title: Thrombin-Inhibiting Anticoagulant Liposomes: Development and Characterization.
abstract: Many peptides and peptidomimetic drugs suffer from rapid clearance in vivo; this can be reduced by increasing their size through oligomerization or covalent conjugation with polymers. As proof of principle, an alternative strategy for drug oligomerization is described, in which peptidomimetic thrombin inhibitors are incorporated into the liposome surface. For this purpose, the inhibitor moieties were covalently coupled to a palmitic acid residue through a short bifunctionalized ethylene glycol spacer. These molecules were directly added to the lipid mixture used for liposome preparation. The obtained liposomes possess strong thrombin inhibitory potency in enzyme kinetic measurements and anticoagulant activity in plasma. Their strong potency and positive ζ potential indicate that large amounts of the benzamidine-derived inhibitors are located on the surface of the liposomes. This concept should be applicable to other drug molecules that suffer from rapid elimination and allow covalent modification with a suitable fatty acid residue.
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032, Marburg, Germany.
authors.forename: Wegderes
authors.initials: W
authors.lastname: Endreas
authors.affiliation: Institute of Pharmaceutical Technology & Biopharmacy, Philipps University, Ketzerbach 63, 35032, Marburg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Brüßler
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032, Marburg, Germany.
authors.forename: Doru
authors.initials: D
authors.lastname: Vornicescu
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032, Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Keusgen
authors.affiliation: Institute of Pharmaceutical Technology & Biopharmacy, Philipps University, Ketzerbach 63, 35032, Marburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Bakowsky
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032, Marburg, Germany. steinmetzer@uni-marburg.de.
authors.forename: Torsten
authors.identifier: http://orcid.org/0000-0001-6523-4754
authors.initials: T
authors.lastname: Steinmetzer
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000991:Antithrombins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008081:Liposomes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D008081:Liposomes; D013917:Thrombin
keywords: anticoagulants; inhibitors; liposomes; peptidomimetics; thrombin