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

• Published in: Colloids and surfaces, B, Biointerfaces B, Biointerfaces, 2016-12, Vol.148, p.116-129
• Main Authors: Sun, Dongdong, Li, Nuan, Zhang, Weiwei, Zhao, Zhiwei, Mou, Zhipeng, Huang, Donghui, Liu, Jie, Wang, Weiyun
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid β; Biocompatibility; Circular Dichroism; Drugs; Human behavior; Humans; Lactic Acid - chemistry; Mice; Microscopy, Electron, Transmission; Nanoparticles; Nanoparticles - chemistry; Nanostructure; PLGA; Polyglycolic Acid - chemistry; Quercetin; Quercetin - chemistry; Spectrophotometry, Ultraviolet; Toxicity
• ISSN: 0927-7765; 1873-4367
• DOI: 10.1016/j.colsurfb.2016.08.052

In this study, we designed PLGA-functionalized quercetin (PLGA@QT) NPs as Aβ42 aggregation inhibitor. Using a combination of in vitro and in vivo experiments, we have shown that PLGA@QT NPs are able to reduce toxic Zn2+-induced Aβ42 aggregates, improved inhibition efficacy, and reduced cytotoxicity. Most importantly, the amelioration of Aβ-induced spatial learning and memory impairment by PLGA@QT NPs could be linked, at least in part, suggesting that the PLGA@QT NPs may be a potential candidate for AD treatment. [Display omitted] •The PLGA@QT NPs effectively inhibited Zn2+-induced Aβ fibrils formation and toxicity.•That injection of PLGA@QT NPs into AD mice ameliorated cognition and memory impairments.•The H&E study unambiguously show negligible toxicity to the mice. 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 (PLGA@QT) NPs on inhibited and disassembled Aβ42 fibrils and the PLGA@QT NPs have low cytotoxicity when tested on SH-SY5Y cells in vitro. As expected, the cytotoxicity studies of the PLGA@QT NPs led to a concentration-related behaviour on the SH-SY5Y human neuroblastoma cells. And, it has demonstrated that PLGA@QT 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 PLGA@QT NPs into APP/PS1 mice ameliorate cognition and memory impairments. Most encouragingly, the in vivo systemic toxicity of PLGA@QT 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 a