title: Efficient intracellular drug and gene delivery using folate receptor-targeted pH-sensitive liposomes composed of cationic/anionic lipid combinations.
abstract: pH-sensitive liposomes are designed to promote efficient release of entrapped agents in response to low pH. In this study, novel pH-sensitive liposomes consisting of cationic/anionic lipid combinations are evaluated for intracellular drug and gene delivery. First, liposomes composed of egg phosphatidylcholine, dimethyldioctadecylammonium bromide (DDAB), cholesteryl hemisuccinate (CHEMS), and Tween-80 (25:25:49:1, mol/mol) were shown to stably entrap calcein at pH 7.4 and undergo rapid content release and irreversible aggregation under acidic pH. Compared to pH-sensitive liposomes incorporating dioleoylphosphatidylethanolamine, these liposomes showed improved retention of pH-sensitivity in the presence of serum. The folate receptor (FR), which is amplified in a wide variety of human tumors, could be targeted by incorporating 0.1 mol% folate-polyethyleneglycol-phosphatidylethanolamine (f-PEG-PE) into liposomes. f-PEG-PE has been shown to facilitate FR-mediated endocytosis of liposomes into KB human oral cancer cells, which express amplified FR. FR-targeted pH-sensitive liposomes produced increased cytosolic release of entrapped calcein, as shown by fluorescence microscopy, and enhanced cytotoxicity of entrapped cytosine-beta-D-arabinofuranoside, as shown by an 11-fold reduction in the IC(50) in KB cells, compared to FR-targeted non-pH-sensitive liposomes. Furthermore, FR-targeted pH-sensitive liposomes composed of DDAB/CHEMS/f-PEG-PE, combined with polylysine-condensed plasmid DNA, were shown to mediate FR-specific delivery of a luciferase reporter gene into KB cells in the presence of 10% serum. These findings suggest that cationic lipid-containing pH-sensitive liposomes, combined with FR targeting, are effective vehicles for intracellular drug and gene delivery.
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Rm 542 LM Parks Hall, 500 W. 12th Ave., Columbus, OH 43210, USA.
authors.forename: Guangfeng
authors.initials: G
authors.lastname: Shi
authors.forename: Wenjin
authors.initials: W
authors.lastname: Guo
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Stephenson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
mesh_terms: D000838:Anions / Q000008:administration & dosage / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000378:metabolism; D002412:Cations / Q000008:administration & dosage / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems / Q000379:methods*; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D008055:Lipids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008081:Liposomes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011956:Receptors, Cell Surface
chemical_list: D000838:Anions; D002352:Carrier Proteins; D002412:Cations; D058973:Folate Receptors, GPI-Anchored; D008055:Lipids; D008081:Liposomes; D011956:Receptors, Cell Surface