Effects of cationic liposome-DNA complexes on pulmonary surfactant function in vitro and in vivo

Cationic liposome-DNA complexes are being evaluated as potential gene therapy agents for the lung. Cations have strong effects on the biophysical functions of lung surfactant. Therefore, we assessed whether cationic liposomes [composed of N-(1-(2,3-dioleyloxy) propyl)-N,N,N-trimethyl-ammonium chloride and dioleylphosphatidylethanolamine] with or without DNA affect behavior of four types of surfactant in vitro. Experiments were carried out using a modified Wilhelmy surface balance. The ability of surfactants that contain protein and anionic lipids to lower surface tension was inhibited in the presence of cationic liposomes. Inactivation was less when DNA was preincubated with cationic liposomes. Surfactant that contained neither protein nor anionic lipids was not inactivated. Mechanical properties of the lung were studied to assess in vivo surfactant function after intratracheal instillation of a cationic liposome-DNA complex into adult rats. Pressure-volume deflation curves were shifted by 18% compared with those from normal (untreated) animals, but this effect was transient and not different from that observed in animals who received a similar volume of saline. These findings indicate that cationic liposomes alone may have deleterious effects on behavior of some surfactants possibly by disrupting charge interactions between negatively charged phospholipids and surfactant proteins. When DNA is added to liposomes before exposure to surfactants, the adverse charge interactions may be obviated by charge neutralization of liposomes by DNA.