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Pharm Res. 2011 Oct;28(10):2516-29. doi: 10.1007/s11095-011-0480-z. Epub 2011 Jun 3.

siRNA-mediated down-regulation of P-glycoprotein in a Xenograft tumor model in NOD-SCID mice.

Author information

1
Department of Biomedical Engineering, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada.

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 3 days. Intratumoral injection of siRNA with the carriers resulted in 60-80% and 20-32% of siRNA retention in tumors after 24 and 96 hr, 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.

PMID:
21638135
DOI:
10.1007/s11095-011-0480-z
[Indexed for MEDLINE]

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