Design of Nanodrug for Neurodegenerative Disease by using Dual-functionalized Mesoporous Silica Nanoparticle
Date Issued
2015
Date
2015
Author(s)
Zheng, Cheng-Shun
Abstract
Alzheimer''s disease (AD), a progressive neurodegenerative disorder (ND) of the elderly, affects more than 44 million people worldwide. So far, there is no effective method that treats or delays the progression of AD. Therefore, development of strategies for AD therapy is very important goal. RhoG, a member of small Rho family guanine nucleotide triphosphatases (GTPases), is able to induce neurite outgrowth through downregulating activation of Rac and cdc42, resulting in reorganizing the actin cytoskeleton and subsequent morphological changes. In addition, a well-known polyphenol compound, Curcumin, which was found from the rhizome of turmeric with antioxidant and anti- inflammatory properties, has already been noted for its therapy potential in neurodegenerative disease especially AD. However, due to limitations of poor bioavailability and aqueous solubility, curcumin is not suitable for biomedical applications. In our work, taking advantage of mesoporous silica nanoparticle (MSN), including its structure, easy modification and good biocompatibility, we proposed a concept of PEGylated MSN-based dual therapy and designed the nanodrug that contains curcumin(CUR) by MSN inner channel loading; MSN surface positive charge modification for RhoG gene adsorption; and TAT peptide enhanced the RhoG gene nuclear delivery and nonendocytosis mechanisms, named CUR@FMSN(+)/RhoG-TAT. MSN as a drug carrier improved the stability and bioavailability of curcumin. On the basis of the results shown in this study, Flow cytometry and confocal microscopy demonstrated the good cell uptake efficiency (approaching 99%) and localization of CUR@FMSN(+)/RhoG-TAT in neuro-2a (N2a) cell line. The expression levels of inflammatory related proteins inhibited by CUR@FMSN(+)/RhoG-TAT were carried out by using Western blotting. The levels of paraquat-induced ROS reduced by nanodrug were stained by DHE assays and quantified by flow cytometry. Our results evaluated that CUR@FMSN(+)/RhoG-TAT not only stimulated neurite outgrowth but also allowed neuron cells to against ROS-induced damage in N2a cells. Hence, the application of MSN might be a promising candidate method for treating NDs.
Subjects
Mesoporous silica nanoparticles
Neurodegenerative diseases
Curcumin
Rho family GTPases
Drug delivery
Gene delivery
Type
thesis
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