In Vitro Blood-Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation against Glioblastoma in 2D and 3D Models

Michael M. Lübtow, Sabrina Oerter, Sabina Quader, Elisabeth Jeanclos, Elisabeth Jeanclos, Alevtina Cubukova, Marion Krafft, Malik Salman Haider, Clemens Schulte, Laura Meier, Maximilian Rist, Oltea Sampetrean, Hiroaki Kinoh, Antje Gohla, Kazunori Kataoka, Kazunori Kataoka, Antje Appelt-Menzel, Antje Appelt-Menzel, Robert Luxenhofer, Robert Luxenhofer

研究成果: Article

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Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the family of statins have been suggested as therapeutic options in various tumors. Atorvastatin is a statin with the potential to cross the blood-brain barrier; however, the concentrations necessary for a cytotoxic effect against cancer cells exceed the concentrations achievable via oral administration, which made the development of a novel atorvastatin formulation necessary. We characterized the drug loading and basic physicochemical characteristics of micellar atorvastatin formulations and tested their cytotoxicity against a panel of different glioblastoma cell lines. In addition, activity against tumor spheroids formed from mouse glioma and mouse cancer stem cells, respectively, was evaluated. Our results show good activity of atorvastatin against all tested cell lines. Interestingly, in the three-dimensional (3D) models, growth inhibition was more pronounced for the micellar formulation compared to free atorvastatin. Finally, atorvastatin penetration across a blood-brain barrier model obtained from human induced-pluripotent stem cells was evaluated. Our results suggest that the presented micelles may enable much higher serum concentrations than possible by oral administration; however, if transport across the blood-brain barrier is sufficient to reach the therapeutic atorvastatin concentration for the treatment of glioblastoma via intravenous administration remains unclear.

元の言語English
ページ(範囲)1835-1847
ページ数13
ジャーナルMolecular Pharmaceutics
17
発行部数6
DOI
出版物ステータスPublished - 2020 6 1

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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    Lübtow, M. M., Oerter, S., Quader, S., Jeanclos, E., Jeanclos, E., Cubukova, A., Krafft, M., Haider, M. S., Schulte, C., Meier, L., Rist, M., Sampetrean, O., Kinoh, H., Gohla, A., Kataoka, K., Kataoka, K., Appelt-Menzel, A., Appelt-Menzel, A., Luxenhofer, R., & Luxenhofer, R. (2020). In Vitro Blood-Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation against Glioblastoma in 2D and 3D Models. Molecular Pharmaceutics, 17(6), 1835-1847. https://doi.org/10.1021/acs.molpharmaceut.9b01117