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Local Radiation Treatment of HER2-Positive Breast Cancer Using Trastuzumab-Modified Gold Nanoparticles Labeled with 177 Lu.
Pharmaceutical Research 2017 March
PURPOSE: To compare the effectiveness of trastuzumab-modified gold nanoparticles (AuNP) labeled with 177 Lu (trastuzumab-AuNP-177 Lu) targeted to HER2 with non-targeted AuNP-177 Lu for killing HER2-overexpressing breast cancer (BC) cells in vitro and inhibiting tumor growth in vivo following intratumoral (i.t.) injection.
METHODS: AuNP (30 nm) were modified with polyethylene glycol (PEG) polymers linked to trastuzumab or to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to complex 177 Lu. The binding and internalization of trastuzumab-AuNP-177 Lu in HER2-positive SK-BR-3, BT-474 and MDA-MB-361 human BC cells were studied. Clonogenic survival and DNA double-strand breaks (DSBs) were measured after exposure of SK-BR-3 or MDA-MB-361 cells to trastuzumab-AuNP-177 Lu or AuNP-177 Lu. NOD/SCID mice with s.c. MDA-MB-361 tumor xenografts were treated by i.t. injection of 3 MBq (0.15 mg) of trastuzumab-AuNP-177 Lu, AuNP-177 Lu or normal saline. Tumor growth was measured over 16 days and normal tissue toxicity evaluated.
RESULTS: Trastuzumab-AuNP-177 Lu was bound and internalized by HER2 positive BC cells (KD = 7.6 ± 2.0 nM). Trastuzumab-AuNP-177 Lu was 42.9 and 2.6-fold more effective than AuNP-177 Lu at decreasing the clonogenic survival of SK-BR-3 (1.3 × 106 HER2/cell) and MDA-MB-361 (5.1 × 105 HER2/cell) cells, respectively, exposed overnight to these agents (1.5 nM; 20 MBq/mg Au). Under the same treatment conditions, 10-fold and 2.8-fold more DNA DSBs were observed in SK-BR-3 and MDA-MB-361 cells, respectively, exposed to trastuzumab-AuNP-177 Lu than AuNP-177 Lu. Trastuzumab-AuNP-177 Lu was 1.8-fold more effective at inhibiting tumor growth than AuNP-177 Lu. No or minimal normal tissue toxicity was observed for trastuzumab-AuNP-177 Lu or AuNP-177 Lu treatments.
CONCLUSION: Trastuzumab-AuNP-177 Lu enables an efficient local radiation treatment of HER2-positive BC.
METHODS: AuNP (30 nm) were modified with polyethylene glycol (PEG) polymers linked to trastuzumab or to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to complex 177 Lu. The binding and internalization of trastuzumab-AuNP-177 Lu in HER2-positive SK-BR-3, BT-474 and MDA-MB-361 human BC cells were studied. Clonogenic survival and DNA double-strand breaks (DSBs) were measured after exposure of SK-BR-3 or MDA-MB-361 cells to trastuzumab-AuNP-177 Lu or AuNP-177 Lu. NOD/SCID mice with s.c. MDA-MB-361 tumor xenografts were treated by i.t. injection of 3 MBq (0.15 mg) of trastuzumab-AuNP-177 Lu, AuNP-177 Lu or normal saline. Tumor growth was measured over 16 days and normal tissue toxicity evaluated.
RESULTS: Trastuzumab-AuNP-177 Lu was bound and internalized by HER2 positive BC cells (KD = 7.6 ± 2.0 nM). Trastuzumab-AuNP-177 Lu was 42.9 and 2.6-fold more effective than AuNP-177 Lu at decreasing the clonogenic survival of SK-BR-3 (1.3 × 106 HER2/cell) and MDA-MB-361 (5.1 × 105 HER2/cell) cells, respectively, exposed overnight to these agents (1.5 nM; 20 MBq/mg Au). Under the same treatment conditions, 10-fold and 2.8-fold more DNA DSBs were observed in SK-BR-3 and MDA-MB-361 cells, respectively, exposed to trastuzumab-AuNP-177 Lu than AuNP-177 Lu. Trastuzumab-AuNP-177 Lu was 1.8-fold more effective at inhibiting tumor growth than AuNP-177 Lu. No or minimal normal tissue toxicity was observed for trastuzumab-AuNP-177 Lu or AuNP-177 Lu treatments.
CONCLUSION: Trastuzumab-AuNP-177 Lu enables an efficient local radiation treatment of HER2-positive BC.
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