Rapid optimization of gene delivery by parallel end-modification of poly(β-amino ester)s
Rapid optimization of gene delivery by parallel end-modification of poly(β-amino ester)s
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DOI：
10.1038/sj.mt.6300132
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发表时间：
2007-07-01
影响因子：
12.4
通讯作者：
Anderson, Daniel G.
中科院分区：
文献类型：
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作者：
Zugates, Gregory T.;Peng, Weidan;Anderson, Daniel G.
聚(β-氨基酯)S是一种阳离子可降解聚合物，具有作为基因传递载体的巨大潜力。在这里，我们提出了一种通用的方法来修饰聚(β-氨基酯)S，以改善其递送性能。开发了端链偶联反应，以便以高通量的方式合成和测试聚合物，而不需要进行纯化。通过这种方式，可以快速评估聚合物末端的许多结构变化。对预先优化的聚β-氨基酯C32的端胺结构进行末端修饰，显著提高了其体外转染率。在体内，使用末端修饰的C32聚合物的腹膜内(IP)基因传递导致在几个腹部器官中的表达水平比未修饰的C32和JET-聚乙烯亚胺(JET-PEI)高一个数量级以上。本文提出的快速末端修饰策略已经发现了许多用于基因传递的有效聚合物，并可能成为开发和优化用于基因治疗的阳离子聚合物的有用方法。
Poly(beta-amino ester)s are cationic degradable polymers that have significant potential as gene delivery vectors. Here we present a generalized method to modify poly(beta-amino ester) s at the chain ends to improve their delivery performance. End-chain coupling reactions were developed so that polymers could be synthesized and tested in a high-throughput manner, without the need for purification. In this way, many structural variations at the polymer terminus could be rapidly evaluated. End-modification of the terminal amine structure of a previously optimized poly(beta-amino ester), C32, significantly enhanced its in vitro transfection efficiency. In vivo, intraperitoneal (IP) gene delivery using end-modified C32 polymers resulted in expression levels over one order of magnitude higher than unmodified C32 and jet-polyethylenimine (jet-PEI) levels in several abdominal organs. The rapid end-modification strategy presented here has led to the discovery of many effective polymers for gene delivery and may be a useful method to develop and optimize cationic polymers for gene therapy.