Preclinical evaluation of 5-methyltetrahydrofolate-based radioconjugates—new perspectives for folate receptor–targeted radionuclide therapy
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...
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Veröffentlicht in: | European journal of nuclear medicine and molecular imaging 2021-04, Vol.48 (4), p.972-983 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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-6
R
-RedFol-1 and [
177
Lu]Lu-6
S
-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
0 → 120h
) were determined for the uptake in tumors and kidneys. [
177
Lu]Lu-6
R
-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-6
R
-RedFol-1 and [
177
Lu]Lu-6
S
-RedFol-1 was significantly increased in comparison with [
177
Lu]Lu-OxFol-1. In the case of [
177
Lu]Lu-6
S
-RedFol-1, also the kidney uptake was increased; however, renal retention of [
177
Lu]Lu-6
R
-RedFol-1 was similar to that of [
177
Lu]Lu-OxFol-1. This led to an almost 4-fold increased tumor-to-kidney AUC
0 → 120h
ratio of [
177
Lu]Lu-6
R
-RedFol-1 as compared with [
177
Lu]Lu-6
S
-RedFol-1 and [
177
Lu]Lu-OxFol-1. At equal activity, the therapeutic effect of [
177
Lu]Lu-6
R
-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-6
R
-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-6
R
-RedFol-1 attractive in view of a future clinical translation. |
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ISSN: | 1619-7070 1619-7089 |
DOI: | 10.1007/s00259-020-04980-y |