title: Reversal of multidrug resistance in breast cancer MCF-7/ADR cells by h-R3-siMDR1-PAMAM complexes.
abstract: Multidrug resistance (MDR) among breast cancer cells is the paramount obstacle for the successful chemotherapy. In this study, anti-EGFR antibody h-R3 was designed to self-assembled h-R3-siRNA-PAMAM-complexes (HSPCs) via electrostatic interactions for siRNA delivery. The physicochemical characterization, cell uptake, MDR1 silencing efficiency, cell migration, cell growth and cell apoptosis were investigated. The HSPCs presented lower cytotoxicity, higher cellular uptake and enhanced endosomal escape ability. Also, HSPCs encapsulating siMDR1 knockdowned 99.4% MDR1 gene with up to ∼6 times of enhancement compared to naked siMDR1, increased the doxorubicin accumulation, down-regulated P-glycoprotein (P-gp) expression and suppressed cellular migration in breast cancer MCF-7/ADR cells. Moreover, the combination of anticancer drug paclitaxel (PTX) and siMDR1 loaded HSPCs showed synergistic effect on overcoming MDR, which inhibited cell growth and induced cell apoptosis. This h-R3-mediated siMDR1 delivery system could be a promising vector for effective siRNA therapy of drug resistant breast cancer.
authors.affiliation: School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Gynaecology and Obstetrics, PLA Navy General Hospital, Beijing 100037, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Guo
authors.affiliation: School of Medicine, Tsinghua University, Beijing 100084, China; Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China. Electronic address: drugman@tsinghua.edu.cn.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000008:administration & dosage / Q000737:chemistry; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D050091:Dendrimers / Q000008:administration & dosage* / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D050091:Dendrimers; C104700:PAMAM Starburst; C501466:nimotuzumab
keywords: Breast cancer; Gene therapy; Multidrug resistance; h-R3; siRNA delivery