title: Fliposomes: pH-Sensitive Liposomes Containing a trans-2-morpholinocyclohexanol-Based Lipid That Performs a Conformational Flip and Triggers an Instant Cargo Release in Acidic Medium.
abstract: 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 (50/45/5)-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.
authors: Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, 751 Brookside Road, Stockton, CA 95211, USA. vsamoshin@pacific.edu.
authors: Nataliya M
authors: NM
authors: Samoshina
authors: Xin
authors: X
authors: Liu
authors: Barbora
authors: B
authors: Brazdova
authors: Andreas H
authors: AH
authors: Franz
authors: Vyacheslav V
authors: VV
authors: Samoshin
authors: Xin
authors: X
authors: Guo