂质体立刻被血浆蛋白质包被,触发被网状内皮系统(RES)摄取,该系统迅速破坏单克隆抗体(mAb)-共轭的脂质体,已经在称为加入聚乙二醇的过程中用聚乙二醇(PEG)处理免疫脂质体。不幸的是,PEG分子干扰mAb,由于空间干扰而使其非特异性。Huwyler等(1996)Proc.Nat′l.Acad.Sci USA 93:14164-14169通过形成在PEG尾端具有马来酰亚胺部分的免疫脂质体避免了这个问题,该免疫脂质体可以与硫醇盐化mAb共轭。制备的这些加入聚乙二醇的OX26免疫脂质体内部具有柔红霉素,显示在血浆中比游离治疗剂或简单、未加入聚乙二醇的脂质体更稳定。但是共焦显微镜方法表明,虽然脂质体被胞吞入鼠脑毛细管中,但是它们并未到达脑细胞,且仍附着于内皮细胞。因此,加入聚乙二醇的和马来酰亚胺处理的脂质体作为药物传递载体似乎相对无效。
1997年,Dehouck等人发现,结合ApoE的LDL受体参与LDL的胞吞转运穿过BBB。在一系列的三篇出版物中,Versluis等人描述了ApoE富集的脂质体用来传递柔红霉素至小鼠中的癌细胞。选择ApoE作为LDL-受体靶向蛋白质是基于以下发现,即肿瘤细胞在其膜上表达高水平的LDL受体。Versluis等(1998)也提出使用天然LDL,但是并未对此进行试验,随后的论文只是集中于ApoE富集的脂质体上。Versluis等(1999)研究了柔红霉素的组织分布,但是没有有关脑摄取的数据,表明并未设想将此方法作为传输道柔红素穿过BBB的途径。
另外,Versluis等人使用的共轭化学不同于本发明。为了将药物固定在脂质体膜上,作者使3a-O-(油酰基)-4β-胆甾烷酸(石胆酸的酯)与四肽Ala-Leu-Ala-Leu偶联,然后与亲水性抗肿瘤剂柔红霉素共价连接。从而用共轭的非游离柔红霉素治疗肿瘤。虽然石胆酸是已经含有可激活酸基的类固醇,但是酸基位于类固醇侧链而非3-OH部位,导致反应产物的性质不够理想。游离柔红霉素可以只在被强酸性溶酶体中的蛋白酶储备裂解之后产生,会使共轭部分或试剂暴露在蛋白酶,酸和其他水解酶的降解作用中。然后治疗剂会释放入溶酶体内空间中,在那里可发生进一步降解并被排出细胞中排出。
相反,本发明的共轭化学优选通过酯键结合治疗剂,酯键容易在细胞液中切割,从而避免了Versluis等人的方法所需要的苛刻溶酶体条件。因此,本发明的共轭治疗剂更可能保持流动到其靶,在靶处以有效方式释放。也比脂质体更可能被传输穿过BBB。
Versluis等人的方法也需要大量固相肽化学步骤来合成四肽,以及若干附加步骤使其与FMOC共轭并使共轭物与石胆酸反应,最终与药物反应。本发明使用少得多的步骤,每个步骤都产生几乎定量的产率。因此本发明还提供改进的效率并降低成本。
目前的临床应用中以阿霉素的其他脂质体制剂作为癌症的可能治疗;但是并没有推广使用LDL的产品。
Deneule等人发现黑素转铁蛋白(p97)通过胞吞转动被传输穿过BBB,可得出涉及LDL受体的结论,建议使用该蛋白质作为药物传递体系。
B.合成聚合物
还尝试过涂有Polysorbate 80的合成聚合物如聚(氰基丙烯酸丁酯)或聚丙烯酰胺。这些聚合物是有吸引力的,因为颗粒的亲水性足以使其变得水溶性,但又能长时间保持其结构形态,从而保护治疗剂免于摄取入肝和肾中,在那里发生自然解毒过程。在两种情况下,通常假设摄取是由通过细胞膜的被动扩散发生的,或者被涂布有网格蛋白的囊泡防御性摄取。在前一种情况下,治疗剂然后被截留在内皮细胞中,不比以前更接近靶,而在后一种情况下,治疗剂被传输至溶酶体,这是细胞中的强酸性区室,其中含有蛋白酶和类似于胃内容物的其他消化酶。因此,在后一种情况中,治疗剂必须能在更极端的条件下保持稳定。在这两种情况下,所载药物都没有穿过细胞并注入脑实质中,这不是理想的结果。因此,不觉惊奇的是,这两种方法都没有获得多大的临床应用。
研究人员们尝试了上述方法的各种改进,以提高穿过BBB的载体摄取,但成功甚微。例如,Kreuter等(2002)J.Drug Target 10(4):317-25设计了使含有多种载脂蛋白的合成颗粒结合位于BBB上的载脂蛋白受体。他们证明了与聚(氰基丙烯酸丁酯)纳米粒结键合的药物传输,并用Polysorbate 80涂布。摄取要求用Polysorbate 80,ApoE或ApoB涂布。载脂蛋白A II,C II和J涂层不起作用。但是由于这些纳米粒不是天然产生的,所以它们可具有不利的副作用。丙烯酸酯聚合物对于引发自身免疫反应是特别众所周知的;通常使用化学相关的聚合物聚(丙烯酰胺)作为助剂。
Alyaudin等(2001)J.Drug Target 9(3):209-21用外涂有Polysorbate80的聚(氰基丙烯酸丁酯)纳米粒传送[3H]-dalargin穿过BBB,估计该过程是胞吞之一,接着可能是胞吞转运。这种聚合物也具有免疫并发症。
C.治疗剂共轭物
还尝试了药剂与可传送穿过BBB的物质如胰岛素的直接共轭。已知胰岛素和胰岛素样生长因子通过专门的促进扩散体系穿过血脑屏障(Reinhard等(1994)Endocrinology 135(5):1753-1761)。胰岛素通过由内皮胰岛素受体介导的胞吞转动被摄取(Pardridge等(1986)Ann.Intern.Med.105(1):82-95)。葡萄糖和大氨基酸如色氨酸也存在特异性转动。但是,已经证明胰岛素转动子的特异性太高,无法允许药剂与胰岛素共价结合而穿入脑中。用葡萄糖和氨基酸共轭物也得到类似结果,观察到摄取遵守与其他低分子量物质相同的一般原则,只有低于700Da的未带电分子才能明显地进入脑中。不方便设计化学合成生物分子的共轭形式,产生出乎意料的毒性效应的危险,以及完全新颖化合物可能需要获得FDA的批准,这减弱了对这种方法的热情。
传输载体,如阳离子化的白蛋白,或运铁蛋白受体的OX26单克隆抗体分别发生通过BBB的吸收性介导和受体介导的胞吞转动。已用来传输少量药物。这种方法具有高开支和难以产生单克隆抗体与阳离子化白蛋白的缺点,不适用于其他类型的分子。同样地,阳离子化蛋白质由于其免疫原性和形成沉积在肾中的免疫复合物,而显示出毒性。
Wu等(2002)J.Drug Target 10(3):239-45证明了使用由链毒抗生物素蛋白(SA)和大运鼠铁蛋白受体的鼠OX26单克隆抗体的共轭物,以及与载体(称为bio-bFGF/OX26-SA)结合的生物素酰化bFGF(bio-bFGF)的共轭物组成的药物传递载体,将一种蛋白质神经保护剂-人碱性成纤细胞生长因子(bFGF)传输穿过BBB。虽然他们证明[125I]标记的bio-bFGF被大量摄取入周围器官中,但是每克脑只摄取0.01%的注射剂量。而且,此方法需要药物的共价修饰,可能只对有限种类的药物有用。载体还包括作为一种组分的小鼠单克隆抗体,会在病人中引起免疫反应。
Kang等(2000)J.Drug Target 8(6):425-34还使用抗生物素蛋白-生物素连接的嵌合肽来传输肽穿过BBB,但是只达到每克组织摄取0.12%注射剂量。Kang和Pardridge(Pharm.Res.11:1257-1264)将阳离子化人血清白蛋白与中性轻抗生物素蛋白共轭,然后使其与放射性标记的生物素结合。生物素/cHSA/NLA复合体在血液中稳定达24小时,但是共轭物在脑中选择性地降解,以释放游离生物素。如上所述,已显示阳离子化蛋白质因为其免疫原性而具有毒性。
还已使用阳离子化的单克隆抗体(mAb)。Pardridge(J.Neurochem.70:1781-2)用共焦显微镜证明只有在蛋白质阳离子化之后,天然人源化的4D5 MAb才通过吸收性介导的胞吞转运穿过BBB。但是,此方法具有生产和化学修饰单克隆抗体的高开支的缺点,且不适用于其他类型的分子。
Witt等(2000)J.Pharmacol.Exp.Ther.295(3):972-8用胰岛素传输δ-阿片样受体选择性肽D-青霉胺(DPDPE)穿过BBB,这是一种蛋氨酸-脑腓肽类似物。但是胰岛素产生许多危害,从而限制其用作一种治疗对策。而且,其他研究者发现胰岛素受体是非常选择性的。因此,除了生产嵌合的困难之外,这种方法局限于狭窄的药剂种类。
其他研究者试图使药物与葡萄糖共轭,例如使用糖肽。但是证明通过BBBGlut1糖载体蛋白转运子不能明显传输任何糖肽。使试图用载体介导的转运子如Glut1葡萄糖转运子,胆碱转过子或LAT1大氨基酸转运子的等高传输率失败的问题是,载体转运子的选择性太高不能接受共轭的基质。问题还在于,作为多药抗性基因一员的P-糖蛋白迅速作用以主动地从脑中除去许多小分子,包括设法穿过屏障的药物。
除了LDL受体之外,BBB还包含结合具有高亲和性的LDL的II型清除受体(SR)。清除受体与LDL的修饰形式如乙酰化LDL特别有效。与SR的结合仅导致胞吞,而不是理想的胞吞转动。Rigotti等(1995)J.Biol.Chem.270:16221-4发现乙酰化LDL不传输穿过BBB,而阳离子化牛IgG更有效,如Bickel等(1993)Adv.Drug.Del.Rev.10:205-245中所述。证明乙酰化LDL胞吞噬转动的失败阻止许多研究者对LDL实验作进一步尝试。
Protter等(WO 87/02061)描述了一种药物传递体系,使用来源于载脂蛋白如ApoE和ApoB,与药剂或含试剂的载体共价结合。但是,使用分子共轭物只局限于少量药物种类,且产生许多与上述相同的问题。
Mller等(美国专利6288040)描述了与ApoE分子共价结合的合成聚(氰基丙烯酸丁酯)颗粒的用途。通过表面活性剂或者共价结合亲水性聚合物进一步修饰颗粒表面。如上所述,因为这些颗粒不是天然产生的,所以它们具有各种不利的副作用。
Samain等(WO 92/21330)描述了合成颗粒载体的用途,载体含与固态亲水性核共价结合的脂质,还含有ApoB,用于传递物质至肿瘤或巨噬细胞。但是他们并没有公开将这种载体用于传递药物穿过BBB的任何实用性。
发明概述
本发明涉及人工低密度脂蛋白(LDL)颗粒靶向和传递物质穿过血脑屏障进入脑中的用途。本发明的另一个目的是合成结构稳定,非免疫原性,能防止多种药物发生降解、灭活、水解、共轭和被摄入非靶组织的LDL载体。本发明提供了用作治疗剂载体的LDL颗粒,以及将这种药物和试剂传递穿过BBB的的改进方法,如与前述方法相比。例如与脂质体不同的是,LDL颗粒是固态颗粒,因此具有大于脂质体的结构稳定性。本发明进一步的目的是提供预防和治疗多种脑疾病的包含LDL载体的组合物、方法和试剂盒。
本发明提供的方法是,使亲水性治疗剂与胆甾醇共轭,以促进共轭的治疗剂掺入本发明的人工LDL颗粒中。在优选实施例中,本发明提供了胆甾醇-共轭的阿霉素和四环素。这些过程和制得的胆甾醇共轭物以及这种共轭物的组合物用于提供能通过胞吞转动传送治疗剂穿过血脑屏障的LDL颗粒,这是一种受体介导的过程,在脑毛细管内皮细胞中操作,作为向脑中输入胆甾醇和必需脂肪酸的途径,便于并改善治疗脑和CNS的各种疾病与障碍。另外,本发明的胆甾醇共轭物用于传递相应的治疗剂穿过BBB,无需将共轭物掺入本发明的LDL颗粒中。
在优选实施例中,本发明的胆甾醇共轭物通过酯键结合,通过普遍存在的内源酯酶的作用,从共轭物中释放治疗剂。将本发明的胆甾醇共轭物掺杂入本发明的LD颗粒中能保护胆甾醇共轭物免受这些酯酶的水解。
本发明进一步提供了包含蛋黄磷脂酰胆碱(EYPC),油酸胆甾醇酯和载脂蛋白E3(ApoE3)的人工LDL颗粒。形成固态颗粒的组成脂类包含三个层:由胆甾醇,胆甾醇酯和活性剂组成的固态脂质核心;由磷脂酰胆碱的脂肪酸链的混合物组成的中间界面层;和由磷脂头基和ApoE3组成的表面层。
本发明的LDL颗粒显著提高活性剂靶向毛细管内皮细胞并通过胞吞转动便于传输穿过血脑连接。包围治疗剂的蛋白质和磷脂组分还起到保护治疗剂免受降解和摄入非靶细胞中的作用。
本发明还涉及根据人工LDL颗粒辅助的试剂传输治疗疾病和症状的方法。例如,本发明为治疗各种脑疾病提供药物组合物和方法,包括使用本发明的人工LDL颗粒将特定试剂靶向脑组织。
本发明提供的人工LDL颗粒包含外部磷脂单层和固态脂质核心,其特征在于外部磷脂单层包含至少一种载脂蛋白,固态脂质核心包含至少一种治疗剂。在实施例中,至少一种载脂蛋白选自ApoA,ApoB,ApoC,ApoD或ApoE,或一种载脂蛋白的异构体,或脂蛋白和/或异构体的组合。在优选实施例中,至少一种载脂蛋白是ApoE。在更优选的实施例中,至少一种载脂蛋白选自ApoE2,ApoE3和ApoE4。本发明还涉及进一步包含其他靶向分子或试剂的人工LDL颗粒,这些其他靶向分子或试剂能增强LDL复合物向脑组织的靶向传递。在最优选的实施例中,至少一种载脂蛋白是ApoE3,单独使用或者与一种或多种氧甾醇和/或其他选自ApoB和ApoE4的载脂蛋白联合使用。
本发明提供的人工LDL颗粒用于传输治疗剂穿过血脑屏障。在优选实施例中,至少一种治疗剂选自:氨基酸,肽,蛋白质,碳水化合物和脂类。在另一个实施例中,至少一种治疗剂是胆甾醇与选自氨基酸,肽,蛋白质,碳水化合物和脂类的试剂之间形成的共轭物。在优选实施例中,至少一种治疗剂选自:神经营养因子,生长因子,酶,神经递质,神经调质,抗生素,抗病毒剂,抗真菌剂和化学治疗剂。
人工LDL颗粒的外部磷脂单层可包含任何磷脂或磷脂的组合,包括但并不限于磷脂酸,磷脂酰胆碱,磷脂酰乙醇胺,磷脂酰丝氨酸,磷脂酰丙三醇等。在优选实施例中,外部磷脂单层包含磷脂酰胆碱和至少一种载脂蛋白。
本发明的人工LDL颗粒优选具有约15到50纳米的直径。在更优选的实施例中,人工LDL颗粒具有约20到30纳米的直径。本发明人工LDL颗粒优选具有约1.00到1.07克/毫升的密度。在更优选的实施例中,人工LDL颗粒具有约1.02到1.06克/毫升的密度。而且,本发明的人工LDL颗粒具有至少2小时的血清稳定性。
本发明提供的人工LDL颗粒能通过胞吞转运用传输穿过BBB。在优选实施例中,脑对本发明颗粒的摄取专一性至少比肝大3倍。
本发明人工LDL颗粒的固态脂质核心可包含一种或多种脂类,包括但并不限于三酰甘油,胆甾醇,胆甾醇酯,脂肪酰酯等。在优选实施例中,固态脂质核心包含胆甾醇酯,其中胆甾醇被饱和脂肪酸酯化,包括但并不限于豆蔻酸酯,棕榈酸酯,硬脂酸酯,花生酸酯,木蜡酸酯等,或不饱和脂肪酸,包括但并不限于棕榈油酸酯,油酸酯,异油酸酯,亚油酸酯,亚麻酸酯,花生四烯酸酯等。在更优选的实施例中,固态脂质核心包含胆甾醇酯,油酸胆甾醇酯。在优选实施例中,本发明人工LDL颗粒的固态脂质核心包含至少一种治疗剂,是胆甾醇和阿霉素或四环素之间形成的共轭物。在优选实施例中,共轭物的胆甾醇和治疗剂通过酯键连接。
本发明还提供了用于传递治疗剂穿过血脑屏障的组合物,该组合物包含本发明的人工LDL颗粒和药学上可接受载体。
