Hydrophobic Gentamicin-Loaded Nanoparticles Are Effective against Brucella melitensis Infection in Mice

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-log 10 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-AOTloaded 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.

Toxicity Studies of Oral and Transdermal Formulations of Gentamicin Loaded PLGA Nanoparticles in Animal Model

“…Both the transaminases values were within normal reference physiological range reported for rabbits (Jones, 1975). The results of study are in compliance with another research which reported no alterations in biochemical parameters of mice after treating them with gentamicin loaded PLGA nanoparticles (Imbuluzqueta et al, 2013).…”

“…Toxicity studies revealed no alterations in the hematological (blood cells count, hemoglobin, hematocrit, MCV, MCHC) and biochemical parameters (total bilirubin, creatinine and urea). Histology of liver and kidney revealed no toxicity in GM-PLGA NPs treatment group animals while animals who received conventional GM showed mild nephrotoxicity indicating the safety of GM-PLGA NPs (Imbuluzqueta et al, 2013).…”

Antibiotic Susceptibility Testing of Brucella Species - Old and New Drugs

“…These antibiotics (especially streptomycin and gentamicin) were either included in liposomes or attached to nanoparticles. Phagocytosis of liposomal or nanoparticle formulations of aminoglycosides by Brucella-infected macrophages resulted in higher intracellular activity compared to free aminoglycosides against B. melitensis, B. abortus, or B. canis [90][91][92][93][94]. These formulations of the aminoglycosides were also significantly more effective in animal models [90,94,95].…”

“…Phagocytosis of liposomal or nanoparticle formulations of aminoglycosides by Brucella-infected macrophages resulted in higher intracellular activity compared to free aminoglycosides against B. melitensis, B. abortus, or B. canis [90][91][92][93][94]. These formulations of the aminoglycosides were also significantly more effective in animal models [90,94,95]. The targeted delivery of aminoglycosides could be a promising therapeutic alternative, both increasing their intracellular activity and reducing their side effects by reducing their concentration in kidneys and the cochleovestibular system.…”

Formulation and evaluation of biodegradable nanoparticles for the oral delivery of fenretinide

“…PLGA and modified PLGA polymers have been used to form nanoparticles as a means of increasing the dissolution and bioavailability of poorly water soluble compounds [13,14]. In these formulations, the PLGA not only serves as a means of reducing the particle size of the drug but also controls the release rate of the drug itself and reduces its intrinsic toxicity [15,16]. In addition, these polymers can be modified to alter a formulation’s pharmacokinetic and biodistribution properties; polyethylene glycol (PEG)/PLGA copolymers can enhance the bioavailability of nanoparticles by increasing drug residence time [13].…”