Manganese-52: applications in cell radiolabelling and liposomal nanomedicine PET imaging using oxine (8-hydroxyquinoline) as an ionophore

• Published in: Dalton transactions : an international journal of inorganic chemistry 2018-07, Vol.47 (28), p.9283-9293
• Main Authors: Gawne, Peter, Man, Francis, Fonslet, Jesper, Radia, Riya, Bordoloi, Jayanta, Cleveland, Matthew, Jimenez-Royo, Pilar, Gabizon, Alberto, Blower, Philip J, Long, Nicholas, de Rosales, Rafael T. M
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Biotechnology; Blood Platelets; Cell death; Cell Line, Tumor; Cell Survival - drug effects; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacokinetics; Drug delivery systems; Efflux; Female; HEK293 Cells; Humans; Hydroxyquinoline; Imaging; In vivo methods and tests; Intraepithelial Lymphocytes; Ionophores - administration & dosage; Ionophores - chemistry; Ionophores - pharmacokinetics; Isotope Labeling; Labeling; Liposomes; Manganese; Mice; Nanomedicine; Oxyquinoline - administration & dosage; Oxyquinoline - chemistry; Oxyquinoline - pharmacokinetics; Pharmacology; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - pharmacokinetics; Positron emission; Positron-Emission Tomography; Radioisotopes; Radiolabelling; Tomography; Tracking; Zirconium isotopes
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c8dt00100f

The ionophore 8-hydroxyquinoline (oxine) has been used to radiolabel cells and liposomal medicines with 111 In and, more recently, 89 Zr, for medical nuclear imaging applications. Oxine has also shown promising ionophore activity for the positron-emitting radionuclide 52 Mn that should allow imaging of labelled cells and nanomedicines for long periods of time (>14 days). However, to date, the radiometal complex formed and its full labelling capabilities have not been fully characterised. Here, we provide supporting evidence of the formation of [ 52 Mn]Mn(oxinate) 2 as the metastable complex responsible for its ionophore activity. The cell labelling properties of [ 52 Mn]Mn(oxinate) 2 were investigated with various cell lines. The liposomal nanomedicine, DOXIL® (Caelyx) was also labelled with [ 52 Mn]Mn(oxinate) 2 and imaged in vivo using PET imaging. [ 52 Mn]Mn(oxinate) 2 was able to label various cell lines with moderate efficiency (15-53%), however low cellular retention of 52 Mn (21-25% after 24 h) was observed which was shown not to be due to cell death. PET imaging of [ 52 Mn]Mn-DOXIL at 1 h and 24 h post-injection showed the expected pharmacokinetics and biodistribution of this stealth liposome, but at 72 h post-injection showed a profile matching that of free 52 Mn, consistent with drug release. We conclude that oxine is an effective ionophore for 52 Mn, but high cellular efflux of the isotope limits its use for prolonged cell tracking. [ 52 Mn]Mn(oxinate) 2 is effective for labelling and tracking DOXIL in vivo . The release of free radionuclide after liposome extravasation could provide a non-invasive method to monitor drug release in vivo . The ionophore 8-hydroxyquinoline (oxine) has been used to radiolabel cells and liposomal nanomedicines with the PET radiometal manganese-52.