Magnetite nanoparticles as a kinetically favorable source of iron to enhance GBM response to chemoradiosensitization with pharmacological ascorbate
M.S. Petronek,
N. Teferi,
J.M. Caster,
J.M. Stolwijk,
A. Zaher,
J.M. Buatti,
D. Hasan,
E.I. Wafa,
A.K. Salem,
E.G. Gillan,
J.J. St – Aubin,
G.R. Buettner,
D.R. Spitz,
V.A. Magnotta,
B.G. Allen
Affiliations
M.S. Petronek
Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA; Corresponding author. Free Radical and Radiation Biology, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, 52242, USA.
N. Teferi
Department of Neurosurgery, University of Iowa, Iowa City, IA, USA
J.M. Caster
Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
J.M. Stolwijk
Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
A. Zaher
Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
J.M. Buatti
Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
D. Hasan
Department of Neurosurgery, Duke University, Durham, NC, USA
E.I. Wafa
Department of Pharmaceutical Sciences, University of Iowa, Iowa City, IA, USA
A.K. Salem
Department of Pharmaceutical Sciences, University of Iowa, Iowa City, IA, USA
E.G. Gillan
Department of Chemistry, University of Iowa, Iowa City, IA, USA
J.J. St – Aubin
Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
G.R. Buettner
Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
D.R. Spitz
Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA
V.A. Magnotta
Department of Radiology, University of Iowa, Iowa City, IA, USA
B.G. Allen
Department of Radiation Oncology, University of Iowa, Iowa City, IA, USA; Corresponding author. Free Radical and Radiation Biology, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, 52242, USA.
Ferumoxytol (FMX) is an FDA-approved magnetite (Fe3O4) nanoparticle used to treat iron deficiency anemia that can also be used as an MR imaging agent in patients that can't receive gadolinium. Pharmacological ascorbate (P-AscH-; IV delivery; plasma levels ≈ 20 mM) has shown promise as an adjuvant to standard of care chemo-radiotherapy in glioblastoma (GBM). Since ascorbate toxicity mediated by H2O2 is enhanced by Fe redox cycling, the current study determined if ascorbate catalyzed the release of ferrous iron (Fe2+) from FMX for enhancing GBM responses to chemo-radiotherapy. Ascorbate interacted with Fe3O4 in FMX to produce redox-active Fe2+ while simultaneously generating increased H2O2 fluxes, that selectively enhanced GBM cell killing (relative to normal human astrocytes) as opposed to a more catalytically active Fe complex (EDTA-Fe3+) in an H2O2 – dependent manner. In vivo, FMX was able to improve GBM xenograft tumor control when combined with pharmacological ascorbate and chemoradiation in U251 tumors that were unresponsive to pharmacological ascorbate therapy. These data support the hypothesis that FMX combined with P-AscH- represents a novel combined modality therapeutic approach to enhance cancer cell selective chemoradiosentization in the management of glioblastoma.
