Update

Holy grails and in vitro blood–brain barrier models

The blood-brain barrier accounts for the high attrition rate of the treatments of most brain disorders, which therefore remain one of the greatest health-care challenges of the twenty first century. Against this background of hindrance to brain delivery, nanomedicine takes advantage of the assembly at the nanoscale of available biomaterials to provide a delivery platform with potential to raising brain levels of either imaging or therapeutic agents. Nevertheless, to prevent later failure due to ineffective drug levels at the target site, researchers have been endeavoring to develop a battery of in vitro screening procedures that can predict earlier in the drug discovery process the ability of these cutting-edge drug delivery platforms to cross the blood-brain barrier for biomedical purposes.

This review provides an in-depth analysis of the currently available in vitro blood-brain barrier models (both cell-based and non-cell-based) with the focus on their suitability for understanding the biological brain distribution of forthcoming nanomedicines. The relationship between experimental factors and underlying physiological assumptions that would ultimately lead to a more predictive capacity of their in vivo performance, and those methods already assayed for the evaluation of the brain distribution of nanomedicines are comprehensively discussed.

The object of the study was to improve the blood–brain barrier (BBB) permeability in vitro–in vivo correlations (IVIVC) between in vitro brain microcapillary endothelial cell (BMEC) models and the well-tested rodent in situ brain perfusion technique. Porcine, bovine, rat, mouse, and human in vitro BMEC apparent permeability values, P_e, (14 studies from several laboratories: 229 P_e, 60 compounds) were analyzed by a novel biophysical model encoded in a weighted nonlinear regression procedure to determine the aqueous boundary layer (ABL) thickness and the paracellular parameters: porosity–pathlength (dual-pore model), pore radius, and water channel electrostatic potential. The refined parameters were then used to transform the P_e values into the transendothelial permeability (P_c) values. Porcine BMEC mono-culture models showed tight junctions comparable to those reported in several Caco-2 studies. Bovine cultures were somewhat leakier. In the human primary cultured cell and the hCMEC/D3 cell line data, IVIVC based on P_e values has r² = 0.14. With transformed permeability values, r² = 0.58. Comparable improvements were found in the other species data. By using the in vitro transendothelial P_c values in place of the apparent P_e values, IVIVC can be dramatically improved.

The inability of molecules to permeate the BBB is a significant source of attrition in Central Nervous System (CNS) drug discovery. Given the increasing medical drivers for new and improved CNS drugs, small molecule transfer across the BBB is attracting a heightened awareness within pharmaceutical industry and medical fields. In order to assess the potential for small CNS molecules to permeate the BBB, a variety of methods and models, from in silico to in vivo going through in vitro models are developed as predictive tools in drug discovery. This review gives a comprehensive overview of different approaches currently considered in drug discovery to circumvent the lack of small molecule transfer through the BBB, together with their inherent advantages and disadvantages. Particularly, special attention is drawn to in silico models, with a detailed and contemporary point of view on prediction tools and guidelines for rational design. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4429–4468, 2009