Synthesis and physicochemical characterization of bipolar amphiphiles for stabilization of liposomes used for oral drug delivery purposes

由磷脂如DPPC或DOPE组成的脂质体被广泛用作药物递送系统。除了静脉内、玻璃体内或透皮给药之外，脂质体配制的药物的口服应用也是合适的。然而，这种口服应用伴随着一些缺点，即脂质体本身的机械不稳定性，即，它们在较长时间内变得渗漏的趋势，特别是当面对体液时，以及脂质体组分（磷脂）在胃肠液中的化学不稳定性（低pH值）。克服这些缺点的一种可能性是使用长链双极性两亲物（bolalipids）。这些bolalipids，起源于某些古细菌的膜脂质，由两个亲水性的头部基团连接一个或两个亲脂性的烷基链。它们可以以拉伸的方式插入磷脂双层中，导致该双层的稳定化，从而稳定脂质体。然而，天然古细菌膜脂质的使用是具有挑战性的，因为古细菌的培养是复杂的和成本密集型的，并且所得的脂质在其化学结构上是多样的。但是这些古细菌脂质的全合成也是耗时且昂贵的。根据最后一个事实，该项目的伟大愿景是开发一种易于合成的bolphoid，可用于稳定口服脂质体。因此，提交的项目的目的是合成新的单链或双链bolalipids与修改的疏水部分的脂质，其次，聚集体结构的表征形成的bolalipids在水悬浮液和调查有关的混合行为，这些bolalipids与膜形成磷脂。将通过量热、IR和NMR测量以及使用电子显微镜、动态光散射、X射线和中子散射以及荧光方法（FCS、FRET）进行理化表征。从这些调查的结果将允许的bolalipids必要的插入在磷脂双层的拉伸，因此，稳定的方式的结构先决条件的结论。如果已经鉴定出表现出这些性质的bolalipids，则该项目的第三部分将集中于关于这些修饰的脂质体在各种介质（例如合成胃液）中的稳定性的研究，以用于这些脂质体用于口服给药的前景适用性，例如，pH敏感药物

Liposomes, composed of phospholipids such as DPPC or DOPE, are widely used as drug delivery systems. Besides the intravenous, intravitreal or transdermal administration also the oral application of liposomally formulated drugs is suitable. However, this oral application is associated with some drawbacks, namely, the mechanical instability of the liposomes itself, i.e., their tendency to become leaky over longer periods of time, particularly when confronted with body fluids, and the chemical instability of the liposomal components (phospholipids) in the gastrointestinal fluid (low pH value). One possibility to overcome these disadvantages is the use of long-chain bipolar amphiphiles (bolalipids). These bolalipids, originating in the membrane lipids of certain archaebacteria, are composed of two hydrophilic headgroups connected by one or two lipophilic alkyl chains. They can be inserted in a stretched manner in a phospholipid bilayer leading to a stabilization of this bilayer and, hence, the liposome. However, the use of natural archaebacterial membrane lipids is challenging since the cultivation of archaebacteria is elaborate and cost-intensive and the resulting lipids are diverse in their chemical structure. But also the total synthesis of these archaebacterial lipids is time-consuming and expensive. Following up the last fact, the great vision of this project is the development of an easy-to-synthesize bolalipid that can be used for the stabilization of orally administered liposomes. Therefore, the aims of the project submitted are the syntheses of novel single- or double-chain bolalipids with modifications in the hydrophobic part of the lipid and, secondly, the characterization of aggregate structures formed of bolalipids in aqueous suspension and investigations regarding the mixing behavior of these bolalipids with membrane-forming phospholipids. The physicochemical characterization will be performed by means of calorimetrical, IR- and NMR-measurements, as well as by the use of electron microscopy, dynamic light scattering, X-ray and neutron scattering, and fluorescence methods (FCS, FRET). Results from these investigations will allow conclusions on the structural prerequisites of the bolalipids necessary for the insertion in a phospholipid bilayer in a stretched and, hence, stabilizing manner. If bolalipids have been identified that exhibit these properties, the third part of the project will be focused on investigations regarding the stability of these modified liposomes in various media, such as synthetic gastric fluid, for the perspective applicability of those liposomes for the oral administration of, e.g., pH-sensitive drugs.