Blood-brain barrier transport kinetics of NOTA-modified proteins : the somatropin case
- Author
- Nathalie Bracke (UGent) , Yorick Janssens (UGent) , Evelien Wynendaele (UGent) , Liesa Tack, Alex Maes, Christophe Van De Wiele (UGent) , Mike Sathekge and Bart De Spiegeleer (UGent)
- Organization
- 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, GROWTH-HORMONE RECEPTOR, DRUG DISCOVERY, BINDING-PROTEIN, IN-VIVO, PEPTIDES, CANCER, PERMEABILITY, EXPRESSION, PLASMA, INTERLEUKIN-1-ALPHA
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8564231
- 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, vol. 64, no. 1, 2020, pp. 105–14, doi:10.23736/S1824-4785.18.03025-X.
- 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, 64(1), 105–114. https://doi.org/10.23736/S1824-4785.18.03025-X
- 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 64 (1): 105–14. https://doi.org/10.23736/S1824-4785.18.03025-X.
- 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 64 (1): 105–114. doi:10.23736/S1824-4785.18.03025-X.
- 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;64(1):105–14.
- 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, vol. 64, no. 1, pp. 105–114, 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,GROWTH-HORMONE RECEPTOR,DRUG DISCOVERY,BINDING-PROTEIN,IN-VIVO,PEPTIDES,CANCER,PERMEABILITY,EXPRESSION,PLASMA,INTERLEUKIN-1-ALPHA}}, language = {{eng}}, number = {{1}}, pages = {{105--114}}, title = {{Blood-brain barrier transport kinetics of NOTA-modified proteins : the somatropin case}}, url = {{http://doi.org/10.23736/S1824-4785.18.03025-X}}, volume = {{64}}, year = {{2020}}, }
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