A reduction-triggered delivery by a liposomal carrier possessing membrane-permeable ligands and a detachable coating.
To control the cellular uptake of drugs and genes, we synthesized a liposomal carrier possessing membrane-permeable ligands and a detachable poly(ethylene glycol) (PEG) coating. For the detachable coating, a lipid having a thiolytic cleavable spacer (PEG-S-S-DOPE) was synthesized by the reaction of dioleoylphosphatidylethanolamine (DOPE) with a PEG chain via a disulfide linkage. The liposomes were prepared from a mixture of dipalmitoylphosphatidylcholine (DPPC), DOPE, PEG-S-S-DOPE, and cholesteryl hemisuccinate (CHEMS). The octamer (R8 peptide) of arginine was chosen as the membrane-permeable ligand and covalently immobilized onto the CHEMS portion of the liposome surface (PEG-S-S-R8-liposome). The disulfide bond of the PEG chain was cleaved to display the R8 peptides on the liposome surface by adding a reducing agent such as L-cysteine, and thereby internalization of the liposomes was significantly facilitated. When L-cysteine was added to the mixture of cells and the liposome that incorporated plasmids encoding the enhanced green fluorescence protein (pEGFP), the expression of EGFP was low but could be observed in almost 100% of the cells.
The Center for Chemical Biology, School of Fundamental Science and Technology, Graduate School of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan.
Takuro
T
Maeda
Keiji
K
Fujimoto
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology; D002788:Cholesterol Esters / Q000737:chemistry; D016503:Drug Delivery Systems; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008024:Ligands; D008081:Liposomes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D008954:Models, Biological; D010084:Oxidation-Reduction; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D013997:Time Factors
D002788:Cholesterol Esters; D008024:Ligands; D008081:Liposomes; D010714:Phosphatidylethanolamines; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C094877:dioleoyl phosphatidylethanolamine; D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols; C013440:cholesteryl succinate