Radiometal-Based PET/MRI Contrast Agents for Sensing Tumor Extracellular pH

Abstract

Acidosis is a useful biomarker for tumor diagnoses and for evaluating early response to anti-cancer treatments. Despite these useful applications, there are few methods for non-invasively measuring tumor extracellular pH, and none are routinely used in clinics. Responsive MRI contrast agents have been developed, and they undergo a change in MRI signal with pH. However, these signal changes are concentration-dependent, and it is difficult to accurately measure the concentration of an MRI contrast agent in vivo. PET/MRI provides a unique opportunity to overcome this concentration dependence issue by using the PET component to report on the concentration of the pH-responsive MRI agent. Herein, we synthesized PET/MRI co-agents based on the design of a pH-dependent MRI agent, and we have correlated pH with the r1 relaxivity of the MRI co-agent. We have also developed a procedure that uses PET radioactivity measurements and MRI R1 relaxation rate measurements to determine the r1 relaxivity of the MRI co-agent, which can then be used to estimate pH. This simultaneous PET/MRI procedure accurately measured pH in solution, with a precision that depended on the concentration of the MRI co-agent. We used our procedure to measure extracellular pH in a subcutaneous flank model of MIA PaCa-2 pancreatic cancer. Although the PET co-agents were stable in serum, post-imaging studies showed evidence that the PET co-agents were degraded in vivo. These results showed that tumor acidosis can be evaluated with simultaneous PET/MRI, although improvements are needed to more precisely measure MRI R1 relaxation rates, and ensure the in vivo stability of the agents.

New anti-cancer explorations based on metal ions

“…On the other hand, the cancer diagnosis can intuitively show the feature information of the tumor [ 8 ], which can be conducive to guiding treatment. The bioimaging technology applied in cancer diagnosis usually requires the assistance of contrast agents [ 9 , 10 ]. Metal ions have previously been used in imaging technology, such as the contrast agents based on Gd 3+ , which have dominated the MRI field for several decades [ 11 ].…”

Exploring the potential of the novel imidazole‐4,5‐dicarboxyamide chemical exchange saturation transfer scaffold for pH and perfusion imaging

“…21 In addition, positron emission tomography (PET)/MRI was used to measure in vivo tumor extracellular pH (pHe) with PET/MRI coagents, and showed great promise in clinical translation. 22 However, all of these methods have limitations for translating to patients: for spectroscopic imaging probes there are sensitivity limitations; for relaxation probe pH mapping of the kidneys there are challenges because of difficulties in teasing out changes in concentration from changes in pH, and for hyperpolarized probes there are limitations imposed by the length of time that the polarization remains based on relaxation; and for PET/MRI there are limitations imposed by requiring to perform both PET and MRI and coregister these images. A method that can more readily separate these changes out with good sensitivity and no time limitations could render MRI-based pH imaging as a good diagnostic for kidney imaging, particularly for managing UTO patients.…”

In Vivo Biomarker Imaging: Paving the Way for Precision Medicine

“…Pathogen-targeting capabilities can also be achieved using immune cell mimetics. Additionally, several other articles in this Special Issue showcase the in vivo imaging of changes in the extracellular pH [ 3 ], hypoxia [ 4 ], or organ function [ 5 , 6 ] associated with diseases.…”

“…Central to in vivo imaging and sensing is the development of sensitive and specific imaging probes, sensors, and contrast agents. In this Special Issue, advanced fluorescence imaging probes and PET/MRI agents are reported to detect cancer-related biomarkers [ 2 , 3 ] and parasites [ 7 ]. These imaging techniques enable the accurate delineation of disease status and treatment guidance in order to achieve elevated success rates.…”

“…In the meantime, multimodal imaging has become an attractive approach by which complementary imaging methods are utilized, as it provides information that a single method is unable to generate. In the Special Issue, two research papers are specifically focused on multimodal approaches [ 2 , 3 ], while another review paper provides a comprehensive overview of the available dual-mode imaging method, focusing on hypoxia-detection [ 4 ]. Another significant advantage of multimodal approaches is their ability to self-validate and even self-calibrate by utilizing the quantitative information detected by each of the two or more imaging methods.…”