Journal
MOLECULAR THERAPY
Volume 16, Issue 5, Pages 942-946Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2008.51
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Funding
- NCI NIH HHS [R01 CA129835, R01 CA129835-01A1] Funding Source: Medline
- NIAID NIH HHS [R56 AI048851-07A1, R56 AI048851] Funding Source: Medline
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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 (IV) 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 IV injections of siRNA in the targeted NP significantly reduced the lung metastasis (similar to 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.
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