Development of non-viral gene vectors which can efficiently and safely transfect plasmid DNA and siRNA into cells is of great importance for gene therapy. Despite lots of efforts spent, it is still imperative to develop suitable gene vectors with better transfection efficiency and low cytotoxicity. To this end, we successfully designed, synthesized and screened a library of 120 polymers (via nucleophilic substitution reaction between dihalides and amines). With cell-based transfection screening assays, 120 polymers were tested to evaluate their transfection efficiency of transporting DNA and siRNA into cells. Our results indicated that hydrophobic modification could greatly enhance cationic polymers’ transfection efficiency, and polymers with long linkers usually showed better transfection performance, especially for polymers with the linker of 1, 12-dibromododecane (L3 linker). Besides, polyalkylamines exhibited better transfection efficiency with the polymer particle size around 200 nm and the zeta potential in the range of + 40 mV to +50 mV. Interestingly, polymer particles made from N15HL3 not only exhibited better DNA transfection efficiency in HEK 293T cells but also showed higher siRNA transfection efficiency in U87 Luc-GFP cells together with low cell toxicity than Lipofectamine 2000 (one of commercial transfection reagents). Therefore, it is hoped that our study here not only provides promising gene vector candidates for further evaluation in gene therapy, but also provides valuable insights for better understanding of the relationship between the chemical structures and gene transfection efficiency to rationally design better non-viral gene vectors for gene therapy in the future.

能够有效且安全地将质粒DNA和siRNA转染到细胞中的非病毒基因载体的开发对于基因治疗非常重要。尽管付出了很多努力，但是仍然必须开发具有更好转染效率和低细胞毒性的合适的基因载体。为此，我们成功设计，合成和筛选了120种聚合物的文库（通过二卤化物和胺之间的亲核取代反应）。使用基于细胞的转染筛选测定法，对120种聚合物进行了测试，以评估其将DNA和siRNA转运到细胞中的转染效率。我们的结果表明，疏水改性可以大大提高阳离子聚合物的转染效率，带有长接头的聚合物通常表现出更好的转染性能，特别是对于具有1，12-二溴十二烷（L3接头）接头的聚合物。此外，聚烷基胺表现出更好的转染效率，聚合物粒径约为200 nm，ζ电位在+ 40 mV至+50 mV的范围内。有趣的是 与Lipofectamine 2000（商业转染试剂之一）相比，由N15HL3制成的聚合物颗粒不仅在HEK 293T细胞中表现出更好的DNA转染效率，而且在U87 Luc-GFP细胞中表现出更高的siRNA转染效率，并且具有较低的细胞毒性。因此，希望我们的研究不仅为基因治疗中的应用提供有前途的候选基因，而且为更好地了解化学结构与基因转染效率之间的关系，合理设计更好的非病毒基因提供有价值的见解。将来用于基因治疗的载体。