Polyplex
micelles formed with plasmid
DNA (pDNA) and poly(
ethylene glycol) (PEG)-block-poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [
PAsp(DET)] exhibit effective endosomal escaping properties based on di-protonation of
diamine side chains with decreasing pH, which improves their transfection efficiency and thus are promising candidates for local in vivo gene transfer. Here,
PEG-PAsp(DET) polyplex
micelles were further improved as in vivo systemic vectors by introduction of
cholesterol (Chole) into the ω-terminus of
PEG-PAsp(DET) to obtain
PEG-PAsp(DET)-Chole. Introduction of the
cholesterol resulted in enhanced association of block copolymers with pDNA, which led to increased stability in proteinous medium and also in the blood stream after systemic injection compared to
PEG-PAsp(DET)
micelles. The synergistic effect between enhanced
polymer association with pDNA and increased
micelle stability of
PEG-PAsp(DET)-Chole polyplex
micelles led to high in vitro gene transfer even at relatively low concentrations, due to efficient cellular uptake and effective endosomal escape of block copolymers and pDNA. Finally,
PEG-PAsp(DET)-Chole
micelles achieved significant suppression of
tumor growth following
intravenous injection into mice bearing a subcutaneous pancreatic
tumor using therapeutic pDNA encoding an anti-
angiogenic protein. These results suggest that
PEG-PAsp(DET)-Chole
micelles can be effective systemic gene vectors for treatment of solid
tumors.