title: Synthesis of poly(amidoamine) dendron-bearing lipids with poly(ethylene glycol) grafts and their use for stabilization of nonviral gene vectors.
abstract: Recently, we developed a new type of cationic lipid that consists of an amine-terminated poly(amidoamine) dendron and two long alkyl groups. These dendron-bearing lipids achieved efficient gene transfection of cells through synergetic action of the proton sponge effect and membrane fusion in combination with fusogenic lipid dioleoylphosphatidylethanolamine. Using those dendron-bearing lipids as a base material, we developed in this study a functional component of gene vectors that stabilizes lipoplexes by multiple PEG chains and promotes gene transfection through the proton sponge effect. We combined a poly(ethylene glycol) (PEG, 550 Da) graft to each of four chain ends of the G2 dendron-bearing lipid (P4-DL). An analogous molecule having single PEG graft was also synthesized using the G0 dendron-bearing lipid (P1-DL). Inclusion of P4-DL decreased the size of the G3 dendron-bearing lipid-based lipoplexes more efficiently than P1-DL. In addition, P4-DL-containing lipoplexes exhibited two-orders-higher transfection efficiency than P1-DL-containing lipoplexes with the same PEG graft density. These results indicate the superiority of multiple attachments of PEG graft chains to a lipid for heightened ability to increase colloidal stability of lipoplexes while retaining their transfection activity. The lipoplexes stabilized by P4-DL were small, around 250 nm, and achieved efficient transfection in the presence of serum. Therefore, P4-DL and its analogues will form the basis for production of efficient nonviral vectors for in vivo use.
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
authors.forename: Toshinari
authors.initials: T
authors.lastname: Takahashi
authors.forename: Jun
authors.initials: J
authors.lastname: Hirose
authors.forename: Chie
authors.initials: C
authors.lastname: Kojima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Harada
authors.forename: Kenji
authors.initials: K
authors.lastname: Kono
mesh_terms: D045744:Cell Line, Tumor; D004247:DNA / Q000008:administration & dosage; D050091:Dendrimers; D005822:Genetic Vectors; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D010957:Plasmids; D011073:Polyamines / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D014162:Transfection / Q000379:methods*
chemical_list: D050091:Dendrimers; D008055:Lipids; C104700:PAMAM Starburst; D011073:Polyamines; D011092:Polyethylene Glycols; D004247:DNA