期刊
BIOMATERIALS
卷 35, 期 35, 页码 9495-9507出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2014.07.049
关键词
Multidrug resistance; P-glycoprotein; Superparamagnetic iron oxide; Small interfering RNAs; Magnetic resonance imaging
资金
- National Key Basic Research Program of China [2013CB933903]
- National Key Technology RD Program [2012BAI23B08]
- National Natural Science Foundation of China [20974065, 51173117, 50830107]
- Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) of China [IRT1272]
Multidrug resistance (MDR) is one of the major barriers in cancer chemotherapy. P-glycoprotein (P-gp), a cell membrane protein in MDR, also a member of ATP-Binding cassette (ABC) transporter, can increase the efflux of various hydrophobic anticancer drugs. In this study, polycation/iron oxide nanocomposites, were chosen as small interfering RNA (siRNA) carriers to overcome MDR through silencing of the target messenger RNA and subsequently reducing the expression of P-gp. Amphiphilic low molecular weight polyethylenimine was designed with different alkylation groups and allcylation degree to form various nanocarriers with clustered iron oxide nanoparticles inside and carrying siRNA through electrostatic interaction. A few optimized formulations can form stable nanocomplexes with siRNA and protect them from degradation during delivery, and lead to effective silencing effect that comparable to a commercial golden standard transfection agent, Lipofectamine 2000. Human breast cancer MCF-7/ADR cells can be vulnerable to doxorubicin treatment after the strong downregulation of P-gp through siRNA tranfection. Once transfected with these nanocomplexes, the cells displayed significant contrast enhancement against non-transfected cells under a 3T clinical MRI scanner. These nanocomposites also demonstrated their downregulation efficacy of P-gp in a MCF-7/ADR orthotopic tumor model in mice. (C) 2014 Elsevier Ltd. All rights reserved.
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