Nanoparticle Delivery
of Pooled siRNA for Effective
Treatment of Non-Small Cell Lung Caner
- Publication date
- 2012
- Publisher
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause
of cancer-related
death. To explore the potential of small interfering RNA (siRNA) therapy
for NSCLC, we have developed anisamide-targeted LCP to efficiently
deliver siRNA into the cytoplasm of sigma receptor-expressing NSCLC
cells. Targeted LCP demonstrated a 9-fold higher siRNA delivery efficiency
compared to nontargeted LCP in A549 cells <i>in vitro</i>. To simultaneously target multiple oncogenic mechanisms, we coformulated
three siRNA sequences targeting HDM2, c-myc and VEGF oncogenes, and
investigated their efficacy of cell-killing in A549 and H460 cells <i>in vitro</i>. The results indicated that the pooled siRNA codelivered
by the targeted LCP could effectively and simultaneously knock down
HDM2, c-myc and VEGF expressions and significantly inhibit tumor cell
growth. After iv injection of mice bearing A549 xenografted tumor
with Texas Red-labeled siRNA formulated in the targeted LCP, siRNA
was successfully delivered to and concentrated in the tumor cells.
Repeated intravenous injections of mice with pooled siRNA formulated
in the targeted LCP significantly impaired NSCLC growth <i>in
vivo</i> (<i>p</i> < 0.01) for both A549 and H460
tumors, demonstrating an ED<sub>50</sub> for the treatment of ∼0.2
mg/kg in A549 tumors. The enhanced antitumor activity is due to the
fact that the silencing of HDM2/c-myc/VEGF could inhibit tumor proliferation
and angiogenesis and also simultaneously induce tumor apoptosis. Our
results demonstrate that the targeted LCP is a promising vector to
deliver pooled siRNA into tumors and to achieve multiple target blocking.
This is potentially a valid therapeutic modality in the gene therapy
of human NSCLC