Abstract
Acid production and transport are currently being studied to identify new targets for efficient cancer treatment, as subpopulations of tumor cells frequently escape conventional therapy owing to their particularly acidic tumor microenvironment. Heterogeneity in intracellular and extracellular tumor pH (pHi, pHe) has been reported, but none of the methods currently available for measuring tissue pH provides quantitative parameters characterizing pH distribution profiles in tissues. To this intent, we present here a multiparametric, noninvasive approach based on in vivo (31)P nuclear magnetic resonance (NMR) spectroscopy and its application to mouse tumor xenografts. First, localized (31)P NMR spectrum signals of pHi and pHe reporter molecules [inorganic phosphate (Pi) and 3-aminopropylphosphonate (3-APP), respectively] were transformed into pH curves using established algorithms. Although Pi is an endogenous compound, 3-APP had to be injected intraperitoneally. Then, we developed algorithms for the calculation of six to eight quantitative pH parameters from the digital points of each pH curve obtained. For this purpose, each pH distribution profile was approximated as a histogram, and intensities were corrected for the nonlinearity between chemical-shift and pH.
Highlights
In physiologic tissues, the interplay of metabolism, ion transport, and pH buffering results in efficient pH regulation
To validate our method, we primarily focused on bimodal and trimodal pH distributions, because the concept of quantitative pH heterogeneity parameters is best tested and verified on the basis of models representing well-defined pH
Most quantitative parameters suggested in this report are universally applicable to any given distribution of pH values; their use does not depend on the existence of distinct pH modes
Summary
The interplay of metabolism, ion transport, and pH buffering results in efficient pH regulation. The presence of macroscopic and microscopic membrane structures, such as the basement membrane and various cell membranes, permits the coexistence of multiple tissue compartments characterized by different pH values. This highlights the necessity to measure average tissue pH values, and to quantitatively assess pH heterogeneity. There is a genuine need for such measurements as a variety of pathologies (cancer and inflammation, among others) are associated with heterogeneous pH regulation [1,2,3] Even normal activity such as muscle exercise can generate complex tissue pH distributions as a function of biologic characteristics [4].
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