本发明还提供了一种共轭物,它包含与选自氨基酸,肽,蛋白质,碳水化合物和脂类的治疗剂连接的胆甾醇。在优选实施例中,治疗剂选自:神经营养因子,生长因子,酶,神经递质,神经调质,抗生素,抗病毒剂,抗真菌剂和化学治疗剂。在更优选的实施例中,本发明共轭物的治疗剂是阿霉素或四环素。在最优选的实施例中,本发明共轭物的胆甾醇和治疗剂通过酯键连接。本发明的每种共轭物可以与上述药学上可接受载体混合,用于本发明药物传递的任何方法。
本发明还提供了生产本发明人工LDL颗粒的方法,包括以下步骤:1)将含有共轭或非共轭治疗剂的磷脂悬浮在缓冲溶液中;2)超声处理溶液,形成外部磷脂单层和固态脂质核心;和3)添加包含至少一种载脂蛋白的溶液,该载脂蛋白掺入外部磷脂单层中。在优选实施例中,由本发明方法制备的人工LDL颗粒具有10到50纳米的直径。
本发明还提供了传递物质穿过血脑屏障的方法,所述方法包括给予需要的哺乳动物施用有效量的任何本发明的组合物。
本发明还提供了传递物质穿过血脑屏障的试剂盒,所述试剂盒包括含有本发明任何组合物的容器和使用说明书。
本发明还提供了共轭物、人工LDL颗粒和本发明组合物用于生产治疗脑和中枢神经系统(CNS)疾病的药物,这些话病症如阿尔茨黑默疾、帕金森氏病、细菌和病毒感染和癌症。
附图简要说明
图1:放射性标记的脂类和LDL的溴化钾密度梯度分布。
图2:脑(左)和肝(右)中LDL和脂类的摄取。
图3:(左)脑和肝中LDL与脂质颗粒的摄取比。(右)LDL和脂质颗粒的脑摄取比。
图4:14C标记的LDL颗粒的血浆浓度的时间过程。
图5:通过酞酸酯与胆甾醇连接的亲水性分子的化学结构。显示特定亲水性分子是阿霉素。不发生共轭时,单独的阿霉素太亲水性不能掺入LDL颗粒中。
图6:通过硫醚酯与胆甾醇连接的亲水性分子的化学结构。显示特定亲水性分子是四环素。不发生共轭时,单独的四环素太亲水性太大不能掺入LDL颗粒中。
发明详述
定义
这里所用术语“人工LDL颗粒”是指包括球形磷脂单层和固态脂质核心的结构。
这里所用术语“脂质体”是指包括球形脂质双层和含水核心的结构。
这里所用术语“摄取专一性”是指脑和肝脏中人工LDL颗粒对脂质颗粒(与人工LDL颗粒相同,除在外部磷脂单层中不包含脱辅蛋白质以外)的摄取比。注射入Sprague-Dawley鼠之后2小时,在脑和肝脏中测量人工LDL颗粒和脂质颗粒的摄取。用脑中人工LDL颗粒摄取对脂质颗粒摄取的比值除以肝脏中人工LDL颗粒摄取对脂质颗粒摄取的比值,计算摄取专一性。
这里所用术语“血清稳定性”是指血浆中保留至少75%注射的人工LDL颗粒的时间长度。
这里所用术语“载脂蛋白”和“脱辅蛋白质”是指与脂蛋白的磷脂单层相关的蛋白质,包括但并不限于ApoA;ApoB;ApoC;ApoD;ApoE;及其所有异构体。
这里所用术语“ApoE”是指ApoE的一种或多种异构体,包括但并不限于ApoE2,ApoE3和ApoE4。
这里所用术语“ApoB”是指ApoB的一种或多种异构体,包括但并不限于ApoB48和ApoB-100。
这里所用术语“外部磷脂单层”是指包括至少一种磷脂的单层,其中磷脂的磷酸酯头基朝向外侧,脂肪酰链朝向内侧的固态脂质核心。磷脂包括但并不限于磷脂酸,磷脂酰胆碱,磷脂酰乙醇胺,磷脂酰丝氨酸,磷脂酰甘油等。
这里所用术语“固态核心”是指被球形磷脂单层包封的人工LDL颗粒部分。固态核心可包含一种或多种脂类,包括但并不限于三酰甘油,胆甾醇,胆甾醇酯,脂肪酰酯等。这里所用术语“胆甾醇酯”是指被饱和脂肪酸酯化的胆甾醇,包括但并不限于肉豆蔻酸酯,棕榈酸酯,硬脂酸酯,花生酸酯,木蜡酸酯等,或不饱和脂肪酸,包括但并不限于棕榈油酸酯,油酸酯,异油酸酯,亚油酸酯,亚麻酸酯,花生四烯酸酯。
这里所用术语“治疗剂”是指治疗有用的氨基酸,肽,蛋白质,核酸,包括但并不限于多核苷酸,寡核苷酸,基因等,碳水化合物和脂类。本发明的治疗剂包括神经营养因子,生长因子,酶,抗体,神经递质,神经调质,抗生素,抗病毒素,抗真菌剂和化学治疗剂等。本发明的治疗剂包括药物,前体药物和当治疗剂传递至靶组织时可激活的前体。
这里所用术语“药学上可接受载体”是指一种化学组合物或化合物与活性组分混合,混合后可用来将活性组分施用给受试者。这里所用术语“生理学上可接受的”酯或盐是指活性组分的酯或盐形式,能与药物组合物的任何其他组分相容,对施用该组合物的受试者没有害处。这里所用术语“药物学上可接受载体”还包括但并不限于以下一种或多种物质:赋形剂;表面活性剂;分散剂;惰性稀释剂;成粒和崩解剂;粘合剂;润滑剂;甜味剂;增香剂;着色剂;防腐剂;生理学上可降解的组合物,如明胶;含水载体和溶剂;油性载体和溶剂;悬浮剂;分散或润湿剂;乳化剂;缓和剂;缓冲剂;盐;增稠剂;填充剂;乳化剂;抗氧化剂;稳定剂;和药学上可接受的聚合或疏水物质。本发明药物组合物中可以包括其他“附加组分”是本领域中已知的,如Genaro编著,1985,《雷明登药物科学》(Remington′s Pharmaceutical Sciences),MackPublishing Co.,Easton,Pa纳入作为参考。
这里所用术语“有效量”是指足以产生治疗反应的量。
LDL颗粒和脱辅蛋白质的性质
本发明涉及发现人工LDL颗粒能通过称为胞吞转运的主动受体介导的过程有效地靶向和传递物质穿过血脑屏障。胞吞转运在脑毛细管内皮细胞中自然发生,作为将胆甾醇和必需脂肪酸输入脑中的途径。因此本发明的人工LDL载体系统提供了有效靶向和传送药物至脑中的方法,其中BBB或其他不利副作用的破坏最小。
天然LDL颗粒的平均直径大约为22纳米。内核由大约150-200个甘油三酯分子和1500-2000个胆甾醇酯分子构成。颗粒表面包含由大约450个磷脂分子,185个神经鞘磷脂分子和1个脱辅蛋白质分子,通常是ApoB-100构成的单层(Hevonoja等(2000)Biochim Biophys Acta 1488(3):189-210)。天然LDL颗粒还可以包含大约600个未酯化的胆甾醇分子和较少量的溶血磷脂酰胆碱,磷脂酰乙醇胺,二酰甘油,神经酰胺和磷脂酰肌醇,以及痕量的其他生物脂类(Hevonoja等(2000)Biochim Biophys Acta 1488(3):189-210)。其他脱辅蛋白质,包括ApoE,在LDL,VLVL和HDL中发现,但是具有不同的受体结合特性(Bradly等(1984)J.Biol.Chem.259(23):14728-35)。
因此,LDL颗粒的表面是非均匀地覆盖着脱辅蛋白质,但由具有不同物理性质的不同区域组成。脱辅蛋白质分子负责保持颗粒的结构完整性,与肝,肾和血脑屏障上的脂蛋白受体结合。脱辅蛋白质根据脂质组分的状态发生结构变化(Mims等(1990)Biochemistry 29(28):6639-47)。
脱辅蛋白质E(ApoE)是参与全身中胆甾醇传输和血浆脂蛋白代谢的蛋白质。在周围细胞中,ApoE通过导向其传输而影响胆甾醇的细胞浓度。在神经元中,胆甾醇浓度的变化影响在阿尔茨海默病中改变的相同位置处微管相关蛋白质tau的磷酸化状态。ApoE具有三种主要异构体:ApoE4,ApoE3和ApoE2,其区别在于单氨基酸取代。ApoE3是正常异构体,而ApoE4和ApoE2是功能异常的。ApoE2与III型高脂蛋白血症相关。ApoE4与动脉粥样硬化和阿尔茨海默病的风险增加,认知功能减低和神经突赘疣的减少相关。除了年龄之外,ApoE4是散发性阿尔茨海默病的最重要风险因素。ApoE4具有取决于钙的毒性作用(Veinbergs等(2002)J.Neurosci.Res.67(3):379-87),但是其主要效应似乎是削弱ApoE3对β-淀粉样蛋白的清除率(Holtzman等(2001)J.Mol.Neurosci.17(2):147-55)。发现这些作用在血脑屏障中发生(Shibata等(2000)J.Clin.Invest.106(12):1489-99),因此可以是重要的治疗应用。
人工LDL颗粒制备
在优选实施例中,本发明的人工LDL颗粒包含蛋黄磷脂酰胆碱(EYPC),油酸胆甾醇酯和ApoE3的混合物。形成固态颗粒的脂类组分由三个层构成(Hevonoja等(2000)Biochim.Biophys.Acta 1488:189-210):含有胆甾醇,胆甾醇酯和活性药剂的固态脂质核心,活性药剂可以与胆甾醇共轭或者非共轭;含有磷脂酰胆碱的脂肪酸链混合物的中间界面层;以及含有磷脂头基和ApoE3的表面层。
固态核心和ApoE3的存在,区分了本发明的LDL颗粒和脂质体,后者由包围含水核心的球形脂质双层构成,是不稳定的。此外,LDL颗粒是由天然非免疫原性组分制成的,这一点区分了天然LDL颗粒与人造纳米粒,分子或化学共轭物,或胶体悬浮液。ApoE3通过胞吞转运的主动细胞介导过程与毛细管内皮细胞上的特异受体结合,传输整个颗粒穿过连接处。一旦在脑内,随着胆甾醇和磷脂逐渐被脑同化和利用,治疗剂从LDL颗粒中自然释放。
虽然上述脂质组分是优选的,但是本发明考虑其他脂类,例如不同脂类组成的LDL颗粒,包括化学改性的脂类,或者其他自然形成的亲脂性分子的混合物,这些脂类也能同样发挥作用。本领域技术人员会理解可以对其进行改进,使LDL载体系统适合于特定治疗剂或治疗应用。
优选由人工LDL和克隆ApoE3制备LDL颗粒。这能大大促进治疗剂有效和稳定地掺入LDL的脂质中心,并避免因为可能的翻译后修改,变异,或从人供体纯化的不纯ApoE3蛋白质的纯化而出现的抗原性问题。还能避免ApoE3或脂类被血源性疾病如HIV或其他病毒无意的污染。这种污染一直是使用人源物质的严重缺点。
在优选实施例中,本发明涉及制备人工LDL颗粒的改进微乳剂方法,包括以下步骤:将含有共轭或非共轭药物的脂类悬浮在磷酸酯缓冲的盐水(PBS)溶液中,并在54℃氮气气氛下使用至少约25瓦的超声波仪(探针振幅18微米,22千赫)对该溶液进行1小时的超声处理。这种功率水平对产生适当尺寸的LDL颗粒以促进传输穿过BBB是重要的,优选直径小于50纳米,更优选直径小于30纳米。利用水夹套的超声室,将含有LDL颗粒的样品保持在恒温下,优选在大约53和56℃之间。超声处理之后,脂质类溶液与ApoE一起温育,以285000,在溴化钾(KBr)分布梯度中超离心分离产生的脂蛋白颗粒。然后对PBS透析除无KBr。可以在4℃保存颗粒以备后用,优选保存达2周。
本领域技术人员会认识到可以对该方法的各个方面进行替换。例如,可以替换其他合适的密度梯度,如氯化铯或蔗糖。在替换实施例中,可以用尺寸排阻层析,电泳或其他方法代替离心分离本发明的LDL颗粒。
这里所述方法产生含药物的LDL颗粒具有能穿过BBB的适当尺寸,并保持不稳定的共掺入分子的活性和结构稳定性。对于传递到脑而言,LDL颗粒尺寸通常应小于50纳米,优选直径是20到30纳米。
在另一个优选实施例中,本发明的LDL颗粒包括EYPC,油酸胆甾醇酯和ApoE3的混合物,以每克脂质体0.02到0.2克比例存在,能有效掺入药剂和胞吞噬转运穿过BBB。在更优选的实施例中,范围是每克脂质体0.08到0.12克。更优选EYPC对油酸胆甾醇酯和ApoE3的摩尔比是23∶2.2(以重量为基础)。
在本发明进一步的实施例中,基于LDL的载体体系可以包含另外的靶向分子共掺入在表面层上,以进一步便于将试剂传输和传递至脑中。例如,胆甾醇的氧化衍生物(氧甾醇),包括胆甾醇氢过氧化物,胆甾醇环氧化物和羟基胆甾醇衍生物也可用来提高摄取。LDL颗粒还可以掺入其他脱辅蛋白质,如ApoB或ApoE4。
本发明还涉及掺入一种或多种物质,包括治疗剂,以治疗各种脑疾病或障碍。LDL载体体系的优点之一是能安全和自然地传递多种药物,包括那些化学不稳定,高度反应活性,或容易在水溶液中水解的药物。
可能的试剂包括但并不限于:神经营养因子,如NGF或从淀粉样蛋白前体蛋白质产生的神经营养片段,用于治疗脑损伤和神经变性疾病;酶,如苯丙氨酸羟化酶,用于代替通过遗传缺损而造成的丧失;酶,如酪氨酸羟化酶和DOPA脱羧酶,用于再生帕金森氏病中丧失的多巴胺;酶激活剂或抑制剂以恢复失去的生物合成功能:抗生素,如四环素,用于治疗传染病;神经递质和神经调节物质,用于治疗疼痛,或包括运动,认知和行为异常的疾病;化学治疗剂和抗-AIDS药物,如依托泊甙,三唑核苷,或抗组胺剂,如洛罗塔丁,非索非那定,或西替利嗪(),与系统地给予可耐受剂量时足量不能到达脑中的试剂一起用于治疗脑肿瘤或其他疾病;诊断剂,包括造影剂,如钆衍生物,碘海醇,或碘克酸盐,或者因为系统施用时对脑的渗透差而目前不使用的试剂;治疗或诊断蛋白质,如抗体,改造和天然的;和编码基因或蛋白质的治疗序列,或其部分,由DNA,RNA,或可非侵入性地引入穿过BBB的氨基酸。
存在于LDL载体中的治疗剂的量很不同,取决于分子的类型。LDL载体中的最佳掺入,治疗剂量应小于0.1摩尔/摩尔胆甾醇。预计较高水平可使LDL颗粒不稳定。本发明进一步考虑可以在相同颗粒中可存在多种药物或其他试剂。
在实施例中,要求活性物质的非共价修饰掺入本发明LDL颗粒中,条件是该物质的疏水性足以保持具有胆甾醇的微乳液。对于大多数中性和适度带电分子同样如此。
在另一个实施例中,如果治疗剂是高度带电的,像DNA或肽,或者为了防止扩散,该试剂可以与胆甾醇共价连接。在优选实施例中,连接是通过酯键完成的,脑组织中发现普遍存在的酯酶能释放试剂(Yordanov等,(2000)J.Med.Chem.45(11):2283-8;Yang等(1995)Pharm.Res.12(3):329-36)。或者,本领域技术人员能够选择其他结合方式起同样作用,它们可与磷脂酰胆碱,一些其他亲脂性化合物,或ApoE本身共价结合。
如上所述,本发明的LDL颗粒与加入聚乙二醇的脂质体,纳米粒和类似的人造物质相比,具有若干优点。本发明的LDL颗粒是由血浆的正常组分制成的,与其天然受体结合,作为脑对外源必需脂肪酸的自然需要的一部分,通过正常途径传输至细胞中。因此,其毒性明显低于聚合物基载体和破坏细胞膜完整性的试剂。目前用于传递药物至脑中的方法是用甘露醇渗透性破坏BBB。但是破坏BBB是严重缺点,事实是它允许毒素和甚至细菌与具有严重间接效应的所需治疗剂一起进入脑中。
本发明的人工LDL载体体系还提供在血浆中保持高浓度至少2小时的优点(附图4)。这对维持足够有效的血浆浓度(通常被称为“血浆浓度曲线下的面积”或AUC),使物质充分摄入和传递到脑中是重要的。
通过特定地靶向脑组织,如实施例3中所示,本发明的人工LDL颗粒显著提高药物的治疗效果,因为药物被肝脏吸收,被解毒途径灭活,包括被肝酶如P450灭活的可能性小得多。
包含人工LDL颗粒的组合物
可以用各种方法配制本发明的LDL颗粒,取决于待治疗的脑疾病类型。因此本发明的药物组合物中包括配制至少一种含药物的LDL颗粒复合体用于人或兽医。这种组合物可以与药学上可接受载体或赋形剂,任选与辅助药剂一起使用。常规载体也能与本发明一起使用。可接受载体包括但并不限于葡萄糖,盐水和磷酸盐缓冲盐水。
