Remote-loading of liposomes with manganese-52 and in vivo evaluation of the stabilities of 52Mn-DOTA and 64Cu-DOTA using radiolabelled liposomes and PET imaging

Publication date: 10 January 2018
Source:Journal of Controlled Release, Volume 269
Author(s): Andreas I. Jensen, Gregory W. Severin, Anders E. Hansen, Frederikke P. Fliedner, Rasmus Eliasen, Ladan Parhamifar, Andreas Kjær, Thomas L. Andresen, Jonas R. Henriksen
Liposomes are nanoparticles used in drug delivery that distribute over several days in humans and larger animals. Radiolabeling with long-lived positron emission tomography (PET) radionuclides, such as manganese-52 (⁵²Mn, T½=5.6days), allow the imaging of this biodistribution. We report optimized protocols for radiolabeling liposomes with ⁵²Mn, through both remote-loading and surface labeling. For comparison, liposomes were also remote-loaded and surface labeled with copper-64 (⁶⁴Cu, T½=12.7h) through conventional means. The chelator DOTA was used in all cases. The in vivo stability of radiometal chelates is widely debated but studies that mimic a realistic in vivo setting are lacking. Therefore, we employed these four radiolabeled liposome types as platforms to demonstrate a new concept for such in vivo evaluation, here of the chelates ⁵²Mn-DOTA and ⁶⁴Cu-DOTA. This was done by comparing “shielded” remote-loaded with “exposed” surface labeled variants in a CT26 tumor-bearing mouse model. Remote loading (90min at 55°C) and surface labeling (55°C for 2h) of ⁵²Mn gave excellent radiolabeling efficiencies of 97–100% and 98–100% respectively, and the liposome biodistribution was imaged by PET for up to 8days. Liposomes with surface-conjugated ⁵²Mn-DOTA exhibited a significantly shorter plasma half-life (T½=14.4h) when compared to the remote-loaded counterpart (T½=21.3h), whereas surface-conjugated ⁶⁴Cu-DOTA cleared only slightly faster and non-significantly, when compared to remote-loaded (17.2±2.9h versus 20.3±1.2h). From our data, we conclude the successful remote-loading of liposomes with ⁵²Mn, and furthermore that ⁵²Mn-DOTA may be unstable in vivo whereas ⁶⁴Cu-DOTA appears suitable for quantitative imaging.

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