CN103432589A - 具治疗效果的脂质体的用途以及对器官/组织有特异性并且有治疗效果的脂质体的生产方法 - Google Patents
具治疗效果的脂质体的用途以及对器官/组织有特异性并且有治疗效果的脂质体的生产方法 Download PDFInfo
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Abstract
本发明了设计和研究了对器官/组织有特异性富集的治疗活性的脂质体在治疗炎症、缺血性或退化性疾病和/或刺激再生的用途，其中，脂质体被施加在载体分子上，器官和/或组织的细胞内存在用于所述载体分子细胞特异性吸收系统。另外，本发明还要求保护对器官/组织有特异性并且具有治疗活性的脂质体的生产方法，所述脂质体用于治疗炎症、缺血性或者退化性疾病和/或刺激再生，尤其治疗炎性肝病，所述生产方法设计成将溶血磷酯酰乙醇胺（LysoPE）偶联于熊去氧胆酸酯（UrsoDOCA）的转化为酯的羧基上，形成LysoPE-DOCA化合物。
Description
本申请是国际申请PCT/DE2006/001651，国际申请日2006年9月18日，中国国家阶段申请号200680037928.0，名称“具治疗效果的脂质体的用途以及对器官/组织有特异性并且有治疗效果的脂质体的生产方法”的发明专利申请的分案申请。
技术领域
本发明涉及对器官/组织有特异性富集且具治疗效果的脂质体在治疗炎症、缺血性或者退化性疾病和/或刺激再生中的用途。本发明还涉及对器官/组织有特异性且具治疗效果的脂质体的生产方法，所述脂质体用于治疗炎症、缺血性或者退化性疾病和/或刺激再生，尤其治疗肝病。
背景技术
某些有治疗价值的脂质体能有效地促炎和/或抗炎（ANES和合作者-Nat.Cell.Biol.2003;5:793-802）。在带有巨噬细胞以及吞噬小体的体外模型中，已经显示磷脂酰胆碱（PC）和溶血磷脂酰胆碱(LysoPC)在各自的细胞内富集时对炎性活动或紊乱的新陈代谢产生治疗效果。（Anes及合作者-Nat.Cell.Biol.2003;5:793-802）。在动物模型中也发现了磷脂酰胆碱的治疗效果，例如在大鼠模型表面施加具有抗炎效果的磷脂酰胆碱可以预防结肠粘膜发生由乙酸和三硝基苯并磺酸诱导的炎症(FABIAN et al.–Digestion1992;53:35–44;MOURELLE et al.–Gastroenterology1996;110:1903–7)。该原理同样已经应用于人类，以治疗常见的慢性炎性肠病溃疡性结肠炎。由此可表明，口服缓释包装形式的磷脂酰胆碱后，在小肠的下游释放出来，在结肠处就能很好地抑制溃疡性结肠炎的炎症活动(STREMMEL et al.–Gut2005;54:966–997,European patent1105141B1)。与使用安慰剂治疗的对照组比较，使用磷脂酰胆碱治疗后的病人中有90% 的临床活性提高了70%。在三个月内，超过一半病人的临床症状甚至有所减轻。同时，内窥镜检查的结果和小肠下游的组织结构、大肠的情况以及病人的生活质量都有改善。
基于目前的结果，除小肠炎和大肠炎之外，其它的细胞、组织和器官的疾病都有可能使用能有效抗炎的脂质体进行治疗。然而，还不能预料到全身性非选择性给予磷脂酰胆碱，例如，可在原位上能达到必要的抗炎有效性，因此需要进行局部给药。例如，对于局部发炎的情况，可以局部施加脂质体本身，譬如，在发炎皮肤部位局部给药，对关节炎的关节腔进行滴注，使支气管系统中吸入适当的制剂以治疗肺炎，或者在诸如食道、胃、十二指肠和直肠等胃肠道内滴注输入脂质体悬浮剂。
