Fucoidan-Manganese Dioxide Nanoparticles Potentiate Radiation Therapy by Co-Targeting Tumor Hypoxia and Angiogenesis

Mar Drugs. 2018 Dec 15;16(12):510. doi: 10.3390/md16120510.


Tumor hypoxia is a major mechanism of resistance to radiation therapy (RT), which is associated with poor prognosis in affected cancer patients. Various approaches to treat hypoxic and radioresistant cancers, including pancreatic cancer, have shown limited success. Fucoidan, a polysaccharide from brown seaweed, has antitumor and antiangiogenesis activities. Here, we discuss the development of fucoidan-coated manganese dioxide nanoparticles (Fuco-MnO₂-NPs) and testing of the therapeutic potential with RT using pancreatic cancer models. In vitro data showed that Fuco-MnO₂-NPs generated oxygen efficiently in the presence of H₂O₂ and substantially suppressed HIF-1 expression under a hypoxic condition in human pancreatic cancer cells. Fuco-MnO₂-NPs reversed hypoxia-induced radioresistance by decreasing clonogenic survival and increasing DNA damage and apoptotic cell death in response to RT. In a BxPC3 xenograft mouse model, the combination treatment with Fuco-MnO₂-NPs and RT resulted in a greater tumor growth delay than RT alone. Fucoidan-coated NPs, but not naked ones, further suppressed tumor angiogenesis, as judged by immunohistochemistry data with diminished expression of phosphorylated vascular endothelial growth factor receptor 2 (VEGFR2) and CD31. These data suggest that Fuco-MnO₂-NPs may potentiate the effects of RT via dual targeting of tumor hypoxia and angiogenesis, and they are of great clinical potential in the treatment of hypoxic, radioresistant pancreatic cancer.

Keywords: fucoidan; nanoparticles; radiation therapy; tumor hypoxia.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Chemoradiotherapy / methods
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Male
  • Manganese Compounds / chemistry
  • Mice
  • Mice, Inbred BALB C
  • Nanoparticles / chemistry
  • Neovascularization, Pathologic / drug therapy*
  • Oxides / chemistry
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy*
  • Polysaccharides / pharmacology*
  • Polysaccharides / therapeutic use
  • Radiation Tolerance / drug effects
  • Seaweed / chemistry
  • Treatment Outcome
  • Tumor Hypoxia / drug effects*
  • Tumor Hypoxia / radiation effects
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Manganese Compounds
  • Oxides
  • Polysaccharides
  • fucoidan
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • manganese dioxide