处理除去游离的治疗剂或其他非掺入分子之后,使药学上可接受载体中的LDL颗粒悬浮液达到所需浓度施用给病人。因为LDL颗粒太大不能在肠道外有效地吸收,设计这些组合物供静脉使用,但也可以设想肌肉内或动脉内施用,或甚至胃肠外给药或口服产生适当的改进。
因此,本发明提供的组合物靶向施用到BBB,其中包括在LDL颗粒中包含的选择的活性试剂溶液和药学上可接受载体,优选是含水载体。制得的组合物可以消毒并包装在试剂盒中使用,或者在无菌条件下过滤并冻干。用于静脉给药的试剂盒(含冻干的制剂)还可包括消毒水溶液,用于施用前混合。
根据接近的生理条件的需要,组合物中可以包含药学上可接受的辅助物质,如pH调节剂和缓冲剂,渗透性调节剂等,如乙酸钠,乳酸钠,氯化钠,氯化钾,氯化钙等。
这些制剂中LDL颗粒的浓度可以很大不同,即从小于约0.5%,通常等于或至少约1%,到多达5到10重量%。制备可静脉内施用LDL颗粒制剂的其他方法是本领域技术人员已知的。这些方法如Goodman和Gilman,《治疗学的药理基础》(The Pharmacological Basis of Therapeutics)Joel G.Hardman(编辑),Lee E.Limbird McGraw-Hill Professional;ISBN:0071354697;第10版(2001年8月13日)中所述。
使用人工LDL载体的治疗方法
在进一步的实施例中,人工LDL颗粒可以给予需要治疗的哺乳动物宿主,有效地传递试剂穿过BBB到脑中。对于治疗应用,可以采用任何方式给予受试者有效量的含药物LDL颗粒,使毛细管内皮细胞摄取LDL颗粒。
在临床应用中,LDL颗粒传递体系显著提高了药物的疗效,例如用于治疗阿尔茨默病,帕金森氏病和脑癌。例如,可以在LDL颗粒中掺入神经营养因子如神经生长因子,使肽能摄入脑中。这会引起新神经的生长过程,有利于一些神经变性疾病。如本文所述,本领域技术人员会认识到使用本发明的LDL载体体系具有各种可供选择的临床应用。
胆甾醇治疗剂的共轭物
胆甾醇是相对化学不活跃的分子。因此,必须在胆甾醇与含胺的治疗剂反应之前活化胆甾醇。例如,可以通过与环酸酐和酞酸酐或琥珀酸酐反应,产生含有羧基的酞酸酯或琥珀酸酯来活化胆甾醇。然后通过与五氟苯酚反应和然后与二异丙基碳化二亚胺反应,产生与含胺治疗剂的酰胺键合来活化羧基。制得的产物是胆甾醇-治疗剂共轭物,其中治疗剂通过酯键合与胆甾醇共轭。胆甾醇-治疗剂共轭物的亲脂性足以允许掺入本发明的人工LDL颗粒中。同样,由于优选的键合是酯键,所以治疗剂可以通过与普遍存在的内源酯酶作用而从胆甾醇部分中释放出来。因此,治疗剂从共轭物中的释放并不取决于苛刻条件和溶酶体中发现的非特异性肽酶的作用。虽然胆甾醇和治疗剂之间的优选键合是酯键,但是本发明考虑其他键合,包括但并不限于醚,酰胺和肽键。
或者,可以通过硫代胆甾醇,治疗剂和双官能交联剂的反应使含胺或含羟基的治疗剂与硫代胆甾醇共轭,双官能交联剂包括但并不限于PMPI。制得的共轭物是胆甾醇和治疗剂通过硫醚键连接的共轭物。如果治疗剂含有一个氨基,则能利用一种市售双官能交联剂与硫代胆甾醇共轭,这些市售双官能交联剂包括但并不限于琥珀酰亚胺-4-[N-马来酰亚胺甲基]环己烷-1-羧酸酯。
一旦形成,胆甾醇-治疗剂共轭物可与未共轭的油酸胆甾醇酯,磷脂,脂蛋白混合,如本文所述,从而产生本发明的人工LDL颗粒。
上述引用的各参考文献都完整纳入本文作为参考。
实施例
以下实施例用于进一步说明本发明,不应认为以任何方式对本发明范围的限制。
实施例1:纯化全长度脱辅蛋白质E(ApoE)
将从Aanti Polar Lipids,Inc.获得的DMPC(1,2-二豆蔻酰-sn-甘油-3-磷酸胆碱)以100毫克/毫升的浓度悬浮在玻璃管内的苯中,用台式超声波仪超声处理。将DMPC悬浮液是壳冷冻的,并冻干过夜,然后再悬浮于30毫升标准缓冲液(10毫摩尔Tris-HCl.pH7.6,0.15摩尔NaCl,1毫摩尔EDTA,0.0005%NaN3)中,形成10-20毫克/毫升DMPC,并转移至50毫升塑料锥形管中。将管置于水浴中,用超声波仪和微型尖管超声处理4个10分钟间隔,2-3分钟交替冷却。重复超声处理,直到溶液变得几乎透明。然后将超声处理的DMPC以2000转/分的速度离心20分钟,除去在超声处理过程中脱落的任何钛。
离心收集表达克隆ApoE的细菌细胞,并在具有大尖管的Branson超声波仪中在冰上进行超声处理,使用4个周期30秒的高强度超声处理,通过2分钟冷却间隔分离。在4℃以39.000xg离心超声处理的悬浮液20分钟,除去细胞碎片,在100毫克/升原始培养基中将悬浮液与DMPC混合。混合物在24℃(这是DMPC的转换温度)水浴中:温育过夜。
然后添加固态KBr,使DMPC-ApoE混合物的密度升到1.21克/毫升,以55000转/分的速度在15℃,在60 Ti Beckman固定角转头中以分步梯度(1.21,1.10和1.006克/毫升)离心过夜。丢弃靠近管顶含有游离DMPC的白色带状物,并取出其下方的ApoE-DMPC复合体,以密度1.009克/毫升漂清的。用凝胶电泳证实ApoE的存在。然后在4℃用0.1摩尔NH4HCO3和0.0005%NaN3对适当组分透析,三次更换缓冲液。
然后用凝血酶消化蛋白质,除去由载体留下的聚组氨酸标记。以1∶500凝血酶∶ApoE重量比将活化的凝血酶与蛋白质混合,在37℃温育至少1小时,用凝胶电泳分析等分试样,以确保蛋白质完全切割。因为存在两个切割位点,所以不完全的切割会导致分子量较高的第二个带状物。一旦证明完全切割,添加β-巯基乙醇至1%最终浓度,停止反应。然后在50毫升经酸洗的管中将ApoE起壳冷冻,并冻干过夜。
用30毫升冷的氯仿/甲醇(2∶1 v/v)洗涤ApoE,并用J6 Beckman离心机在4℃以1500转/分的速度离心10分钟收集。将颗粒再悬浮于小体积的冷甲醇中并涡动,然后用冷甲醇灌满管并离心。这个步骤除去了任何残余的氯仿。倒出甲醇,在管中留下少量,进行涡动,从颗粒形成糊。添加5毫升含有6摩尔胍-HCl,0.1摩尔TrisHCl,pH7.4,0.01%EDTA,1%β-巯基乙醇,和0.005%叠氮化钠的溶液,将溶液装在Sephacryl S-300柱上,该分离柱用4摩尔胍-HCl,0.1摩尔Tris-HCl,pH7.4,0.1%β-巯基乙醇和0.0005%NaN3平衡。用含有0.1%β-巯基乙醇和0.0005%叠氮化钠的4摩尔胍缓冲液洗脱蛋白质。用0.1摩尔NH4HCO3和0.0005%NaN3透析组分,缓冲液更换4次。用YM10 AmiconCentriprep浓缩器(Milllipore)浓缩纯化的ApoE至1-2毫克/毫升的最终浓度,在-20℃储存。
实施例2:LDL-脂质体的ApoE富集
1.制备脂质饼状物:将蛋黄磷脂酰胆碱(25毫克)和油酸胆甾醇酯(2毫克)溶解(比例是25∶1)在甲醇/氯仿(2∶3)中。在氮气下4℃蒸发溶剂。
2.制备脂质体:在12毫升10毫摩尔Tris-HCl缓冲液中水合脂质饼状物,缓冲液pH8.0,含有0.1摩尔预先在氮气下鼓泡的氯化钾。在氮气流下54℃对混合物超声处理1小时,以18微米输出,并离心除去在超声处理过程中产生的任何钛颗粒。
3.制备人工LDL:将步骤2中制备的脂质体与ApoE蛋白质以1/10(w/w)蛋白质/脂质的比在37℃温育30分钟。然后利用密度是1.064,1.019和1.006克/立方厘米的三层KCl分步梯度在4℃以285000xg进行18小时的密度梯度超离心,纯化并浓缩脂质体。向脂质体溶液中添加KBr,提高其密度至1.21,应用于离心管底部。Optiseal管(Beckman)适用于超离心步骤。离心之后,看到的脂质体是距离管顶部大约1/4的乳白色窄层。取出该层并在4℃对含有1毫摩尔EDTA的PBS(磷酸盐缓冲盐水)渗析过夜。LDL悬浮液稳定至少为7,能在氩气或氮气下-20℃储存。
实施例3:人工LDL颗粒在脑中的摄取
将含有大约1毫克脂质的PBS中的14C-LDL悬浮液注射入Sprague-Dawley大鼠(150克)的尾静脉中。以不同的间隔,用含EGTA的注射器通过心脏穿刺获取血样。在水中匀化血浆,RBC和组织,在闪烁计数器中测量14C。
附图2显示脑(左)和肝(右)中LDL和脂类摄取的结果。用含有14C-胆甾醇的LDL或脂质颗粒对雄性Sprague-Dawley大鼠进行静脉内注射,2小时之后测量脑和肝中的放射性。与除了存在ApoE之外相同组成的脂质颗粒相比,脑和肝分别从LDL中摄取19.8和4.7倍的标记物。这表明摄取是由通过LDL受体(p(>T)=0.00055)介导的胞吞转动引起的。
图3(左)显示脑和肝中LDL对脂质颗粒摄取的比值。与肝(p(>T)=0.0003)相比,脑掺入的LDL百分比大于脂质颗粒,表明与肝相比,靶器官具有>4倍的LDL专一性。图3(右)显示LDL和脂质颗粒的脑摄取对肝摄取的比值。脑∶肝比是对器官专一性的另一种测量,LDL的脑∶肝比大于脂质颗粒(p(>T)=0.0003)。换言之,肝摄取的脂质颗粒比脑多5.88倍,而肝摄取的LDL颗粒仅比脑(p(>T)=0.034)多1.36倍。
图4显示14C-标记LDL颗粒的血浆浓度的时间过程。注射LDL之后,血液14c保持恒定至少2小时,表明标记没有被其他器官从循环中除去。
实施例4:伯胺与14C胆甾醇的共轭
制备胆甾醇-酞酸酯:用氮气蒸发胆甾醇(1毫克)并冻干除去乙醇。将固体溶解在最小体积的THF中,转移至玻璃反应瓶中。添加固态酞酸酐(1-2毫克,>4当量),接着是50Et3N。在100℃加热混合物5分钟,添加≈20微升吡啶,使悬浮液变透明。在100℃加热混合物30分钟,直到溶液是红色,在TLC(Silica/UV254板)上用EtOH/甲苯(2∶1)纯化。从板上刮下最暗的UV条带(RP=0.74),并用THF洗脱产物(产率:98=100%)。
用五氟苯酚活化羧基:向酞酸胆甾醇酯中添加THF中的10毫克五氟苯酚(PFP),接着是5微升DIIC(二异丙基碳化二亚胺)。室温下在反应瓶中使溶液反应1小时,用TLC(CHCl3/CH3OH30∶5)纯化活化的胆甾醇-酞酸酯-PFP,并用THF洗脱(产率:100%)。
生产活化酰胺:将THF中的活化胆甾醇-酞酸酯-PFP蒸发至10微升,添加溶解在DMF中的2当量伯胺。DMF可导致副反应,但是如果存在过量胺则不是问题。添加甲醇或乙醇会大大降低产率。添加3微升DIIC,使溶液在室温下反应过夜,并用TCL(CHCl3/CH3OH30∶5)纯化(产率98%)。重要的是,只能使用Silica Gel G-25UV254板(Alltech809021)进行纯化。硅胶60板产生损害纯化的模糊不清条带。
实施例5:合成阿霉素-胆甾醇(1)
将THF中的活化胆甾醇-酞酸酯-PFP蒸发至10微升。添加溶解在DMF中的2当量阿霉素。使用过量胺减少与DMF的副反应。添加甲醇或乙醇会大大降低产率。添加3微升DIIC,在室温下使溶液反应过夜,用TLC(CHCl3/CH3OH30∶5)纯化(产率95%)。此条带含有阿霉素-DIIC共轭物和产物。用100%CH3OH中的C18-反相位HPLC可分离胆甾醇-阿霉素共轭物(流速=0.5毫升/分,检测=A471)。4.7分钟时,大约胆甾醇和阿霉素之间的一半距离,洗脱产物。总产率:95%。阿霉素-胆甾醇共轭物(I)的结构如图5所示。
实施例6:含羟基化合物与14C胆甾醇的共轭
将N-[对-马来酰亚胺苯基]异氰酸酯(PMPI)(5毫克)与200微升DMSO中的1当量含羟基化合物混合,在室温下反应30分钟。添加硫代胆甾醇(6.4毫克)。在室温下温育混合物120分钟,用预先涂布0.1摩尔EDTA pH8.0的硅胶G UV 254板通过薄层色谱法分离产物,使用EtOH/H2O1∶1作为溶剂。
实施例7:合成四环素-胆甾醇(II)
冻干四环素除去任何溶剂,将200微升DMSO中的2.2毫克四环素与5毫克PMPI混合,并在室温下反应30分钟。添加硫代胆甾醇(6.4毫克)。在室温下温育混合物120分钟,使用预先涂布0.1摩尔EDTA pH8.0的硅胶G UV 254板通过薄层色谱法分离产物,使用EtOH/H2O作为溶剂。四环素-胆甾醇共轭物(II)的结构如附图6所示。
参考文献
下列各参考文献整体纳入本文作为参考。
1.Alyaudtin et al.(2001)Interaction of poly(butylcyanoacrylate)nanoparticles with the blood-brain barrier in vivo and in vitro.J.DrugTarget 9(3):209-21.(体内和体外中聚(丁基氰丙烯酸酯)纳米粒与血脑屏障的相互作用)
2.Bickel et al.(1993)Delivery of peptides and proteins throughthe blood brain barrier.Adv Drug.Del.Rev.10:205-245.(传递肽和蛋白质穿过血脑屏障)
3.Bradley et al.(1984)Low-density lipoprotein receptor bindingdeterminants switch from apoprotein E to apoprotein B during conversionof hypertriglyceridemic very-low-density lipoprotein to low-densitylipoproteins.J Biol Chem 259(23):14728-35.(在高甘油三酯血症极低密度脂蛋白向低密度脂蛋白转变期间,低密度脂蛋白受体结合决定子从脱辅蛋白质E转到脱辅蛋白质B。)
4.Goodman & Gilman,The Pharmacological Basis of Therapeutics byJoel G.Hardman(Editor),Lee E.Limbird McGraw-Hill Professional;ISBN:0071354697;10th edition(August 13,2001).(治疗学和药理基础)
5.Hevonoja et al.(2000)Structure of low density lipoprotein(LDL)particles:basis for understanding molecular changes in modifiedLDL.Biochim Biophys Acta 1488(3):189-210.(低密度脂蛋白(LDL)颗粒的结构:了解修饰的LDL中分子变化的基础)
