title: Hydrophobic gentamicin-loaded nanoparticles are effective against Brucella melitensis infection in mice.
abstract: The clinical management of human brucellosis is still challenging and demands in vitro active antibiotics capable of targeting the pathogen-harboring intracellular compartments. A sustained release of the antibiotic at the site of infection would make it possible to reduce the number of required doses and thus the treatment-associated toxicity. In this study, a hydrophobically modified gentamicin, gentamicin-AOT [AOT is bis(2-ethylhexyl) sulfosuccinate sodium salt], was either microstructured or encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles. The efficacy of the formulations developed was studied both in vitro and in vivo. Gentamicin formulations reduced Brucella infection in experimentally infected THP-1 monocytes (>2-log10 unit reduction) when using clinically relevant concentrations (18 mg/liter). Moreover, in vivo studies demonstrated that gentamicin-AOT-loaded nanoparticles efficiently targeted the drug both to the liver and the spleen and maintained an antibiotic therapeutic concentration for up to 4 days in both organs. This resulted in an improved efficacy of the antibiotic in experimentally infected mice. Thus, while 14 doses of free gentamicin did not alter the course of the infection, only 4 doses of gentamicin-AOT-loaded nanoparticles reduced the splenic infection by 3.23 logs and eliminated it from 50% of the infected mice with no evidence of adverse toxic effects. These results strongly suggest that PLGA nanoparticles containing chemically modified hydrophobic gentamicin may be a promising alternative for the treatment of human brucellosis.
authors: Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Pamplona, Spain.
authors: Edurne
authors: E
authors: Imbuluzqueta
authors: Carlos
authors: C
authors: Gamazo
authors: Hugo
authors: H
authors: Lana
authors: Miguel Ángel
authors: MÁ
authors: Campanero
authors: David
authors: D
authors: Salas
authors: Ana Gloria
authors: AG
authors: Gil
authors: Elisa
authors: E
authors: Elizondo
authors: Nora
authors: N
authors: Ventosa
authors: Jaume
authors: J
authors: Veciana
authors: María J
authors: MJ
authors: Blanco-Prieto
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D017347:Brucella melitensis / Q000187:drug effects; D002006:Brucellosis / Q000188:drug therapy*; D002460:Cell Line; D004337:Drug Carriers; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D019344:Lactic Acid; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D053758:Nanoparticles; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D005839:Gentamicins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
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