要在诸如肝、心脏和脑等实质性器官内进行局部施加会产生更复杂的问题。为了在这些器官内达到较高的局部浓度，可能要局部滴注有疗效的脂质体悬浮剂，或使用可逆性栓塞技术，然而，对于滴注的持续时间以及由于使用栓塞技术所引致的风险，局部给药仍未有真正的可选择方案。
发明内容
因此，本发明的目的在于提供一种对器官/组织的富集有特异性并且具有治疗效果的脂质体在治疗炎性、缺血性或者退化性疾病和/或刺激刚才提到的脂质体再生中的用途，消除了全部器官、组织和细胞存在的风险，无需长时间输液，脂质体也能在器官、组织和细胞中达到治疗有效浓度。
根据本发明，上文提到的关于对器官/组织的富集有特异性并且具有治疗效果的脂质体在治疗炎性、缺血性或者退化性疾病和/或刺激再生中的用途这一目的是通过权利要求1的特征实现的。因此，实施有疗效的脂质体的用途，使得脂质体在施加时结合到器官和/或组织内的细胞特异性吸收系统的载体分子。
此外，上文提到的目的，即关于对治疗炎性、缺血性或者退化性疾病和/或刺激再生，尤其是对治疗炎性肝病有疗效并且对器官/组织有特异性的脂质体的生产方法是由权利要求13的特征实现的。因此，实施一种刚才提到那种对器官/组织有特异性并且具有治疗效果的脂质体的生产方法，使得溶血磷酯酰乙醇胺与熊去氧胆酸酯的转化为酯的羟基相连，形成脑磷 脂-脱氧胆酸化合物。
本发明已经发现，利用结合于载体分子的脂质体，当用于这些载体分子的细胞、组织或器官特异性吸收系统存在时，无需使用栓塞或输注技术，这些脂质体可以在实质性的器官内实现特定富集。而且，还已经发现细胞不能吸收复合脂质体，例如磷脂酰胆碱，故溶血磷脂结合于载体分子上，证明磷脂酰胆碱已被吸收进入细胞内。因此，通过这种细胞特异性的“靶向”，有可能将有疗效的脂质体选择性地吸收进入细胞、组织或器官内，直至达到有效治疗浓度。例如，通过根据权利要求13的生产方法得到的脂质体化合物，可以在炎性肝细胞内获得有效治疗浓度的脂质体。
特别有利的是，有治疗功效的脂质体可起着抗炎或促炎作用。当经由载体分子、或直接施加、吸入、或逐滴滴入这些有治疗功效的脂质体如磷脂酰胆碱或溶血磷脂胆酰碱，使脂质体在细胞、组织或器官内达到特定富集时，它们的抗炎效果会发挥出来。除了单纯取代潜在消失的脂质体之外，所述脂质体还通过影响介导剂或信号传输途径的固有抗炎活性实现治疗效果。这样，例如炎症反应可用有抗炎效果的脂质体来加以治疗，可以引发一种对机能/退化的、病原体引起的、缺血的、自由基导致的、免疫传输的或用药、药剂、化合物或放射相关的损害机理应答的生理反应。防御和免疫系统的巨噬细胞或其它细胞吸收了这些脂质体，也可能产生免疫抑制效果。
对于预定再生的情况，特别需要使用有促炎活性的脂质体。由于炎症在如IL6和TNFα等介导剂的帮助下，通常会诱导后来的再生，治疗上使用促炎活性的脂质体-可以局部施加-可促进细胞、组织和器官的再生、修复和增生。例如，在有肿瘤的情况下，利用肝的再生能力，可以在以后增加肝断面的分泌（在肝的其它部分）。然而，这个原理同样适合于其它器官。
