Abstract 4747: Novel HER2-targeted gold nanoparticles; integration of antibody therapy and nanotechnology

Abstract

Abstract Targeted therapies utilizing monoclonal antibodies for malignant tumors has been increasingly developed and applied to clinical practice. Trastuzumab (Tmab) is a humanized monoclonal antibody which binds to the human epidermal growth receptor 2 (HER2), which leads to strong antitumor effects by inducing antibody-dependent cell-mediated cytotoxicity (ADCC) and inhibiting HER2 signaling pathway. While Tmab is clinically applied to HER2-positive breast and gastric cancers, there still remain some issues such as low HER2 expression (only 20%) and resistance to Tmab. Recent progress in nanotechnology has brought significant benefits to medical fields. Gold nanoparticles (AuNPs), marked by the in vivo stability and easy surface functionalization, have been developed as therapeutic and contrast agents in the medical field, and some AuNPs reportedly show some cytotoxicity by inducing autophagy and apoptosis, which indicates that AuNPs could be attractive therapeutic agents in combination with tumor-targeting antibodies. In this study, we created Tmab-conjugated AuNPs and evaluated the antitumor effects on HER2-positive but Tmab-resistant gastric cancer cells (MKN7) and HER2-negative gastric cancer cells (MKN74) in addition to HER2-positive and Tmab-sensitive esophagogastric cancer cells (NCI-N87, TE4, OE19) in vitro and in vivo. IC50 dose of Tmab-AuNPs was 6.5 times smaller than free Tmab on NCI-N87 cells. Tmab-AuNPs exhibited stronger antitumor effects on MKN7, NCI-N87, TE4 and OE19, HER2-positive cells, than the other controls on XTT assay, but not such strong effects on MKN74 and NHLF, HER2-negative cells. Notably, Tmab-AuNPs showed potent antitumor effects even on MKN7, HER2-positive but Tmab-resistant cells. Moreover, once HER2 was overexpressed on MKN74 cells by Ad-HER2/ECD, Tmab-AuNPs became effective on artificially-HER2-overexpressed MKN74 cells. More effective intracellular uptake of Tmab-AuNPs was observed by dark field microscopy and transmission electron microscopy on HER2-positive cells, which seemed to cause stronger induction of oxidative stress, autophagy and apoptosis. Finally, stronger antitumor effects of Tmab-AuNPs were also confirmed in mouse subcutaneous xenograft models using HER2-positive cells. In conclusion, Tmab-AuNPs demonstrated potent antitumor effects on Tmab-resistant cells as well as Tmab-sensitive cells, and if combined with HER2/ECD overexpression, Tmab-AuNPs became effective even on HER2-negative cells. These findings suggest that Tmab-AuNPs could be promising HER2-targeted nanodrugs which were able to overcome shortcomings in Tmab-based therapy. Citation Format: Tetsushi Kubota, Shinji Kuroda, Toshiaki Morihiro, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara. Novel HER2-targeted gold nanoparticles; integration of antibody therapy and nanotechnology. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4747.