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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

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Molecular pharmaceutics 17 (2020), Nr.6, S.1835–1847
ISSN: 1543-8384
ISSN: 1543-8392
Englisch
Zeitschriftenaufsatz
Fraunhofer ISC ()
drug-loaded micelles; poly(2-oxazoline); poly(2-oxazine; nanomedicine; Human induced pluripotent stem cells; cancer stemcells

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.

: http://publica.fraunhofer.de/dokumente/N-593474.html