Hybrid Ofloxacin/eugenol co-loaded solid lipid nanoparticles with enhanced and targetable antimicrobial properties.

In the global context of an imminent emergence of multidrug-resistant microorganisms, the present work combined the use of nanotechnology and the therapeutic benefits of natural compounds as a strategy to potentiate antimicrobial action of the wide-spectrum antibiotic Ofloxacin (Ofx). Hybrid solid lipid nanoparticles (SLN) were synthesized by incorporation of chitosan (Chi, a cationic biopolymer with antimicrobial activity) and eugenol (Eu, a phenolic compound that interferes with bacterial quorum sensing) into a lipid matrix by hot homogenization/ultrasonication method. The developed SLN/Chi/Eu sustainably released the encapsulated Ofx for 24 h. Characterization by DLS, TEM, DSC, TGA and XRD revealed the presence of positively charged spherical nanoparticles with diameters around 300 nm and Ofx entrapped in amorphous state. The SLN exhibited an enhanced bactericidal activity against Pseudomonas aeruginosa and Staphylococcus aureus. The minimum inhibitory concentration (MIC) for free and nanoencapsulated Ofx formulations was below 1.0 µg/ml. The MIC values decreased by 6.1- to 16.1-fold when Ofx was encapsulated in SLN/Chi/Eu. Fluorescent-labeled nanoparticles had the ability to interact with the bacterial cell membrane. Selective toxicity of SLN/Chi/Eu-Ofx was tested in the range of 0.3-30.0 µg/ml and showed no toxicity up to 3.0 µg/ml Ofx in human cell models (A549 and Wi-38) at 24 h and 48 h exposure. It was proved that the administration of hybrid SLN to mice by dry powder inhalation reached therapeutic Ofx levels in lungs.

Carbamazepine-loaded solid lipid nanoparticles and nanostructured lipid carriers: Physicochemical characterization and in vitro/in vivo evaluation.

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) represent promising alternatives for drug delivery to the central nervous system. In the present work, four different nanoformulations of the antiepileptic drug Carbamazepine (CBZ) were designed and prepared by the homogenization/ultrasonication method, with encapsulation efficiencies ranging from 82.8 to 93.8%. The formulations remained stable at 4 °C for at least 3 months. Physicochemical and microscopic characterization were performed by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), atomic force microscopy (AFM); thermal properties by differential scanning calorimetry (DSC), thermogravimetry (TGA) and X-ray diffraction analysis (XRD). The results indicated the presence of spherical shape nanoparticles with a mean particle diameter around 160 nm in a narrow size distribution; the entrapped CBZ displayed an amorphous state. The in vitro release profile of CBZ fitted into a Baker-Lonsdale model for spherical matrices and almost the 100% of the encapsulated drug was released in a controlled manner during the first 24 h. The apparent permeability of CBZ-loaded nanoparticles through a cell monolayer model was similar to that of the free drug. In vivo experiments in a mice model of seizure suggested protection by CBZ-NLC against seizures for at least 2 h after intraperitoneal administration. The developed CBZ-loaded lipid nanocarriers displayed optimal characteristics of size, shape and drug release and possibly represent a promising tool to improve the treatment of refractory epilepsy linked to efflux transporters upregulation.

Hybrid inhalable microparticles for dual controlled release of levofloxacin and DNase: physicochemical characterization and in vivo targeted delivery to the lungs.

Current medical treatments against recurrent pulmonary infections caused by Pseudomonas aeruginosa, such as cystic fibrosis (CF) disorder, involve the administration of inhalable antibiotics. The main challenge is, however, the eradication of microbial biofilms immersed in dense mucus that requires high and recurrent antibiotic doses. Accordingly, the development of novel drug delivery systems capable of providing local and controlled drug release in the lungs is a key factor to improve the therapeutic outcome of such therapeutic molecules. Inhalable hybrid carriers were prepared by co-precipitation of CaCO3 in the presence of alginate and the resulting microparticles were treated with alginate lyase (AL) in order to modify their porosity and enhance the drug loading. The hybrid microparticles were loaded with DNase (mucolytic agent) and levofloxacin (LV, wide-spectrum antibiotic) in the range of 20-40% for LV and 28-67% for DNase, depending on the AL treatment. In vitro studies demonstrated that microparticles were able to control the DNase release for 24 h, while 30-50% of LV was released in 3 days. The morphological characterization was performed by optical, fluorescence and scanning electron microscopies, showing a narrow size distribution (5 µm). FTIR, XRD, DSC and nitrogen adsorption isotherm studies revealed the presence of the drugs in a non-crystalline state. A microcidal effect of microparticles was found on P. aeruginosa in agar plates and corroborated by Live/Dead kit and TEM observations. Finally, to study whether the microparticles improved the localization of LV in the lungs, in vivo studies were performed by pulmonary administration of microparticles to healthy mice via nebulization and dry powder inhalation, followed by the quantification of LV in lung tissue. The results showed that microparticles loaded with LV delivered the antibiotic at least 3 times more efficiently than free LV. The developed system opens the gateway to new drug delivery systems that may provide enhanced therapeutic solutions against bacterial infections and in particular as a potential tool in CF pathology.