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

in Redox biology by 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

TLDR

  • The study investigates whether combining a medicine called ferumoxytol (FMX) with another medicine called pharmacological ascorbate (P-AscH-) can help treat a type of brain tumor called glioblastoma (GBM). The study found that the combination of these two medicines can help kill GBM cells more effectively than using either medicine alone. The study also found that the combination of these two medicines can help improve the control of GBM tumors in mice. The study suggests that this combination of medicines could be a new way to treat GBM.

Abstract

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

Overview

  • The study investigates the potential of combining ferumoxytol (FMX) with pharmacological ascorbate (P-AscH-) to enhance the efficacy of chemo-radiotherapy in glioblastoma (GBM).
  • The study uses FMX as an MR imaging agent in patients that can't receive gadolinium and P-AscH- as an adjuvant to standard of care chemo-radiotherapy. The study aims to determine if ascorbate catalyzes the release of ferrous iron (Fe) from FMX for enhancing GBM responses to chemo-radiotherapy. The study also aims to investigate the in vivo effects of combining FMX with P-AscH- and chemoradiation on GBM xenograft tumor control in U251 tumors that were unresponsive to P-AscH- therapy.

Comparative Analysis & Findings

  • Ascorbate interacted with FeOin FMX to produce redox-active Fewhile simultaneously generating increased HOfluxes, that selectively enhanced GBM cell killing (relative to normal human astrocytes) as opposed to a more catalytically active Fe complex (EDTA-Fe) in an HO- dependent manner. In vivo, FMX was able to improve GBM xenograft tumor control when combined with P-AscH- and chemoradiation in U251 tumors that were unresponsive to P-AscH- therapy.

Implications and Future Directions

  • The study suggests that FMX combined with P-AscH- represents a novel combined modality therapeutic approach to enhance cancer cell selective chemoradiosentization in the management of glioblastoma. The study highlights the potential of using FMX as an MR imaging agent in patients that can't receive gadolinium. The study also identifies the importance of HO-dependent mechanisms in enhancing GBM cell killing. Future studies should investigate the long-term effects of combining FMX with P-AscH- and chemoradiation on GBM xenograft tumor control and patient outcomes. Future studies should also explore the potential of using FMX as an MR imaging agent in other brain tumors and other cancer types.
Read Full Article