Figure 2.

Demonstration of ²³Na peak separation in vivo following TmDOTP⁵⁻ administration into a rat bearing a U251 tumor in the brain. (a) ¹H-MRI of an axial slice displaying the anatomical tumor boundary (white outline). The ²³Na-MRSI is overlaid on top of the ¹H-MRI. Candidate voxels (b) inside and (c) outside the tumor are indicated (yellow boxes). Before TmDOTP⁵⁻ delivery, a single ²³Na peak was observed at 0 ppm, corresponding to total sodium (Na⁺_T), both inside and outside the tumor (black spectra). Following TmDOTP⁵⁻ delivery, compartmental peak separation was achieved to varying extents throughout the brain (blue spectra). (b) Within the tumor, this separation was most pronounced due to a compromised blood–brain barrier (BBB), which permits substantial accumulation of TmDOTP⁵⁻ in the extracellular space. (c) Outside of the tumor, such a high degree of extravasation would not be possible, but some shifting is still observed. The TmDOTP⁵⁻ distribution in the brain warrants labeling the most shifted peak as blood sodium (Na⁺_b), which occurred consistently around 2 ppm. The unshifted peak, which has no access to TmDOTP⁵⁻, is intracellular sodium (Na⁺_i). The intermediate peak, therefore, is extracellular sodium (Na⁺_e), which is shifted more inside the tumor than outside in healthy tissue. Similar spectroscopic patterns are observed throughout all voxels in vivo. See Figure S2 for a slice below the present. (d) In vitro analysis of blood samples from the tumor-bearing rat show that the ²³Na blood peak occurred around 2 ppm, which coincided with the most-shifted peak we observed in tumor voxels. This confirmed that the most-shifted peak in the observed ²³Na spectra after TmDOTP^5- comes from blood. All spectra were magnitude-corrected and line-broadened by 10 Hz.