Deuterium magnetic resonance spectroscopic imaging of tumor cell death in vivo following oral delivery of 2Hlabeled fumarate

Abstract

Purpose

There is an unmet clinical need for direct and sensitive methods to detect cell death in vivo, especially in regard to monitoring tumor treatment response. We have shown previously that tumor cell death can be detected in vivo from 2H magnetic resonance spectroscopy and spectroscopic imaging 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-labelled fumarate.

Methods

Mice with subcutaneously implanted EL4 tumors were fasted for 1 h before administration (200 µl) of [2,3-2H2]fumarate (2g/kg bodyweight) via oral gavage without anesthesia. The animals were then anaesthetized and after 30 minutes 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 minutes. 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).

Results

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). Labelled malate was undetectable in spectroscopic images acquired prior to treatment and increased in the tumor area post-treatment. The increase in the malate/fumarate signal ratio was similar to that observed previously following intravenous administration of labelled fumarate. Conclusion Orally administered [2,3-2H2]fumarate, can be used to detect tumor cell death non-invasively post treatment with a sensitivity that is similar to that obtained with intravenous administration.