Facile synthesis of ⁶⁹Ge-labeled nanoparticles for dual-modality PET/MRI

Objectives ⁶⁹Ge (t_1/2=39.1 h, 21% β⁺, E_max=1205 keV) is a novel and desirable PET isotope. However, due to complex coordination chemistry of Ge ions, it is challenging to prepare ⁶⁹Ge-based tracers using chelator-based approaches. Our goal is to develop a chelator-free strategy to label superparamagnetic iron oxide nanoparticles (SPION) with ⁶⁹Ge for dual-modality PET/MRI.

Methods ⁶⁹Ge was produced by bombarding a Ga/Ni alloy target (thickness: 45 mg/cm²) with 11 MeV protons at 15 μA for 1 h. It was chemically separated and used for labeling poly(acrylic acid) (PAA)-coated SPION at pH 7-8. Specificity of ⁶⁹Ge labeling to SPION was confirmed by incubation of control nanoparticles (e.g. copper sulfide and silica-coated SPION) with ⁶⁹Ge under the same conditions. In vitro stability of ⁶⁹Ge-SPION was assessed in mouse serum, whereas in vivo stability and biodistribution pattern were studied with both PET and MRI using BALB/c mice.

Results ⁶⁹Ge could be readily produced at activity of >65 MBq. Radiolabeling yield of ⁶⁹Ge-SPION was ~60% after 3 h incubation at 37 °C, which increased to >80% after 24 h of incubation. In contrast, no radiolabeling of control nanoparticles was observed under the same conditions, demonstrating the specificity of SPION towards ⁶⁹Ge ions. After 24 h of incubation of ⁶⁹Ge-SPION in mouse serum, only <30% of ⁶⁹Ge was found to have leached out of SPION, indicating good stability. Upon i.v. injection of ⁶⁹Ge-SPION into mice, strong liver uptake was observed in PET imaging and biodistribution studies over a period of 36 h, which showed that ⁶⁹Ge-SPION could retain its integrity in vivo. These results were confirmed by MRI where darkening of the liver (but not kidney) was observed, as expected for i.v. injected nanoparticles.

Conclusions We have developed a chelator-free approach to use ⁶⁹Ge for in vivo PET imaging, which takes advantage of the strong affinity between SPION and ⁶⁹Ge. This is the first in vivo PET/MRI study with a ⁶⁹Ge-based agent, which holds potential for future multimodality molecular imaging after surface conjugation of various targeting ligands.