Endosomolytic Bioreducible Poly(amido amine disulfide) Polymer Conjugates for the in Vivo Systemic Delivery of siRNA Therapeutics

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• 作者：Rubina Giare Parmar ; Marina Busuek ; Eileen S. Walsh ; Karen R. Leander ; Bonnie J. Howell ; Laura Sepp-Lorenzino ; Eric Kemp ; Louis S. Crocker ; Anthony Leone ; Christopher J. Kochansky ; Brian A. Carr ; Robert M. Garbaccio ; Steven L. Colletti ; Weimin Wang
• 刊名：Bioconjugate Chemistry
• 出版年：2013
• 出版时间：April 17, 2013
• 年：2013
• 卷：24
• 期：4
• 页码：640-647
• 全文大小：342K
• 年卷期：v.24,no.4(April 17, 2013)
• ISSN：1520-4812

文摘

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.