title: An in vivo evaluation of amphiphilic, biodegradable peptide copolymers as siRNA delivery agents.
abstract: A series of amphiphilic, biodegradable polypeptide copolymers were prepared for the delivery of siRNA (short interfering ribonucleic acid). The molecular weight (or polymer chain length) of the linear polymer was controlled by reaction stoichiometry for the 11.5, 17.2, and 24.6 kDa polypeptides, and the highest molecular weight polypeptide was prepared using a sequential addition method to obtain a polypeptide having a molecular weight of 38.6 kDa. These polymers were used to prepare polymer conjugate systems designed to target and deliver an apolipoprotein B (ApoB) siRNA to hepatocyte cells and to help delineate the effect of polymer molecular weight or polymer chain length on siRNA delivery in vivo. A clear trend in increasing potency was found with increasing molecular weight of the polymers examined (at a constant polymer:siRNA (w/w) ratio), with minimal toxicity found. Furthermore, the biodegradability of these polymer conjugates was examined and demonstrates the potential of these systems as siRNA delivery vectors.
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: stephanie_barrett@merck.com.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Barrett
authors.affiliation: Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Marc T
authors.initials: MT
authors.lastname: Abrams
authors.affiliation: Department of Pharmacokinetics & Drug Metabolism RNA, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Rob
authors.initials: R
authors.lastname: Burke
authors.affiliation: Department of Pharmacokinetics & Drug Metabolism RNA, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Carr
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Louis S
authors.initials: LS
authors.lastname: Crocker
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.affiliation: Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Bonnie J
authors.initials: BJ
authors.lastname: Howell
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Kemp
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kowtoniuk
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Latham
authors.affiliation: Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Leander
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Leone
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Mihir
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Pechenov
authors.affiliation: Department of Pharmacokinetics & Drug Metabolism RNA, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Nicole T
authors.initials: NT
authors.lastname: Pudvah
authors.affiliation: Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Riley
authors.affiliation: Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.affiliation: Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Walsh
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Williams
authors.affiliation: Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics*; D005260:Female; D008099:Liver / Q000378:metabolism; D008970:Molecular Weight; D009952:Ornithine / Q000737:chemistry*; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D010649:Phenylalanine / Q000737:chemistry*; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D017207:Rats, Sprague-Dawley
chemical_list: D001055:Apolipoproteins B; D010455:Peptides; D011108:Polymers; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D010649:Phenylalanine; D009952:Ornithine
keywords: Poly(peptides); Polymer conjugates; RNA delivery; siRNA