6.Holtzman(2001)Role of ApoE/Abeta interactions in thepathogenesis of Alzheimer’s disease and cerebral amyloid angiopathy,Jmol Neurosci 17(2):147-55.(阿尔茨海默病和大脑淀粉样血管病的发病机制中ApoE/Abeta相互的作用功用)
7.Huwyler et al.(1996)Brain drug delivery of small molecules usingimmunoliposomes.Proc.Nat’l.Acad.Sci.USA93:4164-14169.(使用免疫脂质体传递小分子脑用药物)
8.Kang et al.Brain delievey of biotin bound to a conjugate of neutralavidin and cationized human albumin.Pharm.Res.11,1257-1264.(与神经抗生物素蛋白和阳离子化人白蛋白共轭物结合的生物素脑部传递)
9.Kang et al.(2000)Stability of the disulfide bond in anavidin-biotin linked chimeric peptide during in vivo transcytosisthrough brain endothelial cells.J drug Target 8(6):425-34).(体内胞吞转运穿过脑内皮细胞过程中,抗生物素蛋白-生物素连接的嵌合肽中二硫键的稳定性)
10.Kreuter et al.(2002)Apolipoprotein-mediated transport ofnanoparticle-bound drugs across the blood-brain barrier.J drug Target10(4):317-25.(纳米粒结合药物穿过血脑屏障的载脂蛋白介导的传输)
11.Mims et al.(1990)Effect of particle size and temperature on theconformation and physiological behavior of apolipoprotein E bound tomodel lipoprotein particles.Biochemistry 29(28):6639-47.(粒径和温度对与模型脂蛋白颗粒结合的载脂蛋白E构型和生理行为的影响)
12.Pardrideg(1990)CNS drug design based on principles ofblood-brain barrier transport.J.Neurochem 70:1781-2.(基于血脑屏障传输原理的CNS药物设计)
13.Pardrideg et al.(1986)Blood-brain barrier:interface betweeninternal medicine and the brain.Ann Intern Med 105(1):82-95.(血脑屏障:内科医学和脑之间的界面)
14.Reinhard et al.(1994)Insulin-like growth factors cross theblood-brain barrier.Endocrinology 135(5):1735-1761.(胰岛素样生长因子穿过血脑屏障)
15.Rigotti et al.(1995)The class B scaverger receptors SR-BI andCD36 are receptors for anionic phospholipids.J.Biol.Chem.270,16221-4.(B型清除受体SR-BI和CD36是阴离子磷脂的受体)
16.Shibata et al.(2000)Clearance of Alzheimer’samyloid-ss(1-40)peptide from brain by LDL receptor-related protein-1at the blood-brain barrier.J.Clin.Invest.106(12):1489-99.(通过血脑屏障上的LDL受体相关蛋白质-1从脑中清除阿尔茨海默淀粉样蛋白-ss(1-40)肽)
17.Veinbergs et al.(2002)Neurotoxic effects of apolipoprotein E4are mediated via dysregulation of calcium homeostasis.J neurosci Res67(3):379-89.(通过钙稳态的调节障碍介导载脂蛋白E4的神经毒性作用)
18.Witt et al.(2000)Insulin enhancement of opioid peptidetransport across the blood-brain barrier and assessment of analgesiceffect.Pharmacol Exp Ther 295(3):972-8.(胰岛素增强阿片样肽传输穿过血脑屏障和镇痛效果的评估)
19.Wu et al.(2002)Pharmacokinetics and brain uptake ofbiotinylated basic fibroblast growth factor conjugated to a blood-brainbarrier drug delivery system.J drug Target 10(3):329-45.(与血脑屏障药物传递体系共轭的生物素化的碱性成纤维细胞生长因子的药物动力学和脑摄取)
20.Yang et al.(1995)Soft drugs.XX.Design,synthesis,and evaluationof ultrashort acting beta-blockers.Pharm Res 12(3):329-36.(软药.XX.超短作用的β-阻断剂的设计,合成和评价)
21.Yordanov et al.(2002)Acyl-protected hydroxylamines as spinlabel generators for EPR brain imaging.J.Med.Chem.45(11):2283-8.(酰基保护的羟胺作为EPR脑成像的自旋标记发生剂)
22.Dehouck et al.(1977)A new function for the LDL receptor;transcytosis of LDL across the blood-brain barrier.J.Cell.Biol.138(4):877-89.(LDL受体的新功能:穿过血脑屏障的LDL胞吞噬转运)
23.Versluis et al.(1998)Synthesis of a lipophilic daunorubicinderivative and its incorporation into lipidic carriers developed forLDL receptor-mediated tumor therapy.Pharm.Res.15(4):531-537.(为LDL受体-介导的肿瘤治疗开发的亲脂性柔红霉素衍生物合成及其掺入脂的载体)
24.Versluis et al.(1998)Low-density lipoprotein receptor-mediateddelivery of a lipophilic daunorubicin derivative to B16 tumors in miceusing apolipoprotein E-enriched liposomes.B.r.J.Cancer 78(12):1607-14.(使用载脂蛋白E富集的脂质体将亲脂性柔红霉素衍生物通过低密度脂蛋白受体介导传递至小鼠的B16肿瘤处)
25.Versluis et al.(1999)Stable incorporation of a lipophilicdaunorubicin prodrug into apolipoprotein E-exposing liposomes inducesuptake of prodrug via low-density lipoprotein receptor invivo.J.Pharmacol.Exp.Ther.289(1):1-7.(亲脂性柔红霉素前药稳地掺入载脂蛋白E-暴露的脂质体中,通过体内低密度脂蛋白受体引发前药的摄取)
26.Annunziato et al.(1993)p-Maleimidophenyl isocyanate:a novelheterobifunctional liker for hydroxyl to thiol coupling.BioconjugateChem.4:212-218.(对-马来酰亚胺苯基异氰酸酯:用于羟基与硫醇偶联的新颖异双官能结合剂)
27.Demeule et al.(2002)High transcytosis of malanotransferrin(P97)across the blood-brain barrier.J.Neurochem 83(4):924-33.(穿过血脑屏障的黑素转铁蛋白(P97)的高胞吞转运)。
Claims (8)
1.一种共轭物,包含胆甾醇和阿霉素。
2.如权利要求1所述的共轭物,胆甾醇和阿霉素是通过酯键连接的。
3.一种共轭物,包含胆甾醇和四环素。
4.如权利要求3所述的共轭物,胆甾醇和四环素是通过酯键连接的。
5.一种组合物,包含权利要求1所述的共轭物和药学上可接受的载体。
6.一种组合物,包含权利要求2所述的共轭物和药学上可接受的载体。
7.一种组合物,包含权利要求3所述的共轭物和药学上可接受的载体。
8.一种组合物,包含权利要求4所述的共轭物和药学上可接受的载体。
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Families Citing this family (179)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI433693B (zh) | 2003-02-14 | 2014-04-11 | Childrens Hosp & Res Ct Oak | 親脂藥物傳送媒介物及其使用方法 |
WO2005039534A1 (en) * | 2003-10-01 | 2005-05-06 | Children's Hospital & Research Center At Oakland | Lipophilic drug delivery vehicle and methods of use thereof |
US7199112B2 (en) * | 2005-08-10 | 2007-04-03 | William Llewellyn | Use of phospholipid arachidonic acids for increasing muscle mass in humans |
US8252338B2 (en) * | 2005-11-10 | 2012-08-28 | The Regents Of The University Of California | Synthetic LDL as targeted drug delivery vehicle |
US20070122800A1 (en) * | 2005-11-23 | 2007-05-31 | Seoju Lee | Methods for quantifying polymer attachment to a particle |
JP5358187B2 (ja) | 2005-12-15 | 2013-12-04 | ジェネンテック, インコーポレイテッド | ポリユビキチンを標的とする方法と組成物 |
TWI334784B (en) * | 2006-04-14 | 2010-12-21 | Buck Inst For Age Res | Compositions and methods for suppression of amyloid plaque formation associated with neurodegenerative disorders |
BRPI0710407A2 (pt) | 2006-05-04 | 2012-04-17 | Genentech Inc | poliptìdeos, peixes-zebra transgênicos, modelos de sistemas, métodos de identificação de compostos, de identificação de agentes, métodos de tratamento de disfunções relativas a apoptose, método de identificação de agentes de prevenção ou redução da apoptose, composição de aumento da apoptose, composições de redução ou prevenção de apoptose, composição de apoptose, método de detecção, kits e artigo industrializado |
CL2007002070A1 (es) | 2006-07-14 | 2008-02-08 | Ac Immune S A Genentech Inc | Anticuerpo quimerico o humanizado, o fragmentos de ellos, que se adhieren especificamente a por lo menos un epitopo en la proteina beta-amiloide; molecula de acido nucleico que lo codifica; composicion que lo comprende; su uso para tratar enfermedade |
KR20190003862A (ko) | 2006-07-14 | 2019-01-09 | 에이씨 이뮨 에스.에이. | 아밀로이드 베타에 대해 인간화된 항체 |
