Department of RNA Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
J Control Release. 2014 Jun 10;183:124-37. doi: 10.1016/j.jconrel.2014.03.028. Epub 2014 Mar 21.
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.
有效体内 siRNA 传递的最大挑战是创建一种传递载体，该载体在具有广泛治疗窗口的情况下介导高度疗效。探索了聚（酰胺）聚合物缀合 siRNA 传递平台的关键结构-活性关系，以发现产生肝脏中 mRNA 敲低最高活性的最佳聚合物参数。同时，聚合物的聚（酰胺）主链允许聚合物非常快速地在体内代谢和清除，这是使用放射性标记的聚合物来证明生物分布和从体内排泄的时间过程来建立的。聚合物的快速降解和清除在有效剂量下提供了非常低的毒性，并且基于聚酰胺的 siRNA 传递平台的治疗窗口比可比聚合物平台宽得多。这项工作的结果表明，聚（酰胺）平台在开发用于人体的 siRNA 药物方面具有广阔的前景。
