期刊
MOLECULAR PHARMACEUTICS
卷 12, 期 11, 页码 3963-3972出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.5b00425
关键词
gold nanoparticles; lutetium-177; panitumumab; epidermal growth factor receptor; breast cancer
资金
- Canadian Breast Cancer Foundation - Ontario Region
- Terry Fox Foundation Strategic Initiative for Excellence in Radiation Research for the 21st Century (EIRR21) at the Canadian Institutes of Health Research (CIHR)
- Pharmaceutical Sciences Graduate Student Association Fellowship (GSEF)
- Natural Sciences and Engineering Research Council of Canada
- Canadian Institutes of Health Research
Our objective was to construct a novel radiation nanomedicine for treatment of breast cancer (BC) expressing epidermal growth factor receptors (EGFR), particularly triple-negative tumors (TNBC). Gold nanoparticles (AuNP; 30 nm) were modified with polyethylene glycol (PEG) chains (4 kDa) derivatized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the beta-emitter, Lu-177 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 (Lu-177-T-AuNP) into BC cells was studied and compared to nontargeted Lu-177-NT-AuNP. The cytotoxicity of Lu-177-T-AuNP and Lu-177-NT-AuNP was measured in clonogenic assays using BC cells with widely different EGFR densities: MDA-MB-468 (10(6) receptors/cell), MDA-MB-231 (10(5) receptors/cell), and MCF-7 cells (10(4) 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 Lu-177-T-AuNP were specifically bound by BC cells dependent on their EGFR density whereas the binding and internalization of Lu-177-NT-AuNP was significantly lower. The affinity of binding of Lu-177-T-AuNP to MDA-MB-468 cells was reduced by 2-fold compared to I-123-labeled panitumumab (K-D = 1.3 +/- 0.2 nM vs 0.7 +/- 0.4 nM, respectively). The cytotoxicity of Lu-177-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 <0.001% at the highest amount of Lu-177-T-AuNP tested (4.5 MBq; 6 X 10(11) AuNP per 2.5 X 10(4)-1.2 X 10(5) cells). Lu-177-T-AuNP were less effective for killing MDA-MB-231 cells or MCF-7 cells with moderate or low EGFR density (CS = 33.8 +/- 1.6% and 25.8 +/- 1.2%, respectively). Because the particles emitted by Lu-177 have a 2 mm range, Lu-177-NT-AuNP were also cytotoxic to BC cells due to a cross-fire effect but Lu-177-T-AuNP were significantly more potent for killing MDA-MB-468 cells overexpressing EGFR than Lu-177-NT-AuNP at all amounts tested. The cross-fire effect of the beta-particles emitted by Lu-177 may be valuable for eradicating BC cells in tumors that have low or moderate EGFR expression or cells that are not targeted by Lu-177-T-AuNP as a consequence of heterogeneous intratumoral distribution. The radiation dose to the nucleus of a single MDA-MB-468 cell was 73.2 +/- 6.7 Gy, whereas Lu-177-NT-AuNP delivered 5.6 +/- 0.6 Gy. We conclude that Lu-177-T-AuNP is a promising novel radiation nanomedicine with potential application for treatment of TNBC, in which EGFR are often overexpressed.
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