The Effect of Oxidative Stress and Memantine-Incorporated Reactive Oxygen Species-Sensitive Nanoparticles on the Expression of <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-aspartate Receptor Subunit 1 in Brain Cancer Cells for Alzheimer’s Disease Application

The aim of this study is to fabricate reactive oxygen species (ROS)-sensitive nanoparticles composed of succinyl β-cyclodextrin (bCDsu), memantine and thioketal linkages for application in Alzheimer’s disease, and to investigate the suppression of <i>N</i>-methyl-<span style="fon...

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Autores principales: Jung Sun Park, Taeyeon Kim, Dohoon Kim, Young-IL Jeong
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Publicado: MDPI AG 2021
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spelling oai:doaj.org-article:38a4b5f4b4a245c8bcfc535548a043092021-11-25T17:55:17ZThe Effect of Oxidative Stress and Memantine-Incorporated Reactive Oxygen Species-Sensitive Nanoparticles on the Expression of <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-aspartate Receptor Subunit 1 in Brain Cancer Cells for Alzheimer’s Disease Application10.3390/ijms2222123091422-00671661-6596https://doaj.org/article/38a4b5f4b4a245c8bcfc535548a043092021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12309https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The aim of this study is to fabricate reactive oxygen species (ROS)-sensitive nanoparticles composed of succinyl β-cyclodextrin (bCDsu), memantine and thioketal linkages for application in Alzheimer’s disease, and to investigate the suppression of <i>N</i>-methyl-<span style="font-variant: small-caps;">d</span>-aspartate (NMDA) receptor 1 (NMDAR1) in cells. Thioketal diamine was attached to the carboxyl group of bCDsu to produce thioketal-decorated bCDsu conjugates (bCDsu-thioketal conjugates) and memantine was conjugated with thioketal dicarboxylic acid (memantine-thioketal carboxylic acid conjugates). Memantine-thioketal carboxylic acid conjugates were attached to bCDsu-thioketal conjugates to produce bCDsu-thioketal-memantine (bCDsuMema) conjugates. SH-SY5Y neuroblastoma cells and U87MG cells were used for NMDAR1 protein expression and cellular oxidative stress. Nanoparticles of bCDsuMema conjugates were prepared by means of a dialysis procedure. Nanoparticles of bCDsuMema conjugates had small particle sizes less than 100 nm and their morphology was found to be spherical in transmission electron microscopy observations (TEM). Nanoparticles of bCDsuMema conjugates responded to H<sub>2</sub>O<sub>2</sub> and disintegrated or swelled in aqueous solution. Then, the nanoparticles rapidly released memantine according to the concentration of H<sub>2</sub>O<sub>2</sub>. In an in vivo animal imaging study, thioketal-decorated nanoparticles labelled with fluorescent dye such as chlorin e6 (Ce6) showed that the fluorescence intensity was stronger in the brain than in other organs, indicating that bCDsuMema nanoparticles can efficiently target the brain. When cells were exposed to H<sub>2</sub>O<sub>2</sub>, the viability of cells was time-dependently decreased. Memantine or bCDsuMema nanoparticles did not practically affect the viability of the cells. Furthermore, a western blot assay showed that the oxidative stress produced in cells using H<sub>2</sub>O<sub>2</sub> increased the expression of NMDAR1 protein in both SH-SY5Y and U87MG cells. Memantine or bCDsuMema nanoparticles efficiently suppressed the NMDAR1 protein, which is deeply associated with Alzheimer’s disease. Fluorescence microscopy also showed that H<sub>2</sub>O<sub>2</sub> treatment induced green fluorescence intensity, which represents intracellular ROS levels. Furthermore, H<sub>2</sub>O<sub>2</sub> treatment increased the red fluorescence intensity, which represents the NMDAR1 protein, i.e., oxidative stress increases the expression of NMDAR1 protein level in both SH-SY5Y and U87MG cells. When memantine or bCDsuMema nanoparticles were treated in cells, the oxidative stress-mediated expression of NMDAR1 protein in cells was significantly decreased, indicating that bCDsuMema nanoparticles have the capacity to suppress NMDAR1 expression in brain cells, which has relevance in terms of applications in Alzheimer’s disease.Jung Sun ParkTaeyeon KimDohoon KimYoung-IL JeongMDPI AGarticleAlzheimer’s diseasereactive oxygen speciesmemantinecyclodextrin nanoparticlesROS-sensitive drug deliveryBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12309, p 12309 (2021)
institution DOAJ
collection DOAJ
language EN
topic Alzheimer’s disease
reactive oxygen species
memantine
cyclodextrin nanoparticles
ROS-sensitive drug delivery
Biology (General)
QH301-705.5
Chemistry
QD1-999
spellingShingle Alzheimer’s disease
reactive oxygen species
memantine
cyclodextrin nanoparticles
ROS-sensitive drug delivery
Biology (General)
QH301-705.5
Chemistry
QD1-999
Jung Sun Park
Taeyeon Kim
Dohoon Kim
Young-IL Jeong
