Delivery of siRNA by MRI-visible nanovehicles to overcome drug resistance in MCF-7/ADR human breast cancer cells.1National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China. 2Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China. 3National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China; Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: huaai@scu.edu.cn.
AbstractMultidrug 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 alkylation 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. Copyright © 2014 Elsevier Ltd. All rights reserved. KEYWORDS: Magnetic resonance imaging; Multidrug resistance; P-glycoprotein; Small interfering RNAs; Superparamagnetic iron oxide Biomaterials. 2014 Nov;35（35）:9495-507. doi: 10.1016/j.biomaterials.2014.07.049. Epub 2014 Aug 23. PMID: 25155545 [PubMed - indexed for MEDLINE]
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