Abstract
The effect of H 11-phase induction by dolichol (DOL) (C 80–105, 0–2 wt%) within the bilayers of multilamellar liposomes (MLV, DOPE:DOPC 2:1 or 3:1 w/w) on their permeability, lipid mixing and morphology was determined. Low-angle X-ray diffraction patterns were consistent with mixtures of bilaycr and H 11 phases, the latter increasing with increasing DOL or DOPE content and temperature. Efflux rate constants for 6-carboxyfluorescein (6-CF) from 2:1 DOPE:DOPC vesicles depended on temperature and DOPE/DOL content, increasing as much as 200-fold over DOL-free controls at 2% w/w DOL. Fluorescence resonance energy transfer assays detected lipid mixing with unlabeled target MLV. It was appreciable only when target MLV contained DOPE and increased with DOL content. Confocal scanning fluorescence microscopy was applied to study the morphological structure of fully-hydrated samples and field scanning electron microscopy the ultrastructure of cryo-stabilized samples. 3:1 DOPE/DOPC MLV, stable at pH 9.5, underwent rapid morphological changes at pH 7.4. Within minutes filaments formed and large areas of membrane surface became studded with 10–15 nm bumps and 5 nm holes, resembling in size and shape unilamellarly covered intcrlamellar micellar intermediates and interlamellar attachments (ILA) previously associated with H 11-phase transitions. The filaments, seen in MLV with and without DOL, may represent extensions of IMI into coaxial assemblages of rod micellar intermediates (RMI). These phenomena may have implications for liposomal delivery of therapeutic peptides/proteins if they can be made to trigger the convective release of liposomal contents via controlled formation of ILA between adjacent lamellae of MLV.
Published Version
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