1 research outputs found
A Delicate Balance When Substituting a Small Hydrophobe onto Low Molecular Weight Polyethylenimine to Improve Its Nucleic Acid Delivery Efficiency
High
molecular weight (HMW) polyethylenimine (PEI) is one of the most versatile
nonviral gene vectors that was extensively investigated over the past
two decades. The cytotoxic profile of HMW PEI, however, encouraged
a search for safer alternatives. Because of lack of cytotoxicity of
low molecular weight (LMW) PEI, enhancing its performance via hydrophobic
modifications has been pursued to this end. Since the performance
of modified PEIs depends on the nature and extent of substituents,
we systematically investigated the effect of hydrophobic modification
of LMW (1.2 kDa) PEI with a short propionic acid (PrA). Moderate enhancements
in PEI hydrophobicity resulted in enhanced cellular uptake of polyplexes
and siRNA-induced silencing efficacy, whereas further increase in
PrA substitution abolished the uptake as well as the silencing. We
performed all-atom molecular dynamics simulations to elucidate the
mechanistic details behind these observations. A new assembly mechanism
was observed by the presence of hydrophobic PrA moieties, where PrA
migrated to core of the polyplex. This phenomenon caused higher surface
hydrophobicity and surface charge density at low substitutions, and
it caused deleterious effects on surface hydrophobicity and cationic
charge at higher substitutions. It is evident that an optimal balance
of hydrophobicity/hydrophilicity is needed to achieve the desired
polyplex properties for an efficient siRNA delivery, and our mechanistic
findings should provide valuable insights for the design of improved
substituents on nonviral carriers