Pharmacological ascorbate (P-AscH^-) combined with standard of care (SOC) radiation and temozolomide is being evaluated in a phase 2 clinical trial (NCT02344355) in the treatment of glioblastoma (GBM). Previously published data demonstrated that paramagnetic iron (Fe³⁺) catalyzes ascorbate's oxidation to form diamagnetic iron (Fe²⁺). Because paramagnetic Fe³⁺ may influence relaxation times observed in MR imaging, quantitative MR imaging of P-AscH^--induced changes in redox-active Fe was assessed as a biomarker for therapy response.

Gel phantoms containing either Fe³⁺ or Fe²⁺ were imaged with T2* and quantitative susceptibility mapping (QSM). Fifteen subjects receiving P-AscH^- plus SOC underwent T2* and QSM imaging four weeks into treatment. Subjects were scanned: pre-P-AscH^- infusion, post-P-AscH^- infusion, and post-radiation (3–4 h between scans). Changes in T2* and QSM relaxation times in tumor and normal tissue were calculated and compared to changes in Fe³⁺ and Fe²⁺ gel phantoms. A GBM mouse model was used to study the relationship between the imaging findings and the labile iron pool.

Phantoms containing Fe³⁺ demonstrated detectable changes in T2* and QSM relaxation times relative to Fe²⁺ phantoms. Compared to pre-P-AscH^-, GBM T2* and QSM imaging were significantly changed post-P-AscH^- infusion consistent with conversion of Fe³⁺ to Fe²⁺. No significant changes in T2* or QSM were observed in normal brain tissue. There was moderate concordance between T2* and QSM changes in both progression free survival and overall survival. The GBM mouse model showed similar results with P-AscH^- inducing greater changes in tumor labile iron pools compared to the normal tissue.

Conclusions

T2* and QSM MR-imaging responses are consistent with P-AscH^- reducing Fe³⁺ to Fe²⁺, selectively in GBM tumor volumes and represent a potential biomarker of response. This study is the first application using MR imaging in humans to measure P-AscH^--induced changes in redox-active iron.

中文翻译：

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药理学抗坏血酸诱导的铁氧化还原状态的磁共振成像 (MRI) 作为接受放化疗受试者的生物标志物

药理学抗坏血酸 (P-AscH ^- ) 结合标准护理 (SOC) 辐射和替莫唑胺正在治疗胶质母细胞瘤 (GBM) 的 2 期临床试验 (NCT02344355) 中进行评估。先前公布的数据表明顺磁性铁 (Fe ³⁺ ) 催化抗坏血酸氧化形成抗磁性铁 (Fe ²⁺ )。因为顺磁性 Fe ³⁺可能影响在 MR 成像中观察到的弛豫时间，所以 P-AscH ^-诱导的氧化还原活性 Fe 变化的定量 MR 成像被评估为治疗反应的生物标志物。

含有 Fe ³⁺或 Fe ^{2+ 的}凝胶体模使用 T2* 和定量磁化率映射 (QSM) 成像。15 名接受 P-AscH ^-加上 SOC 的受试者在治疗后 4 周接受了 T2* 和 QSM 成像。对受试者进行扫描：P-AscH 前^-输注、P-AscH 后^-输注和放射后（扫描间隔 3-4 小时）。计算肿瘤和正常组织中 T2* 和 QSM 弛豫时间的变化，并与 Fe ³⁺和 Fe ²⁺凝胶体模的变化进行比较。GBM 小鼠模型用于研究成像结果与不稳定铁池之间的关系。

与 Fe ²⁺体模相比，含有 Fe ^{3+ 的}体模在 T2* 和 QSM 弛豫时间方面表现出可检测的变化。与前 P-AscH ^{- 相比}，GBM T2* 和 QSM 成像在 P-AscH ^-输注后发生了显着变化，与 Fe ³⁺向 Fe ^{2+ 的}转化一致。在正常脑组织中未观察到 T2* 或 QSM 的显着变化。在无进展生存期和总生存期方面，T2* 和 QSM 变化之间存在中等一致性。GBM 小鼠模型显示出与 P-AscH 相似的结果^——与正常组织相比，诱导肿瘤不稳定铁池发生更大的变化。

结论

T2* 和 QSM MR 成像反应与 P-AscH 一致^-将 Fe ³⁺还原为 Fe ²⁺，选择性地在 GBM 肿瘤体积中并代表潜在的反应生物标志物。这项研究是首次在人体中使用 MR 成像来测量 P-AscH ^-引起的氧化还原活性铁的变化。