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Preparation, Biodistribution, and Small Animal PET of ⁴⁵Ti-Transferrin

¹ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
² Department of Chemistry, Washington University in St. Louis, St. Louis, Missouri
³ Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri

Investigation of ⁴⁵Ti-transferrin was pursued to provide insight into the mechanism of action of titanocene dichloride, a chemotherapeutic agent currently in clinical trials. Methods: Plasma protein-binding studies of processed ⁴⁵Ti were performed by solubilizing the ⁴⁵Ti residue in 0.05N HCl, of which 1.22 MBq (33 µCi) in 10 µL were added to 250 µL of dog plasma. ⁴⁵Ti-Transferrin was prepared by redissolving the processed ⁴⁵Ti in 25 µmol/L apotransferrin or by in vivo incorporation through preparation and introduction of ⁴⁵Ti-citrate. Biodistribution studies were performed on normal Sprague–Dawley rats and EMT-6 tumor-bearing BALB/c mice with ⁴⁵Ti-transferrin coinjected with ⁶⁷Ga-citrate for direct comparison. microPET was performed on mice bearing EMT-6 tumors and the images were analyzed for tumor-to-muscle uptake ratios. Results: Direct labeling of apotransferrin in situ with ⁴⁵Ti was achieved as well as in vivo incorporation by 2 h after injection with ⁴⁵Ti-citrate. The biodistribution of ⁴⁵Ti-transferrin and ⁶⁷Ga-citrate showed similar trends. In Sprague–Dawley rats, initial blood uptake was higher for the ⁴⁵Ti-transferrin, whereas bone uptake increased more for the ⁶⁷Ga-citrate. EMT-6 tumor uptake in both cases was relatively high (14.6 ± 1.83 %ID/g for ⁴⁵Ti and 8.72 ± 0.98 %ID/g for ⁶⁷Ga [%ID/g = percentage injected dose per gram]) and remained elevated even out to 24 h after injection. The tumor-to-muscle ratio of the ⁶⁷Ga-citrate reached 6.7 at 24 h, whereas the ratio of the ⁴⁵Ti-transferrin increased to 4.3 at this time point. Uptake of ⁴⁵Ti-transferrin was visualized in the EMT-6 murine mammary carcinoma tumor with microPET. In all cases, the tumor was clearly delineated from the surrounding tissue with tumor-to-muscle ratios on the order of 1.6. Conclusion: ⁴⁵Ti forms a complex with apotransferrin that remains intact in vivo. Results of the biodistribution in mice showed that the tumor had increased uptake compared with nontarget organs (e.g., muscle). The microPET images of tumor-bearing mice clearly delineate the tumors from the surrounding tissue. Comparison of the data suggests that tissue uptake is similar whether injecting ⁴⁵Ti-transferrin directly or as ⁴⁵Ti-citrate, which transchelates to transferrin before the time of imaging.

Key Words: ⁴⁵Ti • transferrin • microPET

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