期刊
NUCLEAR MEDICINE AND BIOLOGY
卷 43, 期 12, 页码 818-826出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.nucmedbio.2016.08.009
关键词
Indium-111; Gold nanoparticles; Radiotherapy; Breast cancer; HER2; Auger electrons
资金
- Canadian Breast Cancer Foundation, Ontario Region
- Canadian Institutes of Health Research
- U.S. Department of Defense Breast Cancer Research Program
- Terry Fox Foundation Excellence in Radiation Research for the 21st Century
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, In-111 (trastuzumab-AuNP-In-111). Our objective was to determine the cytotoxicity of trastuzumab-AuNP-In-111 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-In-111 or non-targeted AuNP-In-111 in SK-BR-3 (1-2 x 10(6) HER2/cell) and MDA-MB-361 (5 x 10(5) HER2/cell) human BC cells were studied. The surviving fraction (SF) of SK-BR-3 or MDA-MB-361 cells exposed to trastuzumab-AuNP-In-111 or AuNP-In-111 was determined. DNA double strand breaks (DSBs) were assayed by probing for gamma-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 x 10(12) AuNP) of trastuzumab-AuNP-In-111 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-In-111 was specifically bound by SK-BR-3 and MDA-MB-361 cells. Trastuzumab-AuNP-In-111 was more efficiently internalized than AuNP-In-111 and localized to a ped-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-In-111. 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-36 1 cells exposed to trastuzumab-AuNP-In-111 compared to AuNP-In-111, but unlabeled trastuzumab-AuNP did not increase DNA DSBs. Local i.t injection of trastuzumab-AuNP-In-111 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-In-111 was 60.5 Gy, while normal organs received <0.9 Gy. Conclusion: These results are promising for further development of trastuzumab-AuNP-In-111 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, In-111 was developed and shown to arrest tumor growth with no normal tissue toxicity. (C) 2016 Elsevier Inc. All rights reserved.
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