Cationic corticosteroid vehicle for gene delivery

Summary form only given. Inflammatory and immune responses to lipoplexes, lipids, and DNA present major obstacles to successful in vivo gene delivery. Several potent hydrophobic drugs inhibit some of these processes and can be made into molecules that resemble cationic lipids. Therefore, we report a one-step synthesis of a water-soluble, dexamethasone-spermine (DS) cationic lipid that has potent gene transfer capability in confluent bovine aortic endothelial cells (BAEC) when used with neutral lipid, dioleylphosphatidylethanolamine (DOPE). Lipofection of confluent BAEC with EGFP plasmid using DS/DOPE resulted in a 4.3-fold increase in percent transfection over Lipofectamine. Lipofection of subconfluent BAEC with DS/DOPE yielded a 4.6-fold increase in percent transfection over Lipofectamine from 16.0% with Lipofectamine to 73.8% transfection with DS/DOPE. DS, designed to be a prodrug lipid, hydrolyzes to DA, a dexamethasone amide (solubility in water DS >20,000 mg/L, dexamethasone 100 mg/L, DA 60 mg/L). Both DS and its hydrolysis product DA induced dose-dependent transcription from a glucocorticoid response element promoter construct (pGRE-SEAP), displaying an EC50 of ∼ 10 to 100 nM relative to dexamethasone in 293 cells. Cationic pharmacophores represent a new approach to gene delivery and localized anti-inflammatory therapy.