Nanotheranostics 2019; 3(2):135-144. doi:10.7150/ntno.29908

Research Paper

Perfluorocarbon nanodroplets can reoxygenate hypoxic tumors in vivo without carbogen breathing

Yun Xiang1*, Nicholas Bernards2*, Bryan Hoang1,2, Jinzi Zheng2,3, Naomi Matsuura1,3,4✉

1. Department of Medical Imaging, University of Toronto, Ontario, Canada
2. TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada
3. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Ontario, Canada
4. Department of Materials Science and Engineering, University of Toronto, Ontario, Canada
*These authors contributed equally to this work.

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Xiang Y, Bernards N, Hoang B, Zheng J, Matsuura N. Perfluorocarbon nanodroplets can reoxygenate hypoxic tumors in vivo without carbogen breathing. Nanotheranostics 2019; 3(2):135-144. doi:10.7150/ntno.29908. Available from

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Nanoscale perfluorocarbon (PFC) droplets have enormous potential as clinical theranostic agents. They are biocompatible and are currently used in vivo as contrast agents for a variety of medical imaging modalities, including ultrasound, computed tomography, photoacoustic and 19F-magnetic resonance imaging. PFC nanodroplets can also carry molecular and nanoparticulate drugs and be activated in situ by ultrasound or light for targeted therapy. Recently, there has been renewed interest in using PFC nanodroplets for hypoxic tumor reoxygenation towards radiosensitization based on the high oxygen solubility of PFCs. Previous studies showed that tumor oxygenation using PFC agents only occurs in combination with enhanced oxygen breathing. However, recent studies suggest that PFC agents that accumulate in solid tumors can contribute to radiosensitization, presumably due to tumor reoxygenation without enhanced oxygen breathing. In this study, we quantify the impact of oxygenation due to PFC nanodroplet accumulation in tumors alone in comparison with other reoxygenation methodologies, in particular, carbogen breathing.

Methods: Lipid-stabilized, PFC (i.e., perfluorooctyl bromide, CF3(CF2)7Br, PFOB) nanoscale droplets were synthesized and evaluated in xenograft prostate (DU145) tumors in male mice. Biodistribution assessment of the nanodroplets was achieved using a fluorescent lipophilic indocarbocyanine dye label (i.e., DiI dye) on the lipid shell in combination with fluorescence imaging in mice (n≥3 per group). Hypoxia reduction in tumors was measured using PET imaging and a known hypoxia radiotracer, [18F]FAZA (n≥ 3 per group).

Results: Lipid-stabilized nanoscale PFOB emulsions (mean diameter of ~250 nm), accumulated in the xenograft prostate tumors in mice 24 hours post-injection. In vivo PET imaging with [18F]FAZA showed that the accumulation of the PFOB nanodroplets in the tumor tissues alone significantly reduced tumor hypoxia, without enhanced oxygen (i.e., carbogen) breathing. This reoxygenation effect was found to be comparable with carbogen breathing alone.

Conclusion: Accumulation of nanoscale PFOB agents in solid tumors alone successfully reoxygenated hypoxic tumors to levels comparable with carbogen breathing alone, an established tumor oxygenation method. This study confirms that PFC agents can be used to reoxygenate hypoxic tumors in addition to their current applications as multifunctional theranostic agents.

Keywords: perfluorocarbon, reoxygenation, tumor hypoxia, nanodroplets, PET imaging