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  4. In Vitro Blood-Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models
 
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2020
Journal Article
Title

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

Abstract
Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA) reductase of the family of statins have been suggestedas therapeutic options in various tumors. Atorvastatin is a statinwith potential to cross the blood-brain-barrier, however, theconcentrations necessary for a cytotoxic effect against cancer cellsexceeds the concentration achievable via oral administration,which made the development of a novel atorvastatin formulationnecessary. We characterized the drug loading and basicphysicochemical characteristics of micellar atorvastatinformulations and tested their cytotoxicity against a panel ofdifferent glioblastoma cell lines. In addition, activity against tumorspheroids formed from mouse glioma and mouse cancer stemcells, respectively, was evaluated. Our results show good activityof atorvastatin against all tested cell lines. Interestingly, in the 3Dmodels, growth inhibition was more pronounced for the micellarformulation compared to free atorvastatin. Finally, atorvastatinpenetration across a blood-brain-barrier model obtained fromhuman induced-pluripotent stem cells was evaluated. Our resultssuggest that the presented micelles may enable much higherserum concentrations than possible by oral administration,however, if transport across the blood-brain-barrier is sufficient toreach therapeutic atorvastatin concentration for the treatment ofglioblastoma via intravenous administration remains unclear.
Author(s)
Lübtow, Michael M.
Functional Polymer Materials, Chair for Advanced Materials Synthesis, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, University of Würzburg, Würzburg, Germany
Oerter, Sabrina
University Hospital Würzburg, Chair Tissue Engineering and Regenerative Medicine (TERM), Würzburg, Germany
Quader, Sabina
Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industrial Promotion, Japan
Jeanclos, Elisabeth
Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany; Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany
Cubukova, Alevtina  
Krafft, Marion
University Hospital Würzburg, Chair Tissue Engineering and Regenerative Medicine (TERM), Röntgenring 11, 97070 Würzburg, Germany
Haider, Malik Salman
Functional Polymer Materials, Chair for Advanced Materials Synthesis, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, University of Würzburg, Würzburg, Germany
Schulte, Clemens
Functional Polymer Materials, Chair for Advanced Materials Synthesis, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, University of Würzburg, Würzburg, Germany
Meier, Laura
Functional Polymer Materials, Chair for Advanced Materials Synthesis, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, University of Würzburg, Würzburg, Germany
Rist, Maximilian
Functional Polymer Materials, Chair for Advanced Materials Synthesis, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, University of Würzburg, Würzburg, Germany
Sampetrean, Oltea
Institute for Advanced Medical Research (IAMR), Division of Gene Regulation, Keio University School of Medicine, Tokyo, Japan
Kinoh, Hiroaki
Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industrial Promotion, Japan
Gohla, Antje
Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany
Kataoka, Kazunori
Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industrial Promotion, Japan
Appelt-Menzel, Antje  
Fraunhofer-Institut für Silicatforschung ISC  
Luxenhofer, Robert
Functional Polymer Materials, Chair for Advanced Materials Synthesis, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, University of Würzburg, Würzburg, Germany
Journal
Molecular pharmaceutics  
Open Access
DOI
10.1021/acs.molpharmaceut.9b01117
Additional full text version
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Language
English
Fraunhofer-Institut für Silicatforschung ISC  
Keyword(s)
  • drug-loaded micelles

  • poly(2-oxazoline)

  • poly(2-oxazine

  • nanomedicine

  • Human induced pluripotent stem cells

  • cancer stemcells

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