A pathway towards clinical translation of hyperpolarized [1,4-¹³C₂,2,3-d₂]fumarate as an imaging biomarker for early cellular necrosis in vivo
Year: 2025
Type: article
Abstract: Purpose: The detection of hyperpolarized ¹³C-fumarate conversion to ¹³C-malate using carbon-13 magnetic resonance spectroscopic imaging (¹³C-MRSI) is a biomarker for early detection of cellular necrosis. Here we describe the translation of hyperpolarized ¹³C-fumarate as a novel human imaging agent, including the evaluation of biocompatibility and scaling up of the hyperpolarization methods for clinical use. Methods: Preclinical biological validation was undertaken in fumarate hydratase-deficient murine tumor models and controls. Safety and biocompatibility of ¹³C-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 hyperpolarized ¹³C-fumarate was optimized in phantoms. Finally, 2D ¹³C-MRSI following injection of hyperpolarized ¹³C-fumarate was performed in an ischemia-reperfusion porcine kidney model (N = 6). Results: Fumarate-to-malate conversion was reduced by 42-71% in the knockdown murine tumor model compared to wildtype tumors. Twice-daily injection of 13C-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 one-hour post-injection. Spectroscopic evidence of fumarate-to-malate conversion was observed in the ischemic porcine kidney (0.96 mg/kg). Conclusion: Hyperpolarized ¹³C-fumarate has shown promise as a novel and safe hyperpolarized agent for monitoring cellular necrosis. This work provides the basis for future imaging of hyperpolarized ¹³C-fumarate metabolism in humans.
Source: Apollo (University of Cambridge)
DOI: 10.17863/cam.117282
Authors: Birchall, Jonathan, Wodtke, Pascal, Grimmer, Ashley, Hansen, Esben, Bertelsen, Lotte, Bogh, Nikolaj, Wylot, Marta, Zamora-Morales, Maria, Arponen, Otso, Horvat-Menih, Ines, Latimer, Elizabeth, Tan, Fung, Pappa, Evita, Graggaber, Johann, Cheriyan, Joseph, Holmes, Kelly, Locke, Matthew, Sladen, Helen, Boren, Joan, Kettunen, Mikko, Chhabra, Anita, Wilkinson, Ian, Laustsen, Christoffer, McLean, Mary, Gallagher, Ferdia
Language: English
Subfield: Spectroscopy
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Awards: G4955999968, G640145969, G8585681489
OpenAlex ID: W6887945216
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