Glycosylated Reversible Addition–Fragmentation Chain Transfer Polymers with Varying Polyethylene Glycol Linkers Produce Different Short Interfering RNA Uptake, Gene Silencing, and Toxicity Profiles
作者:Elizabeth G. L. Williams、Oliver E. Hutt、Tracey M. Hinton、Sophie C. Larnaudie、Tam Le、James M. MacDonald、Pathiraja Gunatillake、San H. Thang、Peter J. Duggan
DOI:10.1021/acs.biomac.7b01168
日期:2017.12.11
Achieving efficient and targeted delivery of short interfering (siRNA) is an important research challenge to overcome to render highly promising siRNA therapies clinically successful. Challenges exist in designing synthetic carriers for these RNAi constructs that provide protection against serum degradation, extended blood retention times, effective cellular uptake through a variety of uptake mechanisms, endosomal escape, and efficient cargo release. These challenges have resulted in a significant body of research and led to many important findings about the chemical composition and structural layout of the delivery vector for optimal gene silencing. The challenge of targeted delivery vectors remains, and strategies to take advantage of nature’s self-selective cellular uptake mechanisms for specific organ cells, such as the liver, have enabled researchers to step closer to achieving this goal. In this work, we report the design, synthesis, and biological evaluation of a novel polymeric delivery vector incorporating galactose moieties to target hepatic cells through clathrin-mediated endocytosis at asialoglycoprotein receptors. An investigation into the density of carbohydrate functionality and its distance from the polymer backbone is conducted using reversible addition–fragmentation chain transfer polymerization and postpolymerization modification.
实现短干扰RNA(siRNA)的高效和靶向递送是克服的一个重要研究挑战,以使前景广阔的siRNA疗法在临床上成功。设计合成输送载体以保护这些RNA干扰构件免受血清降解、延长血液滞留时间、通过多种摄取机制有效细胞摄取、内吞体逃逸和高效货物释放仍然存在挑战。这些挑战促成了大量研究,并导致了关于递送载体化学成分和结构布局的重要发现,以实现最佳基因沉默。靶向递送载体的挑战仍然存在,利用自然自选择性细胞摄取机制(针对特定器官细胞,例如肝脏)的方法使研究人员更接近实现这一目标。在这项工作中,我们报告了一种新型聚合物递送载体的设计、合成和生物评估,该载体通过结合半乳糖基团,通过粘附蛋白介导的内吞作用靶向肝细胞,并与天冬氨酸糖蛋白受体结合。通过可逆加成-断裂链转移聚合和聚合后修饰,研究了碳水化合物功能密度及其与聚合物骨架之间的距离。