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

David Gomez-Zepeda; Méryam Taghi; Jean-Michel Scherrmann; Xavier Decleves; Marie-Claude Menet

doi:10.3390/pharmaceutics12010020

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

Pharmaceutics. 2019 Dec 23;12(1):20. doi: 10.3390/pharmaceutics12010020.

Authors

David Gomez-Zepeda^{1

2

3

4}, Méryam Taghi^{1

2

3}, Jean-Michel Scherrmann^{1

2

3}, Xavier Decleves^{1

2

3

5}, Marie-Claude Menet^{1

2

3

6}

Affiliations

¹ Inserm, UMR-S 1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France.
² Sorbonne Paris Cité, Université Paris Descartes, 75006 Paris, France.
³ Sorbonne Paris Cité, Université Paris Diderot, 75013 Paris, France.
⁴ Current affiliation: Laboratorio Nacional de Genómica para la Biodiversidad (Langebio)-Unidad de Genómica Avanzada, Cinvestav, Irapuato 36824, Guanajuato, Mexico.
⁵ UF Biologie du médicament et toxicologie, Hôpital Cochin, AP HP, 75006 Paris, France.
⁶ UF Hormonologie adulte, Hôpital Cochin, AP HP, 75006 Paris, France.

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.

Keywords: ABC transporters; arachnoid barrier (BAB); blood–brain barrier (BBB); blood–brain tumor barrier (BBTB); blood–cerebrospinal fluid barrier (BCSFB); drug delivery; glioma.

Publication types

Review