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Towards the Magic Radioactive Bullet: Improving Targeted Radionuclide Therapy by Reducing the Renal Retention of
Kim E de Roode1,2, Lieke Joosten1, Martin Behe3
1Department of Medical Imaging, Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
Abstract:
Targeted radionuclide therapy (TRT) is an emerging field and has the potential to become a major pillar in effective cancer treatment. Several pharmaceuticals are already in routine use for treating cancer, and there is still a high potential for new compounds for this application. But, a major issue for many radiolabeled low-to-moderate-molecular-weight molecules is their clearance via the kidneys and their subsequent reuptake. High renal accumulation of radioactive compounds may lead to nephrotoxicity, and therefore, the kidneys are often the dose-limiting organs in TRT with these radioligands. Over the years, different strategies have been developed aiming for reduced kidney retention and enhanced therapeutic efficacy of radioligands. In this review, we will give an overview of the efforts and achievements of the used strategies, with focus on the therapeutic potential of low-to-moderate-molecular-weight molecules. Among the strategies discussed here is coadministration of compounds that compete for binding to the endocytic receptors in the proximal tubuli. In addition, the influence of altering the molecular design of radiolabeled ligands on pharmacokinetics is discussed, which includes changes in their physicochemical properties and implementation of cleavable linkers or albumin-binding moieties. Furthermore, we discuss the influence of chelator and radionuclide choice on reabsorption of radioligands by the kidneys.
Insights
Targeted radionuclide therapy (TRT) faces challenges with kidney reuptake of radiolabeled molecules. Strategies to reduce renal accumulation are crucial for enhancing cancer treatment efficacy and minimizing nephrotoxicity.
Area of Science:
- Oncology
- Radiochemistry
- Pharmacology
Background:
- Targeted radionuclide therapy (TRT) shows promise as a cancer treatment modality.
- Radiolabeled low-to-moderate-molecular-weight molecules can accumulate in kidneys, causing nephrotoxicity and limiting TRT efficacy.
- Kidneys are often dose-limiting organs in TRT due to radioligand reabsorption.
Purpose of the Study:
- To review strategies for reducing kidney retention of radioligands in TRT.
- To discuss the therapeutic potential of low-to-moderate-molecular-weight molecules in TRT.
- To provide an overview of efforts and achievements in optimizing TRT radioligands.
Main Methods:
- Review of existing literature on kidney retention strategies for radioligands.
- Analysis of molecular design alterations to improve radioligand pharmacokinetics.
- Discussion of coadministration therapies and their impact on renal uptake.
Main Results:
- Strategies discussed include receptor competition, molecular design modification, and linker/moiety implementation.
- Altering physicochemical properties, cleavable linkers, and albumin-binding moieties can influence pharmacokinetics.
- Chelator and radionuclide selection impacts radioligand reabsorption by kidneys.
Conclusions:
- Effective strategies exist to mitigate renal accumulation of radioligands in TRT.
- Optimizing radioligand design and administration is key to improving therapeutic outcomes and patient safety.
- Further research into these strategies can enhance the role of TRT in cancer care.
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