Targeting megalin to enhance delivery of anti-clusterin small-interfering RNA nanomedicine to chemo-treated breast cancer.

Abstract

The goal of this study is to evaluate a new targeting strategy to improve nanomedicine delivery to breast cancer cells that survive prior exposure to chemotherapy. These cells are particularly difficult to treat because they often develop drug resistance by upregulation of chemoresistant factors such as clusterin and should be preferably eradicated before they further spread out. In this study, the surface endocytotic receptor megalin was studied for the first time for targeted delivery of anti-clusterin small-interfering RNAs (siRNAs) to these chemo-treated cells. Lipid-polyethylenimine hybrid nanocarriers decorated with apolipoprotein E (Ap-LPNs) were developed for this purpose. Using immunoblotting, we demonstrated induction of both megalin and clusterin in MCF-7 cells by previous paclitaxel treatment. The siRNA transfection of these megalin-rich chemo-treated cancer cells was improved by three-fold when the siRNAs were delivered by Ap-LPNs. This trend was translatable into enhanced clusterin knockdown and improved chemosensitization to subsequent paclitaxel treatment (both p<0.05 versus uncoated LPNs). This proof-of-principle study has validated a novel "chemoresistance-targeting" strategy for siRNA delivery to the cancer cell subpopulation that begins to acquire chemoresistance and is in strong need for chemosensitization.

• Authors: Hui Yi Xue, Ho Lun Wong
• Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Eur J Pharm Biopharm) Vol. 81 Issue 1 Pg. 24-32 (May 2012) ISSN: 1873-3441 [Electronic] Netherlands
• PMID: 22369881 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Apolipoproteins E
• Clusterin
• Lipids
• Low Density Lipoprotein Receptor-Related Protein-2
• RNA, Small Interfering
• Polyethyleneimine
• Paclitaxel

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Apolipoproteins E (chemistry)
• Blotting, Western
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Clusterin (genetics)
• Drug Resistance, Neoplasm
• Female
• Gene Knockdown Techniques
• Humans
• Lipids (chemistry)
• Low Density Lipoprotein Receptor-Related Protein-2 (genetics)
• Nanoparticles
• Paclitaxel (pharmacology)
• Polyethyleneimine (chemistry)
• RNA, Small Interfering (administration & dosage)