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In Vitro Blood-Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models.
Lübtow, Michael M; Oerter, Sabrina; Quader, Sabina; Jeanclos, Elisabeth; Cubukova, Alevtina; Krafft, Marion; Haider, Malik Salman; Schulte, Clemens; Meier, Laura; Rist, Maximilian; Sampetrean, Oltea; Kinoh, Hiroaki; Gohla, Antje; Kataoka, Kazunori; Appelt-Menzel, Antje; Luxenhofer, Robert.
Afiliação
  • Lübtow MM; Functional Polymer Materials, Chair for Advanced Materials Synthesis, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
  • Oerter S; Chair Tissue Engineering and Regenerative Medicine (TERM), University Hospital Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
  • Quader S; Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-Ku, Kawasaki-Shi 210-0821, Japan.
  • Jeanclos E; Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Straße 9, 97078 Würzburg, Germany.
  • Cubukova A; Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, Germany.
  • Krafft M; Fraunhofer Institute for Silicate Research ISC, Translational Center Regenerative Therapies TLC-RT, Röntgenring 11, 97070 Würzburg, Germany.
  • Haider MS; Chair Tissue Engineering and Regenerative Medicine (TERM), University Hospital Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
  • Schulte C; Functional Polymer Materials, Chair for Advanced Materials Synthesis, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
  • Meier L; Functional Polymer Materials, Chair for Advanced Materials Synthesis, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
  • Rist M; Functional Polymer Materials, Chair for Advanced Materials Synthesis, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
  • Sampetrean O; Functional Polymer Materials, Chair for Advanced Materials Synthesis, Department of Chemistry and Pharmacy and Bavarian Polymer Institute, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
  • Kinoh H; Institute for Advanced Medical Research (IAMR), Division of Gene Regulation, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
  • Gohla A; Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-Ku, Kawasaki-Shi 210-0821, Japan.
  • Kataoka K; Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Straße 9, 97078 Würzburg, Germany.
  • Appelt-Menzel A; Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-Ku, Kawasaki-Shi 210-0821, Japan.
  • Luxenhofer R; Policy Alternatives Research Institute, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Mol Pharm ; 17(6): 1835-1847, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315193
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.

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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Tipo de estudo: Estudo prognóstico Idioma: Inglês Revista: Mol Pharm Assunto da revista: Biologia Molecular / Farmácia / Farmacologia Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Alemanha