Deuterium MRSI of tumor cell death in vivo following oral delivery of 2H-labeled fumarate
There is an unmet clinical need for direct and sensitive methods to detect cell death in vivo, especially with regard to monitoring tumor treatment response. We have shown previously that tumor cell death can be detected in vivo from 2H MRS and MRSI measurements of increased [2,3-2H2]malate production following intravenous injection of [2,3-2H2]fumarate. We show here that cell death can be detected with similar sensitivity following oral administration of the 2H-labeled fumarate.
Mice with subcutaneously implanted EL4 tumors were fasted for 1 h before administration (200 μl) of [2,3-2H2]fumarate (2 g/kg bodyweight) via oral gavage without anesthesia. The animals were then anesthetized, and after 30 min, tumor conversion of [2,3-2H2]fumarate to [2,3-2H2]malate was assessed from a series of 13 2H spectra acquired over a period of 65 min. The 2H spectra and 2H spectroscopic images were acquired using a surface coil before and at 48 h after treatment with a chemotherapeutic drug (etoposide, 67 mg/kg).
The malate/fumarate signal ratio increased from 0.022 ± 0.03 before drug treatment to 0.12 ± 0.04 following treatment (p = 0.023, n = 4). Labeled malate was undetectable in spectroscopic images acquired before treatment and increased in the tumor area following treatment. The increase in the malate/fumarate signal ratio was similar to that observed previously following intravenous administration of labeled fumarate.
Orally administered [2,3-2H2]fumarate can be used to detect tumor cell death noninvasively following treatment with a sensitivity that is similar to that obtained with intravenous administration.