Reversing Multidrug Resistance by Multiplexed Gene Silencing for Enhanced Breast Cancer Chemotherapy.

Multidrug resistance (MDR), as one of the main problems in clinical breast cancer chemotherapy, is closely related with the over expression of drug efflux transporter P-glycoprotein (P-gp). In this study, a novel drug-loaded nanosystem was developed for inhibiting the P-gp expression and reversing MDR by multiplexed gene silencing, which composes of graphene oxide (GO) modified with two molecular beacons (MBs) and Doxorubicin (Dox). When the nanosystem was uptaken by the MDR breast cancer cells, Dox was released in the acidic endosomes and MBs were hybridized with target sequences. The intracellular multidrug resistance 1 (MDR1) mRNA and upstream erythroblastosis virus E26 oncogene homolog 1 (ETS1) mRNA can be silenced by MBs, which can effectively inhibit the expression of P-gp and further prevent the efflux of Dox and reverse MDR. In vitro and in vivo studies indicated that the strategy of reversing MDR by multiplexed gene silencing could obviously increase MCF-7/Adr cells' Dox accumulation and enormously enhance the therapeutic efficacy of MDR breast cancer chemotherapy.

[1]  H. Verkooijen,et al.  Risk of death from cardiovascular disease following breast cancer in Southeast Asia: a prospective cohort study , 2017, Scientific Reports.

[2]  Wei Pan,et al.  Multiplexed gene silencing in living cells and in vivo using a DNAzymes-CoOOH nanocomposite. , 2017, Chemical communications.

[3]  Wei Pan,et al.  Hollow Mesoporous Silica Nanoparticles with Tunable Structures for Controlled Drug Delivery. , 2017, ACS applied materials & interfaces.

[4]  Mengli Li,et al.  Large Pore‐Sized Hollow Mesoporous Organosilica for Redox‐Responsive Gene Delivery and Synergistic Cancer Chemotherapy , 2016, Advanced materials.

[5]  Yaping Li,et al.  Intracellularly Acid-Switchable Multifunctional Micelles for Combinational Photo/Chemotherapy of the Drug-Resistant Tumor. , 2016, ACS nano.

[6]  M. Zhang,et al.  Optimized Ultrasound Conditions for Enhanced Sensitivity of Molecular Beacons in the Detection of MDR1 mRNA in Living Cells. , 2016, Analytical chemistry.

[7]  B. Tang,et al.  AuNP flares-capped mesoporous silica nanoplatform for MTH1 detection and inhibition. , 2015, Biomaterials.

[8]  Zhengze Yu,et al.  A Near-Infrared Triggered Nanophotosensitizer Inducing Domino Effect on Mitochondrial Reactive Oxygen Species Burst for Cancer Therapy. , 2015, ACS nano.

[9]  Wei Du,et al.  Intracellular Self-Assembly of Taxol Nanoparticles for Overcoming Multidrug Resistance. , 2015, Angewandte Chemie.

[10]  N. Artzi,et al.  Bioresponsive antisense DNA gold nanobeacons as a hybrid in vivo theranostics platform for the inhibition of cancer cells and metastasis , 2015, Scientific Reports.

[11]  Na Li,et al.  Multiplexed detection and imaging of intracellular mRNAs using a four-color nanoprobe. , 2013, Analytical chemistry.

[12]  Cheng Zong,et al.  Tracking the intracellular drug release from graphene oxide using surface-enhanced Raman spectroscopy. , 2013, Nanoscale.

[13]  Na Li,et al.  Dual-targeted nanocarrier based on cell surface receptor and intracellular mRNA: an effective strategy for cancer cell imaging and therapy. , 2013, Analytical chemistry.

[14]  João Conde,et al.  Gold-nanobeacons for simultaneous gene specific silencing and intracellular tracking of the silencing events. , 2013, Biomaterials.

[15]  Weihong Tan,et al.  DNA micelle flares for intracellular mRNA imaging and gene therapy. , 2013, Angewandte Chemie.

[16]  Yuanyuan Liu,et al.  Graphene oxide used as a carrier for adriamycin can reverse drug resistance in breast cancer cells , 2012, Nanotechnology.

[17]  Na Li,et al.  A multicolor nanoprobe for detection and imaging of tumor-related mRNAs in living cells. , 2012, Angewandte Chemie.

[18]  Po-Jung Jimmy Huang,et al.  Molecular beacon lighting up on graphene oxide. , 2012, Analytical chemistry.

[19]  Afsaneh Lavasanifar,et al.  Traceable multifunctional micellar nanocarriers for cancer-targeted co-delivery of MDR-1 siRNA and doxorubicin. , 2011, ACS nano.

[20]  U. Gündüz,et al.  Drug resistant breast cancer cells overexpress ETS1 gene. , 2010, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[21]  Zongxi Li,et al.  Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line. , 2010, ACS nano.

[22]  M. Gottesman,et al.  Targeting multidrug resistance in cancer , 2006, Nature Reviews Drug Discovery.

[23]  Tymish Y. Ohulchanskyy,et al.  Optical tracking of organically modified silica nanoparticles as DNA carriers: a nonviral, nanomedicine approach for gene delivery. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[24]  P. Johnston,et al.  Molecular mechanisms of drug resistance , 2005, The Journal of pathology.

[25]  M. Duffy,et al.  Overexpression of the Ets-1 transcription factor in human breast cancer , 2004, British Journal of Cancer.

[26]  Kemin Wang,et al.  Bioconjugated nanoparticles for DNA protection from cleavage. , 2003, Journal of the American Chemical Society.

[27]  S. Pillai,et al.  Multiple drug resistance , 1999, Medicinal research reviews.

[28]  D. Patel,et al.  Molecular recognition in the FMN-RNA aptamer complex. , 1996, Journal of molecular biology.

[29]  Limin Yang,et al.  Simultaneous detection of multiple targets involved in the PI3K/AKT pathway for investigating cellular migration and invasion with a multicolor fluorescent nanoprobe. , 2016, Chemical communications.

[30]  Zhengze Yu,et al.  d dual-photosensitizer for drug-resistant cancer therapy with NIR activated multiple ROS † , 2016 .

[31]  M. Gottesman,et al.  Multidrug resistance in cancer: role of ATP–dependent transporters , 2002, Nature Reviews Cancer.