TY - JOUR
T1 - In Vitro Blood-Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation against Glioblastoma in 2D and 3D Models
AU - Lübtow, Michael M.
AU - Oerter, Sabrina
AU - Quader, Sabina
AU - Jeanclos, Elisabeth
AU - Jeanclos, Elisabeth
AU - Cubukova, Alevtina
AU - Krafft, Marion
AU - Haider, Malik Salman
AU - Schulte, Clemens
AU - Meier, Laura
AU - Rist, Maximilian
AU - Sampetrean, Oltea
AU - Kinoh, Hiroaki
AU - Gohla, Antje
AU - Kataoka, Kazunori
AU - Kataoka, Kazunori
AU - Appelt-Menzel, Antje
AU - Appelt-Menzel, Antje
AU - Luxenhofer, Robert
AU - Luxenhofer, Robert
N1 - Funding Information:
This work was supported by the Free State of Bavaria and the Deutsche Forschungsgemeinschaft (Project no. 398461692, awarded to R.L.). Moreover, M.M.L. would like to thank the Evonik Foundation for providing a doctoral fellowship. M.S.H. would like to thank the HEC Pakistan for a doctoral fellowship. We thank Christian May for technical support. Furthermore, we thank Dr. Jorge Tapia-Perez for inspiring this study.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
KW - cancer stem cells
KW - drug-loaded micelles
KW - human induced-pluripotent stem cells
KW - nanomedicine
KW - poly(2-oxazine)
KW - poly(2-oxazoline)
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UR - http://www.scopus.com/inward/citedby.url?scp=85085713928&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.9b01117
DO - 10.1021/acs.molpharmaceut.9b01117
M3 - Article
C2 - 32315193
AN - SCOPUS:85085713928
VL - 17
SP - 1835
EP - 1847
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 6
ER -
