Examination of the effect of increasing the number of intra-disulfide amino functional groups on the performance of small molecule cyclic polyamine disulfide vectors
Examination of the effect of increasing the number of intra-disulfide amino functional groups on the performance of small molecule cyclic polyamine disulfide vectors
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DOI：
10.1016/j.jconrel.2013.02.014
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发表时间：
2013-10-10
影响因子：
10.8
通讯作者：
Miller, Andrew D.
中科院分区：
文献类型：
--
作者：
Drake, Christopher R.;Aissaoui, Abderrahim;Miller, Andrew D.
如果非病毒载体的功效要与其病毒对应物的功效相匹配，那么建立结构-活性关系至关重要。最近，我们报道了一系列的小分子，环状聚胺二硫化物凝聚和笼质粒DNA（pDNA）的能力，通过一个过程中的化学控制的模板聚合，导致一系列相应的pDNA-聚合复合物纳米粒子能够介导高水平的转染，没有相关的细胞毒性。主要的环状多胺二硫化物显示为精胺四胺二硫化物（TetraN-3，4，3）。在这里，我们报告了具有更长的多胺基序的环状二硫醚的合成。两个新的环状多胺二硫化物，六，八胺插入的基础上，制备和他们的转染效率和细胞毒性相比，我们以前报道的环状三，四胺二硫化物。新的环状六-和八-胺二硫化物证明在体外转染更有效，特别是肺上皮A549细胞系。相比之下，我们最初的环状四胺二硫化物仍然是鼻内给药后体内肺上皮细胞转染的最有效试剂。提出了假设的机械原因来解释这一结果。我们的数据在totto支持的概念，较短的环状多胺二硫化物作为优选的代理商的聚阳离子介导的控制缩合和功能性交付的pDNA到肺上皮细胞在体内。(C)2013年由Elsevier B. V.出版
Establishing structure-activity relationships is vital if the efficacy of non-viral vectors is to match that of their viral counter-parts. Recently, we reported on the ability of a series of small molecule, cyclic polyamine disulfides to condense and cage plasmid DNA (pDNA) by a process of thermodynamically controlled templated polymerization, leading to a series of corresponding pDNA-polyplex nanoparticles able to mediate high levels of transfection with no associated cytotoxicities. The leading cyclic polyamine disulfide was shown to be the spermine tetra-amine disulfide (TetraN-3,4,3). Herein we report on the significantly more challenging syntheses of cyclic disulfides with longer polyamine motifs. Two new cyclic polyamine disulfides, based on hexa-and octa-amine inserts, were prepared and their transfection efficacies and cytotoxicities compared with our previously reported cyclic tri- and tetra-amine disulfides. The new cyclic hexa-and octa-amine disulfides prove more effective at transfection in vitro, especially of lung epithelial A549 cell line. By contrast, our original cyclic tetra-amine disulfide remains the most efficient agent for the transfection of lung epithelial cells in vivo following intra-nasal administration. Hypothetical mechanistic reasons are presented to explain this outcome. Our data in toto support the concept of shorter cyclic polyamine disulfides as preferred agents for polycation-mediated controlled condensation and functional delivery of pDNA to lung epithelial cells in vivo. (C) 2013 Published by Elsevier B.V.