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

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.

Scheme illustrating the strategy of using apolipoprotein-decorated LPNs (lipid-polyethyleneimine nanoparticles) for targeting of megalin-upregulated chemo-treated breast cancer cells.Figure optionsDownload high-quality image (123 K)Download as PowerPoint slide