Upon binding to the EGFR, receptor-mediated endocytosis and
Nutlin-3a clinical trial transport to the cytosol of EGF occurs suggesting that the EGFR denotes an excellent target for drug delivery to EGFR overexpressing cancer cells in GBM [9]. To enable immunoliposome therapy to cancer cells in GBM, the immunoliposomes must pass the fenestrated tumor endothelial cells formed by capillaries of the host organism growing towards the tumor, a process called tumor angiogenesis. The size of fenestrations of the tumor endothelial cells allow nanoparticles with size diameters of 100–550nm in intracranial tumor xenografts and up to 380–2000nm in subcutaneous tumor xenografts to pass from the circulation into the tumor interstitium where they Inhibitors,research,lifescience,medical can access the cancer cells. Furthermore, molecules may also become Inhibitors,research,lifescience,medical trapped in this interstitium a phenomenon generally referred to as the enhanced penetration and retention (EPR) effect [10, 11]. The EPR effect will increase the likelihood of trapping molecules inside the tumor where the endothelium is leaky. However, in case of the brain the EPR effect is generally lower than in many other tissues due to molecules released from the vicinity of the ingrowing capillaries and direct contact of nonneuronal
cells forming the neurovascular unit surrounding Inhibitors,research,lifescience,medical the endothelial cells, for example, astrocytes, pericytes, and perivascular macrophages [12–14]. In the present study, we demonstrate that conjugation
with a commercial available monoclonal anti-human EGFR antibody, Cetuximab, significantly enhances the uptake and accumulation of liposomes in a xenograft animal model Inhibitors,research,lifescience,medical of GBM. 2. Materials and Methods 2.1. Materials The reagents were obtained from the following sources: Dulbeccos Modified Eagles Medium (DMEM) (Lonza, Cat. No. BE12-614F), LabTek permanox chamber slides (Nunc, Cat No. 177445), fetal calf serum (FCS) (Invitrogen, Cat. No. 10099-141), fluorescence mounting medium (DAKO, Cat. No. S3023), normal goat serum (DAKO, Cat. No. X0907), PD-10 desalting column (GE-Healthcare, Cat. No. 17-9323-14), penicillin/streptomycin (Invitrogen, Cat. No. 15070-063), polycarbonate Inhibitors,research,lifescience,medical membranes for manual extrusion (Nucleopore Track-Etch Membrane Filtration Products, Whatman, Avanti Polar Lipids), had a pore sizes of 0.2μm (Cat. No. 800281), 0.1μm (Cat. No. 800306), and 0.05μm (Cat. No. 800308), succinimidyl acetylthioacetate (SATA) (Pierce, Cat. Olopatadine No. 26102), TissueTek (Sakura, Cat. No. 4583 O.C.T), 50kDa Vivaspin 6 ultrafiltration device (GE-Healthcare, Cat. No. 28-9323-18). The following reagents were from Avanti Polar Lipids: Cholesterol (Cat. No. 700000P), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000] (mPEG2000-PE) (Cat. No. 880160P), 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide (polyethylene glycol)-2000] (Cat. No. 880126P), soy phosphatidylcholine (Cat. No. 840054P).
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