Phenylene Bolaamphiphiles: Influence of the Substitution Pattern on the Aggregation Behavior and the Miscibility with Classical Phospholipids

The synthesis of two symmetric single-chain phenylene-modified bolaamphiphiles with meta and ortho phenyl substitution pattern is described. The aggregation behavior of both bolaamphiphiles in aqueous suspension was investigated by differential scanning calorimetry (DSC), transmission electron microscopy (TEM), Fourier-transform IR (FTIR) spectroscopy, and small angle neutron scattering (SANS). We could show that a change in the substitution pattern from para to meta or ortho leads to a change in the aggregation behavior so that small micelles instead of nanofibers are formed. Furthermore, the mixing behavior of these bolaamphiphiles with classical bilayer forming phospholipids, such as 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) was studied by means of DSC, TEM, cryo-TEM, and small angle X-ray scattering (SAXS). The aim was to stabilize bilayer membranes formed by classical phospholipids by incorporation of bolaamphiphiles to obtain liposomes with improved stability suitable for drug delivery purposes. We could show that the phenylene-modified bolaamphiphiles are indeed miscible with DPPC and DSPC; however, closed vesicles as observed for pure DPPC and DSPC were not found. Instead, small disk-like aggregates are formed. In the case of mixtures of phenylene-modified bolaamphiphiles with DPPC, these bilayer disks have a higher DSC transition temperature compared to pure DPPC indicating an increased stability of the ordered gel phase inside the disks