SLC and ABC Transporters: Expression, Localization, and Species Differences at the Blood-Brain and the Blood-Cerebrospinal Fluid Barriers

Morris, Marilyn E.; Rodriguez-Cruz, Vivian; Felmlee, Melanie A.

doi:10.1208/s12248-017-0110-8

Cited by 113 publications

(90 citation statements)

References 149 publications

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“…The BMVEC express several transporters with polarized localization at the luminal and/or basolateral membranes to specifically regulate the influx and efflux of molecules, such as nutrients, waste metabolites, toxins, xenobiotics, and small peptides. The main transporter proteins expressed at the BBB are SLC transporters and active efflux pumps from the ABC superfamily [3,20]. The exchange of macromolecules (i.e., larger peptides and proteins) is regulated by limited transendothelial vesicular trafficking.…”

Section: The Blood-brain Barrier and The Neurovascular Unitmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: The Blood-brain Barrier and The Neurovascular Unitmentioning

confidence: 99%

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

et al. 2019

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“…Dorsal sites are subsequently populated by migrating angioblasts (James et al, ). Upon endothelial cell invasion into the developing brain through angiogenesis, the BBB is found to be a functional unit able to selectively transport molecules into the developing brain (Morris, Rodriguez‐Cruz, & Felmlee, ). This occurs due to the interaction of all cell types of the NVU.…”

Section: Bbb Formationmentioning

confidence: 99%

“…For a more detailed discussion on solute movement across the BBB, the reader is referred to the following detailed reviews: (Golden & Pollack, ; Pardridge, ; Sanchez‐Covarrubias, Slosky, Thompson, Davis, & Ronaldson, ; Scherrmann, ). BBB transporters and metabolizing enzymes in the BBB have also been reviewed (Ek et al, ; Morris et al, ). The transport of chemicals across the BBB serves as a primary component of characterizing the pharmacokinetics of potential neurotoxicants, specifically, local metabolism at the site of the barrier and distribution of xenobiotic to the neural compartment.…”

Section: Bbb Formationmentioning

confidence: 99%

Blood‐brain barrier development: Systems modeling and predictive toxicology

Saili

Zurlinden

Schwab

et al. 2017

Birth Defects Research

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The blood-brain barrier (BBB) serves as a gateway for passage of drugs, chemicals, nutrients, metabolites, and hormones between vascular and neural compartments in the brain. Here, we review BBB development with regard to the microphysiology of the neurovascular unit (NVU) and the impact of BBB disruption on brain development. Our focus is on modeling these complex systems. Extant in silico models are available as tools to predict the probability of drug/chemical passage across the BBB; in vitro platforms for high-throughput screening and high-content imaging provide novel data streams for profiling chemical-biological interactions; and engineered human cell-based microphysiological systems provide empirical models with which to investigate the dynamics of NVU function. Computational models are needed that bring together kinetic and dynamic aspects of NVU function across gestation and under various physiological and toxicological scenarios. This integration will inform adverse outcome pathways to reduce uncertainty in translating in vitro data and in silico models for use in risk assessments that aim to protect neurodevelopmental health.

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“…Meanwhile, it also prevents the entry of potential neurotoxins by the way of an active transport mechanism mediated by P‐glycoprotein. In some cases, drugs have to be administered directly into the cerebrospinal fluid (CSF), where it can enter the brain by crossing the blood‐cerebrospinal fluid barrier . However, not all drugs that are delivered directly to the CSF can effectively penetrate the CSF barrier and enter the brain, severely restricting the availability for most anticancer agents .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of enhanced antiglioma efficacy of polysorbate 80‐modified paclitaxel‐loaded PLGA nanoparticles by focused ultrasound

Zhang

et al. 2018

J Cellular Molecular Medi

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The presence of blood‐brain barrier (BBB) greatly limits the availability of drugs and their efficacy against glioma. Focused ultrasound (FUS) can induce transient and local BBB opening for enhanced drug delivery. Here, we developed polysorbate 80‐modified paclitaxel‐loaded PLGA nanoparticles (PS‐80‐PTX‐NPs, PPNP) and examined the enhanced local delivery into the brain for glioma treatment by combining with FUS. Our result showed PPNP had good stability, fast drug release rate and significant toxicity to glioma cells. Combined with FUS, PPNP showed a stronger BBB permeation efficiency both in the in vitro and in vivo BBB models. Mechanism studies revealed the disrupted tight junction, reduced P‐glycoprotein expression and ApoE‐dependent PS‐80 permeation collectively contribute to the enhanced drug delivery, resulting in significantly stronger antitumour efficacy and longer survival time in the tumour‐bearing mice. Our study provided a new strategy to efficiently and locally deliver drugs into the brain to treat glioma.

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SLC and ABC Transporters: Expression, Localization, and Species Differences at the Blood-Brain and the Blood-Cerebrospinal Fluid Barriers

Cited by 113 publications

References 149 publications

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

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

Blood‐brain barrier development: Systems modeling and predictive toxicology

Mechanisms of enhanced antiglioma efficacy of polysorbate 80‐modified paclitaxel‐loaded PLGA nanoparticles by focused ultrasound

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