Design of a Novel PEGylated Liposomal Vector for Systemic Delivery of siRNA to Solid Tumors.

Abstract

A small interfering RNA (siRNA) delivery system using dioleylphosphate-diethylenetriamine conjugate (DOP-DETA)-based liposomes (DL) was assessed for systemic delivery of siRNA to tumors. DL carrying siRNA capable of inducing efficient gene silencing with low doses of siRNA were modified with polyethylene glycol (PEG-DL/siRNA) for systemic injection of siRNA. The biodistribution of DL and siRNA in the PEG-DL/siRNA was studied by using radiolabeled DL and fluorescence-labeled siRNA, respectively. DL in the PEG-DL/siRNA showed a high retention in the plasma, accumulation in the tumor, and low accumulation in the liver and spleen after intravenous injection. The in vivo effects of PEGylation were observed only when distearoylphosphatidylethanolamine (DSPE)-PEG but not distearoylglycerol (DSG)-PEG were used. This result suggests that the electrostatic interaction between lipid molecules on the surface of PEG-DL/siRNA was a critical determinant for the in vivo effect of PEGylation. When PEG-DL/siRNA (0.1 mg/kg siRNA) was intravenously injected into tumor-bearing mice, in vivo gene silencing was observed in subcutaneous tumors. These results indicate that PEG-DL/siRNA designed in this study is a promising formulation for systemic use of siRNA.

• Authors: Furan Song, Naoyuki Sakurai, Ayaka Okamoto, Hiroyuki Koide, Naoto Oku, Takehisa Dewa, Tomohiro Asai
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 42 Issue 6 Pg. 996-1003 ( 2019) ISSN: 1347-5215 [Electronic] Japan
• PMID: 31155597 (Publication Type: Journal Article)

Chemical References

• 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000)
• Cell Cycle Proteins
• Liposomes
• Phosphatidylethanolamines
• Proto-Oncogene Proteins
• RNA, Small Interfering
• Polyethylene Glycols
• Protein Serine-Threonine Kinases

Topics

• Animals
• Cell Cycle Proteins (genetics)
• Cell Line, Tumor
• Gene Silencing
• Genetic Vectors
• Humans
• Liposomes
• Liver (metabolism)
• Male
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neoplasms (genetics, metabolism)
• Phosphatidylethanolamines (administration & dosage, chemistry, pharmacokinetics)
• Polyethylene Glycols (administration & dosage, chemistry, pharmacokinetics)
• Protein Serine-Threonine Kinases (genetics)
• Proto-Oncogene Proteins (genetics)
• RNA, Small Interfering (administration & dosage, blood, chemistry, pharmacokinetics)
• Spleen (metabolism)
• Tissue Distribution
• Polo-Like Kinase 1