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

• Applicant: Privatdozent Dr. Simon Drescher
• Subject Area: Pharmacy
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 276959565

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.

• DFG Programme: Research Grants
• Cooperation Partner: Professor Dr. Dariush Hinderberger