Perifosine induced release of contents of trans cell-barrier transport efficient liposomes

Perifosine (OPP) containing liposomal formulation was previously found to deliver almost half of liposome encapsulated content through a tight cellular barrier in vitro. In order to understand the role of different liposome components, especially perifosine, in transendothelial transport the physical characteristics of liposome membranes composed of phosphatidylcholine, and cholesterol, as a main lipid constituents, and variable amount of helper lipids: dioleoyl phosphatidylethanolamine (DOPE), and alkylphospholipid perifosine. For this purpose, electron paramagnetic resonance (EPR) with computer aided EPR spectra simulation and fluorescence polarization spectroscopy were used to investigate how different membrane components influence membrane characteristics and the release of liposome entrapped substances. Beside methylester of palmitic acid with nitroxide group at different position on acyl chain usually used for such studies, the spin labeled and fluorescent labeled analog of perifosine were introduced. OPP increases membrane fluidity of liposomes as well as the release of liposome encapsulated content. The release of neutral molecules increases with OPP concentration, while the release of charged molecules is about an order of magnitude slower. Optimal OPP concentration, for release of charged molecules, is about 15 mol%. These results are one step further toward the conclusion that the lysolipid-containing liposomes could be promising trans endothelial delivery system, since lysolipids, such as OPP, open tight cellular barriers, as was published before, and in the same time induce the release of liposome encapsulated content at physiological temperature, as shown here. Since many drug delivery systems are being developed, which mainly exploit the transcellular route of delivery through barrier-forming cells, we hope that the uniqueness of lysolipid-containing liposomes, exploiting the paracellular route, and thus avoiding efflux transporters, will foster further research in formulating other lysolipid-containing liposomes as drug delivery systems.