Novel cationic lipid that delivers siRNA and enhances therapeutic effect in lung cancer cells.

Abstract

We have developed lipid-polycation-DNA (LPD) nanoparticles containing DOTAP and targeted with polyethylene glycol (PEG) tethered with anisamide (AA) to specifically deliver siRNA to H460 human lung carcinoma cells which express the sigma receptor. A novel non-glycerol based cationic lipid which contains both a guanidinium and a lysine residue as the cationic headgroup, i.e. DSGLA, downregulated pERK more efficiently in H460 cells than DOTAP. As demonstrated by using fluorescently labeled siRNA, LPD-PEG-AA prepared with DSGLA efficiently delivered siRNA to the cytoplasm of the H460 cells. Although the siRNA delivered by LPD-PEG-AA containing either DOTAP or DSGLA could effectively silence EGFR expression, a synergistic cell killing effect in promoting cellular apoptosis was only observed with DSGLA. The fluorescently labeled siRNA was efficiently delivered into the cytoplasm of H460 xenograft tumor by the LPD-PEG-AA containing either DOTAP or DSGLA 4 h after intravenous injection. Three daily injections (0.6 mg/kg) of siRNA formulated in the LPD-PEG-AA containing either DOTAP or DSGLA could effectively silence the epidermal growth factor receptor (EGFR) in the tumor, but the formulation containing DSGLA could induce more cellular apoptosis. A significant improvement in tumor growth inhibition was observed after dosing with LPD-PEG-AA containing DSGLA. Thus, DSGLA served as both a formulation component as well as a therapeutic agent which synergistically enhanced the activity of siRNA.

• Authors: Yunching Chen, Joyeeta Sen, Surendar Reddy Bathula, Qi Yang, Raffaella Fittipaldi, Leaf Huang
• Journal: Molecular pharmaceutics (Mol Pharm) 2009 May-Jun Vol. 6 Issue 3 Pg. 696-705 ISSN: 1543-8384 [Print] United States
• PMID: 19267451 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Lipids
• RNA, Small Interfering
• Polyethylene Glycols
• ErbB Receptors
• Guanidine
• Lysine

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• ErbB Receptors (genetics)
• Female
• Gene Silencing
• Guanidine (chemistry)
• Humans
• Lipids (chemistry)
• Lysine (chemistry)
• Mice
• Mice, Nude
• Microscopy, Fluorescence
• Nanoparticles (chemistry)
• Polyethylene Glycols
• RNA, Small Interfering (chemical synthesis, pharmacokinetics, pharmacology, therapeutic use)
• Small Cell Lung Carcinoma (drug therapy)