ORIGINAL ARTICLE   

The Quarterly Journal of Nuclear Medicine and Molecular Imaging 2020 March;64(1):105-14

DOI: 10.23736/S1824-4785.18.03025-X

Copyright © 2018 EDIZIONI MINERVA MEDICA

language: English

Blood-brain barrier transport kinetics of NOTA-modified proteins: the somatropin case

Nathalie BRACKE ¹, Yorick JANSSENS ¹, Evelien WYNENDAELE ¹, Liesa TACK ¹, Alex MAES ^{2, 3}, Christophe van de WIELE ⁴, Mike SATHEKGE ⁵, Bart de SPIEGELEER ¹ ✉

¹ Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium; ² Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium; ³ Department of Nuclear Medicine, AZ Groeninge, Kortrijk, Belgium; ⁴ Department of Radiology and Nuclear Medicine, Ghent University, Ghent, Belgium; ⁵ Department of Nuclear Medicine, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa

BACKGROUND: Chemical modifications such as PEG, polyamine and radiolabeling on proteins can alter their pharmacokinetic behavior and their blood-brain barrier (BBB) transport characteristics. NOTA, i.e. 1,4,7-triazacyclononane-1,4,7-triacetic acid, is a bifunctional chelating agent that has attracted the interest of the scientific community for its high complexation constant with metals like gallium. Until now, the comparative BBB transport characteristics of NOTA-modified proteins versus unmodified proteins are not yet described.
METHODS: Somatropin (i.e. recombinant human growth hormone), NOTA-conjugated somatropin and gallium-labelled NOTA-conjugated somatropin were investigated for their brain penetration characteristics (multiple time regression and capillary depletion [CD]) in an in vivo mice model to determine the blood-brain transfer properties.
RESULTS: The three compounds showed comparable initial brain influx, with Kin=0.38±0.14 µL/(g×min), 0.36±0.16 µL/(g×min) and 0.28±0.18 µL/(g×min), respectively. CD indicated that more than 80% of the influxed compounds reached the brain parenchyma. All three compounds were in vivo stable in serum and brain during the time frame of the experiments.
CONCLUSIONS: Our results show that modification of NOTA as well as gallium chelation onto proteins, in casu somatropin, does not lead to a significantly changed pharmacokinetic profile at the blood-brain barrier.

KEY WORDS: Blood-brain barrier; Permeability; Gallium; Chelation therapy; Growth hormone