Abstract 2676: Measuring extracellular pH within in vivo tumors using acidoCEST MRI.

Abstract

Abstract INTRODUCTION. Extracelluar pH (pHe) is a hallmark for tumor microenvironment. We have developed a non-invasive MRI method that can accurately measure pHe to assess tumor acidosis, termed “acidoCEST MRI”. This method measures a ratio of the Chemical Exchange Saturation Transfer (CEST) effects of Iopromide, a FDA approved contrast agent for CT. Iopromide has two amides that generate different CEST effects, and a ratio of these CEST effects is correlated with pH over a range of 6.0-7.2 pH units, with a precision of 0.06 pH units, and in a manner that is independent of the agent's concentration and the sample's T1 relaxation time. We have applied acidoCEST MRI to monitor the effects of bicarbonate treatment on tumors. METHOD. A CEST-FISP pulse sequence (2.8 μT, 5 sec, 90 Hz), with 54 saturation frequencies (+10 to -10 ppm) was used to acquire an acidoCEST image in 4.7 min on 7T MRI scanner. Each CEST spectrum was fitted to a sum of three Lorentzian line shapes (Matlab R2012B). A mouse model of MDA-MB-231 mammary carcinoma subcutaneous flank tumor was treated with 200 mM of bicarbonate ad libitum. acidoCEST MRI was performed 1 day before and 1 day after introducing bicarbonate treatment. A bolus of 200 μL of 976 mM iopromide was injected i.v., followed by an infusion of 150 μL/hour of iopromide. Six series of acidoCEST spectroscopic images were acquired for 28 min. RESULTS: We were able to measure an increased in pH in tumor before and after bicarbonate therapy. As shown in the table, only half of the mice studied showed a significant increase in pH after bicarbonate treatment. This is because the limit of quantification of acidoCEST using Iopromide as contrast agent was pH 7.20. Discussion: acidoCEST MRI using Iopromide as contrast agent can measure pH of the tumor with good precision and can be applied to monitor pH-modulating therapy such as bicarbonate treatment. Our method has strong clinical translation potential because it uses low saturation powers, incomplete saturation, and a clinically approved contrast agent. Summary of acidoCEST measurements on mammary carcinoma tumors before and after bicarbonate treatment Mouse before bicarbonate treatment after bicarbonate treatment #1 pH 6.50 ± 0.09 pH 7.15 ± 0.14 (p < 0.01) #2 pH 6.49 ± 0.09 pH 7.20 ± 0.00 (p < 0.01) #3 pH 6.53 ± 0.10 pH 7.14 ± 0.14 (p < 0.01) #4 pH 6.91 ± 0.11 pH 7.10 ± 0.13 (p < 0.02) #5 pH 7.13 ± 0.12 pH 7.16 ± 0.12 #6 pH 7.02 ± 0.13 pH 7.13 ± 0.10 #7 (necrotic tumor) pH 7.20 ± 0.00 pH 7.19 ± 0.06 #8 (necrotic tumor) pH 7.17 ± 0.09 pH 7.17 ± 0.10 Citation Format: Liu Qi Chen, Christine Howison, Justin Jeffery, Ian Robey, Mark Pagel. Measuring extracellular pH within in vivo tumors using acidoCEST MRI. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2676. doi:10.1158/1538-7445.AM2013-2676