Dual bioresponsive antibiotic and quorum sensing inhibitor combination nanoparticles for treatment of Pseudomonas aeruginosa biofilms in vitro and ex vivo
| Autor: | Patrícia F. Monteiro, Paul Williams, Cameron Alexander, Elena Jordana-Lluch, Alessandra Travanut, Nishant Singh, Manuel Romero, Morgan R. Alexander, Kim R. Hardie |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.drug_class
Swine humanos Antibiotics Biomedical Engineering 02 engineering and technology Microbial Sensitivity Tests 010402 general chemistry Polysaccharide medicine.disease_cause 01 natural sciences nanopartículas Microbiology Cell Line ciprofloxacina concentración de iones hidrógeno Ciprofloxacin medicine Animals Humans General Materials Science Pseudomonas Infections chemistry.chemical_classification infecciones por Pseudomonas Chemistry Pseudomonas aeruginosa Biofilm Quorum Sensing línea celular Hydrogen-Ion Concentration 021001 nanoscience & nanotechnology In vitro 0104 chemical sciences Quorum sensing Biofilms pruebas de sensibilidad microbiana porcinos animales Nanoparticles detección de quórum 0210 nano-technology Ex vivo medicine.drug |
| Zdroj: | Biomaterials science. 7(10) |
| ISSN: | 2047-4849 |
| Popis: | Many debilitating infections result from persistent microbial biofilms that do not respond to conventional antibiotic regimens. A potential method to treat such chronic infections is to combine agents which interfere with bacterial biofilm development together with an antibiotic in a single formulation. Here, we explore the use of a new bioresponsive polymer formulation derived from specifically modified alginate nanoparticles (NPs) in order to deliver ciprofloxacin (CIP) in combination with the quorum sensing inhibitor (QSI) 3-amino-7-chloro-2-nonylquinazolin-4(3H)-one (ACNQ) to mature Pseudomonas aeruginosa biofilms. The alginate NPs were engineered to incorporate a pH-responsive linker between the polysaccharide backbone and the QSI, and to encapsulate CIP via charge-charge interactions of the positively-charged drug with the carboxyl residues of the alginate matrix. In this way, a dual-action release of antibiotic and QSI was designed for the low-pH regions of a biofilm, involving cleavage of the QSI-linker to the alginate matrix and reduced charge-charge interactions between CIP and the polysaccharide as the alginate carboxyl side-chains protonated. When tested in a biofilm model the concomitant release of CIP + QSI from the pH-responsive nanoparticles significantly reduced the viability of the biofilm compared with CIP treatment alone. In addition, the alginate NPs were shown to penetrate deeply into P. aeruginosa biofilms, which we attribute in part to the charges of the NPs and the release of the QSI agent. Finally, we tested the formulation in both a 2D keratinocyte and a 3D ex vivo skin infection model. The dual-action bio-responsive QSI and CIP release nanoparticles effectively cleared the infection in the latter, suggesting considerable promise for combination therapeutics which prevent biofilm formation as well as effectively killing mature P. aeruginosa biofilms. This work was supported by the Engineering and Physical Sciences Research Council [grant numbers EP/N006615/1 and EP/K005138/1, EP/N03371X/1]; the Biotechnology and Biological Sciences Research Council (BBSRC) [grant number BB/R012415/1] and the Royal Society [Wolfson Research Merit Award WM150086] (to CA). This project has received funding from the EMPIR programme co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation programme [grant reference 15HLT01 MetVBadBugs] |
| Databáze: | OpenAIRE |
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