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Targeting integrins with RGD-conjugated gold nanoparticles in radiotherapy decreases the invasive activity of breast cancer cells

Authors Wu PH, Onodera Y, Ichikawa Y, Rankin EB, Giaccia AJ, Watanabe Y, Qian W, Hashimoto T, Shirato H, Nam JM

Received 25 March 2017

Accepted for publication 6 May 2017

Published 14 July 2017 Volume 2017:12 Pages 5069—5085

DOI https://doi.org/10.2147/IJN.S137833

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Farooq Shiekh

Peer reviewer comments 2

Editor who approved publication: Dr Thomas J Webster

Video abstract presented by Dr Ping-Hsiu Wu.

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Ping-Hsiu Wu,1 Yasuhito Onodera,2 Yuki Ichikawa,3,4 Erinn B Rankin,5 Amato J Giaccia,5 Yuko Watanabe,3 Wei Qian,4 Takayuki Hashimoto,1 Hiroki Shirato,1,6,7 Jin-Min Nam1,6,7

1Department of Radiation Medicine, 2Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Hokkaido, 3Innovation Center, Aisin Seiki Co., Ltd., Aichi, Japan; 4IMRA America, Inc., Ann Arbor, MI, 5Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University Medical Center, Stanford, CA, USA; 6Research Center for Cooperative Projects, Graduate School of Medicine, 7Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education, Hokkaido University, Hokkaido, Japan

Abstract: Gold nanoparticles (AuNPs) have recently attracted attention as clinical agents for enhancing the effect of radiotherapy in various cancers. Although radiotherapy is a standard treatment for cancers, invasive recurrence and metastasis are significant clinical problems. Several studies have suggested that radiation promotes the invasion of cancer cells by activating molecular mechanisms involving integrin and fibronectin (FN). In this study, polyethylene-glycolylated AuNPs (P-AuNPs) were conjugated with Arg–Gly–Asp (RGD) peptides (RGD/P-AuNPs) to target cancer cells expressing RGD-binding integrins such as α5- and αv-integrins. RGD/P-AuNPs were internalized more efficiently and colocalized with integrins in the late endosomes and lysosomes of MDA-MB-231 cells. A combination of RGD/P-AuNPs and radiation reduced cancer cell viability and increased DNA damage compared to radiation alone in MDA-MB-231 cells. Moreover, the invasive activity of breast cancer cell lines after radiation treatment was significantly inhibited in the presence of RGD/P-AuNPs. Microarray analyses revealed that the expression of FN in irradiated cells was suppressed by combined use of RGD/P-AuNPs. Reduction of FN and downstream signaling may be involved in suppressing radiation-induced invasive activity by RGD/P-AuNPs. Our study suggests that RGD/P-AuNPs can target integrin-overexpressing cancer cells to improve radiation therapy by suppressing invasive activity in addition to sensitization. Thus, these findings provide a possible clinical strategy for using AuNPs to treat invasive breast cancer following radiotherapy.

Keywords: gold nanoparticles, radiotherapy, breast cancer, invasion, integrin, fibronectin

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