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.

https://www.mdpi.com/1999-4923/12/1/20/pdf

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

Quercetin (QT) as a bioactive flavonoid has a potential therapeutic activity for numerous neuronal injuries and neurodegenerative diseases. However, the low absorption rate of QT, especially through the blood-brain barrier, restricts its bioactivity in the body. The current research took the advantage of superparamagnetic iron oxide nanoparticles (SPIONs) to enhance the bioavailability of quercetin. Quercetin conjugated with SPIONs was prepared by means of nanoprecipitation method and was characterized by X-ray diffractometer, scanning electron microscope, and Fourier transformed infrared spectrometer analyses. Wistar male rats were orally fed by gavage with QT and QT-SPION at 50 and 100 mg/kg daily doses for 7 days. Using high-performance liquid chromatography (HPLC) method, biodistribution of QT was evaluated in plasma and brain tissue. The outcomes of this research revealed a higher concentration in the plasma and brain of the rats fed with QT-SPION in comparison to free QT. The results of this study confirm that SPION as a targeted drug delivery system enhances the bioavailability of quercetin in the brain about ten folds higher than free quercetin and could be used for the treatment of neurodegenerative disorders.

/pdf/using-superparamagnetic-iron-oxide-nanoparticles-to-enhance-sed35xiimf.pdf

Using superparamagnetic iron oxide nanoparticles to enhance bioavailability of quercetin in the intact rat brain

Hydrocephalus is a common neurological disease with complex etiology. It is characterized by the accumulation and continuous growth of cerebrospinal fluid in the ventricular system and subarachnoid space. Hydrocephalus can be caused by congenital genetic factors, brain trauma and cerebral hemorrhage. Through the efforts of many researchers, the pathogenesis of hydrocephalus is being completed, but it has not been fully explained. The imbalance of cerebrospinal fluid production and absorption into the sinus, and disorder of the cerebrospinal fluid circulation pathway or the osmotic pressure maintenance in the ventricle can lead to increased cerebrospinal fluid and ventricular dilatation.

Advances in research on the pathogenesis of hydrocephalus

Neuropharmacokinetics considers cerebral drug distribution as a critical process for central nervous system drug action as well as for drug penetration through the CNS barriers. Brain distribution of small molecules obeys classical rules of drug partition, permeability, binding to fluid proteins or tissue components, and tissue perfusion. The biodistribution of all drugs, including both small molecules and biologics, may also be influenced by specific brain properties related to brain anatomy and physiological barriers, fluid dynamics, and cellular and biochemical composition, each of which can exhibit significant interspecies differences. All of these properties contribute to select optimal dosing paradigms and routes of drug delivery to reach brain targets for classical small molecule drugs as well as for biologics. The importance of these properties for brain delivery and exposure also highlights the need for efficient new analytical technologies to more comprehensively investigate drug distribution in the CNS, a complex multi-compartmentalized organ system.

Brain Distribution of Drugs: Brain Morphology, Delivery Routes, and Species Differences.

Modifications of physical and functional integrity of the blood-brain barrier in an inducible mouse model of neurodegeneration

High brain distribution of a new central nervous system drug candidate despite its P-glycoprotein-mediated efflux at the mouse blood-brain barrier.

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High brain distribution of a new central nervous system drug candidate despite its P-glycoprotein-mediated efflux at the mouse blood-brain barrier.