Clearance of intracellular Klebsiella pneumoniae infection using gentamicin-loaded nanoparticles

JOURNAL OF CONTROLLED RELEASE

卷:279

Article

Jiang, Lai¹  Greene, Michelle K.²  Insua, Jose Luis¹  Pessoa, Joana Sa¹  Small, Donna M.¹  Smyth, Peter²  McCann, Aidan P.³  Cogo, Francesco²  Bengoechea, Jose A.¹  Taggart, Clifford C.¹  Scott, Christopher J.² 

[1] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Ctr Med Expt, 97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland

[2] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Ctr Canc Res & Cell Biol, 97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland

[3] Queens Univ Belfast, Sch Pharm, 97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland

关键词: Gentamicin;    PLGA;    Nanoparticles;    Klebsiella pneumoniae;    Intracellular infection;    Macrophage;    Inflammation;    Pyroptosis;   

DOI  :  10.1016/j.jconrel.2018.04.040

来源: Elsevier

【 摘 要 】

Klebsiella pneumoniae is a foremost gram-negative pathogen that can induce life-threatening nosocomial pulmonary infections. Although it can be phagocytosed successfully by lung resident macrophages, this pathogen remains viable within vacuolar compartments, resulting in chronic infection and limiting therapeutic treatment with antibiotics. In this study, we aimed to generate and evaluate a cell-penetrant antibiotic poly(lactide-coglycolide) (PLGA)-based formulation that could successfully treat intracellular K. pneumoniae infection. Screening of formulation conditions allowed the generation of high drug loaded nanoparticles through a water-in-oil-in-water approach. We demonstrated the therapeutic usefulness of these gentamicin-loaded nanoparticles (GNPs), showing their ability to improve survival and provide extended prophylactic protection towards K. pneumoniae using a Galleria mellonella infection model. We subsequently showed that the GNPs could be phagocytosed by K. pneumoniae infected macrophages, and significantly reduce the viability of the intracellular bacteria without further stimulation of pro-inflammatory or pro-apoptotic effects on the macrophages. Taken together, these results clearly show the potential to use antibiotic loaded NPs to treat intracellular K. pneumoniae infection, reducing bacterial viability without concomitant stimulation of inflammatory or pyroptotic pathways in the treated cells.

【 授权许可】

Free