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: Guangfeng Shi, Wenjin Guo, Stacy M Stephenson, Robert J Lee
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 80 Issue 1-3 Pg. 309-19 (Apr 23 2002) ISSN: 0168-3659 [Print] Netherlands
• PMID: 11943407 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anions
• Carrier Proteins
• Cations
• Folate Receptors, GPI-Anchored
• Lipids
• Liposomes
• Receptors, Cell Surface

Topics

• Anions (administration & dosage, pharmacokinetics)
• Carrier Proteins (metabolism)
• Cations (administration & dosage, pharmacokinetics)
• Chemistry, Pharmaceutical
• Drug Delivery Systems (methods)
• Folate Receptors, GPI-Anchored
• Humans
• Hydrogen-Ion Concentration
• Intracellular Fluid (drug effects, metabolism)
• Lipids (administration & dosage, pharmacokinetics)
• Liposomes (administration & dosage, pharmacokinetics)
• Receptors, Cell Surface