title: Restoration of chemosensitivity by multifunctional micelles mediated by P-gp siRNA to reverse MDR.
abstract: One of the main obstacles in tumor therapy is multiple drug resistance (MDR) and an underlying mechanism of MDR is up-regulation of the transmembrane ATP-binding cassette (ABC) transporter proteins, especially P-glycoprotein (P-gp). In the synergistic treatment of siRNA and anti-cancer drug doxorubicin, it is crucial that both the siRNA and doxorubicin are simultaneously delivered to the tumor cells and the siRNA can fleetly down-regulate P-g before doxorubicin inactivates the P-gp and is pumped out. Herein, a type of micelles comprising a polycationic PEI-CyD shell to condense the siRNA and hydrophobic core to package doxorubicin is reported. The structure of the polymer is determined by (1)H NMR, FT-IR, DSC, and XRD and the micelles are characterized by DLS, 2D-NOESY NMR, and TEM to study the self-assembly of the micelles with siRNA and drugs. In vitro studies demonstrate controlled release and temporal enhancement of the therapeutic efficacy of P-gp siRNA and doxorubicin. Release of siRNA down-regulates the mRNA and protein levels of P-gp in the MCF-7/ADR cell lines effectively and the accumulated doxorubicin facilitates apoptosis of the cells to reverse MDR. Moreover, in vivo research reveals that the siRNA and doxorubicin loaded micelles induce tumor cell apoptosis and inhibit the growth of MDR tumor. The western blotting and RT-PCR results illustrate that the synergistic treatment of siRNA and doxorubicin leads to efficient reduction of the P-gp expression as well as cell apoptotic induction in MDR tumors at a small dosage of 0.5 mg/kg. The micelles have large clinical potential in drug/RNAi synergistic treatment via restoration of the chemosensitivity in MDR cancer therapy.
authors.affiliation: Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, PR China; Department of Physics & Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, PR China; Department of Cardiology, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou 310003, PR China.
authors.forename: Qiwen
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, PR China.
authors.forename: Qida
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, PR China; Department of Physics & Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China.
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Chemical Biology and Pharmaceutical Chemistry, Zhejiang University, Hangzhou 310028, PR China; Department of Physics & Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China. Electronic address: tangguping@zju.edu.cn.
authors.forename: Guping
authors.initials: G
authors.lastname: Tang
authors.affiliation: Department of Physics & Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon, Hong Kong, China. Electronic address: paul.chu@cityu.edu.hk.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Chu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000138:chemical synthesis / Q000737:chemistry; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005453:Fluorescence; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D011094:Polyethyleneimine / Q000138:chemical synthesis / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D034741:RNA, Small Interfering / Q000378:metabolism*; D014961:X-Ray Diffraction; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D008823:Micelles; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D047392:beta-Cyclodextrins; D004317:Doxorubicin; D011094:Polyethyleneimine; D002784:Cholesterol; C031215:betadex
keywords: Doxorubicin; MDR; Micelles; siRNA