Enhanced Positron Annihilation Localization with a Radiolabelled Superparamagnetic Nanoparticle

Background: In PET, the finite range over which positrons travel before annihilating with an electron places a fundamental physical limit on the spatial resolution of PET images. After annihilation, the photon pair detected by the PET instrumentation is emitted from a location that is different from the positron-emitting source, resulting in image blurring. In a previous study (Gholami et al. 2020), we demonstrated that the FDA-approved superparamagnetic iron oxide nanoparticle (SPION) Feraheme® (FH) could, in principle, be radiolabelled with theranostic isotopes: ⁸⁹Zr, ^64,67Cu, ⁹⁰Y, ¹⁷⁷Lu, ²¹²Pb, ²¹³Bi, ¹¹¹In, ^156,157Eu by a chelate-free heat induced direct radiolabelling technique. In separate studies (Gholami et al. 2019 and 2020), we also demonstrated that radiolabelled FH can enhance dose deposition and that ⁸⁹Zr-FH is a highly suitable radio-nanoplatform for hybrid PET/MR imaging. Here, we report on the minimization of positron range, and hence the origin of the annihilation quanta, by the strong nanoscale magnetization of radiolabeled ⁸⁹Zr-FH SPIONs in PET-MRI (Gholami et al. 2020).

Methods: FH SPIONs were radiolabeled with ⁸⁹Zr according to the published protocol (Gholami et al. 2020). A series of dilutions of ⁸⁹Zr-SPION samples were prepared (with [Fe] = 0.1 µM- 3 mM and constant A₀ = 3.7 kBq) in 10 separate phantom vials with deionized water. A control phantom vial was made with ⁸⁹Zr in deionized water only. Phantoms were then scanned using a simultaneous clinical PET-MRI scanner (3T Biograph mMR, Siemens Healthineers). The integrated PET signal intensity for a circular region of interest for each phantom scan was calculated to quantify this positron annihilation localization (PAL) effect. Results: We have demonstrated PAL increases with [Fe] concentration of the ⁸⁹Zr-SPIONs. Interestingly, our results show a significant PAL (≍ 40 %) at a clinically relevant dose of 0.1 mM [Fe]. As the presence of SPIONs increases mass density only by ≍ 0.015%, the effect of collisions on positron range is negligible and thus, the observed PAL can be attributed to SPION nanoscale magnetization. The resulting full width at half maximum of the PET scans showed the spatial resolution improved by up to 30%. The nanoscale magnetic field gradient induced by SPIONs is strongly depended on its saturation magnetization. For instance, SPIONs in the low 1 µM [Fe] solution (containing ≍ 2 ×10¹⁵ SPIONs) in an external 3 T MR magnetic field, can have an induced three dimensional (3D) local magnetic field around the SPION as high as 3 T at the SPION center (Gholami et al. 2020). Thus, an emitted positron from the ⁸⁹Zr atom at the surface of a radiolabeled ⁸⁹Zr-SPION is influenced by the magnetic force (i.e. Lorentz force) from the magnetized SPION that it is labelled to and also the magnetic force of the other 2 ×10¹⁵ SPIONs in its vicinity. Thus, compared to the ⁸⁹Zr-water phantom, phantoms with increasing magnetized ⁸⁹Zr- SPION [Fe] concentrations exhibit PET signals that become increasingly spatially localized. Note this is different from the case of the Lorentz force exerted by the static magnetic field B₀ of the MR magnet, which can restrict positron range in the transaxial direction, as has been reported in previous PET-MRI studies. Conclusion: SPION nanoscale magnetization restricts the range of the positrons emitted by the PET radiopharmaceutical, thus mitigating the fundamental limit imposed by finite positron range on PET image localization in a way that could not be achieved by any other means. As PET-MRI becomes increasingly more accepted clinically and SPIONs become an attractive alternative to existing MRI contrast agents, we anticipate further development and clinical translation of these synergistic technologies. These results may also have implications for emerging cancer theranostic strategies, where charged particles are used as therapeutic as well as diagnostic agents and improved dose localization within a tumor is a determinant of better treatment outcomes.