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  • br Recently increasing attention has been paid to the

    2020-08-30


    Recently, increasing attention has been paid to the presence of specific and strongly over-expressed receptors, notably the epidermal growth factor receptor (EGFR), on the surface of cells of many cancer types including NSCLC [7]. The EGFR plays a key role in signalling
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    pathways that regulate cell proliferation, angiogenesis and tumor me-tastasis [8]. EGFR signal transduction pathways are closely related to the occurrence and development of NSCLC, with about 80% of NSCLC tumors having high expression of the EGFR [9]. Cetuximab (Erbitux®, C225, Cet in the present paper), is a recombinant human/mouse chi-meric monoclonal antibody that binds specifically to the extracellular domain of the human EGFR [10]. The drug was approved by the Food and Drug Administration in 2004 as a second-line treatment for ad-vanced colorectal cancer [11,12]. It can competitively bind to extra-cellular ligand Rituximab and thereby inhibit EGFR activation. As a result, tumor cell proliferation and angiogenesis are suppressed while apoptosis is stimulated. Cet is effective in suppressing proliferation and in enhancing apoptosis of malignant lung cells while it reduces lung cancer metastasis [13,14].
    Both in vitro and in animal models of lung cancer, administering Cetuximab in combination with chemotherapy caused an additive effect on the apoptosis of lung cancer cells [15]. In clinical trials the impact of combination treatment of Cet with chemotherapeutic agents, was more important than with either treatment alone [16,17].
    The combination of chemotherapy plus Cet was better than che-motherapy alone as the first-line treatment of advanced NSCLC in
    improving overall survival [18,19]. At the same time it induced a higher rate of adverse events. Although these side effects were reported to be manageable, both the Food and Drug Administration and the European Medicines Agency decided to not accept the license for Cet in combination with chemotherapy for first-line therapy of advanced NSCLC because the limited improvement of overall survival did not outweigh the increased side effects and costs [19]. The treatment op-tions for patients with locally advanced NSCLC remain thus poor today, with a rapidly declining survival rate from year 1 to year 2 of 88.9% to 51.9%, for stage III patients treated with combined Cet and che-motherapy [20].
    Since the above mentioned decisions of the drug agencies not to accept the license for Cet in combination with chemotherapy for first-line therapy of advanced NSCLC further research in a tumor xenograft model demonstrated that conjugation of Cet with gold nanoparticles increased the cytotoxic effect on the strongly EGFR-expressing NSCLC A549 cell line in a dose-dependent manner [21]. Moreover, conjugation of Cet to dextran-coated superparamagnetic iron oxide nanoparticles led to a significant increase in apoptosis in EGFR-over-expressing cell lines [22]. More recently, Cet conjugated and Doxorubicin (Dox) loaded silica nanoparticles were shown to possess increased anti-cancer ac-tivity as compared with free Dox and Dox-loaded silica nanoparticles [23].
    Dox is a broad-spectrum anticancer drug used for treatment of a number of solid tumors. In NSCLC cells, Dox treatment triggers acti-vation Rituximab of the unfolded protein response which subsequently promotes Dox-mediated apoptosis and caspase activation [24]. Clinical trials for advanced stages of NSCLC have revealed benefit for the treatment of this cancer type [25–27]. However, bone marrow toxicity and severe cardio-toxic effects of Dox limit the achievable therapeutic effect [28,29].
    In earlier work, we have reported a new Dox drug magnetic delivery platform, Dox was loaded on dextran-coated Fe3O4 magnetic nano-particles. In a rabbit model these drug-loaded nanoparticles, guided by an external magnetic field, showed a lower systemic toxicity [30] and led to an anti-tumor efficacy that was superior to that of free Dox [31]. In the present paper, we aimed to develop a convenient drug delivery system based on Fe3O4 magnetic nanoparticles with the potential to be active in locally advanced NSCLC. Dox and Cet conjugated dextran-coated Fe3O4 nanoparticles (Dox-NPs-Cet) were prepared and char-acterised. Then, they were incubated with A549 cells, a NSCLC cell line, which, as mentioned, over-expresses the EGFR [32,33] (Fig. 1), Finally, the internalization of Dox-NPs-Cet was evaluated and the cytotoxic inductive effects were studied. Our tests indicated that the Dox-NPs-Cet conjugate could be a promising candidate for antibody targeted Dox therapy of NSCLC. Further studies will be needed to reveal the cell death mechanism and whether the conjugates may have a superior activity than chemotherapy alone against minimal residual disease in animal models and in NSCLC patients after surgery.