Enhancing Photodynamic Therapy treatment efficacy on oral cancer with Nimotuzumab
Photodiagnosis and Photodynamic Therapy(2015)
Abstract
EGFt is a truncated form of human epidermal growth factor (hEGF) that is non-biologically active but retains binding and internalization into EGFR-positive cells. Our aim was to compare EGFt and hEGF for delivery of 111In to human breast cancer (BC) cells and tumors and evaluate its cytotoxicity against EGFR-positive BC cells, mediated by the Auger electron emissions of 111In.The binding, internalization and nuclear localization of EGFt and hEGF in MDA-MB-468 human BC cells were first assessed by confocal fluorescence microscopy. Subcellular fractionation was then used to quantify the cellular and nuclear uptake of 111In-EGFt and 111In-hEGF in MDA-MB-468 cells. The effect of exposure in vitro to 111In-EGFt or 111In-hEGF on the clonogenic survival of MDA-MB-468 (106 EGFR/cell) or MCF-7 cells (104 EGFR/cell) was determined. The pharmacokinetics and tumor and normal tissue biodistribution of 111In-EGFt was compared to 111In-hEGF in CD-1 athymic mice with s.c. MDA-MB-468 and MCF-7 tumors. Nuclear importation in MDA-MB-468 tumors was determined ex vivo by subcellular fractionation.Fluorescently-labeled EGFt and hEGF were bound, internalized and localized in the nucleus of MDA-MB-468 cells. Binding of 111In-EGFt to MDA-MB-468 cells was 8-fold lower than 111In-hEGF, but nuclear importation as a proportion of cell-bound 111In was 3.6-fold greater than 111In-hEGF. Nuclear uptake of 111In-EGFt was lower than 111In-hEGF when differences in cell binding were taken into account. The cytotoxicity of 111In-EGFt (1.0 MBq/mL; 10 nmols/L) against MDA-MB-468 cells was 9-fold lower than 111In-hEGF but only 2-fold lower at a higher concentration (1.85 MBq/mL; 40 nmols/L). 111In-EGFt and 111In-hEGF exhibited greater cytotoxicity against MDA-MB-468 cells than MCF-7 cells. 111In-EGFt was eliminated more slowly from the blood of tumor-bearing mice and exhibited lower liver uptake but higher kidney accumulation. Uptake of 111In-EGFt in MDA-MB-468 tumors was 2.2-fold lower than 111In-hEGF, and was blocked by anti-EGFR monoclonal antibody, nimotuzumab. Nuclear uptake into MDA-MB-468 tumor cells was higher for 111In-EGFt than 111In-hEGF, but when the lower tumor uptake of 111In-EGFt was considered, there were no overall differences.We conclude that the absence of biological activity of EGFt makes it attractive for delivery of Auger electron-emitting 111In to EGFR-overexpressing BC, but its lower cellular and tumor uptake would limit its effectiveness compared to 111In-hEGF.111In-EGFt may reduce the adverse effects previously observed in patients administered 111In-hEGF since it is not biologically active, but its lower uptake by BC cells and tumors would limit its effectiveness for treatment of breast cancer.
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Key words
photodynamic therapy treatment efficacy,photodynamic therapy,oral cancer
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