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Encapsulation of gentamicin in liposomes can be used to achieve intracellular delivery and broaden the clinical utility of this drug. We have previously described a novel, rationally designed, pH-sensitive liposomal carrier for gentamicin that has superior in vitro efficacy against intracellular infections compared to the efficacies of both free gentamicin and non-pH-sensitive liposomal controls. This liposomal carrier demonstrated pH-sensitive fusion that was dependent on the presence of unsaturated phosphatidylethanolamine (PE) and the pH-sensitive lipid N-succinyldioleoyl-PE. The pharmacokinetics and biodistribution of the free and liposomal gentamicin were examined in mice bearing a systemic Salmonella enterica serovar Typhimurium infection. Encapsulation of gentamicin in pH-sensitive liposomes significantly increased the concentrations of the drug in plasma compared to those of free gentamicin. Furthermore, the levels of accumulation of drug in the infected 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 gentamicin in a murine salmonellosis model. These pH-sensitive liposomal antibiotic carriers with enhanced in vitro activity could be used to improve both in vivo intracellular drug delivery and biological activity.

antimicrobial agents and chemotherapy

Antibacterial Efficacy of Gentamicin Encapsulated in pH-Sensitive Liposomes against an In Vivo <i>Salmonella enterica</i> Serovar Typhimurium Intracellular Infection Model

Antibacterial Efficacy of Gentamicin Encapsulated in pH-Sensitive Liposomes against an In Vivo Salmonella enterica Serovar Typhimurium Intracellular Infection Model