title: Functionalized graphene oxide mediated adriamycin delivery and miR-21 gene silencing to overcome tumor multidrug resistance in vitro.
abstract: Multidrug resistance (MDR) is a major impediment to successful cancer chemotherapy. Co-delivery of novel MDR-reversing agents and anticancer drugs to cancer cells holds great promise for cancer treatment. MicroRNA-21 (miR-21) overexpression is associated with the development and progression of MDR in breast cancer, and it is emerging as a novel and promising MDR-reversing target. In this study, a multifunctional nanocomplex, composed of polyethylenimine (PEI)/poly(sodium 4-styrenesulfonates) (PSS)/graphene oxide (GO) and termed PPG, was prepared using the layer-by-layer assembly method to evaluate the reversal effects of PPG as a carrier for adriamycin (ADR) along with miR-21 targeted siRNA (anti-miR-21) in cancer drug resistance. ADR was firstly loaded onto the PPG surface (PPGADR) by physical mixing and anti-miR-21 was sequentially loaded onto PPGADR through electric absorption to form (anti-miR-21)PPGADR. Cell experiments showed that PPG significantly enhanced the accumulation of ADR in MCF-7/ADR cells (an ADR resistant breast cancer cell line) and exhibited much higher cytotoxicity than free ADR, suggesting that PPG could effectively reverse ADR resistance of MCF-7/ADR. Furthermore, the enhanced therapeutic efficacy of PPG could be correlated with effective silencing of miR-21 and with increased accumulation of ADR in drug-resistant tumor cells. The endocytosis study confirmed that PPG could effectively carry drug molecules into cells via the caveolae and clathrin-mediated endocytosis pathways. These results suggest that this PPG could be a potential and efficient non-viral vector for reversing MDR, and the strategy of combining anticancer drugs with miRNA therapy to overcome MDR could be an attractive approach in cancer treatment.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhi
authors.forename: Haifeng
authors.initials: H
authors.lastname: Dong
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Jia
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guo
authors.forename: Huiting
authors.initials: H
authors.lastname: Lu
authors.forename: Yilin
authors.initials: Y
authors.lastname: Yang
authors.forename: Huangxian
authors.initials: H
authors.lastname: Ju
authors.forename: Xueji
authors.initials: X
authors.lastname: Zhang
authors.forename: Yiqiao
authors.initials: Y
authors.lastname: Hu
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D020868:Gene Silencing / Q000187:drug effects*; D006108:Graphite / Q000008:administration & dosage; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011094:Polyethyleneimine / Q000008:administration & dosage; D011108:Polymers / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013451:Sulfonic Acids / Q000008:administration & dosage
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D011108:Polymers; D034741:RNA, Small Interfering; D013451:Sulfonic Acids; D006108:Graphite; D004317:Doxorubicin; D011094:Polyethyleneimine; C077114:styrenesulfonic acid polymer