title: A novel pH-sensitive liposome formulation containing oleyl alcohol.
abstract: pH-sensitive liposomes are designed to undergo acid-triggered destabilization. First generation pH-sensitive liposomes, based on the cone-shaped lipid dioleoylphosphatidylethanolamine (DOPE), have been shown to lose fusogenicity in the presence of serum. Here, we report the design and evaluation of novel serum-resistant pH-sensitive liposome formulations that are based on the composition of egg phosphatidylcholine (PC), cholesteryl hemisuccinate (CHEMS), oleyl alcohol (OAlc), and Tween-80 (T-80). When loaded with the fluorescent probe calcein, these liposomes exhibited excellent stability at pH 7.4 and underwent rapid destabilization upon acidification as shown by calcein dequenching and particle size increase. Adjusting the mole percentages of T-80 and OAlc in the formulation could regulate the stability and pH-sensitive properties of these liposomes. Liposomes with a higher T-80 content exhibited greater stability but were less sensitive to acid-induced destabilization. Meanwhile, formulations with a higher OAlc content exhibited greater content release in response to low pH. The pH-triggered liposomal destabilization did not produce membrane fusion according to an octadecylrhodamine B chloride (R(18)) lipid-mixing assay. Compared to DOPE-based pH-sensitive liposomes, the above formulations showed much better retention of their pH-sensitive properties in the presence of 10% serum. These liposomes were then evaluated for intracellular delivery of entrapped cytosine-beta-D-arabinofuranoside (araC) in KB human oral cancer cells, which have elevated folate receptor (FR) expression. The FR, which is amplified in many types of human tumors, has been shown to mediate the internalization of folate-derivatized liposomes into an acidic intracellular compartment. FR-targeted OAlc-based pH-sensitive liposomes, entrapping 200 mM araC, showed approximately 17-times greater FR-dependent cytotoxicity in KB cells compared to araC delivered via FR-targeted non-pH-sensitive liposomes. These data indicated that pH-sensitive liposomes based on OAlc, combined with FR-mediated targeting, are promising delivery vehicles for membrane impermeable therapeutic agents.
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Sudimack
authors.forename: Wenjin
authors.initials: W
authors.lastname: Guo
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D003561:Cytarabine / Q000008:administration & dosage; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004355:Drug Stability; D005233:Fatty Alcohols / Q000737:chemistry*; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008081:Liposomes / Q000737:chemistry*; D008561:Membrane Fusion; D015394:Molecular Structure; D010316:Particle Size; D011136:Polysorbates; D011956:Receptors, Cell Surface; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D004337:Drug Carriers; D005233:Fatty Alcohols; D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D011136:Polysorbates; D011956:Receptors, Cell Surface; D003561:Cytarabine; C010268:oleyl alcohol