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

Overview

Journal Adv Radiol

Date 2015 Jan 1

PMID 27761517

Citations 54

Authors

Liu Qi Chen

Mark D Pagel

Affiliations

Soon will be listed here.

Abstract

Tumor acidosis is a consequence of altered metabolism, which can lead to chemoresistance and can be a target of alkalinizing therapies. Noninvasive measurements of the extracellular pH (pHe) of the tumor microenvironment can improve diagnoses and treatment decisions. A variety of noninvasive imaging methods have been developed for measuring tumor pHe. This review provides a detailed description of the advantages and limitations of each method, providing many examples from previous research reports. A substantial emphasis is placed on methods that use MR spectroscopy and MR imaging, including recently developed methods that use chemical exchange saturation transfer MRI that combines some advantages of MR spectroscopy and imaging. Together, this review provides a comprehensive overview of methods for measuring tumor pHe, which may facilitate additional creative approaches in this research field.

Citing Articles

Reduced removal of waste products from energy metabolism takes center stage in human brain aging.

Mangia S, DiNuzzo M, Ponticorvo S, Dienel G, Behar K, Benveniste H Sci Rep. 2025; 15(1):8127.

PMID: 40057554 PMC: 11890754. DOI: 10.1038/s41598-025-90342-3.

The proton resonance enhancement for CEST imaging and shift exchange (PRECISE) family of RF pulse shapes for CEST MRI.

Mohanta Z, Stabinska J, Gilad A, Barker P, McMahon M Magn Reson Med. 2025; 93(5):1954-1968.

PMID: 39831452 PMC: 11893253. DOI: 10.1002/mrm.30410.

The interplay between the tumor microenvironment and tumor-derived small extracellular vesicles in cancer development and therapeutic response.

Guo X, Song J, Liu M, Ou X, Guo Y Cancer Biol Ther. 2024; 25(1):2356831.

PMID: 38767879 PMC: 11110713. DOI: 10.1080/15384047.2024.2356831.

Aiming the magic bullet: targeted delivery of imaging and therapeutic agents to solid tumors by pHLIP peptides.

Reshetnyak Y, Andreev O, Engelman D Front Pharmacol. 2024; 15:1355893.

PMID: 38545547 PMC: 10965573. DOI: 10.3389/fphar.2024.1355893.

Early prediction of pathological response to neoadjuvant chemotherapy of breast tumors: a comparative study using amide proton transfer-weighted, diffusion weighted and dynamic contrast enhanced MRI.

Zhang N, Song Q, Liang H, Wang Z, Wu Q, Zhang H Front Med (Lausanne). 2024; 11:1295478.

PMID: 38298813 PMC: 10827983. DOI: 10.3389/fmed.2024.1295478.

References

Ward K, Balaban R . Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST). Magn Reson Med. 2000; 44(5):799-802. DOI: 10.1002/1522-2594(200011)44:5<799::aid-mrm18>3.0.co;2-s. View

Martin G, Jain R . Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy. Cancer Res. 1994; 54(21):5670-4. View

Ling W, Regatte R, Navon G, Jerschow A . Assessment of glycosaminoglycan concentration in vivo by chemical exchange-dependent saturation transfer (gagCEST). Proc Natl Acad Sci U S A. 2008; 105(7):2266-70. PMC: 2268124. DOI: 10.1073/pnas.0707666105. View

Wolff S, Balaban R . Magnetization transfer contrast (MTC) and tissue water proton relaxation in vivo. Magn Reson Med. 1989; 10(1):135-44. DOI: 10.1002/mrm.1910100113. View

Lokling K, Fossheim S, Skurtveit R, Bjornerud A, Klaveness J . pH-sensitive paramagnetic liposomes as MRI contrast agents: in vitro feasibility studies. Magn Reson Imaging. 2001; 19(5):731-8. DOI: 10.1016/s0730-725x(01)00380-0. View

Lin Y, Wu T, Gmitro A . Error analysis of ratiometric imaging of extracellular pH in a window chamber model. J Biomed Opt. 2012; 17(4):046004. PMC: 4572359. DOI: 10.1117/1.JBO.17.4.046004. View

