COMPARISON BETWEEN INTRATRACHEAL AND INTRAVENOUS ADMINISTRATION OF LIPOSOME-DNA COMPLEXES FOR CYSTIC-FIBROSIS LUNG GENE-THERAPY

Intratracheal (i.t.) and intravenous (i.v.) delivery of DNA-vector for mulations are tow strategies to obtain gene transfer to the lung. It i s still uncertain, however, which of these two modes of delivery will be more effective in the treatment of cystic fibrosis and other lung d iseases. In this study, we attempted to optimize formulations of the c ationic liposome DODAC:DOPE mmonium-chloride:dioleoylphosphatidylethan olamine) complexed to plasmids encoding chloramphenicol acetyltransfer ase for i.t. and i.v. injection into CD-1 mice and compared the two me thods. Our results showed that both methods conferred reporter gene ex pression in the lung that was significantly higher relative to injecti on of plasmid DNA alone. Expression using either mode of administratio n was maximal 24 h after injection and declined to around 10% of day 1 levels 2 weeks after injection. For i.v. delivery of DODAC:DOPE-DNA c omplexes multilamellar vesicles were more effective than large unilame llar vesicles in all organs investigated. Recombinant DNA could be det ected in the distal lung region following either route of administrati on. However, i.t. administration predominantly led to DNA deposition i n epithelial cells lining the brochioles, eg in clara cells, whereas i .v. administration resulted in DNA deposition in the alveolar region o f the lung including type II alveolar epithelial cells.