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

The goal of this study was to investigate whether F-18-labeled transferrin (Tf), which has a molecular weight (M-r) of similar to 79,000, binds to Tf receptor sites in tumors in a specific manner within the time frame commens urate with the half-life of F-18 (109.7 min). We have previously shown that [F-18]holo-Tf ([F-18]TI) maintains all properties of native Tf in vitro an d that it can specifically target liver Tf receptor sites in vivo. Methods: The distribution of [F-18]Tf, using [F-18]albumin (Alb) or [C-14]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: M easurements of Tf receptor concentration in the tumor extracts suggest simi lar binding capacities. In vivo, liver uptake values were higher for [F-18] Tf than for both [F-18]Alb and [C-14]Alb throughout the study, indicating s pecific binding. In contrast, tumor Tf uptake values remained below those o f the Alb tracers, and tumor-to-brood ratios of [F-18]Tf in each xenograft increased in parallel with those of the Alb tracers. The permeabilities of [C-14]Alb and [F-18]Tf in LS174T were calculated to be 1.29 +/- 0.49 and 1. 03 +/- 0.38 mu L/min/g (mean +/- SD), respectively, whereas the permeabilit ies of the two tracers in A431 were 0.79 +/- 0.24 and 0.44 +/- 0.04 mu L/mi n/g. Pharmacokinetic modeling of the data using these permeabilities and th e 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 [F-18]Tf binding to receptors compared with the [C -14]Alb control, within 5 min after injection. Conclusion: Receptor-mediate d accumulation of [F-18]Tf in tumor xenografts is impaired by rate-determin ing permeability and competition from endogenous Tf and is not achieved in a time frame of 6 h.