Abstract 2391: Transdermal alkalinization treatment induces pH changes in a murine melanoma model as measured with MRI-CEST pH imaging
Authors: Irrera Pietro , Jardim-Perassi Bruna Victorasso , Abrahams Dominique , Sherlock Thomas , Byrne Samantha , Ojeda Andrew , Lau Justin Y. , Fitzsimmons Nathan , Rice Audrene , Harbert Chuck , Arakawa Renee , Ibrahim-Hashim Arig , Beal Ryan , Pilon-Thomas Shari 
Published: April 2023

Abstract
Tumor acidosis plays a major role in tumor aggressiveness, invasion, and resistance. Therefore, it is considered an important target for novel anticancer strategies. In this study, we tested the efficacy of a transdermal treatment applied directly to the tumor area to reduce interstitial acidosis. The product involved is a patented transdermal cream formulation (DYV800) produced by Dyve Biosciences that contains 33% sodium bicarbonate and serves as a buffer medicament. C57BL/6 mice bearing B16-F10 melanoma subcutaneous tumors were treated with DYV800, and pH was measured at different time points after cream application. The MRI pH imaging technique used in this study is the Chemical Exchange Saturation Transfer (CEST) method, which involves the injection of an iodinated contrast agent, iopamidol (Isovue, Bracco Imaging), to measure extracellular pH (pHe) in vivo. In the first experiment to examine the time-course effect of DYV800 on tumor acidosis, mice (N=30, 15 untreated and 15 treated) were treated only once with 100 µL of cream. pH acquisitions were done with untreated mice for baseline pH measurements (N=15) and at different time points after cream application in another set of mice (1, 2, 4 and 24 hours; N=15). As revealed by the pH measurements, the highest increase in pH was reported after 2 hours of the cream application (6.71 vs. 6.84, untreated vs. post 2hrs, p-value 0.025 ANOVA with Bonferroni comparison test), and although pH was higher for all the other time points compared to baseline values, no statistical significance was found (post 1hr 6.75; post 4hrs 6.78; post 24hrs 6.75). In a second experiment, mice (N=10) were untreated (N=3) or received prolonged treatment that lasted 5 days, with one group of mice treated once-a-day (N=3) and the second group of mice treated twice-a-day (N=4) with 100 µL of cream for each application. MRI pH imaging was performed the next day after the treatment regimen was completed. Baseline measurements confirmed that B16 tumors have an acidic pH of 6.7 that increased to 6.82 in the once-a-day treated group (p-value 0.037 unpaired t-test vs. baseline) and to 6.77 in the twice-a-day treated group (not significant compared to baseline). To complete the pH evaluations, untreated mice reported a slight reduction in pHe (6.65) after 6 days of the baseline acquisitions. These experiments demonstrate for the first time that the extracellular pH of tumors can be increased upon application of a buffer formulation transdermally delivered to mice. Future experiments are expected to provide insights into the effect of DYV800 cream application on tumor growth and immune cell migration and activation in the tumor microenvironment.
Citation Format: Pietro Irrera, Bruna Victorasso Jardim-Perassi, Dominique Abrahams, Thomas Sherlock, Samantha Byrne, Andrew Ojeda, Justin Y. Lau, Nathan Fitzsimmons, Audrene Rice, Chuck Harbert, Renee Arakawa, Arig Ibrahim-Hashim, Ryan Beal, Shari Pilon-Thomas. Transdermal alkalinization treatment induces pH changes in a murine melanoma model as measured with MRI-CEST pH imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2391.