期刊
MOLECULAR THERAPY
卷 16, 期 1, 页码 163-169出版社
CELL PRESS
DOI: 10.1038/sj.mt.6300323
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资金
- NCI NIH HHS [R01 CA129835-01A1, R01 CA129835] Funding Source: Medline
- NIAID NIH HHS [R56 AI048851-07A1, R56 AI048851] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA129835] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R56AI048851] Funding Source: NIH RePORTER
We have developed a self-assembled nanoparticle (NP) that efficiently delivers small interfering RNA ( siRNA) to the tumor by intravenous (IV) administration. The NP was obtained by mixing carrier DNA, siRNA, protamine, and lipids, followed by post-modification with polyethylene glycol and a ligand, anisamide. Four hours after IV injection of the formulation into a xenograft model, 70-80% of injected siRNA/g accumulated in the tumor, similar to 10% was detected in the liver and similar to 20% recovered in the lung. Confocal microscopy showed that fluorescent-labeled siRNA was efficiently delivered into the cytoplasm of the sigma receptor expressing NCI-H460 xenograft tumor by the targeted NPs, whereas free siRNA and non-targeted NPs showed little uptake. Three daily injections (1.2 mg/kg) of siRNA formulated in the targeted NPs silenced the epidermal growth factor receptor ( EGFR) in the tumor and induced similar to 15% tumor cell apoptosis. Forty percent tumor growth inhibition was achieved by treatment with targeted NPs, while complete inhibition lasted for 1 week when combined with cisplatin. The serum level of liver enzymes and body weight monitoring during the treatment indicated a low level of toxicity of the formulation. The carrier itself also showed little immunotoxicity (IMT).
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