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1. Eur J Pharm Biopharm. 2012 Jan 28. [Epub ahead of print]

Effective down-regulation of Breast Cancer Resistance Protein (BCRP) by siRNA
delivery using lipid-substituted aliphatic polymers.

Aliabadi HM, Landry B, Mahdipoor P, Hsu CY, Uludağ H.

Department of Chemical & Material Engineering, University of Alberta, Edmonton,
Canada.

Breast Cancer Resistance Protein (BCRP, ABCG2) is an efflux protein whose
aberrant activity has been linked to multidrug resistance in cancer. Although
siRNA delivery to down-regulate BCRP expression is promising to sensitize tumor
cells against drugs, therapeutic use of siRNA requires effective carriers that
can deliver siRNA intracellularly with minimal toxicity on target cells. This
study explored the feasibility of special class of cationic polymers, namely
lipid-substituted low molecular weight (2kDa) polyethyleneimine (PEI), as a
carrier for siRNA-mediated BCRP down-regulation. Structure-function studies
methodically evaluated the effect of a range of lipophilic substitutions for
siRNA delivery and BCRP down-regulation. Our results showed a significant
increase in siRNA delivery as a function of lipid substitution for a range of
lipids ranging from C8 to C18. The BCRP silencing was correlated to siRNA
delivery efficiency of the polymers, and effectively lasted for ∼5days after a
single treatment of siRNA. BCRP down-regulation sensitized the drug-resistant
cells to cytotoxic effect of mitoxantrone by a ∼14-fold decrease in the IC(50)
value, whose effect was evident even after 14days. This study demonstrated the
possibility of functional siRNA delivery by lipid-modified low molecular weight
PEI and highlighted the importance of the extent and nature of lipid substitution
in effective siRNA delivery.

Copyright © 2012 Elsevier B.V. All rights reserved.

PMID: 22311298 [PubMed - as supplied by publisher]