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

JOURNAL OF CONTROLLED RELEASE

卷:269

Article

Jensen, Andreas I.^1,6  Severin, Gregory W.^1,2,6  Hansen, Anders E.^3,4,5,6  Fliedner, Frederikke P.^3,4  Eliasen, Rasmus^5,6  Parhamifar, Ladan^5,6  Kjaer, Andreas^3,4  Andresen, Thomas L.^5,6  Henriksen, Jonas R.^5,6 

[1] Tech Univ Denmark, Ctr Nucl Technol DTU Nutech, Frederiksborgvej 399, DK-4000 Roskilde, Denmark

[2] Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA

[3] Rigshosp, DK-2100 Copenhagen, Denmark

[4] Univ Copenhagen, Dept Clin Physiol Nucl Med & PET, Cluster Mol Imaging, DK-2100 Copenhagen, Denmark

[5] Tech Univ Denmark, Dept Micro & Nanotechnol, Produkt Torvet,Bldg 423, DK-2800 Lyngby, Denmark

[6] Ctr Nanomed & Theranost, Lyngby, Denmark

关键词: Manganese-52;    Copper-64;    Liposomes;    DOTA;    Remote-loading;    Ionophore;   

DOI  :  10.1016/j.jconrel.2017.11.006

来源: Elsevier

【 摘 要 】

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 (Mn-52, T 1/2 = 5.6 days), allow the imaging of this biodistribution. We report optimized protocols for radiolabeling liposomes with Mn-52, through both remote-loading and surface labeling. For comparison, liposomes were also remote-loaded and surface labeled with copper-64 (Cu-64, T 1/2 = 12.7 h) 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 Mn-52-DOTA and Cu-64-DOTA. This was done by comparing shielded remote-loaded with exposed surface labeled variants in a CT26 tumor-bearing mouse model. Remote loading (90 min at 55 degrees C) and surface labeling (55 degrees C for 2 h) of Mn-52 gave excellent radiolabeling efficiencies of 97-100% and 98-100% respectively, and the liposome biodistribution was imaged by PET for up to 8 days. Liposomes with surface-conjugated Mn-52-DOTA exhibited a significantly shorter plasma half-life (T 1/2 = 14.4 h) when compared to the remote-loaded counterpart (T 1/2 = 21.3 h), whereas surface-conjugated Cu-64-DOTA cleared only slightly faster and non-significantly, when compared to remote-loaded (17.2 +/- 2.9 h versus 20.3 +/- 1.2 h). From our data, we conclude the successful remote-loading of liposomes with 52Mn, and furthermore that Mn-52-DOTA may be unstable in vivo whereas Cu-64-DOTA appears suitable for quantitative imaging.

【 授权许可】

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