Evaluation of coumarin-tagged deferoxamine as a Zr(IV)-based PET/fluorescence dual imaging probe

• Published in: Journal of inorganic biochemistry Vol. 245; p. 112259
• Main Authors: Romano, Giammarco Maria, Zizi, Virginia, Salvatore, Giulia, Bani, Riccardo, Mangoni, Monica, Nistri, Silvia, Anichini, Giulia, Simonini Steiner, Yschtar Tecla, Bani, Daniele, Bianchi, Antonio, Bencini, Andrea, Savastano, Matteo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2023
• Subjects: Cell Line, Tumor; Chelating Agents - chemistry; Coumarins; Deferoxamine; Deferoxamine - chemistry; Dual imaging- metal complexes; Ferric Compounds; Fluorescence; Optical imaging; Positron-Emission Tomography - methods; Radioisotopes - chemistry; Tissue Distribution; Zr(IV) - PET imaging; PBS; FDA; Optical imaging; DFOC; DFO; MTT; Dual imaging- metal complexes; Deferoxamine; TEA; DMEM; ESI MS; TEM; Zr(IV) - PET imaging; PET
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2023.112259

Desferoxamine (DFO) is currently the golden standard chelator for 89Zr4+, a promising nuclide for positron emission tomography imaging (PET). The natural siderophore DFO had previously been conjugated with fluorophores to obtain Fe(III) sensing molecules. In this study, a fluorescent coumarin derivative of DFO (DFOC) has been prepared and characterized (potentiometry, UV–Vis spectroscopy) for what concerns its protonation and metal coordination properties towards PET-relevant ions (Cu(II), Zr(IV)), evidencing strong similarity with pristine DFO. Retention of DFOC fluorescence emission upon metal binding has been checked (fluorescence spectrophotometry), as it would – and does – allow for optical (fluorescent) imaging, thus unlocking bimodal (PET/fluorescence) imaging for 89Zr(IV) tracers. Crystal violet and MTT assays on NIH-3 T3 fibroblasts and MDA-MB 231 mammary adenocarcinoma cell lines demonstrated, respectively, no cytotoxicity nor metabolic impairment at usual radiodiagnostic concentrations of ZrDFOC. Clonogenic colony-forming assay performed on X-irradiated MDA-MB 231 cells showed no interference of ZrDFOC with radiosensitivity. Morphological biodistribution (confocal fluorescence, transmission electron microscopy) assays on the same cells suggested internalization of the complex through endocytosis. Overall, these results support fluorophore-tagged DFO as a suitable option to achieve dual imaging (PET/fluorescence) probes based on 89Zr. A Deferoxamine derivative bearing a coumarin fluorophore has been investigated as potential candidate for Positron Emission Tomography/Optical dual imaging. It remains emissive on Cu(II) or Zr(IV) coordination. The Zr(IV) complex is not cytotoxic, nor impairs cell metabolism, nor interferes with cell radiosensitivity. The complex can be followed by fluorescence microscopy. [Display omitted] •A fluorophore-tagged deferoxamine derivative has been prepared and characterized.•Its coordination properties towards Cu(II) and Zr(IV) are similar to native deferoxamine.•Metal complexes are emissive and can be optically detected.•The Zr(IV) complex has no cytotoxicity at radiodiagnostic concentrations.•The Zr(IV) complex does not interfere with radiosensitivity.