Review Article

Evaluating pH in the Extracellular Tumor Microenvironment Using CEST MRI and Other Imaging Methods

Table 1

Summary of pH measurement methods with various instruments.

MethodSampling time
Spatial resolution
Agent []
Advantages and disadvantagesReference

MicroelectrodeFast, sec
Localized measurement
No agent required
Fast; accurate if calibrated with an external buffer 
Limited to surface-accessible tumors; requires MRI to guide electrodes into tumors
[1618]

Fluorescence imagingFast, sec
5 µm
µM–nM
Sensitive; low cost; can be used during clinical fluorescence guided surgery 
Limited to surface-accessible tumors
[14, 1921, 2529]

PET10 min
2 mm
nM
Fast; whole body imaging 
Requires radioactive isotope; coarse resolution; and limited accuracy
[2224, 31]

1H MRS>30 min
1 mm3
mM
Simultaneous measurement of pHe and detection of metabolites 
Poor sensitivity; some agents are pH buffers that change tissue pHe
[34, 39, 40]

31P MRS40 min
1 cm3
mM
Can simultaneously measure pHi and pHe 
Requires a MRI transceiver coil
[41, 4346]

19F MRS5 min
1 cm3
µM–mM
Fast; good sensitivity 
Requires a MRI transceiver coil
[42, 47, 49]

Hyperpolarized 13C MRS5 sec
0.375 mm3
mM
Very fast  
Requires a MRI transceiver coil; requires a hyperpolarizer instrument
Short hyperpolarized life time;
Measures pHi and pHe
[48]

pH dependent relaxation <1 min
0.1 mm3
mM
Fast; high resolution  
Requires a cocktail of contrast agents
[5053]

CEST MRI~5 min
µm–mm
mM
Good specificity  
Poor sensitivity
[37]