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Pharmaceutics 2011, 3(3), 379-405; doi:10.3390/pharmaceutics3030379
Article

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

1,2, 2, 2, 2, 2,*  and 1,*
1 Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, 751 Brookside Road, Stockton, CA 95211, USA 2 Department of Chemistry, University of the Pacific, 3601 Pacific Ave., Stockton, CA 95211, USA
* Authors to whom correspondence should be addressed.
Received: 4 May 2011 / Revised: 7 June 2011 / Accepted: 30 June 2011 / Published: 11 July 2011
(This article belongs to the Special Issue Colloidal Drug Carrier Systems)
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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.
Keywords: pH-sensitive liposomes; fliposomes; polyethyleneglycol (PEG); conformational switch; controlled drug release; triggered release pH-sensitive liposomes; fliposomes; polyethyleneglycol (PEG); conformational switch; controlled drug release; triggered release
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Samoshina, N.M.; Liu, X.; Brazdova, B.; Franz, A.H.; Samoshin, V.V.; Guo, X. 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. Pharmaceutics 2011, 3, 379-405.

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