title: Epidermal growth factor receptor-targeted immunoliposomes significantly enhance the efficacy of multiple anticancer drugs in vivo.
abstract: We previously reported the development of epidermal growth factor receptor (EGFR)-targeted immunoliposomes that bind and internalize in tumor cells which overexpress EGFR and/or mutant EGFR variant III (EGFRvIII), enabling intracellular delivery of potent anticancer agents in vitro. We now describe in vivo proof-of-concept for this approach for the delivery of multiple anticancer drugs in EGFR-overexpressing tumor models. Anti-EGFR immunoliposomes were constructed modularly with Fab' fragments of cetuximab (IMC-C225), covalently linked to liposomes containing probes and/or anticancer drugs. Pharmacokinetic and biodistribution studies confirmed long circulation times (t(1/2) = 21 hours) and efficient accumulation in tumors (up to 15% ID/g) irrespective of the presence of the targeting ligand. Although total accumulations of anti-EGFR immunoliposomes and nontargeted liposomes in EGFR-overexpressing tumors were comparable, only immunoliposomes internalized extensively within tumor cells (92% of analyzed cells versus <5% for nontargeted liposomes), indicating different mechanisms of delivery at the cellular level. In vivo therapy studies in a series of xenograft models featuring overexpression of EGFR and/or EGFRvIII showed the superiority of immunoliposomal delivery of encapsulated drugs, which included doxorubicin, epirubicin, and vinorelbine. For each of these drugs, anti-EGFR immunoliposome delivery showed significant antitumor effects and was significantly superior to all other treatments, including the corresponding free or liposomal drug (P < 0.001-0.003). We conclude that anti-EGFR immunoliposomes provide efficient and targeted drug delivery of anticancer compounds and may represent a useful new treatment approach for tumors that overexpress the EGFR.
authors.affiliation: Division of Hematology-Oncology, University of California at San Francisco, 94115, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mamot
authors.forename: Daryl C
authors.initials: DC
authors.lastname: Drummond
authors.forename: Charles O
authors.initials: CO
authors.lastname: Noble
authors.forename: Verena
authors.initials: V
authors.lastname: Kallab
authors.forename: Zexiong
authors.initials: Z
authors.lastname: Guo
authors.forename: Keelung
authors.initials: K
authors.lastname: Hong
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Kirpotin
authors.forename: John W
authors.initials: JW
authors.lastname: Park
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D000068818:Cetuximab; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D015251:Epirubicin / Q000008:administration & dosage; D066246:ErbB Receptors / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D008081:Liposomes / Q000008:administration & dosage*; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D008081:Liposomes; C410723:epidermal growth factor receptor VIII; D015251:Epirubicin; D014747:Vinblastine; D004317:Doxorubicin; D066246:ErbB Receptors; D000068818:Cetuximab; D000077235:Vinorelbine