title: Discovery of siRNA lipid nanoparticles to transfect suspension leukemia cells and provide in vivo delivery capability.
abstract: As a powerful research tool, siRNA's therapeutic and target validation utility with leukemia cells and long-term gene knockdown is severely restricted by the lack of omnipotent, safe, stable, and convenient delivery. Here, we detail our discovery of siRNA-containing lipid nanoparticles (LNPs) able to effectively transfect several leukemia and difficult-to-transfect adherent cell lines also providing in vivo delivery to mouse spleen and bone marrow tissues through tail-vein administration. We disclose a series of novel structurally related lipids accounting for the superior transfection ability, and reveal a correlation between expression of Caveolins and successful transfection. These LNPs, bearing low toxicity and long stability of >6 months, are ideal for continuous long-term dosing. Our discovery represents the first effective siRNA-containing LNPs for leukemia cells, which not only enables high-throughput siRNA screening with leukemia cells and difficult-to-transfect adherent cells but also paves the way for the development of therapeutic siRNA for leukemia treatment.
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc., Nutley, New Jersey, USA; Current Addresses: Early Discovery, AbbVie Inc., North Chicago, Illinois, USA (W.H.); Monsanto, Davis, California, USA (M.J.B.); Discovery Oncology, Celgene, San Diego, California, USA (J.F.B.). Electronic address: whe@abbvie.com.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: PARD, Hoffmann-La Roche Inc., Nutley, New Jersey, USA; Current Addresses: Early Discovery, AbbVie Inc., North Chicago, Illinois, USA (W.H.); Monsanto, Davis, California, USA (M.J.B.); Discovery Oncology, Celgene, San Diego, California, USA (J.F.B.).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bennett
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Luistro
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: Daisy
authors.initials: D
authors.lastname: Carvajal
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nevins
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Smith
authors.affiliation: Non-clinical Safety, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Tyagi
authors.affiliation: pRED Informatics, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: James
authors.initials: J
authors.lastname: Cai
authors.affiliation: pRED Informatics, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: Tai-An
authors.initials: TA
authors.lastname: Lin
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Heimbrook
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.affiliation: Discovery Oncology, Hoffmann-La Roche Inc., Nutley, New Jersey, USA; Current Addresses: Early Discovery, AbbVie Inc., North Chicago, Illinois, USA (W.H.); Monsanto, Davis, California, USA (M.J.B.); Discovery Oncology, Celgene, San Diego, California, USA (J.F.B.). Electronic address: jboylan@celgene.com.
authors.forename: John F
authors.initials: JF
authors.lastname: Boylan
mesh_terms: D000818:Animals; D000838:Anions / Q000737:chemistry; D002412:Cations / Q000737:chemistry; D022461:Caveolins / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006801:Humans; D007938:Leukemia / Q000235:genetics; D008055:Lipids / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D014162:Transfection / Q000379:methods
chemical_list: D000838:Anions; D002412:Cations; D022461:Caveolins; D008055:Lipids; D011108:Polymers; D034741:RNA, Small Interfering