Delli Castelli D, Ferrauto G, Cutrin J, Terreno E, Aime S . In vivo maps of extracellular pH in murine melanoma by CEST-MRI. Magn Reson Med. 2013; 71(1):326-32. DOI: 10.1002/mrm.24664. View

Wojciechowski F, Suchy M, Li A, Azab H, Bartha R, Hudson R . A robust and convergent synthesis of dipeptide-DOTAM conjugates as chelators for lanthanide ions: new PARACEST MRI agents. Bioconjug Chem. 2007; 18(5):1625-36. DOI: 10.1021/bc0701287. View

Vermathen P, Capizzano A, Maudsley A . Administration and (1)H MRS detection of histidine in human brain: application to in vivo pH measurement. Magn Reson Med. 2000; 43(5):665-75. DOI: 10.1002/(sici)1522-2594(200005)43:5<665::aid-mrm8>3.0.co;2-3. View

10.

Weerakkody D, Moshnikova A, Thakur M, Moshnikova V, Daniels J, Engelman D . Family of pH (low) insertion peptides for tumor targeting. Proc Natl Acad Sci U S A. 2013; 110(15):5834-9. PMC: 3625278. DOI: 10.1073/pnas.1303708110. View

11.

Vavere A, Biddlecombe G, Spees W, Garbow J, Wijesinghe D, Andreev O . A novel technology for the imaging of acidic prostate tumors by positron emission tomography. Cancer Res. 2009; 69(10):4510-6. PMC: 2690701. DOI: 10.1158/0008-5472.CAN-08-3781. View

12.

Stummer W, Pichlmeier U, Meinel T, Wiestler O, Zanella F, Reulen H . Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006; 7(5):392-401. DOI: 10.1016/S1470-2045(06)70665-9. View

13.

Garcia-Martin M, Herigault G, Remy C, Farion R, Ballesteros P, COLES J . Mapping extracellular pH in rat brain gliomas in vivo by 1H magnetic resonance spectroscopic imaging: comparison with maps of metabolites. Cancer Res. 2001; 61(17):6524-31. View

14.

van Zijl P, Jones C, Ren J, Malloy C, Sherry A . MRI detection of glycogen in vivo by using chemical exchange saturation transfer imaging (glycoCEST). Proc Natl Acad Sci U S A. 2007; 104(11):4359-64. PMC: 1838607. DOI: 10.1073/pnas.0700281104. View

15.

Bottomley P . Spatial localization in NMR spectroscopy in vivo. Ann N Y Acad Sci. 1987; 508:333-48. DOI: 10.1111/j.1749-6632.1987.tb32915.x. View

16.

Raghunand N, Zhang S, Sherry A, Gillies R . In vivo magnetic resonance imaging of tissue pH using a novel pH-sensitive contrast agent, GdDOTA-4AmP. Acad Radiol. 2002; 9 Suppl 2:S481-3. DOI: 10.1016/s1076-6332(03)80270-2. View

17.

Silva A, Yunes J, Gillies R, Gatenby R . The potential role of systemic buffers in reducing intratumoral extracellular pH and acid-mediated invasion. Cancer Res. 2009; 69(6):2677-84. PMC: 3718046. DOI: 10.1158/0008-5472.CAN-08-2394. View

18.

Jokivarsi K, Grohn H, Grohn O, Kauppinen R . Proton transfer ratio, lactate, and intracellular pH in acute cerebral ischemia. Magn Reson Med. 2007; 57(4):647-53. DOI: 10.1002/mrm.21181. View

19.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

20.

Terreno E, Castelli D, Cravotto G, Milone L, Aime S . Ln(III)-DOTAMGly complexes: a versatile series to assess the determinants of the efficacy of paramagnetic chemical exchange saturation transfer agents for magnetic resonance imaging applications. Invest Radiol. 2004; 39(4):235-43. DOI: 10.1097/01.rli.0000116607.26372.d0. View