In vivo specific delivery of c-Met siRNA to glioblastoma using cationic solid lipid nanoparticles.

Abstract

RNA interference is a powerful strategy that inhibits gene expression through specific mRNA degradation. In vivo, however, the application of small interfering RNAs (siRNAs) is severely limited by their instability and their poor delivery into target cells and tissues. This is especially true with glioblastomas (GBMs), the most frequent and malignant form of brain tumor, that has limited treatment options due to the largely impenetrable blood-brain barrier. Here, cationic solid lipid nanoparticles (SLN), reconstituted from natural components of protein-free low-density lipoprotein, was conjugated to PEGylated c-Met siRNA. The c-Met siRNA-PEG/SLN complex efficiently down-regulated c-Met expression level, as well as decreased cell proliferation in U-87MG in vitro. In orthotopic U-87MG xenograft tumor model, intravenous administration of the complex significantly inhibited c-Met expression at the tumor tissue and suppressed tumor growth without showing any systemic toxicity in mice. Use of Cy5.5 conjugated SLN revealed enhanced accumulation of the siRNA-PEG/SLN complexes specifically in the brain tumor. Our data demonstrates the feasibility of using siRNA-PEG/SLN complexes as a potential carrier of therapeutic siRNAs for the systemic treatment of GBM in the clinic.

• Authors: Juyoun Jin, Ki Hyun Bae, Heekyoung Yang, Se Jeong Lee, Hyein Kim, Yonghyun Kim, Kyeung Min Joo, Soo Won Seo, Tae Gwan Park, Do-Hyun Nam
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 22 Issue 12 Pg. 2568-72 (Dec 21 2011) ISSN: 1520-4812 [Electronic] United States
• PMID: 22070554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipids
• Lipoproteins, LDL
• RNA, Small Interfering
• Polyethylene Glycols
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Brain (metabolism, pathology)
• Brain Neoplasms (genetics)
• Cell Line, Tumor
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Glioblastoma (genetics, pathology)
• Humans
• Lipids (chemistry)
• Lipoproteins, LDL (chemistry)
• Male
• Mice
• Mice, Inbred BALB C
• Nanoparticles (chemistry)
• Polyethylene Glycols (chemistry)
• Proto-Oncogene Proteins c-met (genetics)
• RNA, Small Interfering (administration & dosage, genetics)