US20080025961A1 (en) | 2006-07-28 | 2008-01-31 | Alkon Daniel L | Methods of stimulating cellular growth, synaptic remodeling and consolidation of long-term memory |
DE102007006663A1 (de) * | 2007-02-10 | 2008-08-21 | Lts Lohmann Therapie-Systeme Ag | Transport von Arzneistoffen über die Blut-Hirn-Schranke mittels Apolipoproteinen |
US7960139B2 (en) | 2007-03-23 | 2011-06-14 | Academia Sinica | Alkynyl sugar analogs for the labeling and visualization of glycoconjugates in cells |
US20090110739A1 (en) * | 2007-05-15 | 2009-04-30 | University Of North Texas Health Science Center At Forth Worth | Targeted cancer chemotherapy using synthetic nanoparticles |
NZ601843A (en) | 2007-06-12 | 2014-01-31 | Ac Immune Sa | Monoclonal anti beta amyloid antibody |
EP2574345A1 (en) | 2007-06-12 | 2013-04-03 | AC Immune S.A. | Humanized antibodies to amyloid beta |
EP2650308A3 (en) | 2007-10-05 | 2014-11-12 | Genentech, Inc. | Use of anti-amyloid beta antibody in ocular diseases |
KR101198354B1 (ko) * | 2007-10-17 | 2013-03-14 | 주식회사 삼양바이오팜 | 핵산 전달용 저밀도 지단백질 유사(LDL-like) 양이온성 나노입자, 그의 제조방법 및 이를 이용한 핵산의 전달 방법 |
WO2009052454A2 (en) | 2007-10-19 | 2009-04-23 | University Of California | Compositions and methods for ameliorating cns inflammation, psychosis, delirium, ptsd or ptss |
US7902147B2 (en) | 2007-11-05 | 2011-03-08 | Duke University | Chronic lymphocytic leukemia prognosis and treatment |
TWI580694B (zh) | 2007-11-30 | 2017-05-01 | 建南德克公司 | 抗-vegf抗體 |
CA2708719A1 (en) * | 2007-12-12 | 2009-06-18 | University Health Network | High-density lipoprotein-like peptide-phospholipid scaffold ("hpps") nanoparticles |
US8268796B2 (en) | 2008-06-27 | 2012-09-18 | Children's Hospital & Research Center At Oakland | Lipophilic nucleic acid delivery vehicle and methods of use thereof |
US8680020B2 (en) | 2008-07-15 | 2014-03-25 | Academia Sinica | Glycan arrays on PTFE-like aluminum coated glass slides and related methods |
TWI572357B (zh) | 2008-10-14 | 2017-03-01 | 建南德克公司 | 免疫球蛋白變異體及其用途 |
JP5851838B2 (ja) | 2008-10-22 | 2016-02-03 | ジェネンテック, インコーポレイテッド | 軸索変性の調節 |
US8734853B2 (en) | 2008-11-17 | 2014-05-27 | University Of North Texas Health Science Center At Fort Worth | HDL particles for delivery of nucleic acids |
BRPI0918204A2 (pt) | 2008-12-23 | 2015-12-08 | Genentech Inc | igv variante composição farmaceutica e kit |
WO2011028950A1 (en) | 2009-09-02 | 2011-03-10 | Genentech, Inc. | Mutant smoothened and methods of using the same |
AU2010310589A1 (en) | 2009-10-22 | 2012-05-10 | Genentech, Inc. | Modulation of axon degeneration |
US11377485B2 (en) | 2009-12-02 | 2022-07-05 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US10087236B2 (en) | 2009-12-02 | 2018-10-02 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US8486397B2 (en) | 2009-12-11 | 2013-07-16 | Genentech, Inc. | Anti-VEGF-C antibodies and methods using same |
AU2010336485B2 (en) | 2009-12-23 | 2015-03-26 | Genentech, Inc. | Anti-Bv8 antibodies and uses thereof |
TWI472348B (zh) | 2009-12-30 | 2015-02-11 | Ind Tech Res Inst | 可通過血腦障壁之胜肽及包含此胜肽之傳輸系統 |
WO2011130332A1 (en) | 2010-04-12 | 2011-10-20 | Academia Sinica | Glycan arrays for high throughput screening of viruses |
EP2568976B1 (en) | 2010-05-10 | 2015-09-30 | Academia Sinica | Zanamivir phosphonate congeners with anti-influenza activity and determining oseltamivir susceptibility of influenza viruses |
WO2012006516A2 (en) | 2010-07-08 | 2012-01-12 | Alkon Daniel L | Dag-type and indirect protein kinase c activators and anticoagulant for the treatment of stroke |
NZ606357A (en) | 2010-07-30 | 2015-05-29 | Genentech Inc | Safe and functional humanized anti beta-amyloid antibody |
WO2012020124A1 (en) | 2010-08-12 | 2012-02-16 | Ac Immune S.A. | Vaccine engineering |
CA2808660A1 (en) | 2010-08-19 | 2012-02-23 | Blanchette Rockefeller Neurosciences Institute | Treatment of cognitive disorders associated with abnormal dendritic spines using pkc activators |
AU2011312205B2 (en) | 2010-10-05 | 2015-08-13 | Curis, Inc. | Mutant smoothened and methods of using the same |
CA2812865C (en) | 2010-10-07 | 2021-01-26 | Ac Immune S.A. | Phosphospecific antibodies recognising tau |
KR101854943B1 (ko) | 2010-10-26 | 2018-05-04 | 에이씨 이뮨 에스.에이. | 소수성 부분을 통해 변형된 펩티드를 포함하는 리포솜 기반 구조체 |
CN103228674B (zh) | 2010-11-10 | 2019-07-05 | 霍夫曼-拉罗奇有限公司 | 用于神经疾病免疫疗法的方法和组合物 |
TW201305200A (zh) | 2010-11-30 | 2013-02-01 | Genentech Inc | 低親和力血腦障壁受體抗體及其用途 |
WO2012110835A2 (en) | 2011-02-15 | 2012-08-23 | Semmelweis Egyetem | Prussian blue based nanoparticle as multimodal imaging contrast material |
US10227387B2 (en) | 2011-05-18 | 2019-03-12 | Children's Hospital Medical Center | Targeted delivery of proteins across the blood-brain barrier |
WO2013043864A1 (en) * | 2011-09-23 | 2013-03-28 | The Board Of Regents Of The University Of Texas System | Compositions and methods related to endothelial targeting |
EP3135689B1 (en) | 2011-10-07 | 2018-12-19 | AC Immune S.A. | Phosphospecific antibodies recognising tau |
CN106977587A (zh) | 2011-10-14 | 2017-07-25 | 霍夫曼-拉罗奇有限公司 | Bace1的肽抑制剂 |
RU2014123511A (ru) | 2011-11-10 | 2015-12-20 | Дженентек, Инк | Способы лечения, диагностики и мониторинга болезни альцгеймера |
EP2780316B1 (en) | 2011-11-13 | 2020-04-15 | Blanchette Rockefeller Neurosciences Institute | Esters of dcpla and methods of treatment using the same |
EP3967299A1 (en) | 2011-11-13 | 2022-03-16 | Cognitive Research Enterprises, Inc. | Pkc activators and combinations thereof |
US9644038B2 (en) | 2011-12-21 | 2017-05-09 | The Regents Of The University Of California | Apolipoprotein nanodiscs with telodendrimer |
BR112014024769A2 (pt) | 2012-04-05 | 2017-12-12 | Ac Immune Sa | anticorpo humanizado tau |
US10130714B2 (en) | 2012-04-14 | 2018-11-20 | Academia Sinica | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
EA026393B1 (ru) | 2012-05-22 | 2017-04-28 | Дженентек, Инк. | N-замещенные бензамиды и их применение в лечении боли |
RU2014148732A (ru) | 2012-05-22 | 2016-07-20 | Ф. Хоффманн-Ля Рош Аг | Замещенные дипиридиламины и их применение |
US8877236B2 (en) * | 2012-06-28 | 2014-11-04 | Universita Degli Studi Di Milano-Bicocca | Liposomes active in-vivo on neurodegenerative diseases |
JP6309519B2 (ja) | 2012-07-06 | 2018-04-11 | ジェネンテック, インコーポレイテッド | N置換ベンズアミド及びその使用方法 |
