MRI Detection and Therapeutic Enhancement of Ferumoxytol Internalization in Glioblastoma Cells.

Recently, the FDA-approved iron oxide nanoparticle, ferumoxytol, has been found to enhance the efficacy of pharmacological ascorbate (AscH ^- ) in treating glioblastoma, as AscH ^- reduces the Fe ³⁺ sites in the nanoparticle core. Given the iron oxidation state specificity of T2* relaxation mapping, this study aims to investigate the ability of T2* relaxation to monitor the reduction of ferumoxytol by AscH ^- with respect to its in vitro therapeutic enhancement. This study employed an in vitro glioblastoma MRI model system to investigate the chemical interaction of ferumoxytol with T ₂ * mapping. Lipofectamine was utilized to facilitate ferumoxytol internalization and assess intracellular versus extracellular chemistry. In vitro T ₂ * mapping successfully detected an AscH ^- -mediated reduction of ferumoxytol (25.6 ms versus 2.8 ms for FMX alone). The T ₂ * relaxation technique identified the release of Fe ²⁺ from ferumoxytol by AscH ^- in glioblastoma cells. However, the high iron content of ferumoxytol limited T2* ability to differentiate between the external and internal reduction of ferumoxytol by AscH ^- (ΔT ₂ * = +839% for external FMX and +1112% for internal FMX reduction). Notably, the internalization of ferumoxytol significantly enhances its ability to promote AscH ^- toxicity (dose enhancement ratio for extracellular FMX = 1.16 versus 1.54 for intracellular FMX). These data provide valuable insights into the MR-based nanotheranostic application of ferumoxytol and AscH ^- therapy for glioblastoma management. Future developmental efforts, such as FMX surface modifications, may be warranted to enhance this approach further.