RESUMO
CONTEXT: Neurotoxin (NT), an analgesic peptide which was separated from the venom of Naja naja atra, is endowed an exceptional specificity of action that blocks transmission of the nerve impulse by binding to the acetylcholine receptor in the membrane. However, it has limited permeability across the blood-brain barrier (BBB). OBJECTIVE: The purpose of this study was to encapsulate NT within polylactic acid (PLA) nanoparticles (NPs) modified with chitosan (NT-PLA-cNPs) and to evaluate their brain pharmacokinetic behaviors after intranasal (i.n.) administration using a microdialysis technique in free-moving rats. METHODS: NT-PLA-cNPs (NT labeled with fluorescein isothiocyanate) were prepared and characterized. Then, NT-PLA-cNPs were i.n. administered to rats and the fluorescence intensity in the periaqueductal gray (PAG) was monitored for up to 480 min, with NT-PLA-NPs and NT solution as control groups. RESULTS: The NPs prepared were spherical with a homogenous size distribution. The mean particle size, zeta potential, and entrapment efficiency were 140.5 ± 5.4 nm, +33.71 ± 3.24 mV, and 83.51 ± 2.65%, respectively. The brain transport results showed that Tmax of NT-PLA-cNPs was equal with that of NT-PLA-NPs after i.n. administration (150 min). The Cmax and AUC(0-8 h) of each group followed the following order: NT-PLA-cNPs > NT-PLA-NPs. The corresponding absolute bioavailability (Fabs) of NT-PLA-cNPs was about 151% with NT-PLA-NPs as reference preparations. CONCLUSION: These results suggest that NPs modified with chitosan have better brain targeting efficiency and are a promising approach for i.n. delivery of large hydrophilic peptides and proteins in improving the treatment of central nervous system (CNS) disorders.
Assuntos
Analgésicos não Narcóticos/farmacocinética , Barreira Hematoencefálica/metabolismo , Quitosana/química , Proteínas Neurotóxicas de Elapídeos/farmacocinética , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Substância Cinzenta Periaquedutal/metabolismo , Administração Intranasal , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/farmacologia , Animais , Disponibilidade Biológica , Barreira Hematoencefálica/efeitos dos fármacos , Proteínas Neurotóxicas de Elapídeos/administração & dosagem , Proteínas Neurotóxicas de Elapídeos/farmacologia , Composição de Medicamentos , Corantes Fluorescentes/química , Meia-Vida , Ácido Láctico/química , Masculino , Microdiálise , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Poliésteres , Polímeros/química , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície , Distribuição TecidualRESUMO
OBJECTIVE: To investigate the absorption enhancen effect of borneol/mentholum eutectic mixture (BO/ME) on nasal-brain delivery of neurotoxin loaded nanoparticles. METHOD: Using microdialysis sampling technique in awake freely-moving rats, the counter per minute (cpm) of dialysates in right PAG of NT-loaded nanoparticles with the BO/ME (BO/ME-NT-NP), radiolabeled with sodium 125I-Iodide, were measured in a gamma-counter for radioactivity. After converting cpm into corresponding concentrations of NT byin vivorecovery of microdialysis probes, the pharmacokinetic parameters were calculated. RESULT: The BO/ME-NT-NP could be absorbed into the brain, much better to NT-NP and the nanoparticles with borneol or menthdlum only, and the pharmacokinetics accorded with the two-compartment model. The parameters tmax, cmax, AUC, t 1/2(beta) were 0.68 h, 27.32 ng x mL(-1), 132.68 ng x h x mL(-1), 3.1076 h. CONCLUSION: With adding BO/ME as absorption enhancer, NT could be significantly increased in the brain with the help of nanopartilces as carriers, and the time to maximal concentration was short, the elimination process was prolonged.
