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Development of a liver-targeted siRNA delivery platform with a broad therapeutic window utilizing biodegradable polypeptide-based polymer conjugates.
Barrett, Stephanie E; Burke, Rob S; Abrams, Marc T; Bason, Carol; Busuek, Marina; Carlini, Edward; Carr, Brian A; Crocker, Louis S; Fan, Haihong; Garbaccio, Robert M; Guidry, Erin N; Heo, Jun H; Howell, Bonnie J; Kemp, Eric A; Kowtoniuk, Robert A; Latham, Andrew H; Leone, Anthony M; Lyman, Michael; Parmar, Rubina G; Patel, Mihir; Pechenov, Sergey Y; Pei, Tao; Pudvah, Nicole T; Raab, Conrad; Riley, Sean; Sepp-Lorenzino, Laura; Smith, Sheri; Soli, Eric D; Staskiewicz, Steven; Stern, Melissa; Truong, Quang; Vavrek, Marissa; Waldman, Jacob H; Walsh, Eileen S; Williams, J Michael; Young, Stephanie; Colletti, Steven L.
Affiliation
  • Barrett SE; Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: stephanie_barrett@merck.com.
  • Burke RS; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Abrams MT; Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Bason C; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Busuek M; Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Carlini E; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Carr BA; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Crocker LS; Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Fan H; Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Garbaccio RM; Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Guidry EN; Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Heo JH; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Howell BJ; Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Kemp EA; Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Kowtoniuk RA; Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Latham AH; Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Leone AM; Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Lyman M; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Parmar RG; Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Patel M; Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Pechenov SY; Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Pei T; Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Pudvah NT; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Raab C; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Riley S; Department of RNAi Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Sepp-Lorenzino L; Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Smith S; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Soli ED; Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Staskiewicz S; Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Stern M; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Truong Q; Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Vavrek M; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Waldman JH; Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065, USA.
  • Walsh ES; Department of RNA Biology, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Williams JM; Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Young S; Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
  • Colletti SL; Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
J Control Release ; 183: 124-37, 2014 Jun 10.
Article in En | MEDLINE | ID: mdl-24657948
ABSTRACT
The greatest challenge standing in the way of effective in vivo siRNA delivery is creating a delivery vehicle that mediates a high degree of efficacy with a broad therapeutic window. Key structure-activity relationships of a poly(amide) polymer conjugate siRNA delivery platform were explored to discover the optimized polymer parameters that yield the highest activity of mRNA knockdown in the liver. At the same time, the poly(amide) backbone of the polymers allowed for the metabolism and clearance of the polymer from the body very quickly, which was established using radiolabeled polymers to demonstrate the time course of biodistribution and excretion from the body. The fast degradation and clearance of the polymers provided for very low toxicity at efficacious doses, and the therapeutic window of this poly(amide)-based siRNA delivery platform was shown to be much broader than a comparable polymer platform. The results of this work illustrate that the poly(amide) platform has a promising future in the development of a siRNA-based drug approved for human use.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Peptides / Biocompatible Materials / Drug Carriers / RNA, Small Interfering / Liver / Nylons Limits: Animals / Female / Humans Language: En Journal: J Control Release Journal subject: FARMACOLOGIA Year: 2014 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Peptides / Biocompatible Materials / Drug Carriers / RNA, Small Interfering / Liver / Nylons Limits: Animals / Female / Humans Language: En Journal: J Control Release Journal subject: FARMACOLOGIA Year: 2014 Document type: Article