title: Versatile cationic lipids for siRNA delivery.
abstract: Exploitation of the RNA interference (RNAi) pathway offers the promise of new and effective therapies for a wide variety of diseases. Clinical development of new drugs based on this platform technology is still limited, however, by a lack of safe and efficient delivery systems. Here we report the development of a class of structurally versatile cationic lipopolyamines designed specifically for delivery of siRNA which show high levels of target transcript knockdown in a range of cell types in vitro. A primary benefit of these lipids is the ease with which they may be covalently modified by the addition of functional molecules. For in vivo applications one of the core lipids (Staramine) was modified with methoxypolyethylene glycols (mPEGs) of varying lengths. Upon systemic administration, PEGylated Staramine nanoparticles containing siRNA targeting the caveolin-1 (Cav-1) transcript caused a reduction of the Cav-1 transcript of up to 60%, depending on the mPEG length, specifically in lung tissue after 48h compared to treatment with non-silencing siRNA. In addition, modification with mPEG reduced toxicity associated with intravenous administration. The ability to produce a high level of target gene knockdown in the lung with minimal toxicity demonstrates the potential of these lipopolyamines for use in developing RNAi therapeutics for pulmonary disease.
authors.affiliation: EGEN Inc., 601 Genome Way, Huntsville AL 35806, USA. jsparks@egeninc.com
authors.forename: Jeff
authors.initials: J
authors.lastname: Sparks
authors.forename: Gregory
authors.initials: G
authors.lastname: Slobodkin
authors.forename: Majed
authors.initials: M
authors.lastname: Matar
authors.forename: Richard
authors.initials: R
authors.lastname: Congo
authors.forename: David
authors.initials: D
authors.lastname: Ulkoski
authors.forename: Angela
authors.initials: A
authors.lastname: Rea-Ramsey
authors.forename: Casey
authors.initials: C
authors.lastname: Pence
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rice
authors.forename: Diane
authors.initials: D
authors.lastname: McClure
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Polach
authors.forename: Elaine
authors.initials: E
authors.lastname: Brunhoeber
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilkinson
authors.forename: Kirby
authors.initials: K
authors.lastname: Wallace
authors.forename: Khursheed
authors.initials: K
authors.lastname: Anwer
authors.forename: Jason G
authors.initials: JG
authors.lastname: Fewell
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018014:Gene Transfer Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008055:Lipids / Q000008:administration & dosage* / Q000138:chemical synthesis; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D011073:Polyamines / Q000008:administration & dosage* / Q000138:chemical synthesis; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics*
chemical_list: D051242:Caveolin 1; D008055:Lipids; D011073:Polyamines; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D007770:L-Lactate Dehydrogenase