Magnetite nanoparticles as a kinetically favorable source of iron to enhance GBM response to chemoradiosensitization with pharmacological ascorbate

Ferumoxytol (FMX) is an FDA-approved magnetite (Fe(3)O(4)) 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 H(2)O(2) is enhanced by Fe redox cycling, the current study determined if ascorbate catalyzed the release of ferrous iron (Fe(2+)) from FMX for enhancing GBM responses to chemo-radiotherapy. Ascorbate interacted with Fe(3)O(4) in FMX to produce redox-active Fe(2+) while simultaneously generating increased H(2)O(2) fluxes, that selectively enhanced GBM cell killing (relative to normal human astrocytes) as opposed to a more catalytically active Fe complex (EDTA-Fe(3+)) in an H(2)O(2) – 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.