Direct radiolabeling of Zr-89-silica gadolinium nanoparticles (Zr-89-AGuIX (R)) for tumor targeting via long term EPR effect and in vivo clearance characterization in 9L brain tumor model

Complete text of publication follows: Aim/Introduction: High-Z nanoparticles (NP) are attracting great attention as sensitizers for radiotherapy.1 A major challenge is to characterize and quantify intratumoral NP distribution spatially and temporally in order to optimize delivered dose in the tumor area with minimal effect on normal tissues. Our aim is to assess the use of PET to quantitatively image ultra small silica gadolinium NP (AGuIX), a promising nano-sensitizer currently under phase 2 clinical trial.2 We are interested in using ⁸⁹Zr, a long-lived positron emitter, which allows longitudinal monitoring of tumor-specific accumulation of NP. Labeling ⁸⁹Zr on a nanostructure often requires introducing a chelator such as DFO.3 This would probably affect its properties in vivo and necessitates new approval application. In this study, we have shown that AGuIX can be directly labeled with ⁸⁹Zr. Then labeled particles can be used to follow tumor uptake in a preclinical glioma model. Materials and Methods: AGuIX was labeled while taking advantage of free DOTA groups on the particle with ⁸⁹Zr-oxalic acid in different conditions. Stability of the radiotracer has been tested in vitro with fetal bovine serum and mouse plasma. Transmetalation assays have been performed with different endogenous ions i.e. Fe³⁺, Zn²⁺, Ca²⁺, Cu²⁺. Syngeneic tumor model was established by stereotactically implanting 9L gliosarcoma cells into the striatum of Fisher rats-brain. PET-CT images were acquired at different time points after injection of labeled NP. Organs were collected for ex vivo analysis. Results: Complete labeling was achieved even at mild condition. ⁸⁹Zr- AGuIX were stable in different in vitro conditions. 9L tumor growth was assessed by ¹⁸F-FDG PET and histology. Expectedly, PET images post ⁸⁹Zr-AGuIX injection showed NP accumulation in the tumor. Long half-life of ⁸⁹Zr allowed longitudinal follow-up of this accumulation, which lasted more than 24 h in accordance with previous studies. NP accumulation was confirmed by autoradiograms of brain sections. In addition, ex vivo biodistribution indicated that labeled NP were not retained in major organs and eliminated mainly via the kidneys. Conclusion: We have demonstrated that AGuIX can be directly labeled with ⁸⁹Zr in simple conditions, which can be readily applied for GMP manufacturing. Labeled NP was stable and showed promising results for translational brain tumor imaging