A new type of pH-sensitive liposome (fliposomes) was designed based on the amphiphiles that are able to perform a pH-triggered conformational flip (flipids). This flip disrupts the liposome membrane and causes rapid release of the liposome cargo, specifically in the areas of increased acidity. The flipids (1-3) are equipped with a trans-2-morpholinocyclohexanol conformational switch. pH-Sensitive flipsomoes containing one of these flipids, POPC, and PEG-ceramide (molar ratio 50/45/4) were constructed and characterized. These compositions were stable at 4°C and pH 7.4 for several months. Fliposomes loaded with ANTS/DPX demonstrated an unusually quick content release (in a few seconds) at pH below 5.5 which was more efficient in the case of flipid 1 with the shorter linear c12-tails. The pH-titration curve for the flipsomoe leakage paralleled the curve for the acid-induced conformational flip of 1-3 studied by 1
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