Extracellular pH mapping of liver cancer on a clinical 3T MRI scanner

To demonstrate feasibility of developing a noninvasive extracellular pH (pH_e ) mapping method on a clinical MRI scanner for molecular imaging of liver cancer.

In vivo pH_e mapping has been demonstrated on preclinical scanners (e.g., 9.4T, 11.7T) with Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), where the pH_e readout by 3D chemical shift imaging (CSI) depends on hyperfine shifts emanating from paramagnetic macrocyclic chelates like TmDOTP^5- which upon extravasation from blood resides in the extracellular space. We implemented BIRDS-based pH_e mapping on a clinical 3T Siemens scanner, where typically diamagnetic ¹ H signals are detected using millisecond-long radiofrequency (RF) pulses, and ¹ H shifts span over ±10 ppm with long transverse (T₂ , 10² ms) and longitudinal (T₁ , 10³ ms) relaxation times. We modified this 3D-CSI method for ultra-fast acquisition with microsecond-long RF pulses, because even at 3T the paramagnetic ¹ H shifts of TmDOTP^5- have millisecond-long T₂ and T₁ and ultra-wide chemical shifts (±200 ppm) as previously observed in ultra-high magnetic fields.

We validated BIRDS-based pH in vitro with a pH electrode. We measured pH_e in a rabbit model for liver cancer using VX2 tumors, which are highly vascularized and hyperglycolytic. Compared to intratumoral pH_e (6.8 ± 0.1; P < 10^-9 ) and tumor's edge pH_e (6.9 ± 0.1; P < 10^-7 ), liver parenchyma pH_e was significantly higher (7.2 ± 0.1). Tumor localization was confirmed with histopathological markers of necrosis (hematoxylin and eosin), glucose uptake (glucose transporter 1), and tissue acidosis (lysosome-associated membrane protein 2).

This work demonstrates feasibility and potential clinical translatability of high-resolution pH_e mapping to monitor tumor aggressiveness and therapeutic outcome, all to improve personalized cancer treatment planning.