Cationic and hydrolysable branched polymers by RAFT for complexation and controlled release of dsRNA
Cationic and hydrolysable branched polymers by RAFT for complexation and controlled release of dsRNA
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DOI：
10.1039/c8py00804c
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发表时间：
2018-08-07
影响因子：
4.6
通讯作者：
Perrier, Sebastien
中科院分区：
文献类型：
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作者：
Cook, Alexander B.;Peltier, Raoul;Perrier, Sebastien
核酸从阳离子聚合物的受控释放是设计基因递送系统的重要标准，并且由于最初复合核酸所需的持续正电荷而难以实现。在这里，我们报告了使用高度支化的叔胺丰富的聚合物的络合和释放的dsRNA在一段较长的时间。通过聚合物侧链的自催化水解和相关的静电荷变化获得dsRNA的受控释放。采用可逆加成-断裂链转移（RAFT）聚合法合成了一系列丙烯酸二甲氨基乙酯（DMAEA）、丙烯酸二甲氨基丙酯（DMAPA）和甲基丙烯酸二甲氨基乙酯（DMAEMA）的支化聚合物（分子量约为60 000-200 000 g mol（-1））及其共聚物。所有合成的聚合物材料的水解动力学通过H-1 NMR光谱进行跟踪。与dsRNA的复合导致形成尺寸约为400 nm且表面电荷为+15 mV的复合物纳米颗粒（N/P比为5）。琼脂糖凝胶阻滞测定显示dsRNA从p（DMAEA-co-DMAEMA）持续释放超过2周的时间。与通常用于基因递送的支链PEI不同，这些系统中的大多数对细胞（NIH 3 T3成纤维细胞）显示出很小的毒性。结果表明pDMAPA和p（DMAEA-co-DMAEMA）是用于长时间受控释放核酸的有前景的聚合物。
The controlled release of nucleic acids from cationic polymers is an important criteria for the design of gene delivery systems, and can be difficult to achieve due to the persistent positive charges required to initially complex the nucleic acids. Here, we report the use of highly branched tertiary amine-rich polymers for the complexation and release of dsRNA over a prolonged period of time. Controlled release of dsRNA is obtained via self-catalysed hydrolysis of the polymer side chains and associated change in electrostatic charge. Reversible addition-fragmentation chain transfer (RAFT) polymerization was utilised to synthesise a series of branched polymers of 2-(dimethylamino) ethyl acrylate (DMAEA), 3-(dimethylamino) propyl acrylate (DMAPA), and 2-(dimethylamino) ethyl methacrylate (DMAEMA) (MW similar to 60 000-200 000 g mol(-1)) and copolymers thereof. The hydrolysis kinetics of all synthesised polymer materials were followed by H-1 NMR spectroscopy. Complexation with dsRNA resulted in the formation of polyplex nanoparticles (N/P ratio of 5) with sizes of approximately 400 nm and surface charges of +15 mV. An agarose gel retardation assay showed sustained release of dsRNA from p(DMAEA-co-DMAEMA) for a period of more than 2 weeks. Unlike branched PEI commonly used for gene delivery, the majority of these systems showed little toxicity to cells (NIH3T3 fibroblasts). The results point towards pDMAPA and p(DMAEA-co-DMAEMA) being promising polymers for the controlled release of nucleic acids over prolonged periods.