Effects of Ultrafine Single-Nanometer Oxygen Bubbles on Radiation Sensitivity in a Tumor-Bearing Mouse Model

Int J Mol Sci. 2022 Jun 20;23(12):6838. doi: 10.3390/ijms23126838.


Radiation therapy against cancer cells often causes radiation resistance via accumulation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) under hypoxic conditions and severe side effects. Radiation sensitizers without side effects are required to overcome hypoxia-induced radiation resistance and decrease radiation-related side effects in patients with refractory cancer. We previously developed oxygen nanobubble water (NBO2 water) and demonstrated that it suppresses hypoxia-induced radiation resistance in cancer cell lines within the single-nanometer range. This study aimed to elucidate whether NBO2 water could act as a radiosensitizer via regulation of HIF-1α in a tumor-bearing mouse model. Six-week-old female BALB/c mice subcutaneously injected with tumor cells received control water or NBO2 water for 28 days, after which biochemical examinations and radiation treatment were performed. Hypoxic tumor regions were detected immunohistochemically. We found that NBO2 water sensitized radiation reactivity in the xenografted tumors. Notably, NBO2 water administration downregulated the accumulation of HIF-1α in xenografted tumors and did not affect the vital organs of healthy mice. The combination of radiation and single-nanometer NBO2 water without severe side effects may be a promising therapeutic option to improve radiation sensitivity in cancer patients without tolerance to invasive treatments.

Keywords: HIFs; hypoxia; radiation sensitizer; tumor-bearing mouse model; ultrafine nanobubble oxygen.

MeSH terms

  • Animals
  • Cell Hypoxia
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mice
  • Mice, Inbred BALB C
  • Oxygen* / pharmacology
  • Radiation Tolerance
  • Radiation-Sensitizing Agents* / pharmacology
  • Water / pharmacology


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Radiation-Sensitizing Agents
  • Water
  • Oxygen