Tumor pH and its measurement

Abstract

Studies over the last few decades have demonstrated that the intracellular pH of solid tumors is maintained within a range of 7.0-7.2, whereas the extracellular pH is acidic. A low extracellular pH may be an important factor inducing more aggressive cancer phenotypes. Research into the causes and consequences of this acidic pH of tumors is highly dependent on accurate, precise, and reproducible measurements, and these have undergone great changes in the last decade. This review focuses on the most recent advances in the in vivo measurement of tumor pH by pH-sensitive PET radiotracers, MR spectroscopy, MRI, and optical imaging.

FIGURE 1. Glucose metabolism in mammalian cells

Afferent blood delivers glucose and oxygen (on haemoglobin) to tissues, where it reaches cells by diffusion. Glucose is taken up by specific transporters, where it is converted first to glucose-6-phosphate by hexokinase and then to pyruvate, generating 2 ATP per glucose. In the presence of oxygen, pyruvate is oxidized to HCO₃, generating 36 additional ATP per glucose. In the absence of oxygen, pyruvate is reduced to lactate, which is exported from the cell. Note that both processes produce hydrogen ions (H⁺), which cause acidification of the extracellular space. HbO₂, oxygenated haemoglobin. (Ref. 1). Reprinted with permission from NPG.

FIGURE 2. A schematic overview of the Single Injection Protocol

In vitro calibrations (upper panel) are used to define a relationship between the molar relaxivity of GdDOTA-4AmP^5- and pH. In vivo calibrations (lower panel) involve co-injection of pH-independent GdDTPA and DyDOTP. These data are used to define an in vivo relationship between [Gd-CR] and the EPSI-measured line-width. In the experiment, the line-width induced by the co-injected [Dy-CR] is used to calculate the per-pixel [Gd-DOTA-4AmP^5-], which is then combined with T1 values to calculate a molar relaxivity and hence, pH. (Ref. 9)

FIGURE 3. pHe map of a mouse tumor model

pH was measured by PARACEST MRI with contrast agent Yb-DO3A-oAA. (Data courtesy M Pagel, Ref. 15)