CA2880701A1 (en) | 2012-08-18 | 2014-02-27 | Academia Sinica | Cell-permeable probes for identification and imaging of sialidases |
AU2013305827A1 (en) | 2012-08-21 | 2015-03-05 | Academia Sinica | Benzocyclooctyne compounds and uses thereof |
CA2885908A1 (en) | 2012-09-27 | 2014-04-03 | F. Hoffmann-La Roche Ag | Substituted sulfonamide compounds |
AU2013204200B2 (en) | 2012-10-11 | 2016-10-20 | Brandeis University | Treatment of amyotrophic lateral sclerosis |
EP2908837B1 (en) * | 2012-10-19 | 2019-02-13 | Vect-Horus | Compositions for drug delivery |
RU2015131314A (ru) | 2013-01-18 | 2017-02-27 | Ф. Хоффманн-Ля Рош Аг | 3-замещенные пиразолы и их применение в качестве ингибиторов dlk |
EP2968280A4 (en) | 2013-03-14 | 2016-08-10 | Genentech Inc | SUBSTITUTED TRIAZOLOPYRIDINES AND METHOD OF USE THEREOF |
MX2015012872A (es) | 2013-03-15 | 2016-02-03 | Ac Immune Sa | Anticuerpos anti-tau y metodos de uso. |
WO2014177060A1 (en) | 2013-05-01 | 2014-11-06 | F.Hoffmann-La Roche Ag | Biheteroaryl compounds and uses thereof |
RU2015147601A (ru) | 2013-05-01 | 2017-06-05 | Ф. Хоффманн-Ля Рош Аг | С-связанные гетероциклоалкилзамещенные пиримидины и их применения |
WO2014210397A1 (en) | 2013-06-26 | 2014-12-31 | Academia Sinica | Rm2 antigens and use thereof |
US9981030B2 (en) | 2013-06-27 | 2018-05-29 | Academia Sinica | Glycan conjugates and use thereof |
US9782476B2 (en) | 2013-09-06 | 2017-10-10 | Academia Sinica | Human iNKT cell activation using glycolipids with altered glycosyl groups |
EP3055302B1 (en) | 2013-10-11 | 2018-12-26 | F. Hoffmann-La Roche AG | Substituted heterocyclic sulfonamide compounds useful as trpa1 modulators |
CA2927675A1 (en) | 2013-10-18 | 2015-04-23 | Blanchette Rockefeller Neurosciences Institute | Halogenated esters of cyclopropanated unsaturated fatty acids for use in the treatment of neurodegenerative diseases |
MX2016008110A (es) | 2013-12-20 | 2016-08-19 | Hoffmann La Roche | Derivados de pirazol como inhibidores de la cinasa de cremallera de leucina dual (dlk) y usos de los mismos. |
US10150818B2 (en) | 2014-01-16 | 2018-12-11 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
WO2016114819A1 (en) | 2015-01-16 | 2016-07-21 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
WO2015109180A2 (en) | 2014-01-16 | 2015-07-23 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
WO2015120075A2 (en) | 2014-02-04 | 2015-08-13 | Genentech, Inc. | Mutant smoothened and methods of using the same |
US9833435B2 (en) | 2014-03-27 | 2017-12-05 | Blanchette Rockefeller Neurosciences Institute | Compositions and methods to treat Niemann-Pick disease |
TWI687428B (zh) | 2014-03-27 | 2020-03-11 | 中央研究院 | 反應性標記化合物及其用途 |
JP7093612B2 (ja) | 2014-05-27 | 2022-06-30 | アカデミア シニカ | Bacteroides由来のフコシダーゼおよびそれを使用する方法 |
JP7062361B2 (ja) | 2014-05-27 | 2022-05-06 | アカデミア シニカ | 抗her2糖操作抗体群およびその使用 |
US10118969B2 (en) | 2014-05-27 | 2018-11-06 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
CN106573971A (zh) | 2014-05-27 | 2017-04-19 | 中央研究院 | 抗cd20醣抗体及其用途 |
JP7063538B2 (ja) | 2014-05-28 | 2022-05-09 | アカデミア シニカ | 抗TNFα糖操作抗体群およびその使用 |
CN106715418A (zh) | 2014-07-07 | 2017-05-24 | 基因泰克公司 | 治疗化合物及其使用方法 |
AU2015315294B2 (en) | 2014-09-08 | 2020-09-17 | Academia Sinica | Human iNKT cell activation using glycolipids |
CN107108745B (zh) | 2014-11-19 | 2021-01-12 | 基因泰克公司 | 抗bace1的抗体和其用于神经疾病免疫疗法的用途 |
RU2020126237A (ru) | 2014-11-19 | 2020-12-01 | Аксон Ньюросайенс Се | Гуманизированные тау-антитела при болезни альцгеймера |
US10495645B2 (en) | 2015-01-16 | 2019-12-03 | Academia Sinica | Cancer markers and methods of use thereof |
US9975965B2 (en) | 2015-01-16 | 2018-05-22 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US10149826B2 (en) * | 2015-01-20 | 2018-12-11 | Hyalo Technologies, LLC | Method of preparing microspheres |
TWI736523B (zh) | 2015-01-24 | 2021-08-21 | 中央研究院 | 新穎聚醣結合物及其使用方法 |
AU2016209056B2 (en) | 2015-01-24 | 2021-01-28 | Academia Sinica | Cancer markers and methods of use thereof |
EP3250590B1 (en) | 2015-01-30 | 2021-09-15 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced anti-ssea4 antibody efficacy |
AU2016215227A1 (en) | 2015-02-04 | 2017-09-21 | Assistance Publique-Hopitaux De Paris | Mutant smoothened and methods of using the same |
EP3268373B1 (en) | 2015-03-09 | 2022-04-27 | F. Hoffmann-La Roche AG | Tricyclic dlk inhibitors and uses thereof |
US20180217163A1 (en) | 2015-05-11 | 2018-08-02 | Daniel L. Alkon | Treatment of neurodegenerative conditions using pkc activators after determining the presence of the apoe4 allele |
CN107835805A (zh) | 2015-05-22 | 2018-03-23 | 基因泰克公司 | 被取代的苯甲酰胺和其使用方法 |
US20160346221A1 (en) | 2015-06-01 | 2016-12-01 | Autotelic Llc | Phospholipid-coated therapeutic agent nanoparticles and related methods |
IL302486A (en) | 2015-06-24 | 2023-06-01 | Hoffmann La Roche | Antibodies against the transnephrine receptor with adapted affinity |
CA2991655A1 (en) | 2015-07-10 | 2017-01-19 | Peptinovo Biopharma, Llc | Formulations for improving the efficacy of hydrophobic drugs |
US11207461B2 (en) | 2015-07-30 | 2021-12-28 | Anoop U. R | Drug delivery system and method for controlled and continuous delivery of drugs into the brain by bypassing the blood brain barrier |
WO2017035271A1 (en) | 2015-08-27 | 2017-03-02 | Genentech, Inc. | Therapeutic compounds and methods of use thereof |
KR20180050339A (ko) | 2015-09-04 | 2018-05-14 | 오비아이 파머 인코퍼레이티드 | 글리칸 어레이 및 사용 방법 |
EP3340972A4 (en) * | 2015-09-18 | 2019-05-01 | Oklahoma Medical Research Foundation | METHOD FOR TRANSPORTING AN ACTIVE AGENT THROUGH THE BLOOD BRAIN, BLOOD COCHLEA OR BLOOD LIQUOR BARRIER |
WO2017053659A1 (en) | 2015-09-23 | 2017-03-30 | Khan Tapan K | Methods for survival and rejuvenation of dermal fibroblasts using pkc activators |
MX2018003822A (es) | 2015-10-02 | 2018-06-22 | Hoffmann La Roche | Anticuerpos biespecificos contra el cd20 humano y el receptor de transferrina humano y metodos de uso. |
AR106189A1 (es) | 2015-10-02 | 2017-12-20 | Hoffmann La Roche | ANTICUERPOS BIESPECÍFICOS CONTRA EL A-b HUMANO Y EL RECEPTOR DE TRANSFERRINA HUMANO Y MÉTODOS DE USO |
WO2017062924A1 (en) | 2015-10-08 | 2017-04-13 | Alkon Daniel L | Dosing regimens of pkc activators |
