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Molecularly targeted gold nanoparticles enhance the radiation response of breast cancer cells and tumor xenografts to X-radiation

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Abstract

The purpose of this study was to evaluate the effect of molecularly targeted gold nanoparticles (AuNPs) on tumor radiosensitization both in vitro and in vivo. Human Epidermal Growth Factor Receptor-2 (HER-2)-targeted AuNPs (Au–T) were synthesized by conjugating trastuzumab (Herceptin) to 30 nm AuNPs. In vitro, the cytotoxicity of Au-T or non-targeted AuNPs (Au–P) was assessed by γ-H2AX immunofluorescence microscopy for DNA damage and clonogenic survival assays. In vivo, athymic mice bearing subcutaneous MDA-MB-361 xenografts were treated with a single dose of 11 Gy of 100 kVp X-rays 24 h after intratumoral injection of Au–T (~0.8 mg of Au) or no X-radiation. Normal tissue toxicity was determined by hematology or biochemistry parameters. The combination of Au–P or Au–T with X-ray exposure increased the formation of γ-H2AX foci by 1.7 (P = 0.054) and 3.3 (P = 0.024) fold in comparison to X-radiation alone, respectively. The clonogenic survival of cells exposed to Au–T and X-rays was significantly lower from that of cells exposed to X-radiation alone, which translated to a dose enhancement factor of 1.6. In contrast, survival of cells exposed to Au–P and X-rays versus X-radiation alone were not significantly different. In vivo, the combination of Au–T and X-radiation resulted in regression of MDA-MB-361 tumors by 46 % as compared to treatment with X-radiation (16.0 % increase in tumor volume). No significant normal tissue toxicity was observed. Radiosensitization of breast cancer to X-radiation with AuNPs was successfully achieved with an optimized therapeutic strategy of molecular targeting of HER-2 and intratumoral administration.

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Acknowledgments

This research was supported by a grant from the Canadian Breast Cancer Research Alliance (Grant 019374) to R.M.R and J.-P.P. N.C. is supported by a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research, a predoctoral fellowship from the U.S Army Department of Defense Breast Cancer Research Program (W81XWH-08-1-0519, P00002), and a predoctoral fellowship from the Connaught Fund, University of Toronto. The authors thank Dr. Patricia Lindsay for her assistance at the STTARR Imaging Facility, University of Toronto. The authors thank Yi Daniel Zhou (McGill University) for his assistance in counting colonies (clonogenic assay) and recording tumor size measurements.

Conflict of interest

The authors declare no conflict of interest with regard to the submission of this manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada

    Niladri Chattopadhyay, Zhongli Cai, Yongkyu Luke Kwon & Raymond M. Reilly

  2. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Eli Lechtman & Jean-Philippe Pignol

  3. Department of Medical Imaging, University of Toronto, Toronto, ON, Canada

    Raymond M. Reilly

  4. Department of Radiation Oncology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Jean-Philippe Pignol

  5. Toronto General Research Institute, University Health Network, Toronto, ON, Canada

    Raymond M. Reilly

  6. Leslie Dan Faculty of Pharmacy, University of Toronto, Room 1204, 144 College Street, Toronto, ON, M5S 3M2, Canada

    Raymond M. Reilly

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  1. Niladri Chattopadhyay
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Correspondence to Raymond M. Reilly.

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Chattopadhyay, N., Cai, Z., Kwon, Y.L. et al. Molecularly targeted gold nanoparticles enhance the radiation response of breast cancer cells and tumor xenografts to X-radiation. Breast Cancer Res Treat 137, 81–91 (2013). https://doi.org/10.1007/s10549-012-2338-4

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  • DOI: https://doi.org/10.1007/s10549-012-2338-4

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