Format

Send to

Choose Destination
J Control Release. 2005 Oct 3;107(2):276-87.

Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids.

Author information

1
Protiva Biotherapeutics Inc., 100-3480 Gilmore Way, Burnaby, B.C., Canada V5G-4Y1.

Abstract

An analogous series of cationic lipids (1,2-distearyloxy-N,N-dimethyl-3-aminopropane (DSDMA), 1,2-dioleyloxy-N,N-dimethyl-3-aminopropane (DODMA), 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane (DLinDMA) and 1,2-dilinolenyloxy-N,N-dimethyl-3-aminopropane (DLenDMA)) possessing 0, 1, 2 or 3 double bonds per alkyl chain respectively, was synthesized to determine the correlation between lipid saturation, fusogenicity and efficiency of intracellular nucleic acid delivery. 31P-NMR analysis suggests that as saturation increases, from 2 to 0 double bonds, lamellar (L(alpha)) to reversed hexagonal (H(II)) phase transition temperature increases, indicating decreasing fusogenicity. This trend is largely reflected by the efficiency of gene silencing observed in vitro when the lipids are formulated as Stable Nucleic Acid Lipid Particles (SNALPs) encapsulating small inhibitory RNA (siRNA). Uptake experiments suggest that despite their lower gene silencing efficiency, the less fusogenic particles are more readily internalized by cells. Microscopic visualization of fluorescently labelled siRNA uptake was supported by quantitative data acquired using radiolabelled preparations. Since electrostatic binding is a precursor to uptake, the pKa of each cationic lipid was determined. The results support a transfection model in which endosomal release, mediated by fusion with the endosomal membrane, results in cytoplasmic translocation of the nucleic acid payload.

PMID:
16054724
DOI:
10.1016/j.jconrel.2005.06.014
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center