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We mechanistically explored the effect of increased hydrophobicity of the polycation on the efficacy and specificity of gene delivery in mice.  N -Alkylated linear PEIs with varying alkyl chain lengths and extent of substitution were synthesized and characterized by biophysical methods. Their  in vivo  transfection efficiency, specificity, and biodistribution were investigated.  N -Ethylation improves the  in vivo  efficacy of gene expression in the mouse lung 26-fold relative to the parent polycation and more than quadruples the ratio of expression in the lung to that in all other organs.  N -Propyl-PEI was the best performer in the liver and heart (581- and 3.5-fold enhancements, resp.) while  N -octyl-PEI improved expression in the kidneys over the parent polymer 221-fold. As these enhancements in gene expression occur without changing the plasmid biodistribution, alkylation does not alter the cellular uptake but rather enhances transfection subsequent to cellular uptake.

Highly Effective Gene Transfection In Vivo by Alkylated Polyethylenimine