Efficient gene silencing in metastatic tumor by siRNA formulated in surface-modified nanoparticles.
We have developed a nanoparticle (NP) formulation for systemically delivering siRNA into metastatic tumors. The NP, composed of nucleic acids, a polycationic peptide and cationic liposome, was prepared in a self-assembling process. The NP was then modified by PEG-lipid containing a targeting ligand, anisamide, and thus was decorated for targeting sigma receptor expressing B16F10 tumor. The activity of the targeted NP was compared with the naked NP (no PEGylation) and non-targeted NP (no ligand). The delivery efficiency of the targeted NP was 4-fold higher than the non-targeted NP and could be competed by excess free ligand. Luciferase siRNA was used to evaluate the gene silencing activity in the B16F10 cells, which were stably transduced with a luciferase gene. The gene silencing activity of the targeted NP was significantly higher than the other formulations and lasted for 4 days. While confocal microscopy showed that the naked NP provided no tissue selectivity and non-targeted NP was ineffective for tumor uptake, the targeted NP effectively penetrated the lung metastasis, but not the liver. It resulted in 70-80% gene silencing in the metastasis model after a single i.v. injection (150 microg siRNA/kg). This effective formulation also showed very little immunotoxicity.
Li
Shyh-Dar
SD
Division of Molecular Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Chono
Sumio
S
Huang
Leaf
L
D000818:Animals; D004247:DNA / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D008156:Luciferases / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy; D008546:Melanoma, Experimental / Q000235:genetics / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics; D013499:Surface Properties
D034741:RNA, Small Interfering; D004247:DNA; C427203:calf thymus DNA; D008156:Luciferases