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Reducing Renal Uptake of Radiolabeled Peptides Using Albumin Fragments

¹ Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; ² Department of Nephrology and Pharmacology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; ³ Department of Nuclear Medicine, Erasmus University Medical Centre, Rotterdam, The Netherlands; and ⁴ Department of Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Correspondence: For correspondence or reprints contact: Erik Vegt, Radboud University Nijmegen Medical Centre, Department of Nuclear Medicine (444), P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: E.Vegt{at}nucmed.umcn.nl

In most types of peptide receptor radionuclide therapy, the maximum activity dose that can be administered is limited by high and persistent renal retention of the radiolabeled peptides, which is, at least partly, mediated by the megalin receptor. Several agents that interfere with renal reabsorption of radiolabeled peptides have been identified (e.g., lysine, arginine, succinylated gelatin solution), but none of these inhibit renal reabsorption completely. Albumin, a naturally abundant megalin ligand, might be a safe and potent alternative. In this study, we analyzed the effects of albumin and fragments of albumin (FRALB) on the renal reabsorption of ¹¹¹In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe¹-octreotide (¹¹¹In-octreotide), [Lys⁴⁰(aminohexoic acid-DTPA-¹¹¹In)NH₂]-exendin-4 (¹¹¹In-exendin), and ¹¹¹In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-Glu¹-minigastrin (¹¹¹In-minigastrin). Methods: The effects of albumin and FRALB on megalin-associated binding of ¹¹¹In-octreotide, ¹¹¹In-exendin, and ¹¹¹In-minigastrin were assessed in vitro using rat yolk sac epithelial (BN16) cells. In vivo, uptake and localization of ¹¹¹In-albumin and ¹¹¹In-FRALB in the kidneys of Wistar rats were determined, as well as the effect of lysine, succinylated gelatin solution, albumin, and FRALB on the kidney uptake of ¹¹¹In-octreotide, ¹¹¹In-exendin, and ¹¹¹In-minigastrin. Results: FRALB significantly reduced binding and uptake of ¹¹¹In-octreotide, ¹¹¹In-exendin, and ¹¹¹In-minigastrin by BN16 cells. In rats, renal uptake of ¹¹¹In-labeled FRALB was significantly higher than that of ¹¹¹In-labeled intact albumin (P < 0.001). FRALB administration effectively reduced renal uptake of ¹¹¹In-octreotide, ¹¹¹In-exendin, and ¹¹¹In-minigastrin. Administration of 1–2 mg of FRALB reduced renal uptake of ¹¹¹In-octreotide as efficiently as 80 mg of lysine. Conclusion: Renal uptake of ¹¹¹In-octreotide and other radiolabeled peptides in rats can be effectively reduced by administration of albumin fragments. Additional studies to identify the albumin fragments responsible for inhibition of renal peptide uptake are warranted.

Key Words: renal reabsorption • octreotide • exendin • minigastrin • albumin

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