The interaction of cubosomes with supported phospholipid bilayers using neutron reflectometry and QCM-D

We present the results of a study of the interaction of lyotropic liquid crystalline dispersions with supported lipid bilayers based on 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) using a quartz crystal microbalance with dissipation monitoring (QCM-D) and neutron reflectometry (NR). We investigated two types of phytantriol-based cubosome formulations, with subtly different internal nanostructures, with one formulation incorporating 2.5% of the biological lipid di-palmitoylphosphatidylserine (DPPS). The QCM-D data showed that cubosomes do not directly attach to the silica supporting surface but they can accumulate on the model membrane, confirming that there is an attractive interaction between POPC bilayers and the cubosome formulations. We have further used NR to quantify the amount of cubosomes adsorbed on the supported POPC bilayers and to examine the structural rearrangement of cubosomes on interaction with the supported lipid bilayer. The data show that the DPPS-containing cubosomes accumulate at the bilayer surface continuously for 15 hours. Pure phytantriol cubosomes accumulated over a longer time period (36 hours), but accumulated to a lesser degree overall. Furthermore, NR data revealed lipid exchange and structural rearrangements for both types of cubosomes, however, for the DPPS-containing cubosomes, these processes were greater in magnitude and faster. Confocal microscopy analysis of cubosome interactions with HeLa cells in vitro, showed increased membrane affinity for the DPPS-containing formulations, which were consistent with the NR and QCM-D observations. We interpret these observations as suggesting that membrane accumulation, cellular uptake and cytotoxicity of cubosome formulations are directly related to their DPPS content, and that this may be the result of increased propensity for liquid crystalline structural rearrangement, as postulated previously (H. H. Shen et al., Biomaterials, 2010, 31, 9473).