Utilize este identificador para referenciar este registo: http://hdl.handle.net/10451/18378
Título: Novel particulate antibiotic-loaded platforms as sustained drug delivery systems for bone infection treatment
Autor: Ferreira, Inês da Fonseca Santos, 1985-
Orientador: Almeida, António José Leitão das Neves, 1963-
Bettencourt, Ana Francisca Campos Simão
Trampuz, Andrej
Palavras-chave: Teses de doutoramento - 2015
Data de Defesa: 2015
Resumo: The most common infecting microorganisms in bone infections are staphylococci, namely Staphylococcus aureus and Staphylococcus epidermidis. Conventionally, complicated bone infections caused by Gram-positive bacteria are treated with vancomycin. However, emergence of resistant staphylococci to vancomycin led to the increased use of daptomycin, which is bactericidal against resistant staphylococci. However, in severe bone infections, daptomycin efficacy is often limited, due to insufficient drug bioavailability at the infected site and biofilm tolerance; hence novel approaches are needed to enhance daptomycin antibiofilm effect. Over the last decades, polymeric nano-/microparticles have emerged as a worthy strategy to enhance the antibiofilm effect of clinically available antibiotics. In this context, daptomycin was encapsulated into polymeric microparticles composed by poly(methyl methacrylate (PMMA), PMMA-Eudragit RL 100 (EUD) and poly-caprolactone (PCL). Vancomycin-loaded microparticles were also prepared as controls. All particles were obtained by an optimised double emulsion-solvent evaporation method and subsequently freeze-died. The final particles presented a spherical morphology within the micrometre size range, high drug encapsulation and yield of preparation. Additionally, the effect of the microparticles on cell viability of ISO-compliant cells, fibroblasts, and osteoblasts was tested. Although some formulations induced a slight decrease in cell viability, none of them was considered cytotoxic. Bearing in mind the main objective of this work, daptomycin-loaded PMMA-EUD and PCL microparticles presented the highest in vitro drug release, with concentrations above the minimal inhibitory and bactericidal concentration of the tested strains. Nevertheless, the antibacterial activity of all formulations was assessed against planktonic and sessile clinically relevant staphylococci by isothermal microcalorimetry (IMC). Further characterization of microparticles-biofilm interaction, as well as assessment of their effect on biofilm size, structure and metabolic state, was performed by fluorescence in situ hybridization (FISH). Daptomycin-loaded PMMA-EUD and PCL microparticles proved to be the most effective against the tested strains with high antibiofilm activity. Finally, the microencapsulation of daptomycin into polymeric carriers proved to be an advantageous approach, thus making them potential candidates as sustained drug delivery systems for bone infections treatment. In addition, the innovative combination of IMC with FISH was essential in order to gain further insights on the antibiofilm effects of microparticulate systems, as well as on their interaction with sessile bacteria.
Descrição: Tese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2015
URI: http://hdl.handle.net/10451/18378
Designação: Doutoramento em Farmácia
Aparece nas colecções:FF - Teses de Doutoramento

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