Dose-dependent effects of (anti)folate preinjection on 99mTc-radiofolate uptake in tumors and kidneys
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Updated: Jul 13, 2026
Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
Cristina Müller1, Roger Schibli, Flavio Forrer
1Department of Nuclear Medicine, Erasmus MC, 3015 CE Rotterdam, The Netherlands. c.muller@erasmusmc.nl
Introduction:
The folate receptor (FR) is frequently overexpressed in tumors and can be targeted with folate-based (radio)pharmaceuticals. However, significant accumulation of radiofolates in FR-positive kidneys represents a drawback. We have shown that preadministration of the antifolate pemetrexed (PMX) significantly improved the tumor-to-kidney ratio of radiofolates in mice. The aim of this study was to investigate the dose dependence of these effects and whether the same results could be achieved with folic acid (FA) or 5-methyl-tetrahydrofolate (5-Me-THF).
Methods:
Biodistribution was assessed 4 h postinjection of the organometallic (99m)Tc-picolylamine monoacetic acid folate in nude mice bearing FR-positive KB tumor xenografts. PMX (50-400 microg/mouse) was injected 1 h previous to radioactivity. The effects of FA and 5-Me-THF (0.5-50 microg/mouse) were investigated likewise. Tissues and organs were collected and counted for radioactivity and the values tabulated as percentage of injected dose per gram tissue (% ID/g).
Results:
PMX administration reduced renal retention (<1.6% ID/g vs. control: >10% ID/g), while the tumor uptake (average 1.35%+/-0.40% ID/g vs. control: 1.79%+/-0.49% ID/g) was only slightly affected independent of the PMX dose. Replacement of PMX by FA or 5-Me-THF (50 microg/mouse) resulted in a significant renal blockade (<0.1% ID/g) but at the same time in an undesired reduction of tumor uptake (<0.2% ID/g).
Conclusions:
Selective reduction of radiofolate uptake in kidneys under retention of high tumor accumulation could be achieved in combination with PMX over a broad dose range but not with FA or 5-Me-THF.
Insights
Pemetrexed (PMX) reduces kidney uptake of radiolabeled folates, improving tumor targeting. Folic acid (FA) and 5-methyl-tetrahydrofolate (5-Me-THF) also block kidney uptake but decrease tumor accumulation.
Area of Science:
- Oncology
- Radiopharmaceutical Science
- Pharmacology
Background:
- Folate receptor (FR) is overexpressed in tumors, making it a target for folate-based radiopharmaceuticals.
- High uptake of radiofolates in FR-positive kidneys is a significant limitation.
- Pemetrexed (PMX) has previously shown potential to improve tumor-to-kidney ratios.
Purpose of the Study:
- To investigate the dose-dependent effects of PMX on radiofolate biodistribution.
- To determine if folic acid (FA) or 5-methyl-tetrahydrofolate (5-Me-THF) can achieve similar improvements in tumor-to-kidney ratios.
Main Methods:
- Biodistribution of a (99m)Tc-labeled folate analog was assessed in mice with FR-positive tumor xenografts.
- Mice received varying doses of PMX, FA, or 5-Me-THF prior to radiopharmaceutical injection.
- Tissue and organ radioactivity was measured 4 hours postinjection.
Main Results:
- PMX significantly reduced kidney radiofolate retention (from >10% ID/g to <1.6% ID/g) with minimal impact on tumor uptake.
- FA and 5-Me-THF effectively blocked renal uptake (<0.1% ID/g) but also substantially reduced tumor accumulation (<0.2% ID/g).
Conclusions:
- Pemetrexed (PMX) allows for selective reduction of kidney radiofolate uptake while maintaining tumor accumulation.
- Folic acid (FA) and 5-methyl-tetrahydrofolate (5-Me-THF) are not suitable alternatives for improving tumor-to-kidney ratios due to decreased tumor uptake.
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