Abstract 4249: Quantification of murine lung tumor pH in vivo by acidoCEST MRI
Authors: Lindeman Leila R. , Randtke Edward A. , Howison Christine M. , Jones Kyle M. , Pagel Mark D. 
Published: July 2016

Abstract
Introduction: Our objective was to accurately measure the extracellular pH (pHe) of lung tumors in vivo using an innovative, non-invasive imaging method known as acidoCEST MRI, to potentially improve the early detection of lung tumors via molecular imaging.
Methods: A spontaneous murine lung tumor model was initiated through orthotopic injections of urethane in seven A/J mice to induce formation of lung adenocarcinomas. Starting at 8 weeks post injection, we performed coronal anatomical scans to monitor tumor growth with Bruker BioSpin 7T small animal MRI instrument. AcidoCEST MRI was then performed when tumors reached a diameter of 1 mm in one dimension at approximately 17 weeks post injection, followed by additional scans each month. For all MRI scans, mice were anesthetized with 2.0% isofluorane, the respiration rate was monitored, and body temperature was maintained at 37 °C. Respiration-triggering (gating) was used in all imaging sequences to compensate for motion artifacts in the lung. For optimal gating, the mouse's respiration rate was maintained at &lt; 40 breaths per minute. Each mouse was scanned with acidoCEST MRI using 370 mg/mL iopamidol (200 μL IV bolus, 400 μL/hr IV infusion), using a 6 sec saturation period at 3.5 μT power, 300 ms acquisition time, with 468×468 μm spatial resolution, updated with improved respiration gating. Parametric maps of pixel-wise pHe values of the tumor were produced by fitting the Bloch-McConnell equations in Matlab 2014a. The average tumor pHe and concentration of iopamidol agent in the tumor tissue were recorded.
Results: AcidoCEST MRI was successfully applied to the in vivo imaging of murine lung tumors. Our innovative, respiration-gated pulse sequence and Bloch-McConnell fitting method were essential to overcome the noise created by motion artifacts inherent in lung imaging. Lung tumors demonstrated successful uptake of the iopamidol contrast agent, with an average concentration of approximately 40 mM. The pH values in the tumor ranged from 6.5 to 7.0 with an average value of 6.64, demonstrating tumor acidosis. Anatomical MRI was used to monitor tumor growth from 1 mm diameter at 17 weeks post injection, to 4 mm diameter at 36 weeks post-injection.
Conclusion: Our study has established that acidoCEST MRI can be used to quantify the pH of murine lung tumors in vivo, showing that this method is promising for improved early detection of lung tumors. These pHe measurements can be compared with tumor growth rates to determine how tumor acidosis correlates with aggressive phenotype. Tumor pHe measurements can also be related to concentration of the agent as a biomarker of vascular perfusion. Furthermore, the spatial heterogeneity of lung tumor pHe can be assessed with this noninvasive imaging method. Further pre-clinical studies are also warranted to determine if the acidoCEST MRI method is suitable for early therapy response monitoring.
Citation Format: Leila R. Lindeman, Edward A. Randtke, Christine M. Howison, Kyle M. Jones, Mark D. Pagel. Quantification of murine lung tumor pH in vivo by acidoCEST MRI. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4249.