Research Article
HER2-targeted gold nanoparticles potentially overcome resistance to trastuzumab in gastric cancer

https://doi.org/10.1016/j.nano.2018.05.019Get rights and content

Abstract

An issue of concern is that no current HER2-targeted therapeutic agent is effective against Trastuzumab (Tmab)-resistant gastric cancer. Gold nanoparticles (AuNPs) are promising drug carriers with unique characteristics of a large surface area available for attachment of materials such as antibodies. Here, we created HER2-targeted AuNPs (T-AuNPs) and examined their therapeutic efficacy and cytotoxic mechanisms using HER2-postive Tmab-resistant (MKN7) or Tmab-sensitive (NCI-N87) gastric cancer cell lines. In vitro, T-AuNPs showed stronger cytotoxic effects than controls against MKN7 and NCI-N87 cells although Tmab had no effect on MKN7 cells. Autophagy played an important role in T-AuNP cytotoxic mechanisms, which was considered to be driven by internalization of T-AuNPs. Finally, T-AuNPs displayed potent antitumor effects against NCI-N87 and MKN7 subcutaneous tumors in in vivo mouse models. In conclusion, HER2-targeted AuNPs with conjugated Tmab is a promising strategy for the development of novel therapeutic agents to overcome Tmab resistance in gastric cancer.

Graphical abstract

HER2-targeted gold nanoparticles (T-AuNPs) (85 nm average diameter), created by conjugating trastuzumab (Tmab) onto the surface of the gold nanoparticles, produced a potent cytotoxic effect on Tmab-resistant gastric cancer cells, against which Tmab did not show any cytotoxicity, through autophagy that was induced by HER2-dependent internalization of the T-AuNPs into cells.

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Section snippets

Synthesis of trastuzumab-conjugated gold nanoparticles (T-AuNPs)

T-AuNPs were synthesized basically according to the protocol outlined by Kumar et al.32 Briefly, Tmab (Roche Ltd., Basel, Switzerland) was attached to the surface of 50 nm AuNPs (Sigma-Aldrich, St. Louis, MO, USA) via a linker (SensoPath Technologies, Bozeman, MT, USA) that consisted of a short polyethylene glycol chain terminated at one end by a hydrazide moiety and at the other end by two thiol groups. Finally, 5 kDa methoxyPEG-SH (Creative PEGWorks, Chapel Hill, NC, USA) was added to the

Characteristics of synthesized T-AuNPs

After the synthesis of T-AuNPs (Figure 1, A) and C-AuNPs, the characteristics of these particles were analyzed using DLS, spectrophotometry and electron microscopy. DLS analysis showed that the size of the T-AuNPs was 85.39 ± 0.68 nm and that the surface was negatively charged with 39.43 ± 0.85 mV (Supplementary Table S1). The size and the Z potential of the C-AuNPs and the naked AuNPs were 94.12 ± 0.32 nm and − 43.70 ± 0.10 mV, and 78.60 ± 0.34 nm and − 52.83 ± 0.93 mV, respectively.

Discussion

No effective HER2-targeted therapeutic agent currently exists for metastatic gastric cancer with acquired resistance to Tmab, which is in contrast to breast cancer for which novel HER2-taregeted agents such as T-DM1, lapatinib and pertuzumab are all in clinical use. Gastric cancer is the third leading cause of death and the fifth most common malignancy in the world, half of which occurs in Eastern Asia.34 Since Tmab therapy in combination with chemotherapy is the first treatment option for

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      Citation Excerpt :

      Moreover, Tmab-AuNCs demonstrated higher potent cytotoxic impacts than controls against NCI-N87 and MKN7 cells, while Tmab alone did not affect MKN7 cells. Besides, the in vivo experiments in MKN7 and NCI-N87 bearing mouse models revealed the significant antitumor effects of Tmab-AuNCs [97]. Photodynamic therapy (PDT) and photothermal therapy (PTT) are photo-based therapy techniques utilizing photo-reactive nanomaterials.

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    Funding: This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant number 26870390).

    Conflict of interest: The authors declare that they have no conflict of interests.

    Prior presentation: We made a presentation of the abstract at the AACR Annual Meeting in 2015 and 2016 regarding this research.

    Acknowledgments: The authors would like to thank Tomoko Sueishi and Tae Yamanishi for their excellent technical support.

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