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Cationic polymer-mediated small interfering RNA delivery for P-glycoprotein down-regulation in tumor cells†
Article first published online: 16 AUG 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 23, pages 5544–5554, 1 December 2010
How to Cite
Abbasi, M., Lavasanifar, A., Berthiaume, L. G., Weinfeld, M. and Uludağ, H. (2010), Cationic polymer-mediated small interfering RNA delivery for P-glycoprotein down-regulation in tumor cells. Cancer, 116: 5544–5554. doi: 10.1002/cncr.25321
We thank Ms. V. Incani for providing the lipid-substituted polymers and Dr. R. Clarke for the cell line used for this study.
- Issue published online: 23 NOV 2010
- Article first published online: 16 AUG 2010
- Manuscript Accepted: 9 FEB 2010
- Manuscript Received: 3 NOV 2009
- permeability glycoprotein;
- small interfering RNA;
- multidrug resistance;
- polymeric carriers;
Among the treatment options that have been developed for cancer, chemotherapy remains 1 of the leading clinical approaches. Chemotherapy can usually control tumor growth at the onset of disease, but its effectiveness becomes limited by the overexpression of transporter proteins responsible for drug efflux, leading to multidrug resistance (MDR). To overcome this obstacle, the authors explored the feasibility of down-regulating the main drug transporter, P-glycoprotein (P-gp), by using nonviral small interfering RNA (siRNA) delivery as means to enhance the accumulation of chemotherapeutic agents in drug-resistant cancer cells.
Several cationic carriers capable of siRNA complexation were investigated for P-gp down-regulation in the MDA435/LCC6 cell line and, consequently, increased cellular uptake of the chemotherapeutic agents doxorubicin and paclitaxel.
Efficient siRNA delivery into tumor cells was demonstrated particularly using a palmitic-acid substituted poly(L-lysine), with no apparent differences in siRNA delivery between the wild type (WT)-expressing and P-gp-expressing phenotype (MDR1) of the cells. Efficient siRNA delivery led to approximately 40% to 50% P-gp suppression (based on the average expression level of the protein), an approximately 3-fold increased DOX uptake, and increased cytotoxicity in MDR1 cells.
The authors concluded that effective siRNA delivery with nonviral carriers can reduce the level of P-gp on cell surfaces and enhance the efficiency of chemotherapeutic agents in vitro. Cancer 2010. © 2010 American Cancer Society.