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Strategies to Reduce Kidney Uptake of Radiolabeled Biomolecules

Wodtke, R.


Peptide receptor radionuclide therapy (PRRT) or radioligand therapy (RLT) represent valuable nuclear medical approaches for the treatment of tumors. It can lead to an unparalleled therapeutic success with [177Lu]Lu-DOTA-TATE1 and [177Lu]Lu-PSMA-6172 being the most striking examples, which were recently approved as Lutathera and Pluvicto, respectively. Besides stimulating the search for further targeted radiopharmaceuticals,3 there are ongoing efforts for optimizing PRRT and RLT apart from the tumor targeting itself. A non-negligible aspect for PRRT and RLT is radiation induced toxicity to healthy tissue, in particular bone marrow and kidneys but also other organs such as salivary glands in case of RLT with [177Lu]Lu-PSMA-617,4,5,6 that also limits the height of the applied activity amount. Due to the high hydrophilicity of somatostatin and PSMA ligands, their primary route of excretion proceeds via the kidney into the urine. This can be accompanied by a significant receptor-mediated reabsorption of the radiopharmaceuticals into the proximal tubular cells followed by lysosomal degradation, which ultimately result in a prolonged retention of the radiolabel and thus, a high dose exposure to the kidneys.7,8 Several nephroprotective strategies are pursued to reduce the tubular reabsorption during PRRT or RLT either by modifying the radiopharmaceutical itself or by co-injection of blocking substances.4,7 The talk will give an overview about the different strategies for reducing the renal uptake with a special emphasis on the targeting of renal brush border enzymes by the introduction of cleavable peptide linkers into targeted radiopharmaceuticals.


1. Strosberg et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N. Engl. J. Med. 2017, 376, 125-135.
2. Sartor et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N. Engl. J. Med. 2021, 385, 1091-1103.
3. Nicolas et al. New Developments in peptide receptor radionuclide therapy. J. Nucl. Med. 2019, 60, 167-171.
4. Geenen et al. Overcoming nephrotoxicity in peptide receptor radionuclide therapy using [177Lu]Lu-DOTA-TATE for the treatment of neuroendocrine tumours. Nucl. Med. Biol. 2021, 102-103, 1-11.
5. Gallyamov et al. Renal outcomes of radioligand therapy: experience of 177lutetium-prostate-specific membrane antigen therapy in metastatic castrate-resistant prostate cancer. 2020, 13, 1049-1055.
6. Kratochwil et al. EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA ligands (177-PSMA-RLT). 2019, 46, 2536-2544.
7. Vegt et al. Renal toxicity of radiolabeled peptides and antibody fragments: Mechanisms, impact on radionuclide therapy, and strategies for prevention. J. Nucl. Med. 2010, 51, 1049-1058.
8. Vegt et al. Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice. Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 623-632.

  • Invited lecture (Conferences)
    35th Annual Congress of the European Association of Nuclear Medicine (EANM), 15.-19.10.2022, Barcelona, Spanien


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