title: 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.affiliation: Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Yunching
authors.initials: Y
authors.lastname: Chen
authors.forename: Joyeeta
authors.initials: J
authors.lastname: Sen
authors.forename: Surendar Reddy
authors.initials: SR
authors.lastname: Bathula
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.forename: Raffaella
authors.initials: R
authors.lastname: Fittipaldi
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D019791:Guanidine / Q000737:chemistry; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry; D011092:Polyethylene Glycols; D034741:RNA, Small Interfering / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy*
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols; D066246:ErbB Receptors; D019791:Guanidine; D008239:Lysine