Novel Endosomolytic Poly(amido amine) Polymer Conjugates for Systemic Delivery of siRNA to Hepatocytes in Rodents and Nonhuman Primates

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• 作者：Rubina Giare Parmar ; Micheal Poslusney ; Marina Busuek ; J. Michael Williams ; Robert Garbaccio ; Karen Leander ; Eileen Walsh ; Bonnie Howell ; Laura Sepp-Lorenzino ; Sean Riley ; Mihir Patel ; Eric Kemp ; Andrew Latham ; Anthony Leone ; Eric Soli ; Rob S. Burke ; Brian Carr ; Steven L. Colletti ; Weimin Wang
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：May 21, 2014
• 年：2014
• 卷：25
• 期：5
• 页码：896-906
• 全文大小：530K
• 年卷期：v.25,no.5(May 21, 2014)
• ISSN：1520-4812

文摘

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.