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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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Chicago
Bracke, Nathalie, Yorick Janssens, Evelien Wynendaele, Liesa Tack, Alex Maes, Christophe Van De Wiele, Mike Sathekge, and Bart De Spiegeleer. 2019. “Blood-brain Barrier Transport Kinetics of NOTA-modified Proteins : the Somatropin Case.” Quarterly Journal of Nuclear Medicine and Molecular Imaging.
APA
Bracke, Nathalie, Janssens, Y., Wynendaele, E., Tack, L., Maes, A., Van De Wiele, C., Sathekge, M., et al. (2019). 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. 2019;
MLA
Bracke, Nathalie, Yorick Janssens, Evelien Wynendaele, et al. “Blood-brain Barrier Transport Kinetics of NOTA-modified Proteins : the Somatropin Case.” QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING (2019): n. pag. Print.
@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 {\textpm} 0.14 {\textmu}L/(g{\texttimes}min), 0.36 {\textpm} 0.16 {\textmu}L/(g{\texttimes}min) and 0.28 {\textpm} 0.18 {\textmu}L/(g{\texttimes}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},
  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         = {2019},
}

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