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

脂质体是由磷脂（如DPPC或DOPE）组成的，被广泛用作药物递送系统。除了静脉、玻璃体内或透皮给药外，脂质体制剂的口服应用也是合适的。然而，这种口服应用与一些缺点有关，即脂质体本身的机械不稳定性，即它们倾向于在较长时间内变得泄漏，特别是当面对体液时，以及脂质体成分（磷脂）在胃肠道液体中的化学不稳定性（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体（bolali脂类）。这些bolali脂起源于某些古细菌的膜脂，由两个亲水头基团组成，由一个或两个亲脂烷基链连接。它们可以以拉伸的方式插入磷脂双分子层中，导致该双分子层和脂质体的稳定。然而，利用天然的古细菌膜脂具有挑战性，因为培养古细菌是复杂的，成本很高，而且所得的脂质在化学结构上是多种多样的。但是，这些古细菌脂质的完全合成既耗时又昂贵。根据最后一个事实，这个项目的伟大愿景是开发一种易于合成的bolali脂，可用于口服脂质体的稳定。因此，提交的项目的目的是合成新的单链或双链bolali脂，并在脂的疏水部分进行修饰，其次，表征bolali脂在水悬浮液中形成的聚集体结构，并研究这些bolali脂与膜形成磷脂的混合行为。物理化学表征将通过量热、红外和核磁共振测量，以及电子显微镜、动态光散射、x射线和中子散射和荧光方法（FCS， FRET）进行。这些研究的结果将得出结论，bol脂的结构先决条件是在磷脂双分子层中以拉伸和稳定的方式插入所必需的。如果已经确定bolali脂具有这些特性，该项目的第三部分将重点研究这些改性脂质体在各种介质（如合成胃液）中的稳定性，以确定这些脂质体在口服给药（如ph敏感药物）中的适用性。

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.