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Interaction of Peptidomimetics with Bilayer Membranes: Biophysical Characterization and Cellular Uptake
journal contribution
posted on 2012-03-20, 00:00 authored by Xiaona Jing, Marina
R. Kasimova, Anders H. Simonsen, Lene Jorgensen, Martin Malmsten, Henrik Franzyk, Camilla Foged, Hanne M. NielsenEnzymatically stable cell-penetrating α-peptide/β-peptoid
peptidomimetics constitute promising drug delivery vehicles for the
transport of therapeutic biomacromolecules across membrane barriers.
The aim of the present study was to elucidate the mechanism of peptidomimetic-lipid
bilayer interactions. A series of peptidomimetics consisting of alternating
cationic and hydrophobic residues displaying variation in length and
N-terminal end group were applied to fluid-phase, anionic lipid bilayers,
and their interaction was investigated using isothermal titration
calorimetry (ITC) and ellipsometry. Titration of lipid vesicles into
solutions of peptidomimetics resulted in exothermic adsorption processes,
and the interaction of all studied peptidomimetics with anionic lipid
membranes was found to be enthalpy-driven. The enthalpy and Gibbs
free energy (ΔG) proved more favorable with
increasing chain length. However, not all charges contribute equally
to the interaction, as evidenced by the charge-normalized ΔG being inversely correlated to the sequence length. Ellipsometry
data suggested that the hydrophobic residues also played an important
role in the interaction process. Furthermore, ΔG extracted from ellipsometry data showed good agreement with that
obtained with ITC. To further elucidate their interaction with biological
membranes, quantitative uptake and cellular distribution were studied
in proliferating HeLa cells by flow cytometry and confocal microscopy.
The cellular uptake of carboxyfluorescein-labeled peptidomimetics
showed a similar ranking as that obtained from the adsorbed amount,
and binding energy to model membranes demonstrated that the initial
interaction with the membrane is of key importance for the cellular
uptake.
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Keywords
chain lengthBiophysical CharacterizationuptakeCellular UptakeEnzymaticallybinding energymodel membranesflow cytometryinteraction processEllipsometry datadrug delivery vehicleslipid bilayerslipid membranestitration calorimetryHeLa cellsmembrane barrierslipid vesiclesITCsequence lengthpeptidomimeticΔ Gconfocal microscopyBilayer Membranesellipsometry dataadsorption processes
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