Protonation-induced conformational change of lipid tails is reported as a novel strategy to render pH-sensitive lipid amphiphiles and lipid colloids.

Incorporation of a pH-sensitive conformational switch into a lipid structure enables a drastic conformational flip upon protonation that disrupts the liposome membrane and causes rapid release of cargo specifically in areas of increased acidity. pH-sensitive liposomes containing the amphiphile (1) with trans-2-morpholinocyclohexanol conformational switch, a phospholipid, and a PEG-lipid conjugate were constructed and characterized. The optimized composition—1/POPC/PEG-ceramide (50/4/5)—could be stored at 4 °C and pH 7.4 for up to 1.5 years, and was stable in blood serum in vitro after 48 h at 37 °C. Liposomes loaded with ANTS/DPX or methotrexate demonstrated an unusually quick content release (in a few seconds) at pH below 5.5, which was independent of inter-liposome contact. The pH-titration curve for the liposome leakage paralleled the curve for the acid-induced conformational flip of 1 studied by 1H-NMR. Freeze-fracture electron microscopy images showed budding and division of the bilayer at pH 5.5. A plausible mechanism of pH-sensitivity involves an acid-triggered conformational flip of 1, shortening of lipid tails, and membrane perturbations, which cause the content leakage. The methotrexate-loaded liposomes demonstrated much higher cytotoxicity in HeLa cells than the free drug indicating that they can serve as viable drug delivery systems.

No abstract

Cyclohexane-based conformationally controlled ionophores, the emerging new class of molecular switches, provide a new and promising approach to allosteric systems with negative cooperativity. Protonation of trans-2-aminocyclohexanols leads to dramatic conformational changes: due to an intramolecular hydrogen bond, a conformer with equatorial position of ammonio-and hydroxy-groups becomes predominant. Thus, these structures can serve as powerful conformational pH-triggers. The trans-2-aminocyclohexanol moiety has been used for pH-triggered conformational switching of a crown ether and a podand, and their complexes with potassium ion.