The protective effects of Trolox-loaded chitosan nanoparticles against hypoxia-mediated cell apoptosis.
Antioxidants have potentials to treat hypoxia-mediated oxidative stress related diseases. However, their therapeutic efficacy is restricted due to its poor cellular uptake efficiency and poor cell membrane permeability. To resolve these issues, we prepare the hydroxyethylated chitosan nanoparticles as drug carriers for the delivery of 6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid (Trolox), which was considered as a model compound. The experiment on cellular uptake and subcellular localization of Trolox-loaded chitosan nanoparticles (Trolox-CSNPs) indicate that Trolox-CSNPs enter the cells via the caveolae-mediated endocytosis pathway and traffic with endosomes. Furthermore, compared with Trolox, Trolox-CSNPs exert a higher protective effect against the hypoxia-mediated oxidative stress. Molecular basis of apoptosis study reveals that Trolox-CSNPs can directly block the mitochondria dependent apoptotic pathway through up-regulation of Bcl-2 expression and inhibiting the activation of Bax, Caspase-3 expression. In conclusion, the hydroxyethylated chitosan is a promising drug nanocarrier to deliver antioxidants for the treatment of hypoxia-mediated disease. From the clinical editor: Antioxidants are potentially beneficial in oxidative stress-related diseases, although cellular uptake of most antioxidants is suboptimal. In this study, hydroxyethylated chitosan nanoparticles are demonstrated as promising drug carriers in a Trolox-model system.
State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China. Electronic address: dulibo@iccas.ac.cn.
Libo
L
Du
China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, 100088, China.
Xiaoxiang
X
Miao
State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
Yanli
Y
Gao
State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
Hongying
H
Jia
Key Laboratory of Bio-resources and Eco-environment, The Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, China.
Ke
K
Liu
State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China. Electronic address: liuke@scu.edu.cn.
Yang
Y
Liu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D015687:Cell Hypoxia; D048271:Chitosan / Q000008:administration & dosage* / Q000494:pharmacology; D002839:Chromans; D053758:Nanoparticles; D016716:PC12 Cells; D051381:Rats
D002839:Chromans; D048271:Chitosan; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
Antioxidants; Apoptosis; Chitosan; Drug delivery; Nanoparticles