Targeting of transferrin receptors in nude mice bearing A431 and LS174T xenografts with [18F]holo-transferrin: permeability and receptor dependence.

UNLABELLED: The goal of this study was to investigate whether 18F-labeled transferrin (Tf), which has a molecular weight (Mr) of approximately 79,000, binds to Tf receptor sites in tumors in a specific manner within the time frame commensurate with the half-life of 18F (109.7 min). We have previously shown that [18F]holo-Tf ([18F]Tf) maintains all properties of native Tf in vitro and that it can specifically target liver Tf receptor sites in vivo.
METHODS: The distribution of [18F]Tf, using [18F]albumin (Alb) or [14C]Alb as a control, was studied over a 6-h period in nude mice bearing LS174T and A431 xenografts of a high- and low-permeability tumor, respectively.
RESULTS: Measurements of Tf receptor concentration in the tumor extracts suggest similar binding capacities. In vivo, liver uptake values were higher for [18F]Tf than for both [18F]Alb and [14C]Alb throughout the study, indicating specific binding. In contrast, tumor Tf uptake values remained below those of the Alb tracers, and tumor-to-blood ratios of [18F]Tf in each xenograft increased in parallel with those of the Alb tracers. The permeabilities of [14C]Alb and [18F]Tf in LS174T were calculated to be 1.29+/-0.49 and 1.03+/-0.38 microL/min/g (mean +/- SD), respectively, whereas the permeabilities of the two tracers in A431 were 0.79+/-0.24 and 0.44+/-0.04 microL/min/g. Pharmacokinetic modeling of the data using these permeabilities and the high plasma and extracellular concentrations of endogenous Tf showed that the observed uptake values in the two xenografts are consistent with a non-receptor-mediated distribution. In the liver, the absence of permeability barriers yields specific [18F]Tf binding to receptors compared with the [14C]Alb control, within 5 min after injection.
CONCLUSION: Receptor-mediated accumulation of [18F]Tf in tumor xenografts is impaired by rate-determining permeability and competition from endogenous Tf and is not achieved in a time frame of 6 h.