Intraperitoneal Delivery of Iopamidol to Assess Extracellular pH of Orthotopic Pancreatic Tumor Model by CEST-MRI

Abstract

The extracellular pH (pHe) of solid tumors is often acidic, as a consequence of the Warburg effect, and an altered metabolic state is often associated with malignancy. It has been shown that acidosis can promote tumor progression; thus, many therapeutic strategies have been adopted against tumor metabolism; one of these involves alkalinization therapies to raise tumor pH to inhibit tumor progression, improve immune surveillance, and overcome resistance to chemotherapies. Chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) is a noninvasive technique that can measure pH in vivo using pH-sensitive contrast agents. Iopamidol, an iodinated contrast agent, clinically used for computed tomography (CT), contains amide group protons with pH-dependent exchange rates that can reveal the pHe of the tumor microenvironment. In this study, we optimized intraperitoneal (IP) delivery of iopamidol to facilitate longitudinal assessments of orthotopic pancreatic tumor pHe by CEST-MRI. Following IV-infusion and IP-bolus injections, we compared the two protocols for assessing tumor pH. Time-resolved CT imaging was used to evaluate the uptake of iopamidol in the tumor, revealing that IP-bolus delivered a high amount of contrast agent 40 min postinjection, which was similar to the amounts reached with the IV-infusion protocol. As expected, both IP and IV injection protocols produced comparable measurements of tumor pHe, showing no statistically significant difference between groups ( p = 0.16 ). In addition, we showed the ability to conduct longitudinal monitoring of tumor pHe using CEST-MRI with the IP injection protocol, revealing a statistically significant increase in tumor pHe following bicarbonate administration ( p < 0.001 ). In conclusion, this study shows the capability to measure pHe using an IP delivery of iopamidol into orthotopic pancreatic tumors, which is important to conduct longitudinal studies.

Tumor acidosis-induced DNA damage response and tetraploidy enhance sensitivity to ATM and ATR inhibitors

“…The current study strongly suggests that evaluating the extent of tumor acidosis could represent an attractive approach to predict responsiveness to these inhibitors, allowing for more personalized treatment approaches. Implementation of this patient stratification strategy could take advantage of recent developments in CEST-MRI, a noninvasive technology offering high spatial resolution and sensitivity for in vivo imaging of tumor acidosis (Anemone et al, 2021 ; Jardim-Perassi et al, 2023 ), and would certainly gain in being combined to composite biomarkers recently set up to identify patients more likely to respond to DDRi (Durinikova et al, 2022 ).…”

L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy

“…Closure of the abdominal cavity was accomplished in two layers, and the skin layer was closed in a simple interrupted pattern with non-absorbable surgical staples, which were removed 10 days post-inoculation. The surgical procedure is described in detail in [26].…”

“…Iopamidol was first developed and used for CT imaging but was later applied as an MR contrast agent since the amide groups in its structure can interact (exchange) with water in a pH-dependent manner [24]. Many previous preclinical studies have used this approach to correlate the acidic state of a tumor with its aggressiveness and invasiveness or to evaluate treatment re-sponse and the onset of resistance [25][26][27][28], thereby establishing the foundations for clinical applications [29][30][31].…”

L-DOS47 enhances response to immunotherapy in pancreatic cancer tumor

“…Closure of the abdominal cavity was accomplished in two layers and the skin layer was closed in a simple interrupted pattern with non-absorbable surgical staples, which were removed 10 days post-inoculation. The surgical procedure is described in detail in [45].…”