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Background: Bacteremia-induced sepsis is a leading cause of mortality in intensive care units. To control a bacterial infection, an immune response is required, but this response might contribute to organ failure. Kidneys are one of the main organs affected by bacteremia. Combination therapies with antibacterial and anti-inflammatory effects may be beneficial in treating bacteremia. This study aimed to develop nanostructured lipid carriers (NLCs) loaded with ciprofloxacin and rolipram that exert a combination of anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-inflammatory effects. Retinol was incorporated into the nanoparticles to transport retinol-binding protein 4 (RBP4) to the kidneys, which abundantly express RBP receptors. The NLCs were fabricated by high-shear homogenization and sonication, and neutrophils were used as a model to assess their anti-inflammatory effects. Mice were injected with MRSA to establish a model of bacteremia with organ injury., Results: The mean nanoparticle size and zeta potential of the NLCs were 171 nm and - 39 mV, respectively. Ciprofloxacin (0.05%, w/v) and rolipram (0.02%) achieved encapsulation percentages of 88% and 96%, respectively, in the nanosystems. The minimum bactericidal concentration of free ciprofloxacin against MRSA increased from 1.95 to 15.63 µg/ml when combined with rolipram, indicating a possible drug-drug interaction that reduced the antibacterial effect. Nanoparticle inclusion promoted the anti-MRSA activity of ciprofloxacin according to time-kill curves. The NLCs were found to be largely internalized into neutrophils and exhibited superior superoxide anion inhibition than free drugs. Retinol incorporation into the nanocarriers facilitated their efficient targeting to the kidneys. The NLCs significantly mitigated MRSA burden and elastase distribution in the organs of MRSA-infected animals, and the greatest inhibition was observed in the kidneys. Bacterial clearance and neutrophil infiltration suppression attenuated the bacteremia-induced cytokine overexpression, leading to an improvement in the survival rate from 22% to 67%., Conclusions: The dual role of our NLCs endowed them with greater efficacy in treating MRSA bacteremia than that of free drugs.

The present work developed lipid nanoparticles to determine whether retinol loading and surface charge influenced liver targeting and biodistribution. Silibinin for treating liver fibrosis was used as the active model. The capability of nanoparticles to suppress hepatic stellate cells (HSCs) was investigated by examining cell viability and α-smooth muscle actin (α-SMA). The biodistribution of the nanocarriers in rats was monitored by real-time and organ bioimaging after an intravenous injection. Silibinin concentration in the organs was detected as well. Anionic nanoparticles showed a mean size of around 260 nm, which was greater than that of cationic nanoparticles (about 170 nm). The encapsulation percentage of silibinin was >98% for both anionic and cationic nanoparticles. All nanoparticles tested were able to be ingested into HSCs, with no difference between the formulations. The positive nanoparticles produced activated HSC apoptosis much more strongly than negative nanoparticles. The α-SMA suppression exhibited a contrary trend. The nanoparticles rapidly accumulated in the liver and spleen. Retinol incorporation in nanoparticles offers an active targeting approach to the liver via retinol binding protein (RBP). The negatively charged formulation containing retinol achieved higher uptake and longer retention in the liver than the other formulations. Silibinin inclusion in nanoparticles significantly decreased lung deposition and increased liver uptake. The lipid nanosystems promoted silibinin distribution to the liver by 2-3-fold compared to the free control. A better liver-specific selectivity was obtained by retinol-loaded anionic nanocarriers. It is important to optimize the formulations of the lipid nanoparticles for maximizing hepatic targeting., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Tuberculosis represents a major global health problem for which improved approaches are needed to shorten the course of treatment and to combat the emergence of resistant strains. The development of effective and safe nanobead-based interventions can be particularly relevant for increasing the concentrations of antitubercular agents within the infected site and reducing the concentrations in the general circulation, thereby avoiding off-target toxic effects. In this work, rifampicin, a first-line antitubercular agent, was encapsulated into biocompatible and biodegradable polyester-based nanoparticles. In a well-established BALB/c mouse model of pulmonary tuberculosis, the nanoparticles provided improved pharmacokinetics and pharmacodynamics. The nanoparticles were well tolerated and much more efficient than an equivalent amount of free rifampicin. Unlabelled Image [ABSTRACT FROM AUTHOR]