Highly Effective Gene TransfectionIn Vivoby Alkylated Polyethylenimine

摘要

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. Theirin vivotransfection efficiency, specificity, and biodistribution were investigated.N-Ethylation improves thein vivoefficacy 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.) whileN-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.