Polymeric Nanodiscs Comprising 5-Fluorouracil for Inhibition of Protein Aggregation and Their Anti-Alzheimer’s Activity in the <i>Drosophila</i> Model

Nanoconjugates are promising for therapeutic drug delivery and targeted applications due to the numerous opportunities to functionalize their surface. The present study reports the synthesis of 5-fluorouracil (5-FU)-entrapped polyvinylpyrrolidone (PVP) nanoconjugates, precisely 5-FU-PVP and 5-FU-PVP-Au, and the evaluation of protein aggregation inhibition efficiency. The 5-FU-loaded polymer nanoconjugates were functionalized with gold nanoparticles and analyzed using characterization techniques like dynamic light scattering, UV-visible spectroscopy, Fourier-transform infrared spectroscopy, and zeta potential analysis. These conjugates exhibit consistent morphology with a spherical, flat, disc-like structure. The 5-FU-PVP and 5-FU-PVP-Au nanoconjugates exhibited a high drug loading, up to 81% and 90%, respectively. The nanoconjugates exhibited prolonged drug delivery of 5-FU from 5-FU-PVP and 5-FU-PVP-Au, wherein 5-FU-PVP-Au depicted a higher drug release. They were investigated for inhibiting the protein hen egg white lysozyme (HEWL) aggregation by ThT fibril size measurement, binding assay, and electron microscopy, and the results showed that conjugates repressed the fibrillogenesis in HEWL. The prominent activity of amyloid aggregation inhibition for HEWL using 5-FU-PVP and 5-FU-PVP-Au was found to be 29 μg.mL^-1 and 27 μg.mL^-1, respectively. The dissociation of amyloid aggregates was achieved against 5-FU-PVP and 5-FU-PVP-Au at 27 μg.mL^-1 and 25 μg.mL^-1, respectively. Furthermore, the nanoconjugates were investigated for anti-Alzheimer's activity in the <i>Drosophila</i> model. A <i>Drosophila</i> model of Alzheimer's disease (AD) was developed that expressed Aβ42 peptides in the neuronal secretory system to comprehend the pathogenic effects of Aβ42 <i>in vivo.</i> All the results demonstrate that polymer nanoconjugates exhibit more effective inhibition of protein aggregation than bare drugs.