pH-sensitive PEG lipids containing orthoester linkers: new potential tools for nonviral gene delivery

The synthesis and properties of pH-sensitive polyethylene glycol (PEG) lipids are described. The sensitivity of these conjugates to slightly acidic pH was clearly related to the structure of the orthoester linkage involved. It was found that pH-sensitive PEG lipids stabilized cationic lipid/DNA isoe...

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Bibliographic Details
Published in:Journal of controlled release 2004-10, Vol.99 (3), p.423-434
Main Authors: Masson, Christophe, Garinot, Marie, Mignet, Nathalie, Wetzer, Barbara, Mailhe, Philippe, Scherman, Daniel, Bessodes, Michel
Format: Article
Language:English
Subjects:
Biological and medical sciences
Colloidal stabilization
Cross-Linking Reagents - chemistry
DNA - chemistry
DNA - drug effects
Esters - chemistry
France
Gene delivery
Gene Transfer Techniques - trends
General pharmacology
Genetic Vectors - chemistry
Genetic Vectors - pharmacokinetics
HeLa Cells
Humans
Hydrogen-Ion Concentration
Hydrolysis
Lipid Bilayers - chemistry
Lipids - chemical synthesis
Lipids - pharmacokinetics
Lipoplex
Medical sciences
pH-sensitive PEG lipids
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Polyethylene Glycols - chemical synthesis
Polyethylene Glycols - pharmacokinetics
Technology, Pharmaceutical - methods
Transfection - methods
Tumor
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Summary:The synthesis and properties of pH-sensitive polyethylene glycol (PEG) lipids are described. The sensitivity of these conjugates to slightly acidic pH was clearly related to the structure of the orthoester linkage involved. It was found that pH-sensitive PEG lipids stabilized cationic lipid/DNA isoelectric complexes as efficiently as their non-pH-sensitive PEG analogs at neutral pH. Lowering the pH resulted in the precipitation of the complexes bearing pH-sensitive PEG lipids as a consequence of their degradation. In contrast, insertion of non-pH-sensitive PEG lipids maintained the complex colloidal stability even at lower pH. In vitro results showed a significant increase in transfection with formulations containing pH-sensitive PEG lipids versus non-pH-sensitive analogs. These conjugates show promising properties as lipoplex-stabilizing agents at neutral pH, which could be triggered by a mild acidic environment such as that occurring in solid tumors, inflammatory tissues, and intracellular endosomal compartments.
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2004.07.016