Nanostructured biomaterials as a platform for the controlled delivery of antibiotics
Palabras clave : 
Materias Investigacion::Farmacia
Intracellular bacteria
Gentamicin
Nanoparticles
Fecha de publicación: 
2013
Fecha de la defensa: 
27-jun-2012
Editorial : 
Servicio de Publicaciones de la Universidad de Navarra
Cita: 
Imbuluzqueta, E. ""Nanostructured biomaterials as a platform for the controlled delivery of antibiotics"". Blanco Prieto, M.J. y Gamaza, C. (dir.). Tesis doctoral. Universidad de Navarra, Pamplona, 2012
Resumen
The clinical management of infections caused by intracellular bacteria remains a difficult task due to the inability of numerous antibiotics to reach the pathogen-harbouring intracellular compartments or to exert their action in the intracellular environment. Aminoglycosides are bactericidal antibiotics showing high in vitro activity, but due to their polar nature, their access to intracellular environment is restricted. As an alternative to current therapy, the present research evaluates the use of biodegradable and biocompatible poly(lactic-co-glycolic acid) (PLGA) nanoparticles for intracellular targeting of gentamicin. The PLGA 752H nanoparticles developed presented mean diameters of 300nm, 100% of encapsulation efficiency and high drug loadings. Moreover, nanoparticles yielded a high intracellular accumulation, mainly localized in the cell cytoplasm, and sustained drug concentrations. This resulted in improved efficacy against Listeria monocytogenes, Staphylococcus aureus and Brucella melitensis-infected macrophages, particularly for PLGA 752H nanoparticles which were selected for in vivo studies. Pharmacokinetic studies in mice demonstrated that while no gentamicin was det3ected in the liver or in the spleen (main target organs for Brucella), nanoparticles efficiently targeted the drug at both tissues and maintained therapeutic antibiotic concentrations for up to 4 days, allowing the design of a therapeutic schedule for nanoparticles with an extended dosing interval. Finally, when mice infected with B. melitensis (chosen a model of intracellular bacteria) were treated with nanoparticles the splenic infection was reduced by 3.2 logs and 50% of the infected mice were cured, with no evidence of adverse toxic effect. In contrast, the classical combined therapy of gentamicin and doxycycline was associated with nephrotoxicity and with a rapid re-emergence of the infection. In summary, encapsulation of gentamicin in PLGA nanoparticles improved the antibiotic therapeutic index and allowed to reduce the required dosing frequency and the treatment-associated side effects, presenting a great therapeutic potential.

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Fichero: 
Tesis_EdurneImbuluzqueta.pdf
Descripción: 
Tamaño: 
18,41 MB
Formato: 
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