The Effect of Oxidative Stress and Memantine-Incorporated Reactive Oxygen Species-Sensitive Nanoparticles on the Expression of <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-aspartate Receptor Subunit 1 in Brain Cancer Cells for Alzheimer’s Disease Application
description The aim of this study is to fabricate reactive oxygen species (ROS)-sensitive nanoparticles composed of succinyl β-cyclodextrin (bCDsu), memantine and thioketal linkages for application in Alzheimer’s disease, and to investigate the suppression of <i>N</i>-methyl-<span style="font-variant: small-caps;">d</span>-aspartate (NMDA) receptor 1 (NMDAR1) in cells. Thioketal diamine was attached to the carboxyl group of bCDsu to produce thioketal-decorated bCDsu conjugates (bCDsu-thioketal conjugates) and memantine was conjugated with thioketal dicarboxylic acid (memantine-thioketal carboxylic acid conjugates). Memantine-thioketal carboxylic acid conjugates were attached to bCDsu-thioketal conjugates to produce bCDsu-thioketal-memantine (bCDsuMema) conjugates. SH-SY5Y neuroblastoma cells and U87MG cells were used for NMDAR1 protein expression and cellular oxidative stress. Nanoparticles of bCDsuMema conjugates were prepared by means of a dialysis procedure. Nanoparticles of bCDsuMema conjugates had small particle sizes less than 100 nm and their morphology was found to be spherical in transmission electron microscopy observations (TEM). Nanoparticles of bCDsuMema conjugates responded to H<sub>2</sub>O<sub>2</sub> and disintegrated or swelled in aqueous solution. Then, the nanoparticles rapidly released memantine according to the concentration of H<sub>2</sub>O<sub>2</sub>. In an in vivo animal imaging study, thioketal-decorated nanoparticles labelled with fluorescent dye such as chlorin e6 (Ce6) showed that the fluorescence intensity was stronger in the brain than in other organs, indicating that bCDsuMema nanoparticles can efficiently target the brain. When cells were exposed to H<sub>2</sub>O<sub>2</sub>, the viability of cells was time-dependently decreased. Memantine or bCDsuMema nanoparticles did not practically affect the viability of the cells. Furthermore, a western blot assay showed that the oxidative stress produced in cells using H<sub>2</sub>O<sub>2</sub> increased the expression of NMDAR1 protein in both SH-SY5Y and U87MG cells. Memantine or bCDsuMema nanoparticles efficiently suppressed the NMDAR1 protein, which is deeply associated with Alzheimer’s disease. Fluorescence microscopy also showed that H<sub>2</sub>O<sub>2</sub> treatment induced green fluorescence intensity, which represents intracellular ROS levels. Furthermore, H<sub>2</sub>O<sub>2</sub> treatment increased the red fluorescence intensity, which represents the NMDAR1 protein, i.e., oxidative stress increases the expression of NMDAR1 protein level in both SH-SY5Y and U87MG cells. When memantine or bCDsuMema nanoparticles were treated in cells, the oxidative stress-mediated expression of NMDAR1 protein in cells was significantly decreased, indicating that bCDsuMema nanoparticles have the capacity to suppress NMDAR1 expression in brain cells, which has relevance in terms of applications in Alzheimer’s disease.
format article
author Jung Sun Park
Taeyeon Kim
Dohoon Kim
Young-IL Jeong
author_facet Jung Sun Park
Taeyeon Kim
Dohoon Kim
Young-IL Jeong
author_sort Jung Sun Park
title The Effect of Oxidative Stress and Memantine-Incorporated Reactive Oxygen Species-Sensitive Nanoparticles on the Expression of <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-aspartate Receptor Subunit 1 in Brain Cancer Cells for Alzheimer’s Disease Application
title_short The Effect of Oxidative Stress and Memantine-Incorporated Reactive Oxygen Species-Sensitive Nanoparticles on the Expression of <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-aspartate Receptor Subunit 1 in Brain Cancer Cells for Alzheimer’s Disease Application
title_full The Effect of Oxidative Stress and Memantine-Incorporated Reactive Oxygen Species-Sensitive Nanoparticles on the Expression of <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-aspartate Receptor Subunit 1 in Brain Cancer Cells for Alzheimer’s Disease Application
title_fullStr The Effect of Oxidative Stress and Memantine-Incorporated Reactive Oxygen Species-Sensitive Nanoparticles on the Expression of <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-aspartate Receptor Subunit 1 in Brain Cancer Cells for Alzheimer’s Disease Application
title_full_unstemmed The Effect of Oxidative Stress and Memantine-Incorporated Reactive Oxygen Species-Sensitive Nanoparticles on the Expression of <i>N</i>-Methyl-<span style="font-variant: small-caps">d</span>-aspartate Receptor Subunit 1 in Brain Cancer Cells for Alzheimer’s Disease Application
title_sort effect of oxidative stress and memantine-incorporated reactive oxygen species-sensitive nanoparticles on the expression of <i>n</i>-methyl-<span style="font-variant: small-caps">d</span>-aspartate receptor subunit 1 in brain cancer cells for alzheimer’s disease application
publisher MDPI AG
publishDate 2021
url https://doaj.org/article/38a4b5f4b4a245c8bcfc535548a04309
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