Antibacterial efficacy of gentamicin encapsulated in pH-sensitive liposomes against an in vivo Salmonella enterica serovar typhimurium intracellular infection model

Encapsulation of gentamicin in liposomes can be used to achieve intracellul ar delivery and broaden the clinical utility of this drug. We have previous ly described a novel, rationally designed, ps-sensitive liposomal carrier f or gentamicin that has superior in vitro efficacy against intracellular inf ections compared to the efficacies of both free gentamicin and non-pH-sensi tive liposomal controls. This liposomal carrier demonstrated pH-sensitive f usion that was dependent on the presence of unsaturated phosphatidylethanol amine (PE) and the pa-sensitive lipid N-succinyldioleoyl-PE. The pharmacoki netics and biodistribution of the free and liposomal gentamicin were examin ed in mice bearing a systemic Salmonella enterica serovar Typhimurium infec tion. Encapsulation of gentamicin in pa-sensitive liposomes significantly i ncreased the concentrations of the drug in plasma compared to those of free gentamicin. Furthermore, the levels of accumulation of drug in the infecte d liver and spleen were increased by 153- and 437-fold, respectively, as a result of liposomal encapsulation. The increased accumulation of gentamicin in the liver and spleen effected by liposomal delivery was associated with 10(4)-fold greater antibacterial activity than that associated with free g entamicin in a murine salmonellosis model, These pH-sensitive liposomal ant ibiotic carriers with enhanced in vitro activity could be used to improve b oth in vivo intracellular drug delivery and biological activity.