title: Modulation of hypoxia by magnetic nanoparticle hyperthermia to augment therapeutic index.
abstract: A hypoxic microenvironment in solid tumors has been known to cause resistance to standard therapies and to increase the malignant potential of tumors. The utilization of magnetic nanoparticle hyperthermia (mNPH) has shown promise in improving therapeutic outcome by (1) killing of hypoxic tumor cells directly and (2) increasing tumor oxygenation and therefore susceptibility to therapies. In this study, the interaction of a hypoxic microenvironment with mNPH efficacy was investigated in a human breast cancer orthotopic xenograft model. Using electron paramagnetic resonance (EPR) to assess in vivo oxygen concentration in tumors repeatedly and non-invasively, we found that mNPH increased tumor pO₂ from 3.5 to 68.8 mmHg on average for up to 10 days. Tumors treated once with mNPH showed growth delay. On Transmission Electron Microscopy, magnetic nanoparticles (mNPs) were localized intracellularly in multiple vesicles in the cytoplasm of cells within tumors 48 h after incubation of mNP. In conclusion, mNPH increased tumor oxygenation in vivo and resulted in decreased growth of hypoxic tumors. Future studies will establish tumor pO₂-guided multimodal therapies, such as mNPH and radiation, to improve therapeutic efficacy.
authors.affiliation: Department of Surgery, Geisel School of Medicine, Hanover, NH, USA. Eunice.Y.Chen@hitchcock.org.|Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, 03756, USA. Eunice.Y.Chen@hitchcock.org.
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Chen
authors.affiliation: Department of Surgery, Geisel School of Medicine, Hanover, NH, USA.|Department of Surgery, Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, 03756, USA.|Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.
authors.forename: Kimberley S
authors.initials: KS
authors.lastname: Samkoe
authors.affiliation: Department of Surgery, Geisel School of Medicine, Hanover, NH, USA.|Department of Surgery, Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Sassan
authors.initials: S
authors.lastname: Hodge
authors.affiliation: Dartmouth College, Hanover, NH, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Tai
authors.affiliation: Department of Radiology, Geisel School of Medicine, Hanover, NH, USA.
authors.forename: Huagang
authors.initials: H
authors.lastname: Hou
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: Petryk
authors.affiliation: Department of Surgery, Geisel School of Medicine, Hanover, NH, USA.|Department of Surgery, Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Rendall
authors.initials: R
authors.lastname: Strawbridge
authors.affiliation: Department of Surgery, Geisel School of Medicine, Hanover, NH, USA.|Department of Surgery, Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, 03756, USA.|Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.
authors.forename: P Jack
authors.initials: PJ
authors.lastname: Hoopes
authors.affiliation: Department of Radiology, Geisel School of Medicine, Hanover, NH, USA.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Khan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology* / Q000628:therapy; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008280:Magnetics; D013058:Mass Spectrometry; D051379:Mice; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles