Abstract
Abstract Background: Antibody-targeted therapy for malignant tumors has been increasingly developed and applied to clinical practice in recent years. Trastuzumab (Tmab) is a humanized monoclonal antibody that binds to the human epidermal growth receptor 2 (HER2) and interferes with its signal transduction leading to tumor progression, and is currently used for patients with breast cancer and gastric cancer. In inoperable recurrent or metastatic gastric cancers, HER2 is reportedly overexpressed in approximately 20% of cases, and Tmab contributes to prolongation of survival for these patients at some level. However, there still remain some issues to be overcome such as limited application of Tmab (only 20%) and limited treatment options for these advanced gastric cancers. Recent progress in nanotechnology is remarkable and various nanomaterials have been developed for medical applications. Gold nanoparticles (AuNPs) have been tested as therapeutic and contrast agents in the medical field, which are stable in vivo and easy to conjugate antibodies, proteins or peptides to the surface. Moreover, reportedly AuNPs show antitumor effect by induction to autophagy and apoptosis. These characteristics make AuNPs more attractive as molecular targeted agents. In this study, we created HER2-targeted AuNPs by conjugating Tmab on the surface of AuNPs, and examined antitumor effects on HER2-positive or negative gastric cancer cells in vitro. Methods: HER2-positive human gastric cancer cell lines (MKN7, NBI-N87), HER2-negative human gastric cancer cell lines (MKN45, MKN74) and normal human lung fibroblast (NHLF) were used in this study. The antitumor effects of Tmab-conjugated AuNPs (Tmab-AuNPs), PEGylated AuNPs (PEG-AuNPs), Tmab only (antibody amount is presumably equivalent to antibody attached on the surface of Tmab-AuNPs), mixture of PEG-AuNPs and Tmab (PEG-AuNPs + Tmab), and PBS were evaluated by XTT assay. Cellular uptake of AuNPs was observed on dark field microscopy and electron microscopy. HER2 expression was examined by western blotting and flow cytometry. Results: Dark field microscopy and electron microscopy showed that Tmab-AuNPs were taken up into cells more effectively on MKN7 and NBI-N87 cells (HER2-positive) than PEG-AuNPs and PEG-AuNPs + Tmab. XTT assay showed that Tmab-AuNPs exhibited a stronger antitumor effect on MKN7 and NBI-N87 cells (HER2-positive) than the other control treatments, but not such a strong effect on MKN45 and MKN74 cells (HER2-negative) and NHLF. The antitumor effect of Tmab-AuNPs on NBI-N87 cells was achieved by more than twice as much as Tmab, which means that Tmab-AuNPs enables to reduce the amount of Tmab to less than half. Conclusions: Tmab-AuNPs proved potent and HER2-dependent antitumor effects on human gastric cancer cells in vitro. Tmab-AuNPs could have the potential to provide more effective and less toxic treatment option for HER2-positive gastric cancer patients. Citation Format: Tetsushi Kubota, Shinji Kuroda, Katsuyuki Aoyama, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara. HER2-targeted gold nanoparticles produce potent antitumor effects on human gastric cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5520. doi:10.1158/1538-7445.AM2015-5520
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