title: Lipopeptide-based micellar and liposomal carriers: Influence of surface charge and particle size on cellular uptake into blood brain barrier cells.
abstract: Lipopeptide-based micelles and liposomes were found to differ in cell recognition and uptake mode into blood brain barrier (BBB) endothelial cells. Here we analyse the role of size and surface charge of micelles and liposomes composed of different lipopeptide sequences with respect to uptake into human brain capillary (HBMEC) and aortic (HAoEC) endothelial cells. Comparable to the dipalmitoylated apolipoprotein E-derived P2A2, lipopeptides of cationic poly-arginine (P2Rn), poly-lysine (P2Kn) and an anionic glutamic-acid sequence (P2En) self assemble into micelles (12-14nm in diameter) with high surface charge density, and bind to small (SUVs, about 24nm in diameter) and large (LUV, about 100nm in diameter) liposomes at variable lipid to peptide ratios. The interaction pattern of the resulting particles with endothelial cells is highly variable as revealed by confocal laser scanning microscopic (CLSM) and fluorescence assisted cell sorting (FACS) studies. Micelles and SUVs with high P2A2 density are efficiently and selectively internalized into HBMEC. P2Kn micelles strongly accumulate in both the cytosol and at the cell membrane, while the interaction of liposomes tagged with a low amount of P2A2 and P2Kn with the cells was reduced. Anionic micelles seem to dissociate in the presence of cells and P2En molecules incorporate into the cellular membrane whereas the negatively charged liposomes hardly interact with cells. Surprisingly, all poly-R-based particles show high selectivity for HBMEC compared to HAoEC, independent of particle size and peptide surface density. The P2Rn-mediated internalization is highly efficient and partially clathrin-dependent. The oligo-R lipopeptide is considered to be most promising to selectively transport different drug carriers into the blood brain barrier.
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP), Robert-Roessle-Str. 10, 13125 Berlin, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Sydow
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP), Robert-Roessle-Str. 10, 13125 Berlin, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Nikolenko
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP), Robert-Roessle-Str. 10, 13125 Berlin, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Lorenz
authors.affiliation: Freie Universität Berlin, Department of Pharmacy, Pharmaceutical Technology, Biopharmaceutics & NutriCosmetics, Berlin, Germany.
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Müller
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP), Robert-Roessle-Str. 10, 13125 Berlin, Germany. Electronic address: dathe@fmp-berlin.de.
authors.forename: Margitta
authors.initials: M
authors.lastname: Dathe
mesh_terms: D001011:Aorta / Q000187:drug effects*; D001057:Apolipoproteins E / Q000737:chemistry; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D002196:Capillaries / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival; D020285:Cryoelectron Microscopy; D004337:Drug Carriers / Q000737:chemistry; D015195:Drug Design; D042783:Endothelial Cells / Q000166:cytology*; D005434:Flow Cytometry; D006801:Humans; D055666:Lipopeptides / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D008823:Micelles; D018613:Microscopy, Confocal; D010316:Particle Size; D010455:Peptides / Q000737:chemistry; D011107:Polylysine / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D013499:Surface Properties
chemical_list: D001057:Apolipoproteins E; D004337:Drug Carriers; D055666:Lipopeptides; D008081:Liposomes; D008823:Micelles; D010455:Peptides; D012997:Solvents; D011107:Polylysine; C015462:polyarginine
keywords: Cellular uptake; Drug carrier; Lipopeptides; Liposomes; Micelles