Cutting-edge advances in modeling the blood-brain barrier and tools for its reversible permeabilization for enhanced drug delivery into the brain

Abstract

The blood-brain barrier (BBB) is a sophisticated structure whose full functionality is required for maintaining the executive functions of the central nervous system (CNS). Tight control of transport across the barrier means that most drugs, particularly large size, which includes powerful biologicals, cannot reach their targets in the brain. Notwithstanding the remarkable advances in characterizing the cellular nature of the BBB and consequences of BBB dysfunction in pathology (brain metastasis, neurological diseases), it remains challenging to deliver drugs to the CNS. Herein, we outline the basic architecture and key molecular constituents of the BBB. In addition, we review the current status of approaches that are being explored to temporarily open the BBB in order to allow accumulation of therapeutics in the CNS. Undoubtedly, the major concern in field is whether it is possible to open the BBB in a meaningful way without causing negative consequences. In this context, we have also listed few other important key considerations that can improve our understanding about the dynamics of the BBB.

Keywords: Blood–brain barrier; Drug delivery; Drug targets; Focused ultrasound; In vitro models; In vivo models; Intra-arterial infusion; Organoid models.

Fig. 1

In vitro BBB models’ permeability translation and drug testing future perspective. I-a Permeability measurements measurement techniques can allow a profiling of the permeability of a library of drugs which can be compared to in vivo values, and b correlated, showing the validity of these models. II Possible future drug testing hybrid platforms, using assembled vascular networks and brain organoids. III is adapted from [55], respectively

Fig. 2

Clinical implementation and theranostic strategies for BBB modulation. Intra-arterial administration (upper section), preclinical and clinical trials using Focused Ultrasound (lower section) are illustrated

Fig. 3

Evaluation of the presence of IA transplanted mRNA-ITGA4 transfected or control (naïve) hBM-MSCs in the rat brain subjected to focal brain damage using MRI scan assessment. A mRNA-ITGA4 transfected and control hBM-MSCs labelled with Molday ION were visible in MRI in T2 and T2* scans up to three days after transplantation (tx). B The box-plot graph shows the percentage of right hemisphere occupied by hypo-intensive signal generated by transplanted mRNA-ITGA4 transfected (red boxes) or Control hBM-MSCs (violet boxes). The type III fixed effects test was used to determine statistical significance, and the LMS method was applied to compare between groups and time points. Box charts present the dispersion and the shape of the data distribution for the test value in the compared populations. The length of the bars is equal to the quarter range (Q1–Q3) of the data, the tips of the mustaches indicate the minimum and maximum values, the line inside of the bar determines the median, while the circle/plus the arithmetic mean, the outliers are presented in the form of circles/pluses; *p < 0.05, **p < 0.01, ***p < 0.001 (n = 6). Reprinted from [162]