Imaging the intratumoral-peritumoral extracellular pH gradient of gliomas.

Solid tumors have an acidic extracellular pH (pH_e) but near neutral intracellular pH (pH_i). Because acidic pH_e milieu is conducive to tumor growth and builds resistance to therapy, simultaneous mapping of pH_e inside and outside the tumor (i.e., intratumoral-peritumoral pH_e gradient) fulfills an important need in cancer imaging. We used Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which utilizes shifts of non-exchangeable protons from macrocyclic chelates (e.g., 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonate) or DOTP⁸⁻) complexed with paramagnetic thulium (Tm³⁺) ion, to generate in vivo pH_e maps in rat brains bearing 9L and RG2 tumors. Upon TmDOTP⁵⁻ infusion, MRI identified the tumor boundary by enhanced water transverse relaxation and BIRDS allowed imaging of intratumoral-peritumoral pH_e gradients. The pH_e measured by BIRDS was compared with pH_i measured with ³¹P-MRS. In normal tissue, pH_e was similar to pH_i, but inside the tumor pH_e was lower than pH_i. While the intratumoral pH_e was acidic for both tumor types, peritumoral pH_e varied with tumor type. The intratumoral-peritumoral pH_e gradient was much larger for 9L than RG2 tumors because in RG2 tumors acidic pH_e was found in distal peritumoral regions. The increased presence of Ki-67 positive cells beyond the RG2 tumor border suggested that RG2 was more invasive than the 9L tumor. These results indicate that extensive acidic pH_e beyond the tumor boundary correlates with tumor cell invasion. In summary, BIRDS has sensitivity to map the in vivo intratumoral-peritumoral pH_e gradient, thereby creating preclinical applications in monitoring cancer therapeutic responses (e.g., with pH_e-altering drugs). Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]