Factors influencing the oligonucleotides release from O-W submicron cationic emulsions

We recently described a positively charged O-W emulsion as a delivery syste m for oligonucleotides (ON) [Teixeira et al.. Pharm. Res. 16 (1999) 30-36]. The present paper investigates the role of the main formulation parameters that may have an influence on the release-rate of a model ON in a protein- containing medium, i.e. the nature of the oily core, the presence of pegyla ted lipids, the lipid phase transition temperature, and the cationic lipid structure. The use of cationic lipids bearing diacyl chains land especially polycations) appeared as the only efficient strategy to reduce the ON rele ase rate. In order to have a better insight on the nature of the interactio ns between the ON and the interfacial lipids, adsorption isotherms at the a ir-water interface. fluorescence resonance energy transfer and zeta -potent ial measurements have been performed. Electrostatic interactions were found to play a crucial role. In contrast, the incorporation of PEG-phospholipid s acted as a barrier and maintained the ON molecules distant from the inter face, leading to a more rapid release. Finally. ON integrity was assessed b y a competitive hybridization assay. The results suggest the existence of a transient ion-pair (ON-cationic lipids) protecting ON against nuclease deg radation even after its release from the emulsions. (C) 2001 Elsevier Scien ce B.V. All rights reserved.