A Neutralized Noncharged Polyethylenimine-Based System for Efficient Delivery of siRNA into Heart without Toxicity.
A Neutralized Noncharged Polyethylenimine-Based System for Efficient Delivery of siRNA into Heart without Toxicity.
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DOI：
10.1021/acsami.6b13295
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发表时间：
2016-12
影响因子：
9.5
通讯作者：
F. Wang;Lu Gao;Liu-Yi Meng;Jing-Ming Xie;Jing Xiong;Ying Luo
中科院分区：
文献类型：
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作者：
F. Wang;Lu Gao;Liu-Yi Meng;Jing-Ming Xie;Jing Xiong;Ying Luo
阳离子聚合物构成了开发用于基于核酸的治疗剂的递送载体的一类重要材料。其中，聚乙烯亚胺（PEI）是一种经典的阳离子载体，被广泛研究用于DNA、RNA和短RNA分子的治疗性递送以治疗疾病。然而，PEI用于体内应用的开发受到与材料相关的固有问题的阻碍，特别是其细胞毒性和通过静电相互作用形成的核酸络合系统的不稳定性。在这里，我们展示了一种通过酰肼化修饰PEI聚合物的策略，以创建用于递送siRNA分子的中和的、稳定的和多功能的系统。通过用中性酰肼基团取代PEI的伯氨基，产生表面修饰有模型靶向配体的交联纳米颗粒。中性交联的siRNA纳米颗粒不仅在体外表现出良好的生物相容性和细胞内化效率，而且在体内斑马鱼心脏中也允许显著的组织摄取和基因沉默效率。我们的研究表明，传统的支化PEI转化为中性聚合物，可以导致一类新的非病毒载体，并产生功能性递送系统可以进一步探索用于治疗心血管疾病/损伤的siRNA疗法的发展。
Cationic polymers constitute an important class of materials in development of delivery vehicles for nucleic acid-based therapeutics. Among them, polyethylenimine (PEI) has been a classical cationic carrier intensively studied for therapeutic delivery of DNA, RNA, and short RNA molecules to treat diseases. However, the development of PEI for in vivo applications has been hampered by the inherent problems associated with the material, particularly its cytotoxicity and the instability of the nucleic acid complexation systems formed via electrostatic interactions. Here, we demonstrate a strategy to modify PEI polymers via hydrazidation to create neutralized, stable, and multifunctional system for delivering siRNA molecules. Through substitution of the primary amino groups of PEI with neutral hydrazide groups, cross-linked nanoparticles with surface decorated with a model targeting ligands were generated. The neutral cross-linked siRNA nanoparticles not only showed favorable biocompatibility and cell internalization efficiency in vitro but also allowed for significant tissue uptake and gene silencing efficiency in zebrafish heart in vivo. Our study suggests transformation of conventional branched PEI into a neutral polymer that can lead to a new category of nonviral carriers, and the resulting functional delivery systems may be further explored for development of siRNA therapeutics for treating cardiovascular disease/injury.