Imaging tumor burden in the brain with 89Zr-transferrin

Abstract

A noninvasive technology that indiscriminately detects tumor tissue in the brain could substantially enhance the management of primary or metastatic brain tumors. Although the documented molecular heterogeneity of diseases that initiate or eventually deposit in the brain may preclude identifying a single smoking-gun molecular biomarker, many classes of brain tumors are generally avid for transferrin. Therefore, we reasoned that applying a radiolabeled derivative of transferrin ((89)Zr-labeled transferrin) may be an effective strategy to more thoroughly identify tumor tissue in the brain, regardless of the tumor's genetic background.

Methods: Transferrin was radiolabeled with (89)Zr, and its properties with respect to human models of glioblastoma multiforme were studied in vivo.

Results: In this report, we show proof of concept that (89)Zr-labeled transferrin ((89)Zr-transferrin) localizes to genetically diverse models of glioblastoma multiforme in vivo. Moreover, we demonstrate that (89)Zr-transferrin can detect an orthotopic lesion with exceptional contrast. Finally, the tumor-to-brain contrast conferred by (89)Zr-transferrin vastly exceeded that observed with (18)F-FDG, currently the most widely used radiotracer to assess tumor burden in the brain.

Conclusion: The results from this study suggest that (89)Zr-transferrin could be a broadly applicable tool for identifying and monitoring tumors in the brain, with realistic potential for near-term clinical translation.

FIGURE 1

Temporal analysis of ⁸⁹Zr-transferrin in tumor-bearing mice. (A) Representative PET images of tumor-bearing mouse show high and persistent uptake of ⁸⁹Zr-transferrin in subcutaneous TS543 xenografts. White arrows indicate position of tumor (T) or liver (L). (B) Biodistribution data (n = 5 per time point) from selected panel of tissues show high uptake of ⁸⁹Zr-transferrin in tumor, compared with other tissues. Although ⁸⁹Zr-transferrin continuously depletes from blood-rich tissues over time (heart, lungs), high and persistent uptake of ⁸⁹Zr-transferrin is observed in tumor over 48 h. Note also low uptake of ⁸⁹Zr-transferrin in normal murine brain. *P < 0.01, compared with biodistribution data in blood. Tf = transferrin; Trans = transverse slice.

FIGURE 2

⁸⁹Zr-transferrin detects orthotopic model of GBM in vivo. (A) Representative MR slices showing tumor development in murine brain. Fourteen days after inoculation, tumor development was confirmed visually with MR imaging, before development of clinical symptoms in cohort. Shown are 2 consecutive coronal slices from 1 animal. Region of contrast showing tumor mass is indicated with red arrow. All MR data are available on request. (B) Representative PET images of tumor-bearing mouse show high contrast achieved with ⁸⁹Zr-transferrin in TS543 graft inoculated in right hemisphere of murine brain. Images were acquired at 24 h after injection of ⁸⁹Zr-transferrin. White arrows indicate position of tumor (T) or liver (L). (C) Histology (left) and autoradiography (right) from murine brain bearing TS543 tumor in right hemisphere. Brain is shown at ×4 magnification, and intensity of radiotracer localization is depicted using semiquantitative red (high) to blue (low) scale. (D) Biodistribution data of right (tumor-bearing) and left (normal) brain hemispheres from cohort of mice (n = 5) treated with ⁸⁹Zr-transferrin. After euthanasia, brain was bisected along medial longitudinal fissure, and ⁸⁹Zr-transferrin uptake in each piece was counted separately on γ-counter. Data were acquired from animals euthanized at 24 h after injection of ⁸⁹Zr-transferrin. *P < 0.05, compared with normal (left) hemispheres. Tf = transferrin; Trans = transverse slice.

FIGURE 3

⁸⁹Zr-transferrin detects multiple subcutaneous GBM models with exceptional tumor-to-brain ratios in vivo. (A) Western blot showing relative expression of TFRC in 4 glioblastoma models used in this study. (B) Biodistribution data from animals used in PET study (n = 5 per group). Tissues were acquired immediately after PET scan. (C) Tumor-to-brain ratios calculated from biodistribution data show high degree of contrast conferred by ⁸⁹Zr-transferrin in all models. As expected, tumor-to-brain ratio for ¹⁸F-FDG was poor. (D) Representative PET images of mice bearing subcutaneous TS543, U87 MG, LN-18, or SF268 xenografts. Separate treatment arms received ⁸⁹Zr-transferrin or ¹⁸F-FDG and were imaged at 24 or 1 h after injection, respectively. Position of tumor is indicated with arrow. Tf = transferrin.