1. Preclinical evaluation of 5-methyltetrahydrofolate-based radioconjugates—new perspectives for folate receptor–targeted radionuclide therapy.
- Author
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Guzik, Patrycja, Benešová, Martina, Ratz, Magdalena, Monné Rodríguez, Josep M., Deberle, Luisa M., Schibli, Roger, and Müller, Cristina
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FOLIC acid ,RADIOISOTOPES ,KIDNEY tumors ,TUMOR growth ,SURVIVAL analysis (Biometry) ,NUCLEAR medicine - 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 [
177 Lu]Lu-OxFol-1. Methods: [177 Lu]Lu-6R-RedFol-1 and [177 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 (AUC0 → 120h ) were determined for the uptake in tumors and kidneys. [177 Lu]Lu-6R-RedFol-1 was compared with [177 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 [177 Lu]Lu-OxFol-1; however, the tumor uptake of [177 Lu]Lu-6R-RedFol-1 and [177 Lu]Lu-6S-RedFol-1 was significantly increased in comparison with [177 Lu]Lu-OxFol-1. In the case of [177 Lu]Lu-6S-RedFol-1, also the kidney uptake was increased; however, renal retention of [177 Lu]Lu-6R-RedFol-1 was similar to that of [177 Lu]Lu-OxFol-1. This led to an almost 4-fold increased tumor-to-kidney AUC0 → 120h ratio of [177 Lu]Lu-6R-RedFol-1 as compared with [177 Lu]Lu-6S-RedFol-1 and [177 Lu]Lu-OxFol-1. At equal activity, the therapeutic effect of [177 Lu]Lu-6R-RedFol-1 was better than that of [177 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 [177 Lu]Lu-6R-RedFol-1 resulted in unprecedentedly high tumor-to-kidney ratios and, as a consequence, a superior therapeutic effect as compared with [177 Lu]Lu-OxFol-1. These findings, together with the absence of early side effects, make [177 Lu]Lu-6R-RedFol-1 attractive in view of a future clinical translation. [ABSTRACT FROM AUTHOR]- Published
- 2021
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