Albumin-derived peptides efficiently reduce renal uptake of radiolabelled peptides

Abstract

Purpose: In peptide-receptor radionuclide therapy (PRRT), the maximum activity dose that can safely be administered is limited by high renal uptake and retention of radiolabelled peptides. The kidney radiation dose can be reduced by coinfusion of agents that competitively inhibit the reabsorption of radiolabelled peptides, such as positively charged amino acids, Gelofusine, or trypsinised albumin. The aim of this study was to identify more specific and potent inhibitors of the kidney reabsorption of radiolabelled peptides, based on albumin.

Methods: Albumin was fragmented using cyanogen bromide and six albumin-derived peptides with different numbers of electric charges were selected and synthesised. The effect of albumin fragments (FRALB-C) and selected albumin-derived peptides on the internalisation of (111)In-albumin, (111)In-minigastrin, (111)In-exendin and (111)In-octreotide by megalin-expressing cells was assessed. In rats, the effect of Gelofusine and albumin-derived peptides on the renal uptake and biodistribution of (111)In-minigastrin, (111)In-exendin and (111)In-octreotide was determined.

Results: FRALB-C significantly reduced the uptake of all radiolabelled peptides in vitro. The albumin-derived peptides showed different potencies in reducing the uptake of (111)In-albumin, (111)In-exendin and (111)In-minigastrin in vitro. The most efficient albumin-derived peptide (peptide #6), was selected for in vivo testing. In rats, 5 mg of peptide #6 very efficiently inhibited the renal uptake of (111)In-minigastrin, by 88%. Uptake of (111)In-exendin and (111)In-octreotide was reduced by 26 and 33%, respectively.

Conclusions: The albumin-derived peptide #6 efficiently inhibited the renal reabsorption of (111)In-minigastrin, (111)In-exendin and (111)In-octreotide and is a promising candidate for kidney protection in PRRT.

Fig. 1

Inhibition of the uptake of ¹¹¹In-albumin (a), ¹¹¹In-minigastrin (b), ¹¹¹In-exendin (c) and ¹¹¹In-octreotide (d) in BN16 cells by Gelo (4 mg) or FRALB-C (100 µg). Results are presented as mean % bound activity; error bars indicate standard error of the mean (SEM). *P < 0.05; **P < 0.005

Fig. 2

Inhibition of the uptake of ¹¹¹In-albumin (a), ¹¹¹In-minigastrin (b) or ¹¹¹In-exendin (c) in BN16 cells by intact BSA (10 mg), Gelo (5 mg) or 100 µg of albumin-derived peptides. Results are presented as mean % bound activity; error bars indicate SEM. *P < 0.05; **P < 0.005

Fig. 3

Kidney activity concentrations 20 h after i.v. injection of ¹¹¹In-octreotide in rats. One to three minutes prior to the injection of ¹¹¹In-octreotide, groups of five rats received 0.5 ml of either PBS, lysine (80 mg), Gelo (20 mg) or FRALB-C (1 mg). Results are presented as mean %ID/g, error bars indicate SEM. *P < 0.05; **P < 0.005

Fig. 4

Kidney activity concentrations 20 h after i.v. injection of ¹¹¹In-minigastrin (a), ¹¹¹In-exendin (b) or ¹¹¹In-octreotide (c) in rats. One to three minutes prior to the injection of the ¹¹¹In-labelled peptide, groups of five rats received 0.5 ml of either PBS, Gelo (20 mg) or albumin-derived peptide #6. Results are presented as mean %ID/g, error bars indicate SEM. *P < 0.05; **P < 0.005

Fig. 5

Biodistribution of ¹¹¹In-octreotide in rats, 20 h post-injection. One to three minutes prior to the injection of ¹¹¹In-octreotide, groups of five rats received 0.5 ml of PBS or peptide #6 (5 mg). Results are presented as mean %ID/g; error bars indicate SEM. **P < 0.005