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

2019 ◽  
Author(s):  
Michael M Lübtow ◽  
Sabrina Oertner ◽  
Sabina Quader ◽  
Elisabeth Jeanclos ◽  
Alevtina Cubukova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Oral Administration ◽  
Blood Brain Barrier ◽  
Cell Lines ◽  
Drug Loading ◽  
3D Models ◽  
Physicochemical Characteristics ◽  
Brain Barrier ◽  
Blood Brain

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.<br>

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

2019 ◽  
Author(s):  
Michael M Lübtow ◽  
Sabrina Oertner ◽  
Sabina Quader ◽  
Elisabeth Jeanclos ◽  
Alevtina Cubukova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Oral Administration ◽  
Blood Brain Barrier ◽  
Cell Lines ◽  
Drug Loading ◽  
3D Models ◽  
Physicochemical Characteristics ◽  
Brain Barrier ◽  
Blood Brain

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.<br>

Refining In Vitro Neurotoxicity Testing — The Development of Blood–Brain Barrier Models

2003 ◽  
Vol 31 (3) ◽  
pp. 273-276 ◽  
Author(s):  
Hanna Tähti ◽  
Heidi Nevala ◽  
Tarja Toimela
Keyword(s):  
Blood Brain Barrier ◽  
Cell Lines ◽  
Three Dimensional ◽  
Brain Barrier ◽  
Culture Methods ◽  
Blood Brain ◽  
Capillary Endothelial Cells ◽  
In Vitro Bbb Model

The purpose of this paper is to review the current state of development of advanced in vitro blood–brain barrier (BBB) models. The BBB is a special capillary bed that separates the blood from the central nervous system (CNS) parenchyma. Astrocytes maintain the integrity of the BBB, and, without astrocytic contacts, isolated brain capillary endothelial cells in culture lose their barrier characteristics. Therefore, when developing in vitro BBB models, it is important to add astrocytic factors into the culture system. Recently, novel filter techniques and co-culture methods have made it possible to develop models which resemble the in vivo functions of the BBB in an effective way. With a BBB model, kinetic factors can be added into the in vitro batteries used for evaluating the neurotoxic potential of chemicals. The in vitro BBB model also represents a useful tool for the in vitro prediction of the BBB permeability of drugs, and offers the possibility to scan a large number of drugs for their potential to enter the CNS. Cultured monolayers of brain endothelial cell lines or selected epithelial cell lines, combined with astrocyte and neuron cultures, form a novel three-dimensional technique for the screening of neurotoxic compounds.

Immortalized endothelial cell lines for in vitro blood–brain barrier models: A systematic review

2016 ◽  
Vol 1642 ◽  
pp. 532-545 ◽  
Author(s):  
Nurul Adhwa Rahman ◽  
Alifah Nur’ain Haji Mat Rasil ◽  
Uta Meyding-Lamade ◽  
Eva Maria Craemer ◽  
Suwarni Diah ◽  
...  
Keyword(s):  
Systematic Review ◽  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Cell Lines ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Establishment of an in Vitro Human Blood-Brain Barrier Model Derived from Induced Pluripotent Stem Cells and Comparison to a Porcine Cell-Based System

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 994 ◽  
Author(s):  
Annalise Di Marco ◽  
Domenico Vignone ◽  
Odalys Gonzalez Paz ◽  
Ivan Fini ◽  
Maria Rosaria Battista ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Blood Brain Barrier ◽  
Pluripotent Stem Cells ◽  
Brain Barrier ◽  
Human Model ◽  
Blood Brain ◽  
Blood Brain Barrier Model ◽  
Induced Pluripotent

The blood-brain barrier (BBB) is responsible for the homeostasis between the cerebral vasculature and the brain and it has a key role in regulating the influx and efflux of substances, in healthy and diseased states. Stem cell technology offers the opportunity to use human brain-specific cells to establish in vitro BBB models. Here, we describe the establishment of a human BBB model in a two-dimensional monolayer culture, derived from human induced pluripotent stem cells (hiPSCs). This model was characterized by a transendothelial electrical resistance (TEER) higher than 2000 Ω∙cm2 and associated with negligible paracellular transport. The hiPSC-derived BBB model maintained the functionality of major endothelial transporter proteins and receptors. Some proprietary molecules from our central nervous system (CNS) programs were evaluated revealing comparable permeability in the human model and in the model from primary porcine brain endothelial cells (PBECs).

scholarly journals Differential Sensitivity of Two Endothelial Cell Lines to Hydrogen Peroxide Toxicity: Relevance for In Vitro Studies of the Blood–Brain Barrier

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 403 ◽  
Author(s):  
Olufemi Alamu ◽  
Mariam Rado ◽  
Okobi Ekpo ◽  
David Fisher
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Blood Brain Barrier ◽  
Cell Lines ◽  
Mouse Brain ◽  
Differential Sensitivity ◽  
Brain Barrier ◽  
Blood Brain ◽  
Mouse Brain Endothelial Cells

