Birchall Jonathan R, Wodtke Pascal, Grimmer Ashley, Hansen Esben S S, Bertelsen Lotte B, Bøgh Nikolaj, Wylot Marta, Zamora-Morales Maria J, Arponen Otso, Horvat-Menih Ines, Latimer Elizabeth C, Tan Fung, Pappa Evita, Graggaber Johann, Cheriyan Joseph, Holmes Kelly, Locke Matthew J, Sladen Helen, Boren Joan, Kettunen Mikko I, Chhabra Anita, Wilkinson Ian B, Laustsen Christoffer, Brindle Kevin, McLean Mary A, Gallagher Ferdia A
Department of Radiology, University of Cambridge, Cambridge, UK.
Cancer Research UK Cambridge Centre, Cambridge, UK.
Magn Reson Med. 2025 Sep;94(3):1202-1217. doi: 10.1002/mrm.30519. Epub 2025 May 7.
The detection of hyperpolarized carbon-13 (HP C)-fumarate conversion to C-malate using C-MRSI is a biomarker for early detection of cellular necrosis. Here, we describe the translation of HP C-fumarate as a novel human imaging agent, including the evaluation of biocompatibility and scaling up of the hyperpolarization methods for clinical use.
Preclinical biological validation was undertaken in fumarate hydratase-deficient murine tumor models and controls. Safety and biocompatibility of C-fumarate was assessed in healthy rats (N = 18) and in healthy human volunteers (N = 9). The dissolution dynamic nuclear polarization process for human doses of HP C-fumarate was optimized in phantoms. Finally, 2D C-MRSI following injection of HP C-fumarate was performed in an ischemia-reperfusion porcine kidney model (N = 6).
Fumarate-to-malate conversion was reduced by 42%-71% in the knockdown murine tumor model compared to wildtype tumors. Twice-daily injection of C-fumarate in healthy rats at the maximum evaluated dose (120 mg/kg/day) showed no significant persistent blood or tissue effects. Healthy human volunteers injected at the maximum dose (3.84 mg/kg) and injection rate (5 mL/s) showed no statistically significant changes in vital signs or blood measurements 1 h post-injection. Spectroscopic evidence of fumarate-to-malate conversion was observed in the ischemic porcine kidney (0.96 mg/kg).
HP C-fumarate has shown promise as a novel and safe hyperpolarized agent for monitoring cellular necrosis. This work provides the basis for future imaging of HP C-fumarate metabolism in humans.
利用碳-13磁共振波谱成像（C-MRSI）检测超极化碳-13（HP C）-富马酸盐转化为C-苹果酸盐是早期检测细胞坏死的生物标志物。在此，我们描述了HP C-富马酸盐作为一种新型人体成像剂的转化研究，包括生物相容性评估以及将超极化方法扩大规模以用于临床。
在富马酸水合酶缺陷型小鼠肿瘤模型和对照中进行临床前生物学验证。在健康大鼠（N = 18）和健康人类志愿者（N = 9）中评估C-富马酸盐的安全性和生物相容性。在体模中优化了人体剂量的HP C-富马酸盐的溶解动态核极化过程。最后，在缺血再灌注猪肾模型（N = 6）中注射HP C-富马酸盐后进行二维C-MRSI。
与野生型肿瘤相比，敲低小鼠肿瘤模型中富马酸盐向苹果酸盐的转化降低了42%-71%。在健康大鼠中以最大评估剂量（120 mg/kg/天）每日两次注射C-富马酸盐，未显示出明显的持续血液或组织效应。以最大剂量（3.84 mg/kg）和注射速率（5 mL/s）注射的健康人类志愿者在注射后1小时生命体征或血液测量值无统计学显著变化。在缺血猪肾（0.96 mg/kg）中观察到了富马酸盐向苹果酸盐转化的光谱证据。
HP C-富马酸盐已显示出作为一种新型安全的超极化剂用于监测细胞坏死的前景。这项工作为未来人类HP C-富马酸盐代谢成像提供了基础。
