Application of T2* relaxation mapping and quantitative susceptibility mapping to monitor iron redox state in the treatment of glioblastoma multiforme with pharmacological ascorbate

Glioblastoma multiforme (GBM), an aggressive brain cancer, kills approximately 10,000 people annually. These numbers have not changed significantly in many years, despite research into the biology and treatment of GBM. Pharmacological ascorbate (P-AscH^-), or high-dose vitamin C (5 g to >100 g) given intravenously, shows promise in combination with current treatment protocols (surgical removal of the bulk of the tumor, radiation, and chemotherapy). P-AscH^- uses iron to produce free radicals within the tumor. Tumors have been shown to accumulate higher concentrations than healthy tissue due to mutations in how iron is absorbed into and removed from the tumor. Free radicals produced by P-AscH^- and iron, in combination with radiation and chemotherapy, may more effectively control tumor growth. As the iron is used by P-AscH^-, it becomes chemically reduced, which lowers its magnetic susceptibility. We propose to image this reduction of iron using magnetic resonance imaging techniques called T₂* relaxation and quantitative susceptibility mapping (QSM). Previous researchers have used these methods to measure the total amount of iron in the brain. We tested the response of these methods to different concentrations of reduced iron (Fe²⁺) and non-reduced iron (Fe³⁺). Both T₂* and QSM are capable of differentiating Fe²⁺ and Fe³⁺. We then acquired T₂* and QSM images from 15 patients with GBM who were receiving P-AscH^- as part of a Phase II clinical trial. We imaged the subjects three times on the same day, once before P-AscH^- administration, ≈30 minutes after administration, and ≈8 hours after administration. We found that before P-AscH^- administration QSM indicated that GBM tumors had a higher concentration of Fe3+, as we would predict. The results from T₂* were less definitive, possibly due to how heterogeneous tumors are. We then compared the scans before and after P-AscH^- administration. Both T₂* and QSM images suggest that P-AscH^- reduced Fe³⁺ to Fe²⁺ in all the patients. Because our data are consistent with Fe³⁺ being reduced in all subjects, we also examined the images to see if different regions of the tumor showed different patterns of iron reduction. We found that areas known as T₁ enhancing regions showed larger changes in T₂* and QSM, suggesting a greater reduction of iron in those regions. Monitoring changes in the redox status of tumors in patients has the potential to provide researchers information necessary to design treatments leveraging iron metabolism and eventually aid clinicians in the implementation of those treatments