Flow reactor-based batch production of direct radiolabelable superparamagnetic iron oxide for PET/MRI dual-modality contrast agent

Radiolabeled superparamagnetic iron oxide nanoparticles (SPIONs) have gained significant attention for their potential in dual-modality imaging, combining positron emission tomography (PET) and magnetic resonance imaging (MRI). The integration provides clinicians with enhanced and complementary imaging information, improving the accuracy of disease diagnosis. However, the complexity of ligand synthesis for functionalization and stable radiolabeling and the difficulty in achieving controlled large-scale production with consistent nanoparticle quality, both of which limit their potential in clinical applications. To overcome these limitations, we report a novel method for preparing SPIONs utilized a simple dual-chelation functional ligand and a continuous synthesis approach to facilitate their clinical translation. The functionalized SPIONs were successfully synthesized by using a flow synthesis technique and the dual-chelation functional ligand (PAsp- g -DA/EA). Compared with traditional synthesis methods, this approach enabled mass production with high reproducibility. The obtained SPIONs showed ultra-small sizes (5.1 ± 0.1 nm), good monodispersity, excellent relaxivity, and superior biocompatibility. The dual-chelation functional ligand enabled direct and efficient radiolabeling of SPIONs with [ 64 Cu]Cu 2+ achieving over 80 % efficiency and outstanding labeling stability. After intravenous injection into rats, high-quality PET and MRI images were obtained. Furthermore, both PET and MRI demonstrated significant nanoprobe accumulation in tumor-bearing mice. In this study, a dual-chelation functional ligand was employed to facilitate the batch and reproducible synthesis of directly radiolabelable SPIONs, thereby addressing key challenges associated with the clinical translation of PET/MRI dual-modality nanoprobes. The nano-probes developed demonstrate excellent biocompatibility, superior imaging efficacy in both PET and MRI, making them potential candidates for medical PET/MRI dual-modality probes.