title: Novel endosomolytic poly(amido amine) polymer conjugates for systemic delivery of siRNA to hepatocytes in rodents and nonhuman primates.
abstract: The application of small interfering (si)RNAs as potential therapeutic agents requires safe and effective methods for their delivery to the cytoplasm of the target cells and tissues. Recent studies have shown significant progress in the development of targeting reagents that facilitate the recognition of, and siRNA delivery to, specific cell types. Among recently reported delivery approaches, polymers with amphipathic properties have been used to enable endosome escape and cytosolic delivery. Here, we describe a linear amphipathic poly(amido amine) polymer conjugate system for the efficient siRNA delivery in vitro and in vivo. This polymer contains a novel amine bearing bis-acrylamide monomer designed for increasing amine density, which resulted in substantial improvement in liver uptake and RNAi activity compared to our previously reported poly(amido amine disulfide) polymer.1 The activity for this liver targeted delivery system was demonstrated in rodents and nonhuman primates.
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Pharmaceutical Sciences, §Department of RNAi Biology, ∥Department of Pharmacokinetics, Pharmacodynamics & Drug Metabolism, ⊥Department of Process Chemistry, Merck & Co. , West Point, Pennsylvania 19438, United States.
authors.forename: Rubina Giare
authors.initials: RG
authors.lastname: Parmar
authors.forename: Micheal
authors.initials: M
authors.lastname: Poslusney
authors.forename: Marina
authors.initials: M
authors.lastname: Busuek
authors.forename: J Michael
authors.initials: JM
authors.lastname: Williams
authors.forename: Robert
authors.initials: R
authors.lastname: Garbaccio
authors.forename: Karen
authors.initials: K
authors.lastname: Leander
authors.forename: Eileen
authors.initials: E
authors.lastname: Walsh
authors.forename: Bonnie
authors.initials: B
authors.lastname: Howell
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.forename: Sean
authors.initials: S
authors.lastname: Riley
authors.forename: Mihir
authors.initials: M
authors.lastname: Patel
authors.forename: Eric
authors.initials: E
authors.lastname: Kemp
authors.forename: Andrew
authors.initials: A
authors.lastname: Latham
authors.forename: Anthony
authors.initials: A
authors.lastname: Leone
authors.forename: Eric
authors.initials: E
authors.lastname: Soli
authors.forename: Rob S
authors.initials: RS
authors.lastname: Burke
authors.forename: Brian
authors.initials: B
authors.lastname: Carr
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
authors.forename: Weimin
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008253:Macaca mulatta; D051379:Mice; D015394:Molecular Structure; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C531249:Poly(amidoamine); D011073:Polyamines; D034741:RNA, Small Interfering