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Hydrophobic gentamicin-loaded nanoparticles are effective against Brucella melitensis infection in mice
Edurne Imbuluzqueta1, Carlos Gamazo, Hugo Lana
1Department of Pharmacy and Pharmaceutical Technology, University of Navarra, Pamplona, Spain.
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.
Insights
Novel gentamicin nanoparticles offer a promising new treatment for brucellosis. These nanoparticles target intracellular bacteria, reduce dosing frequency, and show improved efficacy in mice with fewer toxic effects.
Area of Science:
- Microbiology
- Nanotechnology
- Pharmacology
Background:
- Human brucellosis treatment is challenging due to the intracellular nature of the pathogen.
- Effective antibiotics must target intracellular compartments, and sustained release can reduce toxicity.
Purpose of the Study:
- To develop and evaluate novel hydrophobic gentamicin formulations (gentamicin-AOT) encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles for improved brucellosis treatment.
- To assess the in vitro and in vivo efficacy and biodistribution of these gentamicin-loaded nanoparticles.
Main Methods:
- Chemical modification of gentamicin with AOT (bis(2-ethylhexyl) sulfosuccinate sodium salt) to create hydrophobic gentamicin.
- Encapsulation of gentamicin-AOT into PLGA nanoparticles.
- In vitro testing on infected THP-1 monocytes.
- In vivo studies in experimentally infected mice, assessing drug targeting to liver and spleen, therapeutic concentration duration, and infection reduction.
Main Results:
- Gentamicin formulations achieved a >2-log10 reduction in Brucella infection in vitro at clinically relevant concentrations.
- In vivo, gentamicin-AOT nanoparticles effectively targeted the liver and spleen, maintaining therapeutic concentrations for up to 4 days.
- Compared to 14 doses of free gentamicin, only 4 doses of gentamicin-AOT-loaded nanoparticles significantly reduced splenic infection (3.23 logs) and cleared infection in 50% of mice without adverse effects.
Conclusions:
- PLGA nanoparticles loaded with chemically modified hydrophobic gentamicin demonstrate enhanced efficacy for brucellosis treatment.
- This formulation offers a promising alternative to conventional gentamicin therapy, improving drug targeting and reducing treatment toxicity and dosage frequency.