特别有利的是，器官内最好使用促炎性脂质体，在器官内，由于慢性病或意外/手术引起的损伤，细胞质量已经到达一个临界发生点(critical genesis)。例如，一定要治疗治疗切除肝后短肠综合症、烧灼肝硬化与缺血相关的心肌梗塞损伤、或中枢神经系统的退化性疾病和/或软组织的缺血性损伤。而且，促炎活性脂质体还可以作为治疗手段用于再生免疫系统以及 在化疗和/或放射性治疗后扩增骨髓和淋巴增殖系统，或者用来防止这些器官演变为癌症。
具有促炎功效的脂质体特别有利地在原定大面积切除肝的切除术，例如摘除肝转移瘤之前使用，它可以在剩下的肝内诱导足够的肝细胞质量。为此目的，在手术之前，把促炎活性脂质体选择性地输入手术后剩余的那部分肝内。
此外，促炎效果能增强恶性细胞内的免疫刺激，因此可用于抗肿瘤治疗（如诱导细胞凋亡）。
还有就是，使用在待治疗的生物体内天然存在的配体作为与脂质体共价结合的载体分子具有很多的益处。配体的识别是根据基体外侧膜相关的转送系统的细胞特异性受体，通过该系统，脂质体能够被转移到细胞内。例如，脂质体与对肝细胞有特异性吸收的配体胆汁酸或去唾液酸糖蛋白共价结合。特别是纳离子（Na+）/牛磺胆酸盐共转运多肽（NTCP-转运蛋白）一定会作为肝细胞特异性的转运系统，通过该系统，超过90%的胆汁酸被转送到肝细胞内。
要在细胞内产生抗炎或促炎效果，脂质体，例如溶血磷脂酰胆碱或溶血磷脂酰乙醇胺被吸收进入细胞的细胞间质空间后，能够从配体分离出来。例如，在细胞质内水解就可以分离出脂质体。当溶血磷脂酰乙醇胺被转送到细胞内，如前面提到的那样，从配体分离出来之后，溶血磷脂酰乙醇胺经过酶转化，成为具有抗炎效果的磷脂酰胆碱。
通过各自的配体/吸收系统，以一种有益的方式发生心肌细胞特异性或脑细胞特异性富集。这样，例如，通过对脑细胞有特异性的抗炎脂质体的选择性富集，炎性、缺血性或退化性疾病以及诸如肝性脑病等各种脑病都能被治疗。此外，在心壁的炎性区域的心肌细胞内抗炎脂质体选择性富集，可改善、甚至预防严重的心脏病，如预防心脏病发。
总的来说，使用有治疗功效的脂质体有各种各样施加途径，如直接施加、吸入、滴注（输液）、口服、静脉注射或腹腔内给予。此外，正如前文所述，直接施加尤其适合于使用抗炎脂质体来治疗发炎受损皮肤，或注射入关节或体液空间。吸入方法也是适合的，例如治疗支气管系统的炎症，而通过滴注可使抗炎脂质体在胃肠道或膀胱内富集。口服、静脉注射或腹 腔内给药特别适用于脂质体在有炎症的实质器官、组织和细胞内选择性富集。此处，静脉给予结合于载体分子的脂质体也是合适的，因为它们通过血流能直接地到达各自的器官、组织和细胞，与口服一样，无需预先穿过肠壁，但口服就会有脂质体被肠细胞完全吸收的风险。
除了肝、心、脑、皮肤、肠、关节和肺（支气管系统）的炎症、缺血性或退化性疾病之外，有治疗功效的脂质体还能用于治疗以下疾病：肌肉系统、网状内皮系统（RES）、淋巴系统、内分泌器官、外周神经系统、前列腺、胆管系统、胰腺和骨骼等的炎症、缺血性或退化性疾病。因此，有治疗功效的脂质体的用途不限于特定的器官、组织或细胞，而是能用于治疗所有的有炎症的器官、组织和细胞。
总体上，本文所述的基于脂质体的治疗提供了全面的良好的临床效果，而且只存在很少的或没有副作用，这是因为它涉及天然存在于生物体内的非免疫原性脂质体。本发明为这些脂质体的局部大剂量给药提供了契机，能达到全身性浓度而又保持在生理学许可的范围内。
