Synthesis, colloidal stability and 64Cu labeling of iron oxide nanoparticles bearing different macrocyclic ligands

The synthesis, solution stability and 64Cu2+ labeling of magnetite nanoparticles (NPs) coated with different macrocycles is reported, together with the stability of the resulting radioisotope-labeled NPs to trans-chelation by the competing ligand cyclam, and their stability in blood serum. Three macrocycles, 1,4-bis(2-pyridylmethyl)-1,4,7-tri-aza-cyclononane (dmptacn), 1,4,8,11-tetraaza-cyclo-tetradecane (cyclam) and 1,4,7,10-tetraaza-cyclododecane (cyclen), and 3-aminopropyltriethoxysilane were used to modify the magnetite NPs. The ligands were covalently linked to the surface of the NPs with high efficiency by reaction of the corresponding 3-(3-(triethoxysiloxy)propoxy)propan-2-ol derivatives with the NPs. According to transmission electron microscopy (TEM), the uncoated magnetite NPs and macrocycle-functionalized congeners have an average diameter of 6 to 7 nm. The NPs form stable colloidal suspensions in 0.05 M aqueous 2-(N-morpholino)ethanesulfonic acid (MES) buffer, which consist of larger aggregates with a mean hydrodynamic size of about 200 nm. The NPs with the appended macrocycles can be efficiently labeled with 64Cu2+ ions and the radioactivity persists in rat plasma for at least 24 h. Challenge experiments with cyclam also indicate that the radio-copper complexes are highly stable, with the dmptacn-functionalized NPs showing the highest resistance to metal ion leakage. Overall, the dmptacn-functionalized iron oxide NPs provide an excellent platform for the development of robust multimodal cancer imaging/therapeutic agents. (authors)