title: Targeted lipid-coated nanoparticles: delivery of tumor necrosis factor-functionalized particles to tumor cells.
abstract: Polymeric nanoparticles displaying tumor necrosis factor on their surface (TNF nanocytes) are useful carrier systems capable of mimicking the bioactivity of membrane-bound TNF. Thus, TNF nanocytes are potent activators of TNF receptor 1 and 2 leading to a striking enhancement of apoptosis. However, in vivo applications are hampered by potential systemic toxicity. Here, using TNF nanocytes as a model system, we developed a procedure to generate targeted lipid-coated particles (TLP) in which TNF activity is shielded. The TLPs generated here are composed of an inner single-chain TNF (scTNF)-functionalized, polymeric nanoparticle core surrounded by a lipid coat endowed with polyethylene glycol (PEG) for sterical stabilization and a single-chain Fv (scFv) fragment for targeting. Using a scFv directed against the tumor stroma marker fibroblast activation protein (FAP) we show that TLP and scTNF-TLP specifically bind to FAP-expressing, but not to FAP-negative cells. Lipid coating strongly reduced nonspecific binding of particles and scTNF-mediated cytotoxicity towards FAP-negative cells. In contrast, an increased cytotoxicity of TLP was observed for FAP-positive cells. Thus, through liposome encapsulation, nanoparticles carrying bioactive molecules, which are subject to nonselective uptake and activity towards various cells and tissues, can be converted into target cell-specific composite particles exhibiting a selective activity towards antigen-positive target cells. Besides safe and targeted delivery of death ligands such as TNF, TLP should be suitable for various diagnostic and therapeutic applications, which benefit from a targeted delivery of reagents embedded into the particle core or displayed on the core particle surface.
authors.affiliation: Institut für Zellbiologie und Immunologie, Universität Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
authors.forename: Sylvia K E
authors.initials: SK
authors.lastname: Messerschmidt
authors.forename: Anna
authors.initials: A
authors.lastname: Musyanovych
authors.forename: Martin
authors.initials: M
authors.lastname: Altvater
authors.forename: Peter
authors.initials: P
authors.lastname: Scheurich
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfizenmaier
authors.forename: Katharina
authors.initials: K
authors.lastname: Landfester
authors.forename: Roland E
authors.initials: RE
authors.lastname: Kontermann
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry; D020099:Coated Materials, Biocompatible / Q000737:chemistry; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004337:Drug Carriers / Q000737:chemistry; D010450:Endopeptidases; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology; D018093:Gelatinases; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011137:Polystyrenes / Q000737:chemistry; D011485:Protein Binding / Q000276:immunology; D012208:Rhabdomyosarcoma / Q000378:metabolism / Q000473:pathology; D012697:Serine Endopeptidases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D014408:Biomarkers, Tumor; D002784:Cholesterol; D020099:Coated Materials, Biocompatible; D004337:Drug Carriers; D010450:Endopeptidases; D018093:Gelatinases; D007128:Immunoglobulin Fragments; D008055:Lipids; D008081:Liposomes; D008565:Membrane Proteins; D010743:Phospholipids; D011092:Polyethylene Glycols; D011137:Polystyrenes; D012697:Serine Endopeptidases; D014409:Tumor Necrosis Factor-alpha; D000099167:Fibroblast Activation Protein Alpha; C055966:immunoglobulin Fv