Uptake of Gallium-67 in Transfected Cells and Tumors Absent or Enriched in the Transferrin Receptor

Gallium-67 has been a controversial tumor-imaging agent in nuclear medicine for decades. This controversy centers on why tumors are variable in gallium-avidity, whether 67Ga uptake is a transferrin-independent or dependent process, and whether tumors and normal tissues differ in mechanism of uptake. If the factors that control uptake of 67Ga were understood better, then efforts to improve oncologic imaging with 67Ga by increasing the tumor activity, or by decreasing the background, may be warranted. Conventional systems for evaluating the mechanism and control of 67Ga uptake have significant limitations. We have endeavored to circumvent these by developing a pair of transfected cell lines. One cell line has no transferrin receptor. In the other, the human transferrin receptor has been restored by transfection and is over-expressed constitutively, without the necessity to manipulate factors such as cell growth or iron content. The uptake of 67Ga, both as a citrate salt and as a gallium-transferrin complex, was examined in these pairs of cells in vitro. The effect of calcium and of soluble (ionic) iron concentration on 67Ga uptake also was determined. Tumors were grown as explants of these cells in nude mice and comparisons of uptake of 67Ga by these tumors in vivo were made. The in vivo uptake of 67Ga is significantly increased in tumors in which the transferrin receptor is overexpressed, compared to those without a functional transferrin receptor. However, a notable amount of accumulation of 67Ga also occurs, both in vitro and in vivo, by a transferrin-independent route. In vitro experiments demonstrate that the uptake of 67Ga by the transferrin-independent route can be enhanced further to levels that equal or exceed those achieved by the transferrin-dependent route by increasing the content of calcium or iron salts in the incubation medium. Significant transferrin-independent uptake of 67Ga occurs both in vitro and in vivo. This uptake can be stimulated further in vitro, suggesting that in vivo enhancement might also be possible to enhance the utility of the radiometal for tumor imaging.