caa a22 4500 445313072 CHVBK 20180317142637.0 cr unu---uuuuu 170323e20111001xx s 000 0 eng 10.1007/s11095-011-0480-z doi (NATIONALLICENCE)springer-10.1007/s11095-011-0480-z siRNA-Mediated Down-Regulation of P-glycoprotein in a Xenograft Tumor Model in NOD-SCID Mice [Elektronische Daten] [Meysam Abbasi, Hamidreza Aliabadi, Elaine Moase, Afsaneh Lavasanifar, Kamaljit Kaur, Raymond Lai, Charles Doillon, Hasan Uludağ] ABSTRACT: Purpose: The efficacy of chemotherapy is decreased due to over-expression of the drug transporter P-glycoprotein (P-gp). This study was conducted to determine the feasibility of down-regulating tumor P-gp levels with non-viral siRNA delivery in order to sensitize the tumors to drug therapy. Methods: P-gp over-expressing MDA435/LCC6 MDR1 cells were used to establish xenografts in NOD-SCID mouse. Cationic polymers polyethylenimine (PEI) and stearic acid-substituted poly-L-lysine (PLL-StA) were formulated with P-gp- specific siRNAs and delivered intratumorally to explore the feasibility of P-gp down-regulation in tumors. Intravenous Doxil™ was administered to investigate tumor growth. Results: PEI and PLL-StA effectively delivered siRNA to MDA435/LCC6 MDR1 cells in vitro to reduce P-gp expression for 3days. Intratumoral injection of siRNA with the carriers resulted in 60-80% and 20-32% of siRNA retention in tumors after 24 and 96hr, respectively. This led to ~29.0% and ~61.5% P-gp down-regulation with PEI- and PLL-StA-mediated siRNA delivery, respectively. The P-gp down-regulation by intratumoral siRNA injection led to better response to systemic Doxil™ treatment, resulting in slowed tumor growth in originally doxorubicin-resistant tumors. Conclusion: Effective P-gp down-regulation was feasible with polymeric siRNA delivery in a xenograft model, resulting in an enhanced response to the drug therapy. Springer Science+Business Media, LLC, 2011 multidrug resistance nationallicence non-viral siRNA delivery nationallicence P-glycoprotein nationallicence polymeric biomaterials nationallicence xenograft nationallicence DOX : doxorubicin nationallicence HBSS : Hank's Balanced Salt Solution nationallicence MDR : multi-drug resistance nationallicence MDR1 : multi-drug resistance gene 1 expressing cells nationallicence NOD-SCID : non-obese/severe combined immunodeficient nationallicence PEI : polyethylenimine nationallicence P-gp : P-glycoprotein nationallicence PLL-StA : stearic acid substituted poly-L-lysine nationallicence siRNA : short interfering RNA nationallicence WT : wild-type cells nationallicence Abbasi Meysam Department of Biomedical Engineering, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada aut Aliabadi Hamidreza Department of Chemical & Materials Engineering Faculty of Engineering,, University of Alberta, #830 CME Building, T6G 2 G6, Edmonton, Alberta, Canada aut Moase Elaine Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada aut Lavasanifar Afsaneh Department of Chemical & Materials Engineering Faculty of Engineering,, University of Alberta, #830 CME Building, T6G 2 G6, Edmonton, Alberta, Canada aut Kaur Kamaljit Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada aut Lai Raymond Department of Laboratory Medicine & Pathology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada aut Doillon Charles CHUL's Research Centre, CHUQ, Laval University, Sillery, Quebec, Canada aut Uludağ Hasan Department of Biomedical Engineering, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2516-2529 0724-8741 28:10<2516 2011 28 11095 https://doi.org/10.1007/s11095-011-0480-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0480-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Abbasi Meysam Department of Biomedical Engineering, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada aut NATIONALLICENCE 700 1- Aliabadi Hamidreza Department of Chemical & Materials Engineering Faculty of Engineering,, University of Alberta, #830 CME Building, T6G 2 G6, Edmonton, Alberta, Canada aut NATIONALLICENCE 700 1- Moase Elaine Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada aut NATIONALLICENCE 700 1- Lavasanifar Afsaneh Department of Chemical & Materials Engineering Faculty of Engineering,, University of Alberta, #830 CME Building, T6G 2 G6, Edmonton, Alberta, Canada aut NATIONALLICENCE 700 1- Kaur Kamaljit Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada aut NATIONALLICENCE 700 1- Lai Raymond Department of Laboratory Medicine & Pathology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada aut NATIONALLICENCE 700 1- Doillon Charles CHUL's Research Centre, CHUQ, Laval University, Sillery, Quebec, Canada aut NATIONALLICENCE 700 1- Uludağ Hasan Department of Biomedical Engineering, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2516-2529 0724-8741 28:10<2516 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer