ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

Abstract

Drug delivery into the brain is regulated by the blood–brain interfaces. The blood–brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB), and the blood–arachnoid barrier (BAB) regulate the exchange of substances between the blood and brain parenchyma. These selective barriers present a high impermeability to most substances, with the selective transport of nutrients and transporters preventing the entry and accumulation of possibly toxic molecules, comprising many therapeutic drugs. Transporters of the ATP-binding cassette (ABC) superfamily have an important role in drug delivery, because they extrude a broad molecular diversity of xenobiotics, including several anticancer drugs, preventing their entry into the brain. Gliomas are the most common primary tumors diagnosed in adults, which are often characterized by a poor prognosis, notably in the case of high-grade gliomas. Therapeutic treatments frequently fail due to the difficulty of delivering drugs through the brain barriers, adding to diverse mechanisms developed by the cancer, including the overexpression or expression de novo of ABC transporters in tumoral cells and/or in the endothelial cells forming the blood–brain tumor barrier (BBTB). Many models have been developed to study the phenotype, molecular characteristics, and function of the blood–brain interfaces as well as to evaluate drug permeability into the brain. These include in vitro, in vivo, and in silico models, which together can help us to better understand their implication in drug resistance and to develop new therapeutics or delivery strategies to improve the treatment of pathologies of the central nervous system (CNS). In this review, we present the principal characteristics of the blood–brain interfaces; then, we focus on the ABC transporters present on them and their implication in drug delivery; next, we present some of the most important models used for the study of drug transport; finally, we summarize the implication of ABC transporters in glioma and the BBTB in drug resistance and the strategies to improve the delivery of CNS anticancer drugs.

Development of a human in vitro blood–brain tumor barrier model of diffuse intrinsic pontine glioma to better understand the chemoresistance

“…The BBB ECs represent a physical barrier with the establishment at the paracellular level of a complex of tight junction proteins (claudins, occludin, zonula-occludens..) which seals the intercellular spaces. The crossing of the BBB ECs is also restricted via the transcellular way by the metabolic barrier properties, consisting of the efflux pump system [16] and drug metabolizing enzymes, including detoxification enzymes (e.g. monoamine oxidase, cytochrome P450) described in many organs and also present at the BBB.…”

“…to reach the brain parenchyma at an efficient dose [12,[16][17][18]. Indeed, the cytochrome P450 (CYP) enzymes are involved in the metabolism of many endogenous (e.g.…”

Targeting the Choroid Plexuses for Protein Drug Delivery

“…Like the BBB, various efflux and influx transport systems exist within CPECs to regulate the entry of endogenous and exogenous agents. For instance, members of the solute carrier (SLC) and ATP-binding cassette (ABC) families at the CPECs are involved in the bidirectional movement of small molecules, which have been discussed in our previous review [ 63 ] and other publications [ 64 , 65 ]. However, there is less information on the transport of peptides and proteins across the CPs, which may limit the future development of peptide/protein-based therapies for neurological diseases.…”

Transporter-Targeted Nano-Sized Vehicles for Enhanced and Site-Specific Drug Delivery

“…As such, the plasma membrane transporters function as key determinants in the absorption, distribution, and excretion of drugs [ 14 , 15 ]. ABC transporters in mammalian cells are exclusively exporters for their endogenous and exogenous substrates from the cells coupled to ATP hydrolysis on the cytoplasmic side as the driving force [ 16 , 17 ]. SLC transporters, on the other hand, are more involved in the absorption and distribution of nutrients and drugs because they mediate either the influx or efflux of their substrates depending on the involvement and direction of driving forces, which are ionic gradients and membrane potential.…”