EP3380466A1 (en) | 2015-11-25 | 2018-10-03 | Genentech, Inc. | Substituted benzamides useful as sodium channel blockers |
CN105483076B (zh) * | 2015-12-23 | 2019-01-25 | 中国科学院生物物理研究所 | 一种脂肪体的制备方法及其应用 |
AU2017213826A1 (en) | 2016-02-04 | 2018-08-23 | Curis, Inc. | Mutant smoothened and methods of using the same |
JP2019515876A (ja) | 2016-03-08 | 2019-06-13 | アカデミア シニカAcademia Sinica | N−グリカンおよびそのアレイのモジュール合成のための方法 |
WO2017172990A1 (en) | 2016-03-29 | 2017-10-05 | Obi Pharma, Inc. | Antibodies, pharmaceutical compositions and methods |
US10980894B2 (en) | 2016-03-29 | 2021-04-20 | Obi Pharma, Inc. | Antibodies, pharmaceutical compositions and methods |
US10766858B2 (en) | 2016-03-30 | 2020-09-08 | Genentech, Inc. | Substituted benzamides and methods of use thereof |
IL262296B1 (en) | 2016-04-22 | 2024-05-01 | Obi Pharma Inc | Cancer immunotherapy using immune activation or immune modulation by Globo-series antigens |
WO2018015411A1 (en) | 2016-07-20 | 2018-01-25 | F. Hoffmann-La Roche Ag | Sulfonylcycloalkyl carboxamide compounds as trpa1 modulators |
WO2018015410A1 (en) | 2016-07-20 | 2018-01-25 | F. Hoffmann-La Roche Ag | Bicyclic proline compounds |
KR20230117482A (ko) | 2016-07-27 | 2023-08-08 | 오비아이 파머 인코퍼레이티드 | 면역원성/치료 글리칸 조성물 및 그의 용도 |
EP3491026A4 (en) | 2016-07-29 | 2020-07-29 | OBI Pharma, Inc. | HUMAN ANTIBODIES, PHARMACEUTICAL COMPOSITIONS AND METHODS |
EP3497093B1 (en) | 2016-08-12 | 2021-09-15 | F. Hoffmann-La Roche AG | Sulfonyl pyridyl trp inhibitors |
US10538592B2 (en) | 2016-08-22 | 2020-01-21 | Cho Pharma, Inc. | Antibodies, binding fragments, and methods of use |
WO2018064350A1 (en) * | 2016-09-30 | 2018-04-05 | Eriochem Usa, Llc | Apo-e modified lipid nanoparticles for drug delivery to targeted tissues and therapeutic methods |
EP3526219B1 (en) | 2016-10-17 | 2021-12-15 | F. Hoffmann-La Roche AG | Bicyclic pyridone lactams and methods of use thereof |
AU2017361549B2 (en) | 2016-11-21 | 2023-12-21 | Obi Pharma, Inc. | Conjugated biological molecules, pharmaceutical compositions and methods |
TW201831477A (zh) | 2016-11-28 | 2018-09-01 | 瑞士商赫孚孟拉羅股份公司 | 噁二唑酮瞬時受體電位通道抑制劑 |
US11071721B2 (en) | 2016-12-02 | 2021-07-27 | Genentech, Inc. | Bicyclic amide compounds and methods of use thereof |
US11072607B2 (en) | 2016-12-16 | 2021-07-27 | Genentech, Inc. | Inhibitors of RIP1 kinase and methods of use thereof |
CN110461838B (zh) | 2017-03-07 | 2022-05-06 | 豪夫迈·罗氏有限公司 | 噁二唑瞬时受体电位通道抑制剂 |
US10793550B2 (en) | 2017-03-24 | 2020-10-06 | Genentech, Inc. | 4-piperidin-n-(pyrimidin-4-yl)chroman-7-sulfonamide derivatives as sodium channel inhibitors |
US11207422B2 (en) | 2017-05-02 | 2021-12-28 | Lawrence Livermore National Security, Llc | MOMP telonanoparticles, and related compositions, methods and systems |
EP4397309A2 (en) | 2017-07-14 | 2024-07-10 | F. Hoffmann-La Roche AG | Bicyclic ketone compounds and methods of use thereof |
SG11202003283TA (en) | 2017-10-11 | 2020-05-28 | Hoffmann La Roche | Bicyclic compounds for use as rip1 kinase inhibitors |
AU2018358883A1 (en) | 2017-10-30 | 2020-04-23 | F. Hoffmann-La Roche Ag | Method for in vivo generation of multispecific antibodies from monospecific antibodies |
RU2020115915A (ru) | 2017-10-31 | 2021-12-01 | Ф. Хоффманн-Ля Рош Аг | Бициклические сульфоны и сульфоксиды и способы их применения |
EP4295916A3 (en) | 2017-11-30 | 2024-03-20 | Hanmi Pharm. Co., Ltd. | Salts of 4-amino-n-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide, and crystalline forms thereof |
WO2019164778A1 (en) | 2018-02-20 | 2019-08-29 | Genentech, Inc. | Process for preparing 1-arylsulfonyl-pyrrolidine-2-carboxamide transient receptor potential channel antagonist compounds and crystalline forms thereof |
EP3759098A1 (en) | 2018-02-26 | 2021-01-06 | Genentech, Inc. | Pyridine-sulfonamide compounds and their use against pain and related conditions |
US10710994B2 (en) | 2018-03-19 | 2020-07-14 | Genentech, Inc. | Oxadiazole transient receptor potential channel inhibitors |
MX2020009991A (es) | 2018-03-28 | 2020-10-14 | Axon Neuroscience Se | Metodos basados en anticuerpos para detectar y tratar la enfermedad de alzheimer. |
EP3774801A1 (en) | 2018-03-30 | 2021-02-17 | F. Hoffmann-La Roche AG | Fused ring hydro-pyrido compounds as sodium channel inhibitors |
US20190307892A1 (en) * | 2018-04-04 | 2019-10-10 | Eriochem Usa, Llc | Targeted drug delivery and therapeutic methods using apo-e modified lipid nanoparticles |
WO2019204537A1 (en) | 2018-04-20 | 2019-10-24 | Genentech, Inc. | N-[4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5,6-dihydro-4h-pyrrolo[1,2-b]pyrazol e-2-carboxamide derivatives and related compounds as rip1 kinase inhibitors for treating e.g. irritable bowel syndrome (ibs) |
TW202003490A (zh) | 2018-05-22 | 2020-01-16 | 瑞士商赫孚孟拉羅股份公司 | 治療性化合物及其使用方法 |
CN110604821A (zh) * | 2018-06-14 | 2019-12-24 | 复旦大学 | 一种淀粉样蛋白β短肽介导的脑靶向递送系统 |
US11203645B2 (en) | 2018-06-27 | 2021-12-21 | Obi Pharma, Inc. | Glycosynthase variants for glycoprotein engineering and methods of use |
CN108685875B (zh) * | 2018-07-30 | 2020-11-03 | 中国药科大学 | 一种抗阿尔兹海默症的天然纳米粒-药物组合物及其制备方法和应用 |
US11517685B2 (en) | 2019-01-18 | 2022-12-06 | Qnovia, Inc. | Electronic device for producing an aerosol for inhalation by a person |
US11690963B2 (en) | 2018-08-22 | 2023-07-04 | Qnovia, Inc. | Electronic device for producing an aerosol for inhalation by a person |
CN112805267B (zh) | 2018-09-03 | 2024-03-08 | 豪夫迈·罗氏有限公司 | 用作tead调节剂的甲酰胺和磺酰胺衍生物 |
WO2020081874A1 (en) * | 2018-10-18 | 2020-04-23 | Respira Technologies, Inc. | Electronic device for producing an aerosol for inhalation by a person |
CN109323910B (zh) * | 2018-12-03 | 2021-01-08 | 徐州市中心医院 | 一种高纯度低密度脂蛋白的制备方法 |
AR119673A1 (es) | 2019-01-11 | 2022-01-05 | Hoffmann La Roche | Compuestos bicíclicos de cetona y métodos para utilizarlos |
AU2020381458A1 (en) | 2019-11-13 | 2022-05-12 | Genentech, Inc. | Therapeutic compounds and methods of use |
CA3159964A1 (en) | 2019-12-04 | 2021-06-10 | Ac Immune Sa | Novel molecules for therapy and diagnosis |
CN111150834A (zh) * | 2020-01-06 | 2020-05-15 | 吉林大学 | 一种载脂蛋白e与盐霉素复合纳米粒及制备方法和应用 |
CA3172121A1 (en) * | 2020-03-20 | 2021-09-23 | Gert Fricker | Colloidal carrier systems for transfer of agents to a desired site of action |
US11787775B2 (en) | 2020-07-24 | 2023-10-17 | Genentech, Inc. | Therapeutic compounds and methods of use |
