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

preprint
submitted on 29.10.2019 and posted on 31.10.2019 by Michael M Lübtow, Sabrina Oertner, Sabina Quader, Elisabeth Jeanclos, Alevtina Cubukova, Marion Krafft, Clemens Schulte, Laura Meier, Maximilian Rist, Oltea Sampetrean, Hiroaki Kinoh, Antje Gohla, Kazunori Kataoka, Antje Appelt-Menzel, Robert Luxenhofer
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 potential to cross the blood-brain-barrier, however, the concentrations necessary for a cytotoxic effect against cancer cells exceeds the concentration 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 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 therapeutic atorvastatin concentration for the treatment of glioblastoma via intravenous administration remains unclear.

Funding

Deutsche Forschungsgemeinschaft

History

Email Address of Submitting Author

robert.luxenhofer@uni-wuerzburg.de

Institution

Würzburg University

Country

Germany

ORCID For Submitting Author

0000-0001-5567-7404

Declaration of Conflict of Interest

M.M.L. and R.L. are listed as inventors on patents and patent applications pertinent to the content of the contribution. R.L. is co-founder of DelAQUA Pharmaceuticals, intent on commercialization of poly(2-oxazoline) based drug formulations.

Version Notes

first version submitted for peer review

Licence

Exports