Self-assembled lamellar complexes of siRNA with lipidic aminoglycoside derivatives promote efficient siRNA delivery and interference

L. Desigaux, M. Sainlos, O. Lambert, R. Chevre, E. Letrou-Bonneval, J.-P. Vigneron, P. Lehn, J.-M. Lehn, B. Pitard
Proceedings of the National Academy of Sciences. 2007-10-08; 104(42): 16534-16539
DOI: 10.1073/pnas.0707431104

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1. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16534-9. Epub 2007 Oct 8.

Self-assembled lamellar complexes of siRNA with lipidic aminoglycoside
derivatives promote efficient siRNA delivery and interference.

Desigaux L(1), Sainlos M, Lambert O, Chevre R, Letrou-Bonneval E, Vigneron JP,
Lehn P, Lehn JM, Pitard B.

Author information:
(1)Institut National de la Santé et de la Recherche Médicale, U533, F-44035
Nantes, France.

RNA interference requires efficient delivery of small double-stranded RNA
molecules into the target cells and their subsequent incorporation into
RNA-induced silencing complexes. Although current cationic lipids commonly used
for DNA transfection have also been used for siRNA transfection, a clear need
still exists for better siRNA delivery to improve the gene silencing efficiency.
We synthesized a series of cationic lipids characterized by head groups bearing
various aminoglycosides for specific interaction with RNA. siRNA complexation
with such lipidic aminoglycoside derivatives exhibited three lipid/siRNA
ratio-dependent domains of colloidal stability. Fluorescence and dynamic
light-scattering experiments showed that cationic lipid/siRNA complexes were
formed at lower charge ratios, exhibited a reduced zone of colloidal instability,
and had smaller mean diameters compared with our previously described
guanidinium-based cationic lipids. Cryo-transmission electron microscopy and
x-ray-scattering experiments showed that, although the final in toto morphology
of the lipid/siRNA complexes depended on the aminoglycoside type, there was a
general supramolecular arrangement consisting of ordered lamellar domains with an
even spacing of 67 A. The most active cationic lipid/siRNA complexes for gene
silencing were obtained with 4,5-disubstituted 2-deoxystreptamine aminoglycoside
derivatives and were characterized by the siRNA being entrapped in small
particles exhibiting lamellar microdomains corresponding to siRNA molecules
sandwiched between the lipid bilayers. These results clearly show that lipidic
aminoglycoside derivatives constitute a versatile class of siRNA nanocarriers
allowing efficient gene silencing.

DOI: 10.1073/pnas.0707431104
PMCID: PMC2034216
PMID: 17923669 [Indexed for MEDLINE]

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