Local Radiation Treatment of HER2-Positive Breast Cancer Using Trastuzumab-Modified Gold Nanoparticles Labeled with Lu.

Purpose: To compare the effectiveness of trastuzumab-modified gold nanoparticles (AuNP) labeled with Lu (trastuzumab-AuNP-Lu) targeted to HER2 with non-targeted AuNP-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 Lu. The binding and internalization of trastuzumab-AuNP-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-Lu or AuNP-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-Lu, AuNP-Lu or normal saline. Tumor growth was measured over 16 days and normal tissue toxicity evaluated.

Results: Trastuzumab-AuNP-Lu was bound and internalized by HER2 positive BC cells (K = 7.6 ± 2.0 nM). Trastuzumab-AuNP-Lu was 42.9 and 2.6-fold more effective than AuNP-Lu at decreasing the clonogenic survival of SK-BR-3 (1.3 × 10 HER2/cell) and MDA-MB-361 (5.1 × 10 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-Lu than AuNP-Lu. Trastuzumab-AuNP-Lu was 1.8-fold more effective at inhibiting tumor growth than AuNP-Lu. No or minimal normal tissue toxicity was observed for trastuzumab-AuNP-Lu or AuNP-Lu treatments.

Conclusion: Trastuzumab-AuNP-Lu enables an efficient local radiation treatment of HER2-positive BC.