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Epidermal Growth Factor Receptor–Targeted Immunoliposomes Significantly Enhance the Efficacy of Multiple Anticancer Drugs In vivo

¹ Division of Hematology-Oncology, University of California at San Francisco, San Francisco, California; ² Department of Research and Division of Oncology, University Hospital of Basel, Basel, Switzerland; ³ California Pacific Medical Center Research Institute, Liposome Research Laboratory; and ⁴ Hermes Biosciences, Inc., South San Francisco, California

Requests for reprints: John W. Park, Division of Hematology-Oncology, University of California at San Francisco, 2nd Floor, 1600 Divisadero Street, San Francisco, CA 94115. Phone: 415-502-3844; Fax: 415-353-9571; E-mail: jpark{at}cc.ucsf.edu.

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. (Cancer Res 2005; 65(24): 11631-8)

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