Quality by design endorsed fabrication of xanthohumol loaded solid nanostructured lipid carrier based powder for effective treatment of Alzheimer's disease in rats

Xanthohumol (XH) shows good neuroprotection against Alzheimer's Disease (AD). However, it exhibits poor solubility and low oral bioavailability. The current research presents the formulation, optimization, and characterization of XH-loaded nanostructured lipid carriers (XH-NLCs) to enhance oral bioavailability and therapeutic efficacy of XH in an aluminium chloride-induced rat model of Alzheimer's disease (AD). XH-NLCs were formulated utilizing hot high-pressure homogenization and probe sonication techniques. The processing parameters, including total lipid-to-drug ratio, solid lipid-to-liquid lipid ratio, and surfactant concentration were optimized using the Box-Behnken design. Optimized liquid XH-NLCs showed a mean particle size of 81.48 ± 4.02 nm, zeta potential of −16.3 ± 4.58 mV, and entrapment efficiency of 68 ± 2.46 %, whereas, the reconstituted S-XH-NLCs (post-lyophilization) showed 113.8 nm particle size, −20.3 mV zeta potential, and 65 % entrapment efficiency. Scanning electron microscopy and differential scanning calorimetry revealed that XH was molecularly dispersed in the amorphous state within the NLCs matrix. XH-NLCs showed enhanced in-vitro drug release by 4.93-fold as compared to its naïve form. Pharmacokinetic analysis revealed a 24.7-fold increase in Cmax and a 6.25-fold increase in AUC_0-t (2497.37 ng/mL·h) for XH in NLCs, with 11.3-fold higher brain availability. Pharmacodynamic evaluations indicated significant improvements in cognitive and motor functions, as well as reductions in AChE, Aβ, oxidative stress, and neuroinflammation, demonstrating the potential of XH-NLCs in AD therapy. These results highlight the potential of XH-NLCs for further development as a therapeutic strategy for AD.