Department of Process Chemistry and ∥Department of Analytical Chemistry, Merck & Co. Inc. , , Rahway, New Jersey, United States.
Bioconjug Chem. 2014 Feb 19;25(2):296-307. doi: 10.1021/bc400442p. Epub 2014 Jan 10.
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.
基于聚合物的载体可以帮助实现内体逃逸，已被证明在体外和体内都是有效的 siRNA 递送剂；然而，由于缺乏对内涵体与细胞膜裂解的选择性，大多数载体都存在细胞毒性。为了使基于聚合物的载体能够从实验室走向临床，关键是要找到不仅有效的载体，而且还具有临床相关的安全边际。在本文中，我们报告了三类不同的聚合物缀合物，它们通过依赖于与内涵体运输相关的 pH 变化来提高内涵体膜裂解的选择性，包括低 pKa 杂环、酸可裂解的氨基侧链或羧酸 pH 敏感电荷开关的掺入。此外，我们还确定了我们的聚合物缀合物在体内的治疗指数，并证明 pH 响应元件的掺入将治疗指数显著扩大到 10-15，超过了以前报道的聚合物缀合物的治疗指数（小于 3）。
