Improving the In Vivo Therapeutic Index of siRNA Polymer Conjugates through Increasing pH Responsiveness

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• 作者：Erin N. Guidry ; Julie Farand ; Arash Soheili ; Craig A. Parish ; Nancy J. Kevin ; Brenda Pipik ; Kathleen B. Calati ; Nori Ikemoto ; Jacob H. Waldman ; Andrew H. Latham ; Bonnie J. Howell ; Anthony Leone ; Robert M. Garbaccio ; Stephanie E. Barrett ; Rubina Giare Parmar ; Quang T. Truong ; Bing Mao ; Ian W. Davies ; Steven L. Colletti ; Laura Sepp-Lorenzino
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：February 19, 2014
• 年：2014
• 卷：25
• 期：2
• 页码：296-307
• 全文大小：500K
• ISSN：1520-4812

文摘

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 pK_a 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鈥?5, beyond that of the therapeutic index (less than 3), for polymer conjugates previously reported.