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

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Abstract
BACKGROUND: Chemical modifications such as PEG, polyamine and radiolabeling on proteins can alter their pharmacokinetic behaviour 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) 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. Capillary depletion 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.
Keywords
NOTA-modified somatropins, blood-brain barrier permeability, Gallium chelation, in vivo mice model, growth hormone

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MLA
Bracke, Nathalie, et al. “Blood-Brain Barrier Transport Kinetics of NOTA-Modified Proteins : The Somatropin Case.” QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 2020.
APA
Bracke, N., Janssens, Y., Wynendaele, E., Tack, L., Maes, A., Van De Wiele, C., … De Spiegeleer, B. (2020). Blood-brain barrier transport kinetics of NOTA-modified proteins : the somatropin case. QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING.
Chicago author-date
Bracke, Nathalie, Yorick Janssens, Evelien Wynendaele, Liesa Tack, Alex Maes, Christophe Van De Wiele, Mike Sathekge, and Bart De Spiegeleer. 2020. “Blood-Brain Barrier Transport Kinetics of NOTA-Modified Proteins : The Somatropin Case.” QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING.
Chicago author-date (all authors)
Bracke, Nathalie, Yorick Janssens, Evelien Wynendaele, Liesa Tack, Alex Maes, Christophe Van De Wiele, Mike Sathekge, and Bart De Spiegeleer. 2020. “Blood-Brain Barrier Transport Kinetics of NOTA-Modified Proteins : The Somatropin Case.” QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING.
Vancouver
1.
Bracke N, Janssens Y, Wynendaele E, Tack L, Maes A, Van De Wiele C, et al. Blood-brain barrier transport kinetics of NOTA-modified proteins : the somatropin case. QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING. 2020;
IEEE
[1]
N. Bracke et al., “Blood-brain barrier transport kinetics of NOTA-modified proteins : the somatropin case,” QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 2020.
@article{8564231,
  abstract     = {BACKGROUND: Chemical modifications such as PEG, polyamine and radiolabeling on proteins can alter their pharmacokinetic behaviour 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) 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. Capillary depletion 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.},
  author       = {Bracke, Nathalie and Janssens, Yorick and Wynendaele, Evelien and Tack, Liesa and Maes, Alex and Van De Wiele, Christophe and Sathekge, Mike and De Spiegeleer, Bart},
  issn         = {1824-4785},
  journal      = {QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING},
  keywords     = {NOTA-modified somatropins,blood-brain barrier permeability,Gallium chelation,in vivo mice model,growth hormone},
  language     = {eng},
  title        = {Blood-brain barrier transport kinetics of NOTA-modified proteins : the somatropin case},
  url          = {http://dx.doi.org/10.23736/S1824-4785.18.03025-X},
  year         = {2020},
}

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