Histone H3 Tail Peptides and Poly(ethylenimine) Have Synergistic Effects for Gene Delivery

This goal of this work was to explore histone H3 tail peptides containing transcriptionally activating modifications for their potential as gene delivery materials. We have found that these H3 tail peptides, in combination with the cationic polymer poly­(ethylenimine) (PEI), can effectively bind and protect plasmid DNA. The H3/PEI hybrid polyplexes were found to transfect a substantially larger number of CHO-K1 cells <i>in vitro</i> compared to both polyplexes that were formed with only the H3 peptides and those that were formed with only PEI at the same total charge ratio; however, transfection was similarly high for polyplexes both with and without transcriptionally activating modifications. Transfections with the endolysosomal inhibitors chloroquine and bafilomycin A1 indicated that the H3/PEI hybrid polyplexes exhibited slower uptake and a reduced dependence on endocytic pathways that trafficked to the lysosome, indicating a potentially enhanced reliance on caveolar uptake for efficient gene transfer. In addition, whereas PEI polyplexes typically exhibit a cytotoxic effect, the H3/PEI hybrid polyplexes did not compromise cell viability. In total, the current studies provide new evidence for the potential role for histone-based materials as effective gene transfer agents, and support for the importance of subcellular trafficking for nonviral gene delivery