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Cancer neovasculature-targeted near-infrared photoimmunotherapy (NIR-PIT) for gastric cancer: different mechanisms of phototoxicity compared to cell membrane-targeted NIR-PIT

  • Takashi Nishimura
  • Makoto MitsunagaEmail author
  • Kimihiro Ito
  • Hisataka Kobayashi
  • Masayuki Saruta
Original Article
  • 23 Downloads

Abstract

Background

Near-infrared photoimmunotherapy (NIR-PIT) constitutes a new class of molecular-targeted theranostics utilizing monoclonal antibody (mAb)-photosensitizer conjugates and NIR light. In this study, we developed a new type of NIR-PIT targeting vascular endothelial growth factor receptor 2 (VEGFR-2) expressed on vascular endothelium in an experimental gastric cancer model and evaluated the feasibility by comparing conventional NIR-PIT targeting cancer cell membrane in vitro and in vivo.

Methods

HER2-positive human gastric cancer cells, NCI-N87, were used for the experiments. Anti-HER2 mAb, trastuzumab and anti-VEGFR-2 mAb, DC101 were conjugated to photosensitizer, IR700. Phototoxicity in response to NIR-PIT were investigated in vitro and in vivo. Microvessel densities, as an indicator of angiogenesis, were counted in harvested xenografts after NIR-PIT to elucidate the mechanism.

Results

DC101-IR700 did not induce phototoxic effect in vitro because of the absence of expression of VEGFR-2 in NCI-N87 cancer cells. However, it induced an antitumor effect in NCI-N87 xenograft tumors accompanied with damage in tumor neovasculature as determined by decreasing tumor microvessel density, which represents a different mechanism than that of conventional NIR-PIT targeting antigens expressed on the tumor cell membrane.

Conclusion

We demonstrated a new approach of NIR-PIT utilizing a target on vascular endothelium, such as VEGFR-2, and this treatment might lead to the development of a new therapeutic strategy for human gastric cancer.

Keywords

Near-infrared photoimmunotherapy Monoclonal antibody Photosensitizer VEGFR-2 Cancer neovasculature 

Abbreviations

APC

Monoclonal antibody photosensitizer conjugate

ICD

Immunogenic cell death

DAPI

4′,6′-Diamidino-2-phenylindole

HER2

Human epidermal growth factor receptor 2

IR700

IRDye700DX N-hydroxysuccinimide ester

mAb

Monoclonal antibodies

MVD

Microvessel density

MFI

Mean fluorescence intensity

NIR-PIT

Near-infrared photoimmunotherapy

VEGFR-2

Vascular endothelial growth factor receptor 2

Notes

Acknowledgements

We would like to thank Mr. Kazuya Sakurai and Ms. Mamiko Ohwada for their pathological assistants with the experiments. This study was supported partly by a Grant-in-Aid for Young Scientists (A) (JSPS KAKENHI 26710010), Grant-in-Aid for Scientific Research (B) (JSPS KAKENHI 18H03523), funding from a research Grant of Bristol-Myers Squibb (M.M.), and funding from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (1ZIABC011513).

Author contributions

Conceptualization: MM; data duration: TN, KI and MM; formal analysis: TN, KI and MM; funding acquisition: MM and HK; supervision: HK and MS; writing: TN, MM and HK.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10120_2019_988_MOESM1_ESM.docx (329 kb)
Supplementary file1 (DOCX 329 kb)

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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2019

Authors and Affiliations

  1. 1.Division of Gastroenterology and Hepatology, Department of Internal MedicineThe Jikei University School of MedicineTokyoJapan
  2. 2.Molecular Imaging Program, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaUSA

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