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Preclinical evaluation of 5-methyltetrahydrofolate-based radioconjugates-new perspectives for folate receptor-targeted radionuclide therapy.

Authors
  • Guzik, Patrycja1
  • Benešová, Martina1, 2
  • Ratz, Magdalena1
  • Monné Rodríguez, Josep M3
  • Deberle, Luisa M2
  • Schibli, Roger1, 2
  • Müller, Cristina4, 5
  • 1 Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute - PSI, 5232, Villigen-PSI, Switzerland. , (Switzerland)
  • 2 Department of Chemistry and Applied Biosciences, ETH Zurich, 8093, Zurich, Switzerland. , (Switzerland)
  • 3 Laboratory for Animal Model Pathology (LAMP), Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057, Zurich, Switzerland. , (Switzerland)
  • 4 Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute - PSI, 5232, Villigen-PSI, Switzerland. [email protected] , (Switzerland)
  • 5 Department of Chemistry and Applied Biosciences, ETH Zurich, 8093, Zurich, Switzerland. [email protected] , (Switzerland)
Type
Published Article
Journal
European Journal of Nuclear Medicine
Publisher
Springer-Verlag
Publication Date
Apr 01, 2021
Volume
48
Issue
4
Pages
972–983
Identifiers
DOI: 10.1007/s00259-020-04980-y
PMID: 33063250
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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 [177Lu]Lu-OxFol-1. [177Lu]Lu-6R-RedFol-1 and [177Lu]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 (AUC0 → 120h) were determined for the uptake in tumors and kidneys. [177Lu]Lu-6R-RedFol-1 was compared with [177Lu]Lu-OxFol-1 in a therapy study over 8 weeks using KB tumor-bearing mice. Both radioconjugates demonstrated similar in vitro properties as [177Lu]Lu-OxFol-1; however, the tumor uptake of [177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1 was significantly increased in comparison with [177Lu]Lu-OxFol-1. In the case of [177Lu]Lu-6S-RedFol-1, also the kidney uptake was increased; however, renal retention of [177Lu]Lu-6R-RedFol-1 was similar to that of [177Lu]Lu-OxFol-1. This led to an almost 4-fold increased tumor-to-kidney AUC0 → 120h ratio of [177Lu]Lu-6R-RedFol-1 as compared with [177Lu]Lu-6S-RedFol-1 and [177Lu]Lu-OxFol-1. At equal activity, the therapeutic effect of [177Lu]Lu-6R-RedFol-1 was better than that of [177Lu]Lu-OxFol-1, reflected by a slower tumor growth and, consequently, an increased median survival time (49 days vs. 34 days). This study demonstrated the promising potential of 5-MTHF-based radioconjugates for FR-targeting. Application of [177Lu]Lu-6R-RedFol-1 resulted in unprecedentedly high tumor-to-kidney ratios and, as a consequence, a superior therapeutic effect as compared with [177Lu]Lu-OxFol-1. These findings, together with the absence of early side effects, make [177Lu]Lu-6R-RedFol-1 attractive in view of a future clinical translation.

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