Cetuximab-oxaliplatin-liposomes for epidermal growth factor receptor targeted chemotherapy of colorectal cancer

Sara Zalba Oteiza, AM Contreras, Azadeh Haeri, Timo ten Hagen, I Navarro, G de Koning, MJ Garrido

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74 Citations (Scopus)

Abstract

Oxaliplatin (L-OH), a platinum derivative with good tolerability is currently combined with Cetuximab (CTX), a monoclonal antibody (mAb), for the treatment of certain (wild-type KRAS) metastatic colorectal cancer (CRC) expressing epidermal growth factor receptor (EGFR). Improvement of L-OH pharmacokinetics (PK) can be provided by its encapsulation into liposomes, allowing a more selective accumulation and delivery to the tumor. Here, we aim to associate both agents in a novel liposomal targeted therapy by linking CTX to the drug-loaded liposomes. These EGFR-targeted liposomes potentially combine the therapeutic activity and selectivity of CTX with tumor-cell delivery of L-OH in a single therapeutic approach. L-OH liposomes carrying whole CTX or CTX-Fab' fragments on their surface were designed and characterized. Their functionality was tested in vitro using four human CRC cell lines, expressing different levels of EGFR to investigate the role of CTX-EGFR interactions in the cellular binding and uptake of the nanocarriers and encapsulated drug. Next, those formulations were evaluated in vivo in a colorectal cancer xenograftmodelwith regard to tumor drug accumulation, toxicity and therapeutic activity. In EGFR-overexpressing cell lines, intracellular drug delivery by targeted liposomes increased with receptor density reaching up to 3-fold higher levels than with non-targeted liposomes. Receptor specific uptake was demonstrated by competition with free CTX, which reduced internalization to levels similar to non-targeted liposomes. In a CRC xenograftmodel, drug deliverywas strongly enhanced upon treatmentwith targeted formulations. Liposomes conjugated with monovalent CTX-Fab' fragments showed superior drug accumulation in tumor tissue (2916.0 +/- 507.84 ng/g) compared to CTX liposomes (1546.02 +/- 362.41 ng/g) or non-targeted liposomes (891.06 +/- 155.1 ng/g). Concomitantly, CTX-Fab' targeted L-OH liposomes outperformed CTX-liposomes, which on its turn was still more efficacious than non-targeted liposomes and free drug treatment in CRC bearing mice. These results showthat site-directed conjugation ofmonovalent CTX-Fab' provides targeted L-OHliposomes that display an increased tumor drug delivery and efficacy over a formulation with CTX and non-targeted liposomes. (C) 2015 Elsevier B.V. All rights reserved.
Original languageUndefined/Unknown
Pages (from-to)26-38
Number of pages13
JournalJournal of Controlled Release
Volume210
DOIs
Publication statusPublished - 2015

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