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 bee n synthesized. Such vectors were first proposed to avoid viral vector-induc ed drawbacks. But, it quickly became clear that a thorough knowledge of the ir physical and chemical characteristics was fundamental to use them under optima conditions. Over the last years our laboratory has developed a family of cationic lipid s called phosphonolipids whose structure is based on that of natural phosph onolipids; compared with other vectors, these compounds had to be well-tole rated by biologic membranes. Some of our synthesized molecules exhibited an interesting potential for gene transfer, both in vitro and in vivo. Struct ural changes in the different parts (hydrophobic, hydrophilic, and intermed iary domains) of these vectors were evaluated in vitro on different cell-li nes; these studies led us to select some of these molecules to carry out in vivo tests. So, the plasmid/phosphonolipid complexes were first administer ed to mice by intratracheal and aerosol routes with a beta-galactosidase pl asmid as reporter gene. In a second set of experiments, we explored the pos sibilities offered by intravenous injection; in these studies, we used a lu ciferase plasmid as reporter gene because of its high sensibility. These ex periments revealed a transgene expression essentially localized in the lung s. In a further study, we compared systemic administration with local ones; we, then, observed that the optimum formulation of a given molecule depend ed on its route of administration. (C) 2000 Wiley-Liss, Inc.