Strategies to reduce uptake of radiolabeled peptides in the kidneys.

Contains fulltext : 83246.pdf (publisher's version ) (Open Access)Neuroendocrine tumors overexpressing somatostatin receptors can be treated with peptide-receptor radionuclide therapy (PRRT) using 90Y-DOTATOC or 177Lu-DOTATATE. Several other radiolabeled peptides are studied for use in imaging and therapy of other tumors. However, the maximum activity dose that can safely be administered is limited by renal retention of radiolabeled peptides, which can cause kidney failure. The kidney radiation dose can be reduced by coinfusion of basic amino acids, which reduces the retention of radiolabeled peptides. We aimed to clarify the mechanisms involved in renal uptake of radiolabeled peptides, focusing on the role of megalin, a receptor involved in proximal tubular uptake of several proteins and peptides. Subsequently, we aimed to design and study more efficient strategies to reduce their uptake and the resulting nephrotoxicity. Role of megalin: Renal uptake of various 111In-labeled peptides (octreotide, octreotate, exendin, minigastrin and neurotensin) was measured in megalin-deficient mice and in wild type mice. Renal uptake of all peptides was significantly lower in megalin-deficient mice than in wild types, implying an important role of megalin in their uptake. Reduction of renal uptake of radiolabeled peptides: To reduce uptake of these radiolabeled peptides, we aimed to saturate the megalin receptor (competitive inhibition). We studied the effects of coinfusion of the peptide-based plasma expander Gelofusine (succinylated gelatin) and of fragments of albumin (a megalin ligand) on the renal uptake of radiolabeled peptides in rats and mice. Gelofusine (registered for patient use), was also studied in human volunteers. Both Gelofusine and albumin fragments significantly reduced renal uptake of the radiolabeled peptides in mice and rats. Gelofusine also caused a 50% decrease in uptake of 111In-octreotide in humans. Conclusion: Gelofusine, and possibly also albumin fragments, are very useful for reduction of PRRT-induced nephrotoxicity. This enables administration of higher activity doses, increasing tumor control probability.Radboud Universiteit Nijmegen, 4 februari 2011Promotores : Boerman, O.C., Oyen, W.J.G., Jong, M.B. de171 p