Cationic phosphonolipids as nonviral vectors: in vitro and in vivo applications.
Since the development of the concept of gene therapy using cationic lipids as nonviral vectors by Felgner's group in 1987, numerous molecules have been synthesized. Such vectors were first proposed to avoid viral vector-induced drawbacks. But, it quickly became clear that a thorough knowledge of their physical and chemical characteristics was fundamental to use them under optima conditions. Over the last years our laboratory has developed a family of cationic lipids called phosphonolipids whose structure is based on that of natural phosphonolipids; compared with other vectors, these compounds had to be well-tolerated by biologic membranes. Some of our synthesized molecules exhibited an interesting potential for gene transfer, both in vitro and in vivo. Structural changes in the different parts (hydrophobic, hydrophilic, and intermediary domains) of these vectors were evaluated in vitro on different cell-lines; these studies led us to select some of these molecules to carry out in vivo tests. So, the plasmid/phosphonolipid complexes were first administered to mice by intratracheal and aerosol routes with a beta-galactosidase plasmid as reporter gene. In a second set of experiments, we explored the possibilities offered by intravenous injection; in these studies, we used a luciferase plasmid as reporter gene because of its high sensibility. These experiments revealed a transgene expression essentially localized in the lungs. In a further study, we compared systemic administration with local ones; we, then, observed that the optimum formulation of a given molecule depended on its route of administration.
Delépine
P
P
Centre de Biogénétique, University, Hospital, ETSBO, BP 454, 29275 Brest Cedex, France.
Guillaume
C
C
Floch
V
V
Loisel
S
S
Yaouanc
J
J
Clément
J
J
Des Abbayes
H
H
Férec
C
C
D000336:Aerosols; D000818:Animals; D002412:Cations; D002460:Cell Line; D002478:Cells, Cultured; D004333:Drug Administration Routes; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D007275:Injections, Intravenous; D020014:K562 Cells; D051379:Mice; D010743:Phospholipids / Q000008:administration & dosage / Q000737:chemistry
D000336:Aerosols; D002412:Cations; D010743:Phospholipids; C028299:phosphonolipids