Nanoparticle delivery of pooled siRNA for effective treatment of non-small cell lung cancer.
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 in vitro. 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 in vitro. 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 in vivo (p < 0.01) for both A549 and H460 tumors, demonstrating an ED50 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.
Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Yang
Y
Yang
Yunxia
Y
Hu
Yuhua
Y
Wang
Jun
J
Li
Feng
F
Liu
Leaf
L
Huang
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2