Fe(II)-Targeted PET/F-19 MRI Dual-Modal Molecular Imaging Probe for Early Evaluation of Anticancer Drug-Induced Acute Kidney Injury

Ferroptosis, an iron-dependent regulated cell death, has been emerging as an early mechanism in anticancer drug-induced acute kidney injury (AKI) that may benefit therapeutic intervention. However, the lack of molecular imaging methods for in vivo detection of ferroptosis restricts the early diagnosis of anticancer drug-induced AKI. Herein, we developed a PET/F-19 MRI dual-modal imaging probe for the monitoring of ferroptosis in AKI by chemically conjugating the Fe(II)-sensitive artemisinin (Art) motif and macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to the CF3-modified polyhedral oligomeric silsesquioxane (POSS) clusters, denoted as the PAD probe. The PAD probe could be converted into PA*D in the presence of Fe(II) ions and subsequently be intercepted by biological macromolecules nearby, thereby enhancing the retention effect in ferroptotic cells and tissues. After labeling with Ga-68 isotopes, the Ga-68-labeled PAD probe in cisplatin (CDDP)-induced AKI mice displayed a significantly higher renal uptake level than that in normal mice. Moreover, the PAD probe with a precise chemical structure, relatively high F-19 content, and single F-19 resonance frequency allowed for interference-free and high-performance(19)F MRI that could detect the onset of CDDP-induced AKI at least 24 h earlier than the typical clinical/preclinical assays. Our study provides a robust dual-modal molecular imaging tool for the early diagnosis and mechanistic investigation of various ferroptosis-related diseases.

Automated summary

In this study, a PET/F-19 MRI dual-modal imaging probe was developed for the monitoring of ferroptosis-induced acute kidney injury. The probe can be converted and retained in ferroptotic cells and tissues, enabling early diagnosis and mechanistic investigation.