Molecular Magnetic Resonance Imaging of Inflammation

Massachusetts General Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

Project Summary / Abstract Chronic liver diseases (CLD) contribute to an estimated 3.5% of deaths worldwide. With proper and timely diagnosis, most CLD can be managed and sometimes even reversed. Unfortunately, diagnosis and management of prevalent CLDs such as metabolically associated steatohepatitis (MASH) and chronic hepatitis virus B (CHVB) infection rely on percutaneous biopsy, which is poorly suited to surveil chronic disease. Inflammation in an important driver of CLD progression and is a major component of the histologic systems used to diagnose and grade near every CLD. However, serologic and imaging markers of liver inflammation are underdeveloped, representing a major unmet need. For example, CHVB progression is inflammation driven and decisions regarding antiviral therapy are based in part on liver inflammation activity. MASH can be reversed through lifestyle if diagnosed early, but often goes undetected until an advance stage due in part to a lack of tools for assessing liver inflammation. Pharmaceutical treatments for MASH remain elusive, and drug programs are complicated further by difficulties recruiting patients and conducting trials that rely on histologic endpoints. The liver microenvironment during inflamed, progressive CLD is aberrantly oxidizing owing largely to upregulated production of reactive oxygen species (ROS). Prior work on this project evaluated MRI using the oxidatively activated probe Fe-PyC3A, which switches between the poorly and strongly MR visible Fe2+ and Fe3+ oxidation states, as a noninvasive marker of liver inflammation. Using mice, we demonstrated that MRI using Fe-PyC3A can detect liver inflammatory changes that are not captured in serology, can distinguish MASH vs. nonprogressive MAFL (metabolically associated fatty liver), and is well tolerated at high doses. Through chemistry work performed in parallel, we established structure-reactivity and structure-relaxivity relationships to guide probe optimization. We discovered entirely new chemistry that enables us stabilize Fe2+ against adventitious redox without compromising the detection sensitivity of the oxidatively activated Fe3+ complex. This proposal for renewal seeks to build on our chemistry findings to realize an idealized probe candidate, to elucidate the mechanisms driving probe activation, and to demonstrate our imaging technology as reliable proxy to diagnose and surveil inflammatory disease activity in mouse models recapitulative of human CLD.