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Radiation Nanomedicine for EGFR-Positive Breast Cancer – Panitumumab Modified Gold Nanoparticles Complexed to the #-Particle-Emitter, 177Lu. Simmyung Yook, Zhongli Cai, Yijie Lu, Mitchell A. Winnik, Jean-Philippe Pignol, and Raymond M. Reilly Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 24 Sep 2015 Downloaded from http://pubs.acs.org on October 1, 2015
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Molecular Pharmaceutics
Radiation Nanomedicine for EGFR-Positive Breast Cancer – Panitumumab Modified Gold Nanoparticles Complexed to the β-Particle-Emitter, 177Lu
Simmyung Yook1, Zhongli Cai1, Yijie Lu2, Mitchell A. Winnik2, Jean-Philippe Pignol3,4, and Raymond M. Reilly1, 5, 6, 7 *
1
Department of Pharmaceutical Sciences,
2
Department of Chemistry,
Medical Biophysics, University of Toronto, Toronto, ON, Canada,
3
4
Department of Department of
Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands, Department of Medical Imaging, University of Toronto,
6
5
Toronto General Research
Institute, and 7 Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada
AUTHOR INFORMATION * Corresponding author: Raymond M. Reilly, Ph.D., Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON, Canada, M5S 3M2. Tel: 1-(416)946-5522. Fax: (416)-978-8511. E-mail:
[email protected] Revised: August 27, 2015 Conflict of interest statement: The authors declare no competing financial interest
1 ACS Paragon Plus Environment
Molecular Pharmaceutics
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TABLE OF CONTENTS GRAPHIC
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Molecular Pharmaceutics
ABSTRACT: Our objective was to construct a novel radiation nanomedicine for treatment of breast cancer (BC) expressing epidermal growth factor receptors (EGFR), particularly triplenegative tumors (TNBC). Gold nanoparticles (AuNP; 30 nm) were modified with polyethyleneglycol (PEG) chains (4 kDa) derivatized with 1,4,7,10-tetraazacyclododecane1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the β-emitter,
177
Lu and with
PEG chains (5 kDa) linked to panitumumab for targeting BC cells expressing EGFR. The AuNP were further coated with PEG chains (2 kDa) to stabilize the particles to aggregation. The binding and internalization of EGFR-targeted AuNP (177Lu-T-AuNP) into BC cells was studied and compared to non-targeted 177
Lu-T-AuNP and
177
177
Lu-NT-AuNP. The cytotoxicity of
Lu-NT-AuNP was measured in clonogenic assays using BC cells
with widely different EGFR densities: MDA-MB-468 (106 receptors/cell), MDA-MB-231 (105 receptors/cell) and MCF-7 cells (104 receptors/cell). Radiation absorbed doses to the cell nucleus of MDA-MB-468 cells were estimated based on subcellular distribution. Darkfield and fluorescence microscopy as well as radioligand binding assays revealed that 177
Lu-T-AuNP were specifically bound by BC cells dependent on their EGFR density
whereas the binding and internalization of affinity of binding of
177
177
Lu-NT-AuNP was significantly lower. The
Lu-T-AuNP to MDA-MB-468 cells was reduced by 2-fold
compared to 123I-labeled panitumumab (KD= 1.3 ± 0.2 nM vs. 0.7 ± 0.4 nM, respectively). The cytotoxicity of 177Lu-T-AuNP was dependent on the amount of radioactivity incubated with BC cells, their EGFR density and the radiosensitivity of the cells. The clonogenic survival (CS) of MDA-MB-468 cells overexpressing EGFR was reduced to
