title: Development and characterization of an innovative heparin coating to stabilize and protect liposomes against adverse immune reactions.
abstract: Liposomes have been recognized as excellent drug delivery systems, but when they come in direct contact with different blood components they may trigger an immediate activation of the innate immune system. The aim of the present study was to produce long-circulating, blood-compatible liposomes by developing a construct of liposomes covered by a novel unique heparin complex (CHC; 70 heparin molecules per complex) to avoid recognition by the innate immune system. Unilamellar, cationic liposomes were produced by hand extrusion through a 100-nm polycarbonate membrane. Coating of liposomes with the macromolecular CHC was accomplished by electrostatic interactions. Dynamic light scattering as well as QCM-D measurements were used to verify the electrostatic deposition of the negatively charged CHC to cationic liposomes. The CHC-coated liposomes did not aggregate when in contact with lepirudin anti-coagulated plasma. Unlike previous attempts to coat liposomes with heparin, this technique produced freely moveable heparin strands sticking out from the liposome surface, which exposed AT binding sites reflecting the anticoagulant potentials of the liposomes. In experiments using lepirudin-anticoagulated plasma, CHC-coated liposomes, in contrast to non-coated control liposomes, did not activate the complement system, as evidenced by low C3a and sC5b-9 generation and reduced leakage from the liposomes. In conclusion, we show that liposomes can be successfully coated with the biopolymer CHC, resulting in biocompatible and stable liposomes that have significant application potential.
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden.
authors.forename: Claudia
authors.initials: C
authors.lastname: Duehrkop
authors.affiliation: ABNOBA GmbH, Pforzheim, Germany; Carl Gustav Carus-Institute, Association for the Promotion of Cancer Therapy, Niefern-Öschelbronn, Germany.
authors.forename: Gero
authors.initials: G
authors.lastname: Leneweit
authors.affiliation: ABNOBA GmbH, Pforzheim, Germany; Carl Gustav Carus-Institute, Association for the Promotion of Cancer Therapy, Niefern-Öschelbronn, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Heyder
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Fromell
authors.affiliation: Department of Chemistry-BMC, Biomedical Science Center, Uppsala University, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Edwards
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden; Linnæus Center of Biomaterials Chemistry, Linnæus University, Kalmar, Sweden.
authors.forename: Kristina N
authors.initials: KN
authors.lastname: Ekdahl
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden. Electronic address: bo.nilsson@igp.uu.se.
authors.forename: Bo
authors.initials: B
authors.lastname: Nilsson
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D002412:Cations / Q000737:chemistry; D020099:Coated Materials, Biocompatible / Q000737:chemistry* / Q000378:metabolism; D003167:Complement Activation; D003165:Complement System Proteins / Q000737:chemistry*; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D010949:Plasma; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D055672:Static Electricity; D013499:Surface Properties; D013997:Time Factors
chemical_list: D002412:Cations; D020099:Coated Materials, Biocompatible; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; C046112:didodecyldimethylammonium; D015060:1,2-Dipalmitoylphosphatidylcholine; D006493:Heparin; D003165:Complement System Proteins
keywords: Cationic liposomes; Complement system; Drug delivery system; Novel heparin complex; Surface coating