Abstract
The development of effective, systemic therapies for metastatic cancer is highly desired. We show here that the systemic delivery of sequence-specific small interfering RNA (siRNA) against the EWS-FLI1 gene product by a targeted, nonviral delivery system dramatically inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. The nonviral delivery system uses a cyclodextrin-containing polycation to bind and protect siRNA and transferrin as a targeting ligand for delivery to transferrin receptor-expressing tumor cells. Removal of the targeting ligand or the use of a control siRNA sequence eliminates the antitumor effects. Additionally, no abnormalities in interleukin-12 and IFN-alpha, liver and kidney function tests, complete blood counts, or pathology of major organs are observed from long-term, low-pressure, low-volume tail-vein administrations. These data provide strong evidence for the safety and efficacy of this targeted, nonviral siRNA delivery system.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Growth Processes / genetics
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Cell Line, Tumor
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Disease Models, Animal
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Down-Regulation
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Female
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Gene Silencing
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Luciferases / biosynthesis
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Luciferases / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, SCID
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Neoplasm Metastasis
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Oncogene Proteins, Fusion / antagonists & inhibitors*
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Oncogene Proteins, Fusion / biosynthesis
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Oncogene Proteins, Fusion / genetics
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Proto-Oncogene Protein c-fli-1 / antagonists & inhibitors*
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Proto-Oncogene Protein c-fli-1 / biosynthesis
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Proto-Oncogene Protein c-fli-1 / genetics
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RNA, Small Interfering / administration & dosage*
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RNA, Small Interfering / genetics*
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RNA, Small Interfering / toxicity
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RNA-Binding Protein EWS
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Receptors, Transferrin / metabolism
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Sarcoma, Ewing / genetics
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Sarcoma, Ewing / metabolism
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Sarcoma, Ewing / pathology
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Sarcoma, Ewing / therapy*
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Transduction, Genetic
Substances
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EWS-FLI fusion protein
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Oncogene Proteins, Fusion
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Proto-Oncogene Protein c-fli-1
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RNA, Small Interfering
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RNA-Binding Protein EWS
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Receptors, Transferrin
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Luciferases