期刊
ACTA BIOMATERIALIA
卷 31, 期 -, 页码 197-210出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2015.11.041
关键词
Selenium; siRNA; Drug resistance; P-glycoprotein; Class III beta-tubulin
资金
- National Natural Science Foundation of China [21171070, 21371075]
- Natural Science Foundation of Guangdong Province [2014A030311025, S201301 0011660]
- Chinese Postdoctoral Science Foundation
Drug resistance mediated by P-glycoprotein (P-gp) and class III beta-tubulin (beta-tubulin III) is a major barrier in microtubule-targeting cancer chemotherapy. In this study, layered double hydroxide nanoparticles (LDHs) were employed to simultaneously deliver selenium (Se) and pooled small interfering RNAs (siRNAs) to achieve therapeutic efficacy. LDH-supported Se nanoparticles (Se@LDH) were compacted with siRNAs (anti-P-gp and anti-beta-tubulin III) via electrostatic interactions, which could protect siRNA from degradation. Se@LDH showed excellent abilities to deliver siRNA into cells, including enhancing siRNA internalization, and promoting siRNA escape from endosomes. siRNA transfection experiments further confirmed a higher gene silencing efficiency of Se@LDH than LDH. Interestingly, we found Se@LDH may be a microtubule (MT) stabilizing agent which could inhibit cell proliferation by blocking cell cycle at G2/M phase, disrupting normal mitotic spindle formation and inducing cell apoptosis. When complexed with different specific siRNAs, Se@LDH/siRNA nanoparticles, especially the Se@LDH-pooled siRNAs, exhibit an efficient gene-silencing effect that significantly downregulate the expression of P-gp and beta-tubulin III. Moreover, Se@LDH-pooled siRNAs could induce cell apoptosis, change cell morphology and increase cellular ROS levels through change the expression of Bcl-2/Bax, activation of caspase-3, PI3K/AKT/mTOR and MAPK/ERK pathways. These results suggested that co-delivery of Se and pooled siRNAs may be a promising strategy for overcoming the drug resistance mediated by P-gp and beta-tubulin III in drug-resistant breast cancers. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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