2016-12-01
111In-labeled trastuzumab-modified gold nanoparticles are cytotoxic in vitro to HER2-positive breast cancer cells and arrest tumor growth in vivo in athymic mice after intratumoral injection
Publication
Publication
Nuclear Medicine and Biology , Volume 43 - Issue 12 p. 818- 826
Introduction Gold nanoparticles (AuNP; 30 nm) were modified with polyethylene glycol (PEG) chains linked to trastuzumab for binding to HER2-positive breast cancer (BC) cells and diethylenetriaminepentaacetic acid (DTPA) for complexing the Auger electron-emitter, 111In (trastuzumab-AuNP-111In). Our objective was to determine the cytotoxicity of trastuzumab-AuNP-111In on HER2-positive BC cells in vitro and evaluate its tumor growth inhibition properties and normal tissue toxicity in vivo following intratumoral (i.t.) injection in mice with s.c. HER2-overexpressing BC xenografts. Methods Binding and internalization of trastuzumab-AuNP-111In or non-targeted AuNP-111In in SK-BR-3 (1–2 × 106 HER2/cell) and MDA-MB-361 (5 × 105 HER2/cell) human BC cells were studied. The surviving fraction (SF) of SK-BR-3 or MDA-MB-361 cells exposed to trastuzumab-AuNP-111In or AuNP-111In was determined. DNA double-strand breaks (DSBs) were assayed by probing for γ-H2AX. Tumor growth was monitored over 70 days in CD1 athymic mice with s.c. MDA-MB-361 xenografts after i.t. injection of 10 MBq (0.7 mg; 2.6 × 1012 AuNP) of trastuzumab-AuNP-111In and normal tissue toxicity was assessed by monitoring body weight, complete blood cell (CBC) counts and serum alanine aminotransferase (ALT) and creatinine (Cr). Results Trastuzumab-AuNP-111In was specifically bound by SK-BR-3 and MDA-MB-361 cells. Trastuzumab-AuNP-111In was more efficiently internalized than AuNP-111In and localized to a peri-nuclear region. The SF fraction of SK-BR-3 cells was reduced by 1.8-fold by treatment with 3 nM (7 MBq/mL) of trastuzumab-AuNP-111In. The SF of MDA-MB-361 cells was reduced by 3.7-fold at 14.4 nM (33.6 MBq/mL). In comparison, non-targeted AuNP-111In at these concentrations reduced the SF of SK-BR-3 or MDA-MB-361 cells by 1.2-fold (P = 0.03) and 1.7-fold (P < 0.0001), respectively. DNA DSBs were greater in SK-BR-3 and MDA-MB-361 cells exposed to trastuzumab-AuNP-111In compared to AuNP-111In, but unlabeled trastuzumab-AuNP did not increase DNA DSBs. Local i.t. injection of trastuzumab-AuNP-111In in CD1 athymic mice with s.c. MDA-MB-361 tumors arrested tumor growth for 70 days. There was no apparent normal tissue toxicity. The radiation absorbed dose deposited in the tumor by trastuzumab-AuNP-111In was 60.5 Gy, while normal organs received <0.9 Gy. Conclusion These results are promising for further development of trastuzumab-AuNP-111In as a novel Auger electron-emitting radiation nanomedicine for local treatment of HER2-positive BC. Advances in knowledge and implications for patient care A local radiation treatment for HER2-positive BC based on AuNP modified with trastuzumab and labeled with the Auger electron-emitter, 111In was developed and shown to arrest tumor growth with no normal tissue toxicity.
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doi.org/10.1016/j.nucmedbio.2016.08.009, hdl.handle.net/1765/94082 | |
Nuclear Medicine and Biology | |
Organisation | Erasmus MC: University Medical Center Rotterdam |
Cai, Z., Chattopadhyay, N. (Niladri), Yang, K. (Kaiyu), Kwon, Y.L. (Yongkyu Luke), Yook, S., Pignol, J.-P., & Reilly, R. M. (2016). 111In-labeled trastuzumab-modified gold nanoparticles are cytotoxic in vitro to HER2-positive breast cancer cells and arrest tumor growth in vivo in athymic mice after intratumoral injection. Nuclear Medicine and Biology, 43(12), 818–826. doi:10.1016/j.nucmedbio.2016.08.009 |