Additive nanocomplexes of cationic lipopolymers for improved non-viral gene delivery to mesenchymal stem cells†
Abstract
It has been challenging to modify primary cells with non-viral gene delivery. Herein, we developed a ternary nano-formulation for gene delivery to umbilical cord blood and bone marrow derived mesenchymal stem cells (MSC) by using lipid-modified small (1.2 kDa) molecular weight polyethylenimine (PEI1.2). Linoleic acid (LA) was end-capped with carboxyl functionality by coupling with mercaptopropionic acid through thio-ester linkage, and then grafted onto PEI1.2 via N-acylation. The thio-ester LA grafted PEI1.2 (PEI-tLA) displayed a significantly lower (up to 6-fold) DNA binding capability and a higher propensity to dissociate upon polyanionic challenge. The dissociation ability of the complexes was further enhanced by incorporating hyaluronic acid (HA) into plasmid DNA (pDNA) complexes of PEI-tLA. The HA incorporation influenced the surface charge of complexes more so than the hydrodynamic size, but it clearly increased the propensity for dissociation upon a polyanionic challenge. The PEI-tLAs were less toxic on MSC and displayed significantly higher transgene expression in MSC than conventional PEI-LA. Ternary complexes of with HA (pDNA/HA = 2, w/w) further enhanced the efficiency of PEI-tLAs of low (∼2 lipid/PEI) lipid substitution, which was comparable to or higher than commercial transfection reagents. We conclude that PEI-tLA of low lipid substitution can be employed as a gene carrier to design supersensitive nano-formulations.
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