Complexity\nin a Simple Self-Assembling System: Lecithin-Water–Ethanol\nMixtures Exhibit a Re-Entrant Phase Transition and a Vesicle–Micelle\nTransition (VMT) on Heating

We report surprising results for the self-assembly of\nlecithin\n(a common phospholipid) in water–ethanol mixtures. Lecithin\nforms vesicles (∼100 nm diameter) in water. These vesicles\nare transformed into small micelles (∼5 nm diameter) by a variety\nof destabilizing agents such as single-tailed surfactants and alcohols.\nIn a surfactant-induced vesicle–micelle transition (VMT), vesicles\nsteadily convert to micelles upon adding the surfactantthereby,\nthe turbidity of the solution drops monotonically. Instead, when an\nalcohol like ethanol is added to lecithin vesicles, we find a new,\ndistinctive pattern in phase behavior as the ethanol fraction <i>f</i><sub>eth</sub> in water is increased. The turbidity first\ndecreases (from <i>f</i><sub>eth</sub> = 0 to 37%), then\nrises sharply (<i>f</i><sub>eth</sub> = 37 to 50%), and\nthen eventually decreases again (<i>f</i><sub>eth</sub> >\n55%). Concomitant with the turbidity rise, the vesicles separate into\ntwo phases around <i>f</i><sub>eth</sub> = 50% before a\nsingle phase reappears at higher <i>f</i><sub>eth</sub>in\nother words, there is a “re-entrant” phase transition\nfrom 1-phase to 2-phase and back to 1-phase with increasing <i>f</i><sub>eth</sub>. Vesicles near the phase boundary (∼<i>f</i><sub>eth</sub> = 45%) also show a VMT upon heating. Similar\npatterns are seen with other alcohols such as methanol and propanol.\nWe ascribe these complex trends to the dual role played by alcohols:\n(a) first, alcohols reduce the propensity for flat lipid bilayers\nto bend and form closed spherical vesicles; and (b) second, alcohols\ndiminish the tendency of lipids to self-assemble in the solvent mixture.\nAt low alcohol fractions, (a) dominates, causing the initially unilamellar\nvesicles to grow into multilamellar vesicles (MLVs), which eventually\nphase-separate. Thereafter, (b) dominates, and the vesicles convert\ninto micelles. Support for our hypothesis comes from scattering (SANS)\nand microscopy (cryo-TEM). Thus, we have uncovered a general paradigm\nfor lipid self-assembly in solvent mixtures, and this may even have\nphysiological relevance.