title: Endosomolytic bioreducible poly(amido amine disulfide) polymer conjugates for the in vivo systemic delivery of siRNA therapeutics.
abstract: Efficient siRNA delivery is dependent not only on the ability of the delivery vehicle to target a specific organ but also on its ability to enable siRNA entry into the cytoplasm of the target cells. Polymers with endosomolytic properties are increasingly being used as siRNA delivery vehicles due to their potential to facilitate endosomal escape and intracellular delivery. Addition of disulfide bonds in the backbone of these polymers was expected to provide degradability through reduction by glutathione in cytosol. This paper describes the synthesis of new endosomolytic bioreducible poly(amido amine disulfide) polymers whose lytic potential can be masked at physiological pH, but can be restored at acidic endosomal pH. These polymer conjugates gave good in vitro knockdown (KD) and did not demonstrate cytotoxicity in a MTS assay. Efficient mRNA KD for apolipoprotein B in mouse liver was observed with these polyconjugates following intravenous dosing.
authors.affiliation: Department of Medicinal Chemistry, Merck & Co. Inc, West Point, PA, USA. rubina_parmar@merck.com
authors.forename: Rubina Giare
authors.initials: RG
authors.lastname: Parmar
authors.forename: Marina
authors.initials: M
authors.lastname: Busuek
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Walsh
authors.forename: Karen R
authors.initials: KR
authors.lastname: Leander
authors.forename: Bonnie J
authors.initials: BJ
authors.lastname: Howell
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.forename: Eric
authors.initials: E
authors.lastname: Kemp
authors.forename: Louis S
authors.initials: LS
authors.lastname: Crocker
authors.forename: Anthony
authors.initials: A
authors.lastname: Leone
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kochansky
authors.forename: Brian A
authors.initials: BA
authors.lastname: Carr
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
authors.forename: Weimin
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000172:deficiency / Q000235:genetics; D004220:Disulfides / Q000737:chemistry*; D016503:Drug Delivery Systems; D011992:Endosomes / Q000378:metabolism*; D004912:Erythrocytes / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011073:Polyamines / Q000737:chemistry*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D001055:Apolipoproteins B; D004220:Disulfides; C531249:Poly(amidoamine); D011073:Polyamines; D012333:RNA, Messenger; D034741:RNA, Small Interfering