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A comparison of non-biologically active truncated EGF (EGFt) and full-length hEGF for delivery of Auger electron-emitting 111 In to EGFR-positive breast cancer cells and tumor xenografts in athymic mice
- Source :
- Nuclear Medicine and Biology. 42:931-938
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- Introduction 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 111 In to human breast cancer (BC) cells and tumors and evaluate its cytotoxicity against EGFR-positive BC cells, mediated by the Auger electron emissions of 111 In. Methods 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 111 In-EGFt and 111 In-hEGF in MDA-MB-468 cells. The effect of exposure in vitro to 111 In-EGFt or 111 In-hEGF on the clonogenic survival of MDA-MB-468 (10 6 EGFR/cell) or MCF-7 cells (10 4 EGFR/cell) was determined. The pharmacokinetics and tumor and normal tissue biodistribution of 111 In-EGFt was compared to 111 In-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. Results Fluorescently-labeled EGFt and hEGF were bound, internalized and localized in the nucleus of MDA-MB-468 cells. Binding of 111 In-EGFt to MDA-MB-468 cells was 8-fold lower than 111 In-hEGF, but nuclear importation as a proportion of cell-bound 111 In was 3.6-fold greater than 111 In-hEGF. Nuclear uptake of 111 In-EGFt was lower than 111 In-hEGF when differences in cell binding were taken into account. The cytotoxicity of 111 In-EGFt (1.0MBq/mL; 10 nmols/L) against MDA-MB-468 cells was 9-fold lower than 111 In-hEGF but only 2-fold lower at a higher concentration (1.85MBq/mL; 40 nmols/L). 111 In-EGFt and 111 In-hEGF exhibited greater cytotoxicity against MDA-MB-468 cells than MCF-7 cells. 111 In-EGFt was eliminated more slowly from the blood of tumor-bearing mice and exhibited lower liver uptake but higher kidney accumulation. Uptake of 111 In-EGFt in MDA-MB-468 tumors was 2.2-fold lower than 111 In-hEGF, and was blocked by anti-EGFR monoclonal antibody, nimotuzumab. Nuclear uptake into MDA-MB-468 tumor cells was higher for 111 In-EGFt than 111 In-hEGF, but when the lower tumor uptake of 111 In-EGFt was considered, there were no overall differences. Conclusion We conclude that the absence of biological activity of EGFt makes it attractive for delivery of Auger electron-emitting 111 In to EGFR-overexpressing BC, but its lower cellular and tumor uptake would limit its effectiveness compared to 111 In-hEGF. Advances in Knowledge and Implications for Patient Care 111 In-EGFt may reduce the adverse effects previously observed in patients administered 111 In-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.
- Subjects :
- Cancer Research
Pathology
medicine.medical_specialty
media_common.quotation_subject
Cell
Mice, Nude
Breast Neoplasms
Electrons
Biology
Mice
Drug Delivery Systems
Epidermal growth factor
Tumor Cells, Cultured
medicine
Animals
Humans
Radiology, Nuclear Medicine and imaging
Internalization
Cytotoxicity
Cell Proliferation
media_common
Epidermal Growth Factor
Cell growth
Indium Radioisotopes
Xenograft Model Antitumor Assays
In vitro
Molecular Imaging
Tumor Burden
ErbB Receptors
medicine.anatomical_structure
Cancer research
Molecular Medicine
Female
Radiopharmaceuticals
Cell fractionation
Ex vivo
Subjects
Details
- ISSN :
- 09698051
- Volume :
- 42
- Database :
- OpenAIRE
- Journal :
- Nuclear Medicine and Biology
- Accession number :
- edsair.doi.dedup.....3f1ae44fd49cd18211870f540c3567d9