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Restoration of chemosensitivity by multifunctional micelles mediated by P-gp siRNA to reverse MDR

Author:
Shen, Jie, Wang, Qiwen, Hu, Qida, Li, Yongbing, Tang, Guping, Chu, Paul K.
Source:
Biomaterials 2014 v.35 no.30 pp. 8621-8634
ISSN:
0142-9612
Subject:
Fourier transform infrared spectroscopy, P-glycoproteins, RNA interference, Western blotting, X-ray diffraction, apoptosis, cell lines, doxorubicin, hydrophobicity, in vitro studies, messenger RNA, micelles, multiple drug resistance, neoplasm cells, neoplasms, nuclear magnetic resonance spectroscopy, polymers, protein content, reverse transcriptase polymerase chain reaction, small interfering RNA, therapeutics, transmission electron microscopy
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 ¹H 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.
Agid:
5997265