Proof-of-Concept Study of Drug Brain Permeability Between in Vivo Human Brain and an in Vitro iPSCs-Human Blood-Brain Barrier Model

Roux, G. Le; Jarray, Rafika; Guyot, Anne-Cécile; Pavoni, Serena; Costa, Narciso; Théodoro, Frédéric; Nassor, Férid; Pruvost, Alain; Tournier, Nicolas; Kiyan, Yulia; Langer, Oliver; Yates, F.; Deslys, Jean Philippe; Mabondzo, Aloı̈se

doi:10.1038/s41598-019-52213-6

Cited by 50 publications

(48 citation statements)

References 30 publications

(28 reference statements)

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“…3D structure, cell-cell interaction, and the exposure of shear stress result in better barrier function compared to conventional transwell models. iPSCs-based BBB models are the first human BBB models with in vivo like paracellular barrier properties [138]. Thus, these cells may hold enormous potential for the development of preclinical disease models as well as species-dependent differences [139].…”

Section: Human-induced Pluripotent Stem Cells (Ipscs) Modelingmentioning

confidence: 99%

In vitro modeling of the neurovascular unit: advances in the field

Bhalerao

Sivandzade

Archie

et al. 2020

Fluids Barriers CNS

114

103

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The blood-brain barrier (BBB) is a fundamental component of the central nervous system. Its functional and structural integrity is vital in maintaining the homeostasis of the brain microenvironment. On the other hand, the BBB is also a major hindering obstacle for the delivery of effective therapies to treat disorders of the Central Nervous System (CNS). Over time, various model systems have been established to simulate the complexities of the BBB. The development of realistic in vitro BBB models that accurately mimic the physiological characteristics of the brain microcapillaries in situ is of fundamental importance not only in CNS drug discovery but also in translational research. Successful modeling of the Neurovascular Unit (NVU) would provide an invaluable tool that would aid in dissecting out the pathological factors, mechanisms of action, and corresponding targets prodromal to the onset of CNS disorders. The field of BBB in vitro modeling has seen many fundamental changes in the last few years with the introduction of novel tools and methods to improve existing models and enable new ones. The development of CNS organoids, organ-on-chip, spheroids, 3D printed microfluidics, and other innovative technologies have the potential to advance the field of BBB and NVU modeling. Therefore, in this review, summarize the advances and progress in the design and application of functional in vitro BBB platforms with a focus on rapidly advancing technologies.The BBB consists of highly specialized vascular endothelial cells (EC) lining the brain microvessels in juxtaposition with closely associated pericytes [1], extracellular matrix components, and astrocytic end-feet processes [2]. Along with other cells such as neurons and microglia, this cellular milieu modulates the BBB properties, supports its viability and functions [3]. At the brain microvascular level, the BBB functions as a highly dynamic and active interface between the systemic circulation and the CNS. The BBB maintains a stable brain environment to protect the CNS from unsolicited cells, bacteria, viruses, and potentially harmful substances (either endogenous or exogenous) apart from protecting against systemic fluctuations. The BBB also regulates the transport of essential molecules and nutrients necessary to maintain the optimal CNS environment and support neuronal activities [4]. The BBB responds to many physiological and pathological cues, including rheological changes [5], inflammatory stimuli, oxidative stress [6], diabetes, and hypercholesterolemia [7-10], acute brain injury [3], etc. The intrinsically unique and utmost complex functional interaction between the BBB endothelium and the surrounding cellular milieu (including astrocytes, pericytes, neurons, microglia, myocytes as well as specialized cellular compartments such as endothelial glycocalyx [11,12] has been termed "neurovascular unit (NVU)" [2,13]. In addition, the basement membrane, which exerts essential functions in cellular support and signal transduction,

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Section: Human-induced Pluripotent Stem Cells (Ipscs) Modelingmentioning

confidence: 99%

In vitro modeling of the neurovascular unit: advances in the field

Bhalerao

Sivandzade

Archie

et al. 2020

Fluids Barriers CNS

114

103

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“…In addition, diverse strategies have been developed to study for instance drug-drug interactions of unlabeled molecules in combination with already available tracers [246]. PET was recently employed to validate the permeability and transporter function of a human iPSCs BBB model [172] and the evaluation of ABC transporter-humanized mice models [238,270]. Importantly, it has been used to evaluate drug delivery strategies, such as inhibition [250,251] or focused ultrasounds [273] (see Section 6.5 for details).…”

Section: Imaging Methodsmentioning

confidence: 99%

“…Recently, human brain endothelial cells have been obtained from stem cells such as human cord blood-derived stem cells of circulating endothelial progenitor and hematopoietic lineages [156,157], human pluripotent stem cells (hPSCs) [158], and induced pluripotent stem cells (iPSCs) [170,171]. After differentiation and isolation, the hPSC-derived brain endothelial cells monolayers present key BBB characteristics, including tight junctions and functional ABC transporters [158,159,172].…”

Section: In Vitro Models Of the Bbbmentioning

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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“…Despite these advances in drug permeability testing using iPSC-derived BBB models, limited in vivo human permeability data is available to benchmark in vitro BBB models. Recent work has begun to address this issue by measuring in vitro permeability of positron emission tomography (PET) radioligands, for which in vivo human BBB permeability values are known from clinical PET imaging [74]. Remarkably, iPSC-derived BBB models show highly significant correlation to in vivo values for the 8 radioligands tested.…”

Section: Drug Transport and Deliverymentioning

confidence: 99%

“…Remarkably, iPSC-derived BBB models show highly significant correlation to in vivo values for the 8 radioligands tested. Interestingly, when Le Roux and colleagues [74] tested a suite of other drugs in their radioligand-validated model, they generated relative permeabilities that could not have been predicted based on the physicochemical properties of the drugs alone. In addition to permeability testing of small molecules, iPSCderived BBB models are also being used to test permeability of new classes of CNS drugs such as peptides and antibodies.…”

Section: Drug Transport and Deliverymentioning

confidence: 99%

Recent advances in human iPSC-derived models of the blood–brain barrier

Workman

Svendsen

2020

Fluids Barriers CNS

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The blood-brain barrier (BBB) is a critical component of the central nervous system that protects neurons and other cells of the brain parenchyma from potentially harmful substances found in peripheral circulation. Gaining a thorough understanding of the development and function of the human BBB has been hindered by a lack of relevant models given significant species differences and limited access to in vivo tissue. However, advances in induced pluripotent stem cell (iPSC) and organ-chip technologies now allow us to improve our knowledge of the human BBB in both health and disease. This review focuses on the recent progress in modeling the BBB in vitro using human iPSCs.

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Proof-of-Concept Study of Drug Brain Permeability Between in Vivo Human Brain and an in Vitro iPSCs-Human Blood-Brain Barrier Model

Cited by 50 publications

References 30 publications

In vitro modeling of the neurovascular unit: advances in the field

In vitro modeling of the neurovascular unit: advances in the field

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

Recent advances in human iPSC-derived models of the blood–brain barrier

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