Nose to Brain Delivery of Astaxanthin-Loaded Nanostructured Lipid Carriers in Rat Model of Alzheimer?s Disease: Preparation, in vitro and in vivo Evaluation

Background: Astaxanthin (AST) is a second-generation antioxidant with anti-inflammatory and neuroprotective properties and could be a promising candidate for Alzheimer???s disease (AD) therapy, but is shows poor oral bioavailability due to its high lipophilicity. Purpose: This study aimed to prepare and evaluate AST???loaded nanostructured lipid carriers (NLCs), for enhanced nose-to-brain drug delivery to improve its therapeutic efficacy in rat model of AD. Methods: AST???NLCs were prepared using hot high-pressure homogenization technique, and processing parameters such as total lipid-to-drug ratio, solid lipid-to-liquid lipid ratio, and concentration of surfactant were optimized. Results: The optimized AST???NLCs had a mean particle size of 142.8 ?? 5.02 nm, polydispersity index of 0.247 ?? 0.016, zeta potential of ???32.2 ?? 7.88 mV, entrapment efficiency of 94.1 ?? 2.46%, drug loading of 23.5 ?? 1.48%, and spherical morphology as revealed by transmission electron microscopy. Differential scanning calorimetry showed that AST was molecularly dispersed in the NLC matrix in an amorphous state, whereas Fourier transform infrared spectroscopy indicated that there is no interaction between AST and lipids. AST displayed a biphasic release pattern from NLCs; an initial burst release followed by sustained release for 24 h. AST-NLCs were stable at 4???8 ??2??C for six months. Intranasal treatment of AD-like rats with the optimized AST???NLCs significantly decreased oxidative stress, amyloidogenic pathway, neuroinflammation and apoptosis, and significantly improved the cholinergic neurotransmission compared to AST-solution. This was observed by the significant decline in the levels of malondialdehyde, nuclear factor-kappa B, amyloid beta (A??1-42), caspase-3, acetylcholinesterase, and ??-site amyloid precursor protein cleaving enzyme-1 expression, and significant increase in the contents of acetylcholine and glutathione after treatment with AST-NLCs. Conclusion: NLCs enhanced the intranasal delivery of AST and significantly improved its therapeutic properties.