title: Systemic delivery of siRNA via LCP nanoparticle efficiently inhibits lung metastasis.
abstract: Targeted delivery remains the major challenge for the application of small interfering RNA (siRNA). We have developed a lipid/calcium/phosphate (LCP) nanoparticle (NP) to improve siRNA delivery efficiency. The LCP NP was prepared by using microemulsion technology to form calcium/phosphate (CaP) core and further coated with cationic lipids. The final NP was grafted with polyethylene glycol (PEG) and anisamide (AA) ligand on the surface to target sigma receptor-expressing B16F10 melanoma cells. The LCP NP exhibited a 40 nm particle size, a +25 mV zeta-potential, and 91% siRNA encapsulation efficiency. After a single intravenous (i.v.) injection of antiluciferase siRNA (0.12 mg siRNA/kg) formulated in targeted LCP NP, luciferase activity in metastatic B16F10 tumor-loaded lungs decreased by 78% in C57BL/6 mice. In a therapeutic experiment, siRNA against MDM2, c-myc, and VEGF coformulated in the targeted LCP NP resulted in simultaneous silencing of the respective oncogenes in metastatic nodules. Treatment with siRNA in the targeted NP significantly reduced lung metastases (~70-80%) at a relatively low dose (0.36 mg/kg), whereas control group showed little therapeutic effect. Moreover, this targeted LCP NP significantly prolonged the mean survival time of the animals by 27.8% compared to control group without showing any toxicity at the therapeutic dose.
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D001774:Blood Chemical Analysis; D002130:Calcium Phosphates; D045744:Cell Line, Tumor; D005260:Female; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D008081:Liposomes; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary* / Q000628:therapy*; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*
chemical_list: D002130:Calcium Phosphates; D008081:Liposomes; D034741:RNA, Small Interfering; C020243:calcium phosphate