title: Improving the in vivo therapeutic index of siRNA polymer conjugates through increasing pH responsiveness.
abstract: Polymer based carriers that aid in endosomal escape have proven to be efficacious siRNA delivery agents in vitro and in vivo; however, most suffer from cytotoxicity due in part to a lack of selectivity for endosomal versus cell membrane lysis. For polymer based carriers to move beyond the laboratory and into the clinic, it is critical to find carriers that are not only efficacious, but also have margins that are clinically relevant. In this paper we report three distinct categories of polymer conjugates that improve the selectivity of endosomal membrane lysis by relying on the change in pH associated with endosomal trafficking, including incorporation of low pKa heterocycles, acid cleavable amino side chains, or carboxylic acid pH sensitive charge switches. Additionally, we determine the therapeutic index of our polymer conjugates in vivo and demonstrate that the incorporation of pH responsive elements dramatically expands the therapeutic index to 10-15, beyond that of the therapeutic index (less than 3), for polymer conjugates previously reported.
authors.affiliation: Department of Process Chemistry and ∥Department of Analytical Chemistry, Merck & Co. Inc. , , Rahway, New Jersey, United States.
authors.forename: Erin N
authors.initials: EN
authors.lastname: Guidry
authors.forename: Julie
authors.initials: J
authors.lastname: Farand
authors.forename: Arash
authors.initials: A
authors.lastname: Soheili
authors.forename: Craig A
authors.initials: CA
authors.lastname: Parish
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Kevin
authors.forename: Brenda
authors.initials: B
authors.lastname: Pipik
authors.forename: Kathleen B
authors.initials: KB
authors.lastname: Calati
authors.forename: Nori
authors.initials: N
authors.lastname: Ikemoto
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Waldman
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Latham
authors.forename: Bonnie J
authors.initials: BJ
authors.lastname: Howell
authors.forename: Anthony
authors.initials: A
authors.lastname: Leone
authors.forename: Robert M
authors.initials: RM
authors.lastname: Garbaccio
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Barrett
authors.forename: Rubina Giare
authors.initials: RG
authors.lastname: Parmar
authors.forename: Quang T
authors.initials: QT
authors.lastname: Truong
authors.forename: Bing
authors.initials: B
authors.lastname: Mao
authors.forename: Ian W
authors.initials: IW
authors.lastname: Davies
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
mesh_terms: D000818:Animals; D006863:Hydrogen-Ion Concentration; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats
chemical_list: D011108:Polymers; D034741:RNA, Small Interfering