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Nanoparticle Delivery of Pooled siRNA for Effective Treatment of Non-Small Cell Lung Caner

By Yang Yang (45629), Yunxia Hu (1723300), Yuhua Wang (289796), Jun Li (6494), Feng Liu (72874) and Leaf Huang (643562)


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

Topics: Biophysics, Biochemistry, Cell Biology, Genetics, Molecular Biology, Pharmacology, Biotechnology, Cancer, Biological Sciences not elsewhere classified, Physical Sciences not elsewhere classified, siRNA sequences, tumor apoptosis, oncogenic mechanisms, 549 tumors, siRNA codelivered, 549 xenografted tumor, 549 cells, HDM, antitumor activity, VEGF expressions, tumor proliferation, H 460 tumors, Pooled siRNA, tumor cells, nontargeted LCP, siRNA delivery efficiency, Targeted LCP, Effective Treatment, tumor cell growth, iv injection, gene therapy, NSCLC growth, Nanoparticle Delivery, VEGF oncogenes, ED 50, H 460 cells
Year: 2012
DOI identifier: 10.1021/mp300152v.s001
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Provided by: FigShare
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