title: Cytotoxic targeting of F9 teratocarcinoma tumours with anti-ED-B fibronectin scFv antibody modified liposomes.
abstract: We prepared small unilamellar liposomes derivatised with single chain antibody fragments specific for the ED-B domain of B-fibronectin. This extracellular matrix associated protein is expressed around newly forming blood vessels in the vicinity of many types of tumours. The single chain antibody fragments were functionalised by introduction of C-terminal cysteines and linked to liposomes via maleimide groups located at the terminal ends of poly(ethylene glycol) modified phospholipids. The properties of these anti-ED-B single chain antibody fragments-liposomes were analysed in vitro on ED-B fibronectin expressing Caco-2 cells and in vivo by studying their biodistribution and their therapeutic potential in mice bearing subcutanous F9 teratocarcinoma tumours. Radioactively labelled ((114m)Indium) single chain antibody fragments-liposomes accumulated in the tumours at 2-3-fold higher concentrations during the first 2 h after i.v. injection compared to unmodified liposomes. After 6-24 h both liposome types were found in similar amounts (8-10% injected dose g(-1)) in the tumours. Animals treated i.v. with single chain antibody fragments-liposomes containing the new cytotoxic agent 2'-deoxy-5-fluorouridylyl-N(4)-octadecyl-1-beta-D-arabinofuranosylcytosine (30 mg kg(-1) per dose, five times every 24 h) showed a reduction of tumour growth by 62-90% determined on days 5 and 8, respectively, compared to animals receiving control liposomes. Histological analysis revealed a marked reduction of F9 tumour cells and excessive deposition of fibronectin in the extracellular matrix after treatment with single chain antibody fragments-2-dioxy-5-fluorouridylyl-N(4)-octadecyl-1-beta-D-arabinofuranosylcytosine-liposomes. Single chain antibody fragments-liposomes targeted to ED-B fibronectin positive tumours therefore represent a promising and versatile novel drug delivery system for the treatment of tumours.
authors.affiliation: Department of Pathology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Marty
authors.forename: B
authors.initials: B
authors.lastname: Odermatt
authors.forename: H
authors.initials: H
authors.lastname: Schott
authors.forename: D
authors.initials: D
authors.lastname: Neri
authors.forename: K
authors.initials: K
authors.lastname: Ballmer-Hofer
authors.forename: R
authors.initials: R
authors.lastname: Klemenz
authors.forename: R A
authors.initials: RA
authors.lastname: Schwendener
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D005353:Fibronectins; D005468:Fluorodeoxyuridylate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007128:Immunoglobulin Fragments / Q000276:immunology* / Q000494:pharmacology; D007275:Injections, Intravenous; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018243:Teratocarcinoma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: C413287:2'-deoxy-5-fluorouridylyl-(5'-5')-N(4)-octadecyl-1-arabinofuranosylcytosine; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D005353:Fibronectins; D007128:Immunoglobulin Fragments; D008081:Liposomes; D003561:Cytarabine; D005468:Fluorodeoxyuridylate