现在，本发明的内容有多种方式进行实施，且可有利地进一步改进。一方面可参考从属权利要求，另一方面，可参考在下文描述的优选实施例，这些实施例解释了要求保护的生产器官/组织特异性且有治疗效果的脂质体的方法。在优选实施例的描述中，解释了优选的实施例及其教导的进一步改进，而不仅仅限于这些教导。
具体实施方式
抗炎性磷脂在肝细胞内的示范性富集用于抑制肝炎。
复合脂质体，如磷脂胆酰碱本身不能被吸收进入细胞。与配体（例如胆汁酸或去唾液酸糖蛋白）共价结合的溶血磷脂质形式才能被吸收，它经由在肝细胞基体外侧质膜上的胆汁酸转运蛋白（如NTCP）被吸收进入细胞的细胞间质空间内。为此目的，例如溶血磷脂酰胆碱（LysoPC）与胆汁酸，如脱氧胆酸酯（DOCA）共价结合。然而，偶合的溶血磷脂质-DODC-化合物与溶血磷脂酰乙醇胺（LysoPE）的合成从化学上来说更为有利。可进行下述的反应，例如：首先，用碳二亚胺把UrsoDOCA的羧基转化为活性酯，接着与LPE结合。这种头基结构形式使得溶血磷脂酰乙醇胺-DOCA 化合物由胆汁酸转运蛋白可以进入肝细胞内。通过水解分离，溶血磷脂酰乙醇胺（LysoPE）被再一次分离出来，接着经过酶解转变成具有抗炎效果的磷脂酰胆碱（PC）。
使用酰基链偶联物也能取得与上述同样的效果，其中，DOCA结合到PC的Sn-1或Sn-2位的酰基侧链。在与磷脂酶A2或A1接触后，Sn-1或Sn-2侧基一定会转变成乙醇化合物。这需要与中间体结合，该中间体来自嘧啶与激活的DOCA酯以及碳二亚胺反应后得到的产物。
下面的反应图表示了上述的反应过程。
为控制LysoPE-DOCA化合物的选择性富集，把HepG2-细胞（肝细胞）在37°C与有荧光标记的熊去氧胆酸酯-1-棕榈酰基、2-NBD-PE-偶联物（以50μM）培养10分钟，再清洗，接着用5％的牛血清白蛋白处理，从细胞的外部浆膜中去除偶联物。然后，以相位对比法和荧光灯对细胞进行显微镜控制。
图1中的影象A表示在HepG2细胞与熊去氧胆酸酯-1-棕榈酰基、2 -NBD-PE-结合物培养后，用光学显微镜的相位对比法观察到的HepG2-细胞的影像，影像B则为用荧光显微镜观察影象A所示的细胞的影像。
如图1所示，影象A和影象B都是HepG2-细胞（肝细胞）与本发明具有治疗功效的脂质体（熊去氧胆酸酯-1-棕榈酰基、2-NBD-PE-结合物）培养后的影像，所述脂质体用荧光标记物标记，显示出细胞内的富集情况。与影像A中用相位对比法观察到的HepG2-细胞不同，在荧光显微镜下观察同样的细胞，可看到细胞质内而非细胞的中心呈现深的黄绿色，。
最后，需要特别指出的是，前述的实施例和附图只用于说明本发明的教导，并不限于这些例子和附图。
Claims (7)
1.共价结合胆汁酸或去唾液酸糖蛋白的溶血磷脂用于制造药物组合物的用途，所述药物组合物用于治疗炎性肝病。
2.如权利要求1所述的用途，所述溶血磷脂是溶血磷脂酰胆碱或溶血磷脂酰乙醇胺。
3.如权利要求1所述的用途，所述胆汁酸是熊去氧胆酸酯或脱氧胆酸酯。
4.如权利要求1至3中任一项所述的用途，其特征在于，吸收进入细胞后溶血磷脂从配体上释放。
5.如权利要求1至4中任一项所述的用途，所述药物组合物是直接给药、吸入给药、滴注给予、口服给药、静脉给药或腹腔内给药的药物组合物。
6.与配体共价结合的溶血磷脂。
7.如权利要求6所述的溶血磷脂，所述配体是胆汁酸或去唾液酸糖蛋白。
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