(478f) Novel Cationic Steroid Family and Its Application in Gene Delivery and as Antibacterials

Randazzo, R. A., University of Pennsylvania
Diamond, S. L., University of Pennsylvania
Bucki, R., University of Pennsylvania
Janmey, P. A., University of Pennsylvania

A novel family of cationic steroids has been synthesized and found to display potential both in non-viral gene delivery and as antimicrobials. The compounds were formed by amide couplings of the polyamines spermine, spermidine, and putrescine with cholenic and cholanic acid derivatives and span a hydrophobicity range of 0.64 to 5.63 logD (octanol-water distribution coefficients). On liposomal formulation with the neutral helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 5β-cholanyl-spermide-3α-ol and 8-cholenyl-spermide-3α,12α-diol were the most successful as gene delivery vectors achieving transfection efficiencies comparable to those found with Lipofectamine2000™ in bovine aortic endothelial cells. The toxicity to the cells was reduced by nearly half that of Lipofectamine2000™ for both of these compounds. For the more hydrophilic 5β-cholanyl-spermide-3α,7α,12α-triol, transfection efficiency was enhanced by over 50% through incorporating 20-30mol% bis-substituted amide in the liposome formulation without increasing the toxicity. Evaluation of antibacterial activity against gram positive bacteria (B. Subtilis ATCC 6051) revealed MIC50 (concentration required to inhibit the growth of 50% of the organism) of less than 25 mg/L for the majority of the compounds. When tested against gram negative bacteria (E. Coli MG 1655), the MIC50 values of 5β-cholanyl-spermide-3α-ol and 8-cholenyl-spermide-3α,12α-diol were less than 25 mg/ml and the effective therapeutic indexes (ratio of hemolytic activity over MIC50) were 37 and 53, respectively.