Brain pharmacokinetics of neurotoxin-loaded PLA nanoparticles modified with chitosan after intranasal administration in awake rats

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 T-max of NT-PLA-cNPs was equal with that of NT-PLA-NPs after i.n. administration (150 min). The C-max and AUC(0-8 h) of each group followed the following order: NT-PLA-cNPs > NT-PLA-NPs. The corresponding absolute bioavailability (F-abs) 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.