Bioreducible Polyspermine-Based Gene Carriers for Efficient siRNA Delivery: Effects of PEG Conjugation on Gene Silencing Efficiency
Bioreducible Polyspermine-Based Gene Carriers for Efficient siRNA Delivery: Effects of PEG Conjugation on Gene Silencing Efficiency
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DOI：
10.1007/s13233-019-7027-2
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发表时间：
2018-12-01
影响因子：
2.4
通讯作者：
Shim, Min Suk
中科院分区：
文献类型：
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作者：
Bhang, Suk Ho;Kim, Kyuwon;Shim, Min Suk
合成了一种聚精胺衍生的生物可还原聚合物作为有效的siRNA载体。精胺聚合使用二硫化物轴承交联剂，产生聚（二硫化物精胺）（PDS）。PDS还与聚（乙二醇）（PEG）缀合以定制聚合物的siRNA缩合效率。PEG-缀合的PDS（PEG-PDS）能够在高N/P比下将siRNA缩合成纳米尺寸的聚合复合物。PEG化降低了PDS的siRNA缩合效率，这是由于PDS的阳离子电荷密度降低导致其与siRNA的相互作用减弱。溴化乙锭排除测定表明，与稳定的PDS复合物相比，siRNA更有效地从不太稳定的PEG-PDS复合物中释放。此外，生物可还原的siRNA/PEG-PDS聚合复合物在还原条件下有效分解，导致促进siRNA释放到细胞质中。与PDS相比，PEG-PDS降低的siRNA凝聚但有效的siRNA细胞质释放诱导更高的基因沉默效率。此外，PEG-PDS表现出较低的细胞毒性相比，PDS和非生物降解的支链聚乙烯亚胺。这些结果表明，阳离子基因载体的siRNA递送效率可以通过PEG缀合来定制它们的siRNA复合物来提高。这项研究表明，生物可还原的PEG-PDS是一个有前途的候选人安全和有效的siRNA交付。
A polyspermine-derived bioreducible polymer was synthesized as efficient siRNA carriers. Spermine was polymerized using disulfide-bearing cross-linkers, resulting in poly(disulfide spermine) (PDS). PDS was also conjugated with poly(ethylene glycol) (PEG) to tailor siRNA condensation efficiency of the polymer. PEG-conjugated PDS (PEG-PDS) was able to condense siRNA into nano-sized polyplexes at high N/P ratios. siRNA condensation efficiency of PDS was reduced by PEGylation due to its weakened interaction with siRNA caused by its decreased cationic charge density. An ethidium bromide exclusion assay demonstrated that siRNA was more efficiently released from the less stable PEG-PDS polyplexes compared to stable PDS polyplexes. In addition, bioreducible siRNA/PEG-PDS polyplexes were efficiently disassembled in the reductive conditions, leading to facilitated siRNA release into the cytoplasm. The lowered siRNA condensation but efficient cytoplasmic release of siRNA by PEG-PDS induced higher gene silencing efficiency in comparison with PDS. Moreover, PEG-PDS exhibited lower cytotoxicity compared to PDS and non-biodegradable branched polyethylenimine. These results suggest that siRNA delivery efficiency of cationic gene carriers can be improved by tailoring their siRNA complexation through PEG conjugation. This study demonstrates that bioreducible PEG-PDS is a promising candidate for safe and efficient siRNA delivery.