Reducing renal uptake of radiolabeled peptides using albumin fragments

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 In-111-diethylenetriaminepentaacetic acid (DTPA)-D-Phe(1)-octreotide (In-111-octreotide), [Lys(40)(aminohexoic acid-DTPA-In-111)NH2]-exendin-4 (In-111-exendin), and In-111-1,4,7,10-tetraazacyclododecane-N,N',N '',N'''-tetraacetic acid (DOTA)-Glu(1)-minigastrin (In-111-minigastrin). Methods: The effects of albumin and FRALB on megalin-associated binding of In-111-octreotide, In-111-exendin, and In-111-minigastrin were assessed in vitro using rat yolk sac epithelial (BN16) cells. In vivo, uptake and localization of In-111-albumin and In-111-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 In-111-octreotide, In-111-exendin, and In-111-minigastrin. Results: FRALB significantly reduced binding and uptake of In-111-octreotide, In-111-exendin, and In-111-minigastrin by BN16 cells. In rats, renal uptake of In-111-labeled FRALB was significantly higher than that of In-111-labeled intact albumin (P < 0.001). FRALB administration effectively reduced renal uptake of In-111-octreotide, In-111-exendin, and In-111-minigastrin. Administration of 1-2 mg of FRALB reduced renal uptake of In-111-octreotide as efficiently as 80 mg of lysine. Conclusion: Renal uptake of In-111-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.