In Vitro Models of the Blood–Brain Barrier for the Study of Drug Delivery to the Brain

Abstract

The most important obstacle to the drug delivery into the brain is the presence of the blood-brain barrier, which limits the traffic of substances between the blood and the nervous tissue. Therefore, adequate in vitro models need to be developed in order to characterize the penetration properties of drug candidates into the central nervous system. This review article summarizes the presently used and the most promising in vitro BBB models based on the culture of brain endothelial cells. Robust models can be obtained using primary porcine brain endothelial cells and rodent coculture models, which have low paracellular permeability and express functional efflux transporters, showing good correlation of drug penetration data with in vivo results. Models mimicking the in vivo anatomophysiological complexity of the BBB are also available, including triple coculture (culture of brain endothelial cells in the presence of pericytes and astrocytes), dynamic, and microfluidic models; however, these are not suitable for rapid, high throughput studies. Potent human cell lines would be needed for easily available and reproducible models which avoid interspecies differences.

The Translational Significance of the Neurovascular Unit

“…Numerous ex vivo BBB models have been designed, frequently employing Transwellstyle assays that include several of the cellular components of the NVU, and can be used to test drug delivery (88). Advanced imaging modalities, including super-resolution microscopy, live imaging using two-photon microscopy, improved transmission electron microscopy, and PET-MRI, can now be applied to study transport mechanisms in and out of the NVU from the nanoscale to whole brain.…”

Brain infiltration by cancer cells: different roads to the same target?

“…The development and refinement of existing in vitro three-dimension models of BBB, traditionally employed in the screening of drugs or molecule designed to cross the BBB, could be used as a novel approach to investigate the genotype and phenotype of cancer cells that migrate through artifi cial BBBs. [114,115] Also, the previous mentioned breakthrough discovery of the presence of lymphatic vessels in the brain could open an avenue of cutting edge experimental approaches in the study of CTCs and BM.…”

Reproducibility in biological models of the blood-brain barrier

“…For instance, different in vitro BBB models have slightly or radically different levels of protein, receptor and transporter expression depending on the type of the model (29,58). It is also known that primary models have higher TEER values than immortalized models, which means that their junctional protein level expression is higher (23).…”

“…In the past few decades, various in vitro BBB models have been developed, including cell based, non-cell based (24), and stem cell based models (25)(26)(27) [for the most recent reviews about different in vitro models of the BBB see refs (23,28,29)]. The cell-based in vitro models include primary, immortalized, and conditionally immortalized models from brain endothelial cells of different species, including rat (30)(31)(32)(33), mouse (34,35), bovine (36), porcine (37,38), and human (39)(40)(41) [the reader can find more examples in a recent review by Bicker et al (28)].…”