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The highly complex pathophysiology of Alzheimer's disease (AD) and the low bioavailability of the currently used drugs make it necessary to offer versatile treatment options. In this study, polyvinyl alcohol (PVA)/polyvinylpyrrolidone (PVP) nanofibers (NFs) were loaded with rivastigmine (RIV), memantine (MM), and Gingko biloba(GB) extract, and their anti-Alzheimer's effects were investigated in vitroby cell culture and in vivoby animal experiments. The characterization studies, including FTIR, XRD, and DSC analysis, showed that the fibers exhibited a good compatibility. The rapid disintegration (in 5.2 s) and complete dissolution (in 120 s) of RIV/MM/GB-loaded NF indicated their suitability for sublingual application. Cell viability analysis revealed that RIV/MM/GB-loaded NFs can be considered as safe and promising candidates. RIV/MM/GB-loaded NFs tremendously improved the learning and memory impairment seen in the AD model created by the injection of intracerebroventricular-streptozotocin into rats. Moreover, RIV/MM/GB-loaded NF stimulated stem cells to improve neuronal differentiation properties and significantly decreased the level of β-amyloid, tau, APP, TNF-α, AChE, and GSK-3β in the brain. The histopathological and immunostaining assays demonstrated that RIV/MM/GB-loaded NF reduced β-amyloid formation and tau hyperphosphorylation in the hippocampus and cerebral cortex. Thus, a novel and promising treatment strategy could be developed that has several advantages, such as ease of sublingual administration, reduced frequency of administration associated with lower drug amounts, and finally reduced toxicity and cost.

Nanocarriers are used to deliver bioactive substances in the treatment of neurodegenerative diseases such as Alzheimer's disease (AD). These nanocarriers have shown many benefits over traditional treatments due to their properties such as efficient distribution and controlled release of bioactive material to the brain and loading of various drugs simultaneously. In this study, polyvinyl alcohol (PVA), PVA/bismuth ferrite (BiFeO3), and PVA/BiFeO3/donepezil hydrochloride (DO) monodisperse polymeric nanoparticles were manufactured with bursting microbubbles by a T-junction device. Here, BiFeO3nanoparticles were synthesized by the co-precipitation method, and these magnetic nanoparticles and DO were loaded in PVA nanoparticles. Nanoparticles had a smooth and monodisperse structure according to SEM images. Also, the diameters of PVA, PVA/BiFeO3, and PVA/BiFeO3/DO nanoparticles were 148 ± 15 nm, 159 ± 21 nm, and 164 ± 12 nm, respectively. It was confirmed by X-ray diffraction and infrared spectroscopy that BiFeO3magnetic nanoparticles and DO were successfully loaded into nanoparticles produced with PVA. There was no cytotoxic effect on healthy L929 cells for all nanoparticle samples. A systematic electrical circuit has been established to investigate the electrically controlled release behaviour of PVA/BiFeO3/DO nanoparticles at different voltages (0 V, −1.0 V, −0.5 V, +0.5 V, +1.0 V), different currents (−50 μA, −100 μA, −200 μA, and −300 μA), and 200 rpm. To apply electric stimulus increased the release except for +1.0 V and the release of DO increased at more negative voltages with a total release of 68.9% of DO after 15 stimulus with −1.0 V. Higher R2values were obtained with the Higuchi model for almost all conditions and DO was released from nanoparticles through the non-Fickian diffusion mechanism (0.45 < n < 1). The possibility of affecting the release of DO by modifying the current and voltage in the presence of BiFeO3leads to an immensely controllable and delicately tunable drug release for AD treatment.