Three-Dimensional in vitro Models of Healthy and Tumor Brain Microvasculature for Drug and Toxicity Screening

Abstract

Tissue vascularization is essential for its oxygenation and the homogenous diffusion of nutrients. Cutting-edge studies are focusing on the vascularization of three-dimensional (3D) in vitro models of human tissues. The reproduction of the brain vasculature is particularly challenging as numerous cell types are involved. Moreover, the blood-brain barrier, which acts as a selective filter between the vascular system and the brain, is a complex structure to replicate. Nevertheless, tremendous advances have been made in recent years, and several works have proposed promising 3D in vitro models of the brain microvasculature. They incorporate cell co-cultures organized in 3D scaffolds, often consisting of components of the native extracellular matrix (ECM), to obtain a micro-environment similar to the in vivo physiological state. These models are particularly useful for studying adverse effects on the healthy brain vasculature. They provide insights into the molecular and cellular events involved in the pathological evolutions of this vasculature, such as those supporting the appearance of brain cancers. Glioblastoma multiform (GBM) is the most common form of brain cancer and one of the most vascularized solid tumors. It is characterized by a high aggressiveness and therapy resistance. Current conventional therapies are unable to prevent the high risk of recurrence of the disease. Most of the new drug candidates fail to pass clinical trials, despite the promising results shown in vitro. The conventional in vitro models are unable to efficiently reproduce the specific features of GBM tumors. Recent studies have indeed suggested a high heterogeneity of the tumor brain vasculature, with the coexistence of intact and leaky regions resulting from the constant remodeling of the ECM by glioma cells. In this review paper, after summarizing the advances in 3D in vitro brain vasculature models, we focus on the latest achievements in vascularized GBM modeling, and the potential applications for both healthy and pathological models as platforms for drug screening and toxicological assays. Particular attention will be paid to discuss the relevance of these models in terms of cell-cell, cell-ECM interactions, vascularization and permeability properties, which are crucial parameters for improving in vitro testing accuracy.

Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors

“…The cellular composition and tightness of the BBB have been shown to differ between murine and human brains ( Jacobs et al, 2011 ). Thus, confirmatory studies should be performed using in vitro brain tumor models constituting human BBB (e.g., 3D organoid; Piantino et al, 2021 ) and patient samples of brain tumors before developing any clinical application based on our findings.…”

Drug Penetration into the Central Nervous System: Pharmacokinetic Concepts and In Vitro Model Systems

“…Whereas microfluidic-based dynamic models promise to more closely reflect the in vivo microcirculatory system, most of these models are still in the proof-of-principle phase and their application is limited to laboratories with significant bioengineering expertise. The same applies to more complex three-dimensional models of the brain microvasculature, which are still in development and have not been addressed in the present article, but could once allow for in vitro studies on BBB permeability under pathophysiological conditions that are difficult to reproduce with current models (for review see [266]). Nevertheless, even simple, commercially available static systems can be very useful in small-to moderate-scale pre-clinical studies to facilitate early identification of slowly BBB penetrating compounds and/or substrates for the most important efflux transporters.…”

The Vascular Microenvironment in Glioblastoma: A Comprehensive Review

“…Among chemokines, IL-8 is a paradigmatic example, acting over two cell-surface G-protein-coupled receptors (CXCR1 and CXCR2). Endothelial cells secrete IL-8 and other chemotactic factors to activate GBM invasion and vascular mimicry [ 52 , 97 ]. Chemokines have also been implicated in the tumor resistance to anti-angiogenic drugs.…”

“…The movement of fluid recreates shear stress over the vessel wall, which is indeed an important regulator of permeability [ 115 ]. The main defect of these models is the vessel diameter, which exceeds by far the dimensions of the human microvasculature [ 97 ].…”