Drastic differences between the release kinetics of two highly related porphyrins in liposomal membranes: mTHPP and pTHPP.

[Display omitted] • Minor structural differences of hydrophobic porphyrins can distinctly influence their release properties from liposomes. • mTHPP (meta OH) redistributes much slower than pTHPP (para OH) from liposomal membranes. • Reversed-phase HPLC experiments indicate a higher partition coefficient for mTHPP. • In MD simulations, mTHPP has a higher tendency for hydrogen bonding, a larger tilt angle and locates deeper in the membrane. • Both HPLC and MD simulation results support the observed differences in release and redistribution of mTHPP and pTHPP from liposomal membranes. The release of hydrophobic compounds from liposomal membranes occurs by partitioning and is thus determined by the physicochemical properties (e.g. logP and water solubility) of the drug. We postulate that even minor structural differences, e.g. the position of the phenolic OH-group of the hydrophobic porphyrins mTHPP and pTHPP (meta vs. para substitution), distinctly affect their partitioning and release behavior from liposomes. The release and redistribution of mTHPP and pTHPP from lecithin or POPC/POPG liposomes to different acceptor particles (DSPE-mPEG micelles and liposomes) was studied by asymmetrical flow field-flow fractionation to separate donor and acceptor particles. Reversed phase HPLC was applied to detect differences in partitioning. Molecular dynamics (MD) simulations were carried out to obtain molecular insight in the different behavior of the two compounds inside a lipid bilayer. Despite the minor differences in chemical structure, mTHPP is more hydrophobic and redistributes much slower to both acceptor phases than pTHPP. MD simulations indicate that compared to pTHPP, mTHPP makes stronger hydrogen bonds with the lipid head groups, is oriented more parallel to the lipid tails and is embedded slightly deeper in the membrane. [ABSTRACT FROM AUTHOR]