RESUMO
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 24â¯h. Characterization by DLS, TEM, DSC, TGA and XRD revealed the presence of positively charged spherical nanoparticles with diameters around 300â¯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⯵g/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⯵g/ml and showed no toxicity up to 3.0⯵g/ml Ofx in human cell models (A549 and Wi-38) at 24â¯h and 48â¯h exposure. It was proved that the administration of hybrid SLN to mice by dry powder inhalation reached therapeutic Ofx levels in lungs.
Assuntos
Anti-Infecciosos , Portadores de Fármacos , Eugenol , Nanopartículas , Ofloxacino , Células A549 , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/química , Anti-Infecciosos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Eugenol/administração & dosagem , Eugenol/química , Eugenol/farmacocinética , Humanos , Lipídeos/administração & dosagem , Lipídeos/química , Lipídeos/farmacocinética , Pulmão/metabolismo , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Ofloxacino/administração & dosagem , Ofloxacino/química , Ofloxacino/farmacocinética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimentoRESUMO
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 160â¯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 24â¯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 2â¯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.
Assuntos
Anticonvulsivantes/química , Carbamazepina/química , Lipídeos/química , Nanopartículas/química , Nanoestruturas/química , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Varredura Diferencial de Calorimetria , Carbamazepina/administração & dosagem , Carbamazepina/farmacocinética , Cães , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Células Madin Darby de Rim Canino , Camundongos , Microscopia de Força Atômica , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Termogravimetria , Difração de Raios XRESUMO
CNS drug development is characterized by an especially high attrition rate, despite clear unmet medical needs in the field of neuro-pharmacology and significant investment in R of novel CNS drug treatments. Here, we overview the issues underlying the intrinsic difficulty of CNS drugs development, including obstacles of pharmacokinetic nature and lack of predictivity of preclinical tests. We highlight current efforts to overcome these limitations, with an emphasis on modeling opportunities towards early recognition of CNS candidates (stressing the possibilities of multi-target directed ligands or "magic shotguns") and different approaches to improve CNS bioavailability.