CN116615452A (zh) | 2020-08-14 | 2023-08-18 | Ac免疫有限公司 | 人源化抗tdp-43结合分子及其用途 |
KR20230079123A (ko) | 2020-10-02 | 2023-06-05 | 제넨테크, 인크. | 비헤테로아릴 화합물 및 이의 결정 형태의 제조 공정 |
WO2022081484A2 (en) * | 2020-10-12 | 2022-04-21 | Durect Corporation | Crystalline thiocholesterol |
WO2022079297A1 (en) | 2020-10-16 | 2022-04-21 | Ac Immune Sa | Antibodies binding to alpha-synuclein for therapy and diagnosis |
CN114762679B (zh) | 2021-01-13 | 2023-04-07 | 上海交通大学医学院 | 一种纳米复合物及其制备方法和用途 |
JP2024526202A (ja) * | 2021-06-22 | 2024-07-17 | バイオ-トリップ ベーフェー | ナノ粒子を含有する核酸 |
WO2023028077A1 (en) | 2021-08-24 | 2023-03-02 | Genentech, Inc. | Sodium channel inhibitors and methods of designing same |
WO2023028056A1 (en) | 2021-08-24 | 2023-03-02 | Genentech, Inc. | 3-amino piperidyl sodium channel inhibitors |
US20230202984A1 (en) | 2021-11-24 | 2023-06-29 | Genentech, Inc. | Therapeutic compounds and methods of use |
US20230203062A1 (en) | 2021-11-24 | 2023-06-29 | Genentech, Inc. | Therapeutic compounds and methods of use |
AR128540A1 (es) | 2022-02-16 | 2024-05-22 | Ac Immune Sa | Moléculas de unión anti-tdp-43 humanizadas y usos de las mismas |
US11951177B2 (en) | 2022-03-23 | 2024-04-09 | Nanovation Therapeutics Inc. | High sterol-containing lipid nanoparticles |
WO2023194565A1 (en) | 2022-04-08 | 2023-10-12 | Ac Immune Sa | Anti-tdp-43 binding molecules |
WO2023233042A1 (en) * | 2022-06-03 | 2023-12-07 | Bio-Trip B.V. | Polyvalent molecule based lipid nanoparticles for nucleic acid delivery |
WO2023243997A1 (ko) * | 2022-06-13 | 2023-12-21 | (주) 멥스젠 | 아포지단백질을 포함하는 하이브리드 나노입자의 합성 방법 |
WO2024079662A1 (en) | 2022-10-11 | 2024-04-18 | Meiragtx Uk Ii Limited | Upf1 expression constructs |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000064484A2 (en) * | 1999-04-23 | 2000-11-02 | Alza Corporation | Conjugate having a cleavable linkage for use in a liposome |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3828106A (en) * | 1972-01-03 | 1974-08-06 | Biolog Concepts Inc | Novel oral pharmaceutical dosage form |
EP0238645A1 (en) | 1985-10-03 | 1987-09-30 | Biotechnology Research Partners, Ltd. | Novel lipoprotein-based drug-delivery systems |
FR2609399A1 (fr) * | 1987-01-13 | 1988-07-15 | Ire Celltarg Sa | Procede d'incorporation d'un ou plusieurs principes actifs lipophiles dans des lipoproteines, lipoproteines obtenues et composition pharmaceutique les contenant |
FR2664500B1 (fr) | 1990-07-13 | 1994-10-28 | Lille Ii Universite Droit Sant | Procede de preparation d'une lipoproteine modifiee par incorporation d'une substance active lipophile, lipoproteine modifiee ainsi obtenue et composition pharmaceutique ou cosmetique la contenant. |
FR2677272B1 (fr) | 1991-06-05 | 1995-03-03 | Biovecteurs As | Vecteur particulaire a tropisme selectif, procede de preparation et composition pharmaceutique. |
BR9201168A (pt) * | 1992-04-02 | 1994-04-12 | Zerbini E J Fundacao | Microemulsoes usadas como velculo para carregar quimioterapicos as celulas neoplasicas |
US5851510A (en) * | 1994-05-16 | 1998-12-22 | The Board Of Regents Of The University Of Michigan | Hepatocyte-selective oil-in-water emulsion |
GB9620153D0 (en) * | 1996-09-27 | 1996-11-13 | Univ Strathclyde | Non-naturally occurring lipoprotein particle |
CA2276267C (en) * | 1996-10-15 | 2009-12-22 | The Liposome Company, Inc. | Peptide-lipid conjugates, liposomes and liposomal drug delivery |
US6261537B1 (en) * | 1996-10-28 | 2001-07-17 | Nycomed Imaging As | Diagnostic/therapeutic agents having microbubbles coupled to one or more vectors |
SE9702776D0 (sv) | 1997-07-22 | 1997-07-22 | Pharmacia & Upjohn Ab | Method of preparing pharmaceutical compositions |
DE19745950A1 (de) | 1997-10-17 | 1999-04-22 | Dds Drug Delivery Service Ges | Arzneistoffträgerpartikel für die gewebespezifische Arzneistoffapplikation |
KR100314496B1 (ko) * | 1998-05-28 | 2001-11-22 | 윤동진 | 항혈전성이 있는 헤파린 유도체, 그의 제조방법 및 용도 |
US6703381B1 (en) * | 1998-08-14 | 2004-03-09 | Nobex Corporation | Methods for delivery therapeutic compounds across the blood-brain barrier |
-
2003
- 2003-12-02 CN CNA2008100866051A patent/CN101284136A/zh active Pending
- 2003-12-02 CA CA2507762A patent/CA2507762C/en not_active Expired - Fee Related
- 2003-12-02 EP EP03812239A patent/EP1581186A2/en not_active Withdrawn
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- 2003-12-02 CN CNB2003801045635A patent/CN100386068C/zh not_active Expired - Fee Related
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- 2003-12-02 AU AU2003302676A patent/AU2003302676A1/en not_active Abandoned
- 2003-12-02 WO PCT/IB2003/005558 patent/WO2004050062A2/en active Application Filing
- 2003-12-02 KR KR1020057010146A patent/KR101186210B1/ko active IP Right Grant
- 2003-12-02 KR KR1020117016597A patent/KR101111477B1/ko active IP Right Grant
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- 2003-12-03 TW TW092134096A patent/TWI347196B/zh not_active IP Right Cessation
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2007
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000064484A2 (en) * | 1999-04-23 | 2000-11-02 | Alza Corporation | Conjugate having a cleavable linkage for use in a liposome |
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TW200501999A (en) | 2005-01-16 |
US20070264351A1 (en) | 2007-11-15 |
US7682627B2 (en) | 2010-03-23 |
KR20050084163A (ko) | 2005-08-26 |
AU2003302676A1 (en) | 2004-06-23 |
EP1581186A2 (en) | 2005-10-05 |
US7576055B2 (en) | 2009-08-18 |
KR101111477B1 (ko) | 2012-02-23 |
CA2507762C (en) | 2013-02-05 |
WO2004050062A2 (en) | 2004-06-17 |
CN1717223A (zh) | 2006-01-04 |
CA2791165A1 (en) | 2004-06-17 |
CA2791165C (en) | 2015-02-24 |
US7514402B2 (en) | 2009-04-07 |
US20070292413A1 (en) | 2007-12-20 |
AU2003302676A8 (en) | 2004-06-23 |
US20040204354A1 (en) | 2004-10-14 |
US20070134313A1 (en) | 2007-06-14 |
JP2006516539A (ja) | 2006-07-06 |
JP5587352B2 (ja) | 2014-09-10 |
WO2004050062A3 (en) | 2004-12-29 |
CN100386068C (zh) | 2008-05-07 |
US7220833B2 (en) | 2007-05-22 |
KR20110086775A (ko) | 2011-07-29 |
TWI347196B (en) | 2011-08-21 |
JP4995423B2 (ja) | 2012-08-08 |
CA2507762A1 (en) | 2004-06-17 |
KR101186210B1 (ko) | 2012-10-08 |
JP2012131799A (ja) | 2012-07-12 |
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