Phenylene bolaamphiphiles: Influence of the substitution pattern on the aggregation behavior and the miscibility with classical phospholipids. Issue 9 (22nd July 2014) - Drescher, Simon
Abstract 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. Practical applications: Vesicles composed of classical phospholipids are widely used as drug delivery systems for pharmaceutical applications. The stability of these vesicles in, e.g., body fluids is an important prerequisite for long‐term applications and it can possibly be enhanced by the incorporation of bipolar amphiphiles (bolaamphiphiles) into phospholipid bilayers. With the use of novel single‐chain phenylene‐modified bolaamphiphiles, synthesized in this work, we are able to generate small lipid‐disks in mixtures with classical phospholipids that have an increased stability of the ordered gel phase inside these disks compared to pure phospholipids. These disks might be further used as nano‐dimensioned drug carrier systems. The incorporation of ortho‐substituted phenylene‐modified bolaamphiphiles (PC‐C17oPhC17‐PC) into DPPC bilayer leads to the formation of small disk‐like aggregates with an increased stability compared to pure DPPC vesicles.