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

Permeability and receptor dependence

Luigi Aloj, Elaine Jagoda, Lixin Lang, Corradina Caracò, Ronald D. Neumann, Cynthia Sung, William C. Eckelman

Research output: Contribution to journalArticle

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Abstract

The goal of this study was to investigate whether 18F-labeled transferrin (Tf), which has a molecular weight (M(r)) of ~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 μL/min/g (mean ± SD), respectively, whereas the permeabilities of the two tracers in A431 were 0.79 ± 0.24 and 0.44 ± 0.04 μL/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.

Original languageEnglish
Pages (from-to)1547-1555
Number of pages9
JournalJournal of Nuclear Medicine
Volume40
Issue number9
Publication statusPublished - Sep 1999

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Transferrin Receptors
Transferrin
Heterografts
Nude Mice
Permeability
Albumins
Neoplasms
Liver
Half-Life
Pharmacokinetics
Molecular Weight

Keywords

  • F
  • Liver
  • Neoplasms
  • Pharmacokinetics
  • Transferrin

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Targeting of transferrin receptors in nude mice bearing A431 and LS174T xenografts with [18F]holo-transferrin : Permeability and receptor dependence. / Aloj, Luigi; Jagoda, Elaine; Lang, Lixin; Caracò, Corradina; Neumann, Ronald D.; Sung, Cynthia; Eckelman, William C.

In: Journal of Nuclear Medicine, Vol. 40, No. 9, 09.1999, p. 1547-1555.

Research output: Contribution to journalArticle

Aloj, Luigi ; Jagoda, Elaine ; Lang, Lixin ; Caracò, Corradina ; Neumann, Ronald D. ; Sung, Cynthia ; Eckelman, William C. / Targeting of transferrin receptors in nude mice bearing A431 and LS174T xenografts with [18F]holo-transferrin : Permeability and receptor dependence. In: Journal of Nuclear Medicine. 1999 ; Vol. 40, No. 9. pp. 1547-1555.
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abstract = "The goal of this study was to investigate whether 18F-labeled transferrin (Tf), which has a molecular weight (M(r)) of ~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 μL/min/g (mean ± SD), respectively, whereas the permeabilities of the two tracers in A431 were 0.79 ± 0.24 and 0.44 ± 0.04 μL/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.",
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T1 - Targeting of transferrin receptors in nude mice bearing A431 and LS174T xenografts with [18F]holo-transferrin

T2 - Permeability and receptor dependence

AU - Aloj, Luigi

AU - Jagoda, Elaine

AU - Lang, Lixin

AU - Caracò, Corradina

AU - Neumann, Ronald D.

AU - Sung, Cynthia

AU - Eckelman, William C.

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N2 - The goal of this study was to investigate whether 18F-labeled transferrin (Tf), which has a molecular weight (M(r)) of ~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 μL/min/g (mean ± SD), respectively, whereas the permeabilities of the two tracers in A431 were 0.79 ± 0.24 and 0.44 ± 0.04 μL/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.

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KW - Neoplasms

KW - Pharmacokinetics

KW - Transferrin

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