Nanolipoparticles-mediated MDR1 siRNA delivery reduces doxorubicin resistance in breast cancer cells and silences MDR1 expression in xenograft model of human breast cancer

Abstract

<em>Objective(s):</em> P-glycoprotein (P-gp) is an efflux protein, the overexpression of which has been associated with multidrug resistance in various cancers. Although siRNA delivery to reverse P-gp expression may be promising for sensitizing of tumor cells to cytotoxic drugs, the therapeutic use of siRNA requires effective carriers that can deliver siRNA intracellularly with minimal toxicity on target cells. We investigated a special class of PEGylated lipid-based nanoparticles (NP), named nanolipoparticles (NLPs), for siRNA-mediated P-gp downregulation. <em>Materials and Methods:</em> NLPs were prepared based on low detergent dialysis method. After characterization, we evaluated the effect of NLPs on siRNA delivery, and P-gp downregulation compared to oligofectamine^TM (OFA) in<em> vitro</em> and <em>in vivo</em>. <em>Results: </em>Our results showed a significant decrease in P-gp expression and subsequent enhancement of chemosensitivity to doxorubicin <em>in vitro</em>. Although the effectiveness of NLPs for <em>in vitro</em> siRNA delivery compared to OFA was limited, the results of <em>in vivo</em> studies showed noticeable effectiveness of NLPs for systemic siRNA delivery. siRNA delivery using NLPs could downregulate <em>MDR1 </em>in tumor cells more than 80%, while OFA had a reverse effect on <em>MDR1</em> expression <em>in vivo</em>. <em>Conclusion:</em> The results indicated that the prepared NLPs could be suitable siRNA delivery systems for tumor therapy.