Fliposomes: new amphiphiles based on trans-3,4-bis(acyloxy)-piperidine able to perform a pH-triggered conformational flip and cause an instant cargo release from liposomes

Amphiphilic trans-3,4-bis(acyloxy)-1-benzylpiperidines able to perform a pH-triggered conformational flip (flipids) have been suggested as components of a new type of pH-sensitive liposomes (fliposomes). According to 1H NMR, their acid-induced conformational flip occurs in methanol-d4 when the apparent pD decreases from 6 to 3. The protonation-generated intramolecular hydrogen bond and electrostatic interactions make the conformer with axial acyloxy-groups predominant, which drastically increases the separation of hydrocarbon chains. The power of this trigger was estimated as ⩾10 kJ/mol. This flip perturbs the liposome membrane causing rapid release of the liposome cargo specifically in response to lowered pH. The pH-sensitive fliposomes containing one of these flipids, POPC and PEG-ceramide, and loaded with ANTS/DPX performed a content release within a few seconds at pH <5 demonstrating a potential of the piperidine derivatives as pH-switches for the design of liposomes for drug/gene delivery.