Structure/function relationship in the polyplexes containing cationic polypeptides for gene delivery.

Various cationic polypeptides of linear or highly branched structures were synthesized by introducing tertiary or quaternary ammonium groups and hydroxyl groups to poly(L-lysine) (PL) or polyamideamine (PAMAM) dendrimers. These polycations were mixed with plasmid DNA to form polyplexes and subjected to in vitro gene introduction experiment. The transient gene expression was greatly affected by the side groups of PL derivatives or the surface cation charge density of PAMAM dendrimers. This difference in gene expression was found to result from two independent factors as follows: one is the cellular uptake of the polyplexes and the other is the compaction of the polyplexes. Lower charge density of PAMAM dendrimers suppressed the polyplex formation and cellular uptake, resulting the lower gene expression. Only the polycations that form polyplexes compacted at an adequate extent lead an effective gene expression, suggesting that the physicochemical properties of the polyplexes defined by the chemical structures of the polycations play an important role in the effective gene transfer.