Design of PLGA-functionalized quercetin nanoparticles for potential use in Alzheimer’s disease

Dysfunctional interaction of amyloid-β (Aβ) with excess metal ions is proved to be related to the etiology of Alzheimer’s disease (AD). Hence, disruption of these metal-peptide interactions using nanoparticles (NPs) holds considerable promise as a therapeutic strategy to combat this incurable disease. Given that quercetin is a natural product, the biocompatibility and small size essential for permeating the blood-brain barrier make it a potential therapeutic drug candidate for treating AD. Nanocarriers formulated with the US Food and Drug Administration-approved biocompatible and biodegradable polymer PLGA are being widely explored for the controlled delivery of therapeutic drugs, proteins, peptides, oligonucleotides, and genes. With this background, the present study was undertaken to investigate the effects of PLGA-functionalized quercetin ([email protected]) NPs on inhibited and disassembled Aβ42 fibrils and the [email protected] NPs have low cytotoxicity when tested on SH-SY5Y cells in vitro. As expected, the cytotoxicity studies of the [email protected] NPs led to a concentration-related behaviour on the SH-SY5Y human neuroblastoma cells. And, it has demonstrated that [email protected] NPs can inhibit the neurotoxicity of Zn2+-Aβ42 system and enhance the viability of neuron cells. The results from behavioral tests indicate that injection of [email protected] NPs into APP/PS1 mice ameliorate cognition and memory impairments. Most encouragingly, the in vivo systemic toxicity of [email protected] NPs examined by histological analysis in major organs did not show any signs of adverse effect to mice. Thus, the prepared quercetin based nanoscale drug delivery carrier efficiently enhanced the therapeutic index and reduced the side effects. Our findings are highly encouraging, providing substantial evidence of the safety of [email protected] NPs for biomedical application. We expect these findings will be relevant for other NPs for treatment of AD and have broad implications in NP-based studies and applications.