Phospholipid-subclass-specific partitioning of lipophilic ions in membrane-water systems

Herein, we systematically investigate phospholipid-subclass-specific altera tions in the partitioning of both cationic and anionic amphiphiles to ident ify the importance of ester, ether and vinyl ether linkages at the sn-l pos ition of phospholipids in the partitioning of charged amphiphiles. The resu lts demonstrated that the membrane-water partition coefficient of a prototy pic cationic amphiphile (i.e. 3,3'-dipropylthiadicarbocyanine iodide) was a pproximately 2.5 times higher in membranes comprised of plasmenylcholine in comparison with membranes comprised of either phosphatidylcholine or plasm anylcholine. In striking contrast, the membrane-water partition coefficient of a prototypic anionic amphiphile [i.e. bis-(1,3-dibutylbarbituric acid)t rimethine oxonol] in membranes comprised of plasmenylcholine was approximat e to 2.5 times lower than that manifest in membranes comprised of phosphati dylcholine or plasmanylcholine. Utilizing these experimentally determined p artition coefficients, the relative membrane dipole potential of membranes comprised of plasmenylcholine was calculated and found to be approximate to 25 mV lower than in membranes comprised of phosphatidylcholine or plasmany lcholine. This lower membrane dipole potential in membranes comprised of pl asmenylcholine is equivalent to the membrane potential induced by incorpora tion of approximate to 25 mol % of anionic phospholipids in membranes compr ised of phosphatidylcholine. Collectively, these results demonstrate that p hospholipid-subclass-specific differences in the membrane dipole potential contribute to alterations in the partitioning of lipophilic ions in membran e bilayers comprised of distinct phospholipid subclasses. Moreover, they su ggest that these physicochemical differences can be exploited to facilitate the targeting of charged lipophilic drugs to specific cells and subcellula r membrane compartments.