title: Delivery of siRNA to the mouse lung via a functionalized lipopolyamine.
abstract: We have designed a series of versatile lipopolyamines which are amenable to chemical modification for in vivo delivery of small interfering RNA (siRNA). This report focuses on one such lipopolyamine (Staramine), its functionalized derivatives and the lipid nanocomplexes it forms with siRNA. Intravenous (i.v.) administration of Staramine/siRNA nanocomplexes modified with methoxypolyethylene glycol (mPEG) provides safe and effective delivery of siRNA and significant target gene knockdown in the lungs of normal mice, with much lower knockdown in liver, spleen, and kidney. Although siRNA delivered via Staramine is initially distributed across all these organs, the observed clearance rate from the lung tissue is considerably slower than in other tissues resulting in prolonged siRNA accumulation on the timescale of RNA interference (RNAi)-mediated transcript depletion. Complete blood count (CBC) analysis, serum chemistry analysis, and histopathology results are all consistent with minimal toxicity. An in vivo screen of mPEG modified Staramine nanocomplexes-containing siRNAs targeting lung cell-specific marker proteins reveal exclusive transfection of endothelial cells. Safe and effective delivery of siRNA to the lung with chemically versatile lipopolyamine systems provides opportunities for investigation of pulmonary cell function in vivo as well as potential treatments of pulmonary disease with RNAi-based therapeutics.
authors: EGEN Inc., Huntsville, Alabama 35806, USA. kpolach@egeninc.com
authors: Kevin J
authors: KJ
authors: Polach
authors: Majed
authors: M
authors: Matar
authors: Jennifer
authors: J
authors: Rice
authors: Gregory
authors: G
authors: Slobodkin
authors: Jeff
authors: J
authors: Sparks
authors: Richard
authors: R
authors: Congo
authors: Angela
authors: A
authors: Rea-Ramsey
authors: Diane
authors: D
authors: McClure
authors: Elaine
authors: E
authors: Brunhoeber
authors: Monika
authors: M
authors: Krampert
authors: Andrea
authors: A
authors: Schuster
authors: Kerstin
authors: K
authors: Jahn-Hofmann
authors: Matthias
authors: M
authors: John
authors: Hans-Peter
authors: HP
authors: Vornlocher
authors: Jason G
authors: JG
authors: Fewell
authors: Khursheed
authors: K
authors: Anwer
authors: Anke
authors: A
authors: Geick
mesh_terms: D000818:Animals; D015317:Biogenic Polyamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001772:Blood Cell Count; D005260:Female; D020868:Gene Silencing; D007275:Injections, Intravenous; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D058726:Nanoconjugates / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
chemical_list: D015317:Biogenic Polyamines; D058726:Nanoconjugates; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol