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

Gastric Cancer. 2020 Jan;23(1):82-94. doi: 10.1007/s10120-019-00988-y. Epub 2019 Jul 13.

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: Cancer neovasculature; Monoclonal antibody; Near-infrared photoimmunotherapy; Photosensitizer; VEGFR-2.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / pharmacology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Female
  • Humans
  • Immunotherapy / methods*
  • Mice, Inbred BALB C
  • Microvessels / drug effects
  • Microvessels / pathology
  • Molecular Targeted Therapy
  • Photosensitizing Agents / pharmacokinetics
  • Photosensitizing Agents / pharmacology
  • Phototherapy / methods*
  • Receptor, ErbB-2 / metabolism
  • Stomach Neoplasms / blood supply
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / therapy*
  • Tissue Distribution
  • Trastuzumab / pharmacokinetics
  • Trastuzumab / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • DC101 monoclonal antibody
  • Photosensitizing Agents
  • ERBB2 protein, human
  • KDR protein, human
  • Receptor, ErbB-2
  • Vascular Endothelial Growth Factor Receptor-2
  • Trastuzumab