Co-delivery of ETS1 siRNA and doxorubicin using supramolecular nanoparticles to overcome adriamycin resistance via downregulation of MDR1 transcription

摘要

The Erythroblastosis virus E26 oncogene homolog 1 (ETS1) transcription factor is over-expressed in drug-resistant human breast cancer cells, which lead to the upregulation of the transcription of MDR1 gene. In the combined treatment of ETS1 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 down-regulate ETS1 protein and MDR1 transcription before doxorubicin inactivates the P-gp and is pumped outi. In order to treat breast cancer successfully by reverse of chemosensitivity, Herein, a novel type of delivery systems HPAD produced by (2-Hydroxypropyl)-γ-cyclodextrin-PEI600 (HP) and 1-Adamantane-conjugated doxorubicin (AD) to deliver DOX and ETS1 siRNA(siETSI) to breast cancer cells. AD as core was assembled into the system by host-guest interaction, and the outer HP is condensed with siRNA by electrostatic interaction. The structure of the polymer was determined by 2D-NOESY NMR.SEM.and DLS. In vitro studies, the release of DOX and siRNA from HPAD/siRNA complexe and the cell uptake of the siRNA complexes weres demonstrated effectively. Release of siETSI down-regulates the mRNA and protein levels of ETS1 and MDR1 in the MCF-7/ADR cell lines effectively and the accumulated doxorubicin facilitates apoptosis of the cells to reverse MDR. Furthermore, in vivo studies proved that the siETSI and doxombicin loaded nanoparticles induced tumor cell apoptosis and inhibited the growth of MCF-7/MDR tumor. The western blotting and quantitative PCR results illustrate that the synergistic treatment of siETSI and doxorubicin leads to efficient reduction of the ETS1 and MDR1 expression. To summarized, this study describes a delivery system of siRNA for overcoming multiple drug resistance (MDR) which first trough controlling the expression of transcription factor to downregulation of MDR1 transcription and combinational therapy with DOX. These results suggest HPAD/siETS1 nanoparticles have great clinical potential in the MDR cancer therapy via restoration of the chemosensitivity.