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 FabVfragments 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)

Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin

“…p = phosphorylation chemotherapeutics (Vega et al 2003, Mamot et al 2005 and EGFR targeted radioimmonotherapy (Li et al 2004). EGFR targeted toxins is also an interesting approach in cancer therapy (Engebraaten et al 2002, Sampson et al 2008.…”

Antitumor activity of an epithelial cell adhesion molecule–targeted nanovesicular drug delivery system

“…The EpCAM-targeted immunoliposomes described here, with their long circulation half-lives, achieved double the uptake of nontargeted liposomes into tumors 24 h after injection, although both types of liposomes showed similar biodistribution patterns for the other major organs. Other investigators have reported that the tumor localization was similar for either targeted or nontargeted liposomes (18,40). Given that both types of liposomes reach solid tumors by the passive targeting mechanism, the reason for the increased tumor localization of the EpCAM-targeted liposomes versus the nontargeted liposomes may be due to both the high affinity of the scFv fragment, for the antigen, its rapid internalization, and its stability, as a high percentage of scFv remains intact after coupling and during 48 h in the body (30).…”

“…Long-circulating liposomes seem to be needed for improved tumor localization (17,18,48) and increased antitumor activity (9,17,18,49,50). The EpCAM-targeted immunoliposomes described here, with their long circulation half-lives, achieved double the uptake of nontargeted liposomes into tumors 24 h after injection, although both types of liposomes showed similar biodistribution patterns for the other major organs.…”

“…SIL-Dox and nontargeted SLDox liposomes were labeled with [ 3 H]CHE (18,38) and injected i.v. at a single dose of 4 mg doxorubicin/kg (0.66 Amol phospholipids per mouse).…”

In vivo and in situ imaging of head and neck squamous cell carcinoma using near-infrared fluorescent quantum dot probes conjugated with epidermal growth factor receptor monoclonal antibodies in mice

“…Currently, QDs have been applied in the imaging of biological macromolecules and cells both in vitro and in vivo (5)(6)(7). Non-invasive in vivo imaging has been used for the investigation of tumor development (8)(9)(10), early diagnosis of cancer (10), the transportation of drugs in vivo (11), and monitoring of therapeutic responses in vivo (11)(12)(13). These studies have demonstrated the unique advantages of QDs in the imaging of cells both in vitro and in vivo.…”