Oxidative stress (OS) has been linked to blood–brain barrier (BBB) dysfunction which in turn has been implicated in the initiation and propagation of some neurological diseases. In this study, we profiled, for the first time, two endothelioma cell lines of mouse brain origin, commonly used as in vitro models of the blood–brain barrier, for their resistance against oxidative stress using viability measures and glutathione contents as markers. OS was induced by exposing cultured cells to varying concentrations of hydrogen peroxide and fluorescence microscopy/spectrometry was used to detect and estimate cellular glutathione contents. A colorimetric viability assay was used to determine changes in the viability of OS-exposed cells. Both the b.End5 and bEnd.3 cell lines investigated showed demonstrable content of glutathione with a statistically insignificant difference in glutathione quantity per unit cell, but with a statistically significant higher capacity for the b.End5 cell line for de novo glutathione synthesis. Furthermore, the b.End5 cells demonstrated greater oxidant buffering capacity to higher concentrations of hydrogen peroxide than the bEnd.3 cells. We concluded that mouse brain endothelial cells, derived from different types of cell lines, differ enormously in their antioxidant characteristics. We hereby recommend caution in making comparisons across BBB models utilizing distinctly different cell lines and require further prerequisites to ensure that in vitro BBB models involving these cell lines are reliable and reproducible.

scholarly journals In vitro Models of the Blood–Brain Barrier: Tools in Translational Medicine

2021 ◽  
Vol 2 ◽  
Author(s):  
Alberto Williams-Medina ◽  
Michael Deblock ◽  
Damir Janigro
Keyword(s):  
Blood Brain Barrier ◽  
3D Models ◽  
Rapid Expansion ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Laboratory Research ◽  
Disease Etiology ◽  
Medical Progress ◽  
Blood Brain

Medical progress has historically depended on scientific discoveries. Until recently, science was driven by technological advancements that, once translated to the clinic, fostered new treatments and interventions. More recently, technology-driven medical progress has often outpaced laboratory research. For example, intravascular devices, pacemakers for the heart and brain, spinal cord stimulators, and surgical robots are used routinely to treat a variety of diseases. The rapid expansion of science into ever more advanced molecular and genetic mechanisms of disease has often distanced laboratory-based research from day-to-day clinical realities that remain based on evidence and outcomes. A recognized reason for this hiatus is the lack of laboratory tools that recapitulate the clinical reality faced by physicians and surgeons. To overcome this, the NIH and FDA have in the recent past joined forces to support the development of a “human-on-a-chip” that will allow research scientists to perform experiments on a realistic replica when testing the effectiveness of novel experimental therapies. The development of a “human-on-a-chip” rests on the capacity to grow in vitro various organs-on-a-chip, connected with appropriate vascular supplies and nerves, and our ability to measure and perform experiments on these virtually invisible organs. One of the tissue structures to be scaled down on a chip is the human blood–brain barrier. This review gives a historical perspective on in vitro models of the BBB and summarizes the most recent 3D models that attempt to fill the gap between research modeling and patient care. We also present a summary of how these in vitro models of the BBB can be applied to study human brain diseases and their treatments. We have chosen NeuroAIDS, COVID-19, multiple sclerosis, and Alzheimer's disease as examples of in vitro model application to neurological disorders. Major insight pertaining to these illnesses as a consequence of more profound understanding of the BBB can reveal new avenues for the development of diagnostics, more efficient therapies, and definitive clarity of disease etiology and pathological progression.

scholarly journals Wnt signaling mediates acquisition of blood-brain barrier properties in naïve endothelium derived from human pluripotent stem cells

2021 ◽  
Author(s):  
Benjamin D Gastfriend ◽  
Hideaki Nishihara ◽  
Scott G Canfield ◽  
Koji L Foreman ◽  
Britta Engelhardt ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wnt Signaling ◽  
Blood Brain Barrier ◽  
Pluripotent Stem Cells ◽  
Barrier Properties ◽  
Human Pluripotent Stem Cells ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System

Endothelial cells (ECs) in the central nervous system (CNS) acquire their specialized blood-brain barrier (BBB) properties in response to extrinsic signals, with Wnt/β-catenin signaling coordinating multiple aspects of this process. Our knowledge of CNS EC development has been advanced largely by animal models, and human pluripotent stem cells (hPSCs) offer the opportunity to examine BBB development in an in vitro human system. Here we show that activation of Wnt signaling in hPSC-derived naïve endothelial progenitors, but not in matured ECs, leads to robust acquisition of canonical BBB phenotypes including expression of GLUT-1, increased claudin-5, and decreased PLVAP. RNA-seq revealed a transcriptome profile resembling ECs with CNS-like characteristics, including Wnt-upregulated expression of LEF1, APCDD1, and ZIC3. Together, our work defines effects of Wnt activation in naïve ECs and establishes an improved hPSC-based model for interrogation of CNS barriergenesis.

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