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Adryana Clementino,1,2 Mellissa Batger,3 Gabriela Garrastazu,2,3 Michele Pozzoli,3 Elena Del Favero,4 Valeria Rondelli,4 Bianca Gutfilen,5 Thiago Barboza,5 Maria B Sukkar,3 Sergio A L Souza,5 Laura Cantù,4 Fabio Sonvico1,3 1Department of Pharmacy, University of Parma, Parma, Italy; 2National Council for Scientific and Technological Development – CNPq, Brasilia, Brazil; 3Graduate School of Health – Pharmacy, University of Technology Sydney, Ultimo, NSW, Australia; 4Department of Medical Biotechnologies and Translational Medicine, LITA, University of Milan, Segrate, Italy; 5Laboratório de Marcação de Células e Moléculas, Department of Radiology, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Purpose: Along with their cholesterol-lowering effect, statins have shown a wide range of pleiotropic effects potentially beneficial to neurodegenerative diseases. However, such effects are extremely elusive via the conventional oral administration. The purpose of the present study was to prepare and characterize the physicochemical properties and the in vivo biodistribution of simvastatin-loaded lecithin/chitosan nanoparticles (SVT-LCNs) suitable for nasal administration in view of an improved delivery of the statins to the brain. Materials and methods: Chitosan, lecithin, and different oil excipients were used to prepare nanocapsules loaded with simvastatin. Particle size distribution, surface charge, structure, simvastatin loading and release, and interaction with mucus of nanoparticles were determined. The nanoparticle nasal toxicity was evaluated in vitro using RPMI 2651 nasal cell lines. Finally, in vivo biodistribution was assessed by gamma scintigraphy via Tc99m labeling of the particles. Results: Among the different types of nanoparticles produced, the SVT-LCN_MaiLab showed the most ideal physicochemical characteristics, with small diameter (200 nm), positive surface charge (+48 mV) and high encapsulation efficiency (EE; 98%). Size distribution was further confirmed by nanoparticle tracking analysis and electron microscopy. The particles showed a relatively fast release of simvastatin in vitro (35.6%±4.2% in 6 hours) in simulated nasal fluid. Blank nanoparticles did not show cytotoxicity, evidencing that the formulation is safe for nasal administration, while cytotoxicity of simvastatin-loaded nanoparticles (IC50) was found to be three times lower than the drug solution (9.92 vs 3.50 µM). In rats, a significantly higher radioactivity was evidenced in the brain after nasal delivery of simvastatin-loaded nanoparticles in comparison to the administration of a similar dose of simvastatin suspension. Conclusion: The SVT-LCNs developed presented some of the most desirable characteristics for mucosal delivery, that is, small particle size, positive surface charge, long-term stability, high EE, and mucoadhesion. In addition, they displayed two exciting features: First was their biodegradability by enzymes present in the mucus layer, such as lysozyme. This indicates a new Trojan-horse strategy which may enhance drug release in the proximity of the nasal mucosa. Second was their ability to enhance the nose-to-brain transport as evidenced by preliminary gamma scintigraphy studies. Keywords: nose-to-brain, simvastatin, nanoparticles, neurodegenerative diseases, gamma scintigraphy, small-angle X-ray scattering (SAXS), lysozyme, biodegradable nanoparticles |
