title: Tumor-targeted delivery of siRNA by self-assembled nanoparticles.
abstract: 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, approximately 10% was detected in the liver and approximately 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 approximately 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).
authors.affiliation: Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Shyh-Dar
authors.initials: SD
authors.lastname: Li
authors.forename: Yun-Ching
authors.initials: YC
authors.lastname: Chen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hackett
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage*; D009928:Organ Specificity / Q000235:genetics; D034622:RNA Interference / Q000502:physiology*; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D034741:RNA, Small Interfering; D066246:ErbB Receptors