Efficient oncogene silencing and metastasis inhibition via systemic delivery of siRNA.
The selective delivery of small interfering RNA (siRNA) to metastatic tumors remains a challenging task. We have developed a nanoparticle (NP) formulation composed of siRNA, a carrier DNA, a polycationic peptide, and cationic liposomes. The NP was obtained by a self-assembling process, followed by surface modification with a polyethylene glycol (PEG)-conjugated ligand, anisamide. The NP was PEGylated and a ligand was presented to target sigma receptor-expressing murine melanoma cells, B16F10. The lung metastasis model was established by intravenous (i.v.) injection of the B16F10 cells into C57BL/6 mice. A mixture of siRNA against MDM2, c-myc, and vascular endothelial growth factor (VEGF) co-formulated in the targeted NP caused simultaneous silencing of each of the oncogenes in the metastatic nodules. Two consecutive i.v. injections of siRNA in the targeted NP significantly reduced the lung metastasis (approximately 70-80%) at a relatively low dose (0.45 mg/kg), whereas free siRNA and the nontargeted NP showed little effect. This targeted NP formulation significantly prolonged the mean survival time of the animals by 30% as compared to the untreated controls. At the therapeutic dose, the targeted NP showed little local and systemic immunotoxicity and did not decrease the body weight or damage the major organs.
Li
Shyh-Dar
SD
Division of Molecular Pharmaceutics, Department of Pharmaceutical Sciences, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Chono
Sumio
S
Huang
Leaf
L
D000818:Animals; D002412:Cations; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D008024:Ligands; D008081:Liposomes / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D009857:Oncogenes; D034741:RNA, Small Interfering / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D002412:Cations; D008024:Ligands; D008081:Liposomes; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A