Imaging the Transmembrane and Transendothelial Sodium Gradients in Gliomas

High sodium (Na+) in extracellular (Na+e) and blood (Na+b) compartments and low Na+ in intracellular milieu (Na+i) produce strong transmembrane ({Delta}Na+mem) and weak transendothelial ({Delta}Na+end) gradients respectively, which reflect cell membrane potential (Vm) and blood-brain barrier (BBB) integrity. We developed a sodium (23Na) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic contrast agent to measure {Delta}Na+mem and {Delta}Na+end. In vitro 23Na-MRSI established that the 23Na signal is strongly shifted by the agent compared to biological factors. In vivo 23Na-MRSI showed Na+i remained unshifted and Na+b was more shifted than Na+e, and these together created weakened {Delta}Na+mem and enhanced {Delta}Na+end in rat gliomas. Specifically, RG2 and U87 tumors maintained weakened {Delta}Na+mem (i.e., depolarized Vm) implying an aggressive state for proliferation, and RG2 tumors displayed elevated {Delta}Na+end suggesting altered BBB integrity. 23Na-MRSI will allow explorations of perturbed Na+ homeostasis in vivo for the tumor neurovascular unit.