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Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/29548

Title: 111In-labeled Nimotuzumab Modified with Nuclear Localization Sequences (NLS): An Auger Electron-emitting Radiotherapeutic Agent for EGFR-overexpressing and Trastuzumab-resistant Breast Cancer
Authors: Fasih, Aisha
Advisor: Reilly, Raymond Matthew
Department: Pharmaceutical Sciences
Keywords: Herceptin resistant breast cancer
Auger eletron radiotherapy
Nimotuzumab (mAb of EGFR)
Issue Date: 24-Aug-2011
Abstract: Objective: The cytotoxic property of anti-EGFR-1 monoclonal-antibody nimotuzumab modified with nuclear localization sequence and radiolabeled with 111In was evaluated in trastuzumab-resistant breast cancer cells. Methods: 111In-nimotuzumab-NLS was constructed and its immunoreactivity was determined. Cellular and nuclear uptake was evaluated by cell fractionation. Finally, the cytotoxicity of conjugates (111In-nimotuzumab/111In-nimotuzumab-NLS) was studied by clonogenic assays. Results: The immunoreactivity of 111In-nimotuzumab-NLS was conserved. 111In-nimotuzumab-NLS exhibited 2-fold higher nuclear translocation as compared to 111In-nimotuzumab in MDA-MB-468 cells. Nuclear importation of 111In-nimotuzumab-NLS in MDA-MB-468 cells was 4-fold and 6-fold higher than moderate and low EGFR expressing cell lines, respectively. Clonogenic survival (CS) for MDA-MB-468 cells showed 111In-nimotuzumab-NLS to be 10-folds and 60-folds more potent than 111In-nimotuzumab and nimotuzumab, respectively. Moderate killing for TrR1 and MDA-MB-231 was observed. 111In-hEGF showed significantly higher cytotoxicity and 2-fold higher γ-H2AX foci integrated density/nuclear-area as compared to 111In-nimotuzumab-NLS. Preserved selectivity of 111In-nimotuzumab-NLS makes it an excellent drug for treating cancers.
URI: http://hdl.handle.net/1807/29548
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