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Basic Science Investigation |
1 Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, Villigen, Switzerland; 2 Department of Nuclear Medicine, Cantonal Hospital Aarau, Aarau, Switzerland; and 3 Department of Chemistry and Applied Biosciences, ETH Zürich, Zürich, Switzerland
Correspondence: For correspondence or reprints contact: Roger Schibli, PhD, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland. E-mail: roger.schibli{at}pharma.ethz.ch
Targeting the folate receptor (
-FR) with radiolabeled folates for the noninvasive diagnosis and therapy of -FR–overexpressing neoplastic tissue is of great interest. However, the tumor uptake of folate-based radiotracers was shown to be low compared with the high renal retention of radioactivity attributable to -FR expression in the proximal tubule cells. In order to increase the tumor uptake of radiofolates, we wanted to stimulate -FR expression or transport through coapplication of the antifolates methotrexate (MTX), raltitrexed (RTX), and pemetrexed (PMX). Methods: 99mTc-picolylamine monoacetic acid folate (99mTc-PAMA-folate) was used for these studies. The in vitro experiments with antifolates were performed with -FR–positive KB cancer cells. In vivo experiments were performed with KB tumor–bearing athymic nude mice. In vivo images were acquired with a small-animal SPECT/CT scanner. Results: KB cells incubated with solutions (10 µmol/L) of MTX, RTX, or PMX for 24 h displayed twice as much 99mTc-PAMA-folate uptake as untreated cells. In contrast, KB tumor–bearing mice that received MTX intravenously 24 h before 99mTc-PAMA-folate showed significantly lower uptake of the radiofolate in tumors (1.35 ± 0.33 percentage injected dose per gram of tissue [%ID/g] [mean ± SD]) and the -FR–positive kidneys (9.35 ± 1.73 %ID/g) than did control mice (2.33 ± 0.36 and 18.48 ± 0.72 %ID/g, respectively, at 4 h after injection). When the antifolate PMX and 99mTc-PAMA-folate were injected 1 h apart, the tumor uptake of the radiotracer was unaffected (2.21 ± 0.34 %ID/g at 4 h after injection), whereas radioactivity in the kidneys was significantly decreased (1.14 ± 0.18 %ID/g at 4 h after injection). In vivo SPECT/CT studies demonstrated the specific accumulation of 99mTc-PAMA-folate in tumors and almost a complete absence of radioactivity in the renal tissue of mice preinjected with PMX. Conclusion: Our data suggest that the preadministration of antifolates improves tumor-to-kidney ratios of radiofolates and opens a "therapeutic window" for folates radiolabeled with particle-emitting nuclides, which could otherwise be nephrotoxic.
Key Words: folate receptor • antifolate • radiopharmaceutical • 99mTc
COPYRIGHT © 2006 by the Society of Nuclear Medicine, Inc.
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