Strategies to Reduce Kidney Uptake of Radiolabeled Biomolecules

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.

References:

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