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

The ionophore 8-hydroxyquinoline (oxine) has been used to radiolabel cells and liposomal medicines with In-111 and, more recently, Zr-89, for medical nuclear imaging applications. Oxine has also shown promising ionophore activity for the positron-emitting radionuclide Mn-52 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 [Mn-52]Mn(oxinate)(2) as the metastable complex responsible for its ionophore activity. The cell labelling properties of [Mn-52] Mn(oxinate)(2) were investigated with various cell lines. The liposomal nanomedicine, DOXIL (R) (Caelyx) was also labelled with [Mn-52] Mn(oxinate)(2) and imaged in vivo using PET imaging. [Mn-52] Mn(oxinate)(2) was able to label various cell lines with moderate efficiency (15-53%), however low cellular retention of Mn-52 (21-25% after 24 h) was observed which was shown not to be due to cell death. PET imaging of [Mn-52] 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 Mn-52, consistent with drug release. We conclude that oxine is an effective ionophore for Mn-52, but high cellular efflux of the isotope limits its use for prolonged cell tracking. [52Mn] 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.