Gene therapy is a potent tool for the treatment of cancer and other gene defect diseases, which involves using DNA that encodes a functional, therapeutic gene to replace a mutated gene. However, the DNA transfection efficiency is restricted by its negative charges and low susceptibility to endonucleases which prevent them penetrating tissue and cellular membranes. Both viral and non-viral vectors have been used for gene delivery, but the former are limited by their immunogenicity, while the latter are less efficient than their viral counterpart. Cationic amphiphilic lipopeptides whose structures can be easily modified and transformed have been used as non-viral vectors in gene delivery system due to their low cytotoxicity and high transfection efficiency. In this study, a series of cationic amphiphilic N-phosphoryl oligopeptides with varied lengths of hydrophobic tails and oligopeptide headgroups (C12-K6, C14-K6, C16-K6, Chol-K6 and C12-H6) were synthesized and used as gene delivery vectors. The affinities, abilities to condense pDNA and transfection efficiencies of the K6-lipopeptides were better than those of the H6-lipopeptides. In addition, the hydrophobic chains of the lipopeptides also affected their transfection efficiencies. The K6-lipopeptide with a hydrophobic chain of twelve carbons (C12-K6) showed the highest transfection efficiency in all these synthetic lipopeptides. At an optimal P/N ratio of 20, C12-K6 showed comparable pDNA transfection efficiency to PEI-25k, a well-defined gene delivery vector, but the cytotoxicity of C12-K6 was much lower. With acceptable gene transfection efficiency and low cytotoxicity, this cationic amphiphilic lipopeptide will have promising applications in gene therapy.
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