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Preclinical evaluation of 5-methyltetrahydrofolate-based radioconjugates—new perspectives for folate receptor–targeted radionuclide therapy.
- Source :
- European Journal of Nuclear Medicine & Molecular Imaging; Apr2021, Vol. 48 Issue 4, p972-983, 12p, 1 Color Photograph, 2 Diagrams, 3 Charts, 2 Graphs
- Publication Year :
- 2021
-
Abstract
- Purpose: The folate receptor (FR) is frequently overexpressed in a variety of tumor types and, hence, an interesting target for radionuclide therapy. The aim of this study was to evaluate a new class of albumin-binding radioconjugates comprising 5-methyltetrahydrofolate (5-MTHF) as a targeting agent and to compare their properties with those of the previously established folic acid-based [<superscript>177</superscript>Lu]Lu-OxFol-1. Methods: [<superscript>177</superscript>Lu]Lu-6R-RedFol-1 and [<superscript>177</superscript>Lu]Lu-6S-RedFol-1 were investigated in vitro using FR-positive KB tumor cells. Biodistribution studies were performed in KB tumor-bearing mice, and the areas under the curve (AUC<subscript>0 → 120h</subscript>) were determined for the uptake in tumors and kidneys. [<superscript>177</superscript>Lu]Lu-6R-RedFol-1 was compared with [<superscript>177</superscript>Lu]Lu-OxFol-1 in a therapy study over 8 weeks using KB tumor-bearing mice. Results: Both radioconjugates demonstrated similar in vitro properties as [<superscript>177</superscript>Lu]Lu-OxFol-1; however, the tumor uptake of [<superscript>177</superscript>Lu]Lu-6R-RedFol-1 and [<superscript>177</superscript>Lu]Lu-6S-RedFol-1 was significantly increased in comparison with [<superscript>177</superscript>Lu]Lu-OxFol-1. In the case of [<superscript>177</superscript>Lu]Lu-6S-RedFol-1, also the kidney uptake was increased; however, renal retention of [<superscript>177</superscript>Lu]Lu-6R-RedFol-1 was similar to that of [<superscript>177</superscript>Lu]Lu-OxFol-1. This led to an almost 4-fold increased tumor-to-kidney AUC<subscript>0 → 120h</subscript> ratio of [<superscript>177</superscript>Lu]Lu-6R-RedFol-1 as compared with [<superscript>177</superscript>Lu]Lu-6S-RedFol-1 and [<superscript>177</superscript>Lu]Lu-OxFol-1. At equal activity, the therapeutic effect of [<superscript>177</superscript>Lu]Lu-6R-RedFol-1 was better than that of [<superscript>177</superscript>Lu]Lu-OxFol-1, reflected by a slower tumor growth and, consequently, an increased median survival time (49 days vs. 34 days). Conclusion: This study demonstrated the promising potential of 5-MTHF-based radioconjugates for FR-targeting. Application of [<superscript>177</superscript>Lu]Lu-6R-RedFol-1 resulted in unprecedentedly high tumor-to-kidney ratios and, as a consequence, a superior therapeutic effect as compared with [<superscript>177</superscript>Lu]Lu-OxFol-1. These findings, together with the absence of early side effects, make [<superscript>177</superscript>Lu]Lu-6R-RedFol-1 attractive in view of a future clinical translation. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 16197070
- Volume :
- 48
- Issue :
- 4
- Database :
- Complementary Index
- Journal :
- European Journal of Nuclear Medicine & Molecular Imaging
- Publication Type :
- Academic Journal
- Accession number :
- 149789241
- Full Text :
- https://doi.org/10.1007/s00259-020-04980-y