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Published on: April 25, 2025
Preclinical evaluation of 5-methyltetrahydrofolate-based radioconjugates-new perspectives for folate
Patrycja Guzik1, Martina Benešová1,2, Magdalena Ratz1
1Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute - PSI, 5232, Villigen-PSI, Switzerland.
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 [177Lu]Lu-OxFol-1.
Methods:
[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.
Results:
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).
Conclusion:
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.
Insights
New 5-methyltetrahydrofolate (5-MTHF) radioconjugates show enhanced tumor targeting for folate receptor (FR) radionuclide therapy. The [177Lu]Lu-6R-RedFol-1 agent demonstrated superior therapeutic effects and high tumor-to-kidney ratios compared to existing treatments.
Area of Science:
- Nuclear medicine
- Radiopharmaceutical chemistry
- Oncology
Background:
- Folate receptor (FR) is overexpressed in various cancers, making it a key target for radionuclide therapy.
- Albumin-binding radioconjugates offer potential for improved drug delivery and efficacy.
- 5-methyltetrahydrofolate (5-MTHF) is a novel targeting agent for FR-positive tumors.
Purpose of the Study:
- To evaluate novel albumin-binding radioconjugates using 5-MTHF as the targeting agent.
- To compare the properties of these new radioconjugates with the established folic acid-based [177Lu]Lu-OxFol-1.
- To assess their potential for FR-targeted radionuclide therapy.
Main Methods:
- In vitro evaluation of [177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1 using FR-positive KB tumor cells.
- Biodistribution studies in KB tumor-bearing mice to determine tumor and kidney uptake (AUC0–120h).
- Therapy study comparing [177Lu]Lu-6R-RedFol-1 with [177Lu]Lu-OxFol-1 in KB tumor-bearing mice over 8 weeks.
Main Results:
- Both 5-MTHF radioconjugates ([177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1) showed increased tumor uptake compared to [177Lu]Lu-OxFol-1.
- [177Lu]Lu-6R-RedFol-1 exhibited a significantly higher tumor-to-kidney AUC ratio (4-fold increase) than [177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-OxFol-1.
- Therapeutic efficacy showed [177Lu]Lu-6R-RedFol-1 resulted in slower tumor growth and longer median survival (49 days vs. 34 days) compared to [177Lu]Lu-OxFol-1.
Conclusions:
- 5-MTHF-based radioconjugates show significant promise for FR-targeted radionuclide therapy.
- [177Lu]Lu-6R-RedFol-1 demonstrates superior tumor targeting and therapeutic effect with high tumor-to-kidney ratios.
- The favorable profile of [177Lu]Lu-6R-RedFol-1 suggests its potential for clinical translation in FR-positive cancers.
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