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Publications à Abstracts |
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Dipalmitoylation
of a cellular uptake-mediating apolipoprotein E-derived peptide as a
promising modification for stable anchorage in liposomal drug carriers Ines Sauer, Heike Nikolenko, Sandro
Keller, Khalid Abu Ajaj, Michael Bienert, Margitta Dathe Biochimica et Biophysica Acta (BBA) - Biomembranes, 2006, 1758 (4), 552–561 Keywords: lipid-binding domains; apolipoprotein E; peptide–liposome complex; cellular
uptake Abstract: Liposomes
equipped with cellular uptake-mediating peptidic vector compounds have
attracted much attention as target-specific drug delivery systems. Aside from
the development of the target recognition motif itself, vector coupling to
liposomes while conserving the active conformation constitutes an important
element in carrier development. To elucidate the most efficient way for
adsorptive peptide binding to liposomes, we synthesized and characterized
two-domain peptides comprising a cationic sequence derived from the binding
domain of apolipoprotein E (apoE) for the low-density lipoprotein receptor
and different lipid-binding motifs, that is, an amphipathic helix, a
transmembrane helix, single fatty acids or two palmitoyl chains. Peptide
properties considered relevant for peptide–liposome complexes to initiate an
endocytotic cellular uptake such as lipid binding, helicity, stability of
anchorage, bilayer-disturbing activity, and toxicity showed that the
dipalmitoyl derivative was the most suitable to associate the apoE peptide to
the surface of liposomes. The peptide showed pronounced lipid affinity and
was stably anchored within the lipid bilayer on a time scale of at least
30 min. The helicity of about 40% in the lipid-bound state and the
location of the amphipathic helix on the liposomal surface provided the
prerequisites for interaction of the complex with the cell surface-located
receptor. The concentration of
the dipalmitoylated peptide to permeabilize neutral lipid bilayers (lipid
concentration 25 μM) was 0.06 μM and a 2 μM
concentration reduced cell viability to about 80%. Efficient internalization
of liposomes bearing about 180 peptide derivatives on the surface into brain
capillary endothelial cells was monitored by confocal laser scanning
microscopy. The concept of complexation using dipalmitoylated peptides may
offer an efficient substitute to covalent vector coupling and a prospective
way to optimize the capacity of liposomes as drug delivery systems also for
different targets. |
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