title: Reducing renal uptake of radiolabeled peptides using albumin fragments.
abstract: 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 (111)In-diethylenetriaminepentaacetic acid (DTPA)-d-Phe(1)-octreotide ((111)In-octreotide), [Lys(40)(aminohexoic acid-DTPA-(111)In)NH(2)]-exendin-4 ((111)In-exendin), and (111)In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-Glu(1)-minigastrin ((111)In-minigastrin).
  
  
  METHODS
  The effects of albumin and FRALB on megalin-associated binding of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin were assessed in vitro using rat yolk sac epithelial (BN16) cells. In vivo, uptake and localization of (111)In-albumin and (111)In-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 (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin.
  
  
  RESULTS
  FRALB significantly reduced binding and uptake of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin by BN16 cells. In rats, renal uptake of (111)In-labeled FRALB was significantly higher than that of (111)In-labeled intact albumin (P<0.001). FRALB administration effectively reduced renal uptake of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin. Administration of 1-2 mg of FRALB reduced renal uptake of (111)In-octreotide as efficiently as 80 mg of lysine.
  
  
  CONCLUSIONS
  Renal uptake of (111)In-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.
authors.affiliation: Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. E.Vegt@nucmed.umcn.nl
authors.forename: Erik
authors.initials: E
authors.lastname: Vegt
authors.forename: Julliëtte E M
authors.initials: JE
authors.lastname: van Eerd
authors.forename: Annemarie
authors.initials: A
authors.lastname: Eek
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Jack F M
authors.initials: JF
authors.lastname: Wetzels
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.forename: Martin
authors.initials: M
authors.lastname: Gotthardt
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D007553:Isotope Labeling; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010446:Peptide Fragments / Q000493:pharmacokinetics; D010455:Peptides / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D010446:Peptide Fragments; D010455:Peptides; D019275:Radiopharmaceuticals; D012709:Serum Albumin