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

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1835-1847
Number of pages13
JournalMolecular Pharmaceutics
Volume17
Issue number6
DOIs
Publication statusPublished - 2020 Jun 1

Keywords

  • cancer stem cells
  • drug-loaded micelles
  • human induced-pluripotent stem cells
  • nanomedicine
  • poly(2-oxazine)
  • poly(2-oxazoline)

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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  • Cite this

    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