Fe-Doped Carbon Dots as Dual-Mode T1/T2 Nano-Contrast Agents for Ultra-High Field MRI

Abstract

Carbon Dots (CDs) doped with iron are valuable nano-contrast agents (nCAs) for Magnetic Resonance Imaging (MRI), owing to their optimal compatibility, stability and interesting relaxivity, even at ultra-high field (UHF-MRI, ≥ 7 T). Moreover, they represent suitable alternatives to the Gd based contrast agents, frequently associated to moderate toxicity. Notably, UHF-MRI offers enhanced spatial resolution and improved signal-to-noise ratios, challenging some limitations encountered for standard MRI of vascular tissues, brain or applications demanding high sensitivity. The design of nCAs for UHF-MRI is not straightforward, due to their tendency to show predominant T2-character at high fields, hence leading to image darkening and resolution loss. For this reason, we propose novel Fe-doped CDs (Fe@CDs) working as dual mode T1/T2 nCAs at UHF-MRI: as grounding concept, our synthesis were supported by stringent purification, a practice extremely overlooked in the CD field. Pure Fe@CDs (Fe content 3.7 %) were isolated from fluorescent molecular-like subproducts and uncoordinated metals by size exclusion chromatography (SEC-HPLC): the particles showed good dimensional homogeneity (AFM = 5.0 ± 2.2 nm; TEM = 4.0 ± 1.3 nm), with blue centered and the typical wavelength-dependent fluorescence. The structure of Fe@CDs was enriched in carboxylic moieties, enabling stable coordination of iron (in mixed +2/+3 oxidation state) and optimal in vitro safety was observed on A549 cell line, at the highest concentration investigated (500 mg/mL). Fe@CDs presented low r2/r1 ratios at UHF-MRI, behaving as T1/T2 dual-mode probes (r2/r1@7 T = 2.78 and r2/r1@11.7 T = 3.23): notably, the magnetic properties remained almost unaltered for 8 days, in water and cellular medium. Our results provide a combined and wide approach for synthetizing artifact-free Fe-doped CDs with potentialities in advanced UHF-MRI technique.