title: Delivery of siRNA by MRI-visible nanovehicles to overcome drug resistance in MCF-7/ADR human breast cancer cells.
abstract: 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 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.
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Gan
authors.initials: G
authors.lastname: Lin
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Zhu
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Lin
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xu
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Zhuzhong
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Chunchao
authors.initials: C
authors.lastname: Xia
authors.affiliation: Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Qiyong
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Song
authors.affiliation: National 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.
authors.forename: Hua
authors.initials: H
authors.lastname: Ai
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D020868:Gene Silencing; D006801:Humans; D061986:MCF-7 Cells; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008970:Molecular Weight; D049329:Nanostructures / Q000737:chemistry*; D011094:Polyethyleneimine / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004317:Doxorubicin; D011094:Polyethyleneimine
keywords: Magnetic resonance imaging; Multidrug resistance; P-glycoprotein; Small interfering RNAs; Superparamagnetic iron oxide