Storming the gate: New approaches for targeting the dynamic tight junction for improved drug delivery

Ramirez-Velez, Isabela; Belardi, Brian

doi:10.1016/j.addr.2023.114905

Cited by 17 publications

(6 citation statements)

References 272 publications

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“…Conversely, temporary loosening of the TJ barrier would be very useful to allow the delivery of drugs across tissue barriers, such as the blood–brain barrier, and to enhance fluid efflux, which promotes intestinal pathogen clearance. Several small molecules, peptides, antibodies and other reagents have been developed that directly or indirectly target TJ components, mostly transmembrane proteins, to modulate TJ organization, barrier function, and TJ-related cytoskeletal remodeling and signaling ( Ramirez-Velez and Belardi, 2023 ). Finally, it must be noted that some transmembrane TJ proteins act as cell-entry factors for viruses, including hepatitis C virus (HCV), reovirus, coxsackievirus and adenovirus, West Nile virus, and rotavirus.…”

Section: Tjs In Disease and As Drug Targetsmentioning

confidence: 99%

A short guide to the tight junction

Citi,

Fromm,

Furuse

et al. 2024

Journal of Cell Science

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Tight junctions (TJs) are specialized regions of contact between cells of epithelial and endothelial tissues that form selective semipermeable paracellular barriers that establish and maintain body compartments with different fluid compositions. As such, the formation of TJs represents a critical step in metazoan evolution, allowing the formation of multicompartmental organisms and true, barrier-forming epithelia and endothelia. In the six decades that have passed since the first observations of TJs by transmission electron microscopy, much progress has been made in understanding the structure, function, molecular composition and regulation of TJs. The goal of this Perspective is to highlight the key concepts that have emerged through this research and the future challenges that lie ahead for the field.

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Section: Tjs In Disease and As Drug Targetsmentioning

confidence: 99%

A short guide to the tight junction

Citi,

Fromm,

Furuse

et al. 2024

Journal of Cell Science

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“…To analyze concentration changes, we performed LC-MS/MS. Samples were collected from the blood and brain channels during 0-1, 1-4, 4-9, and 9-24 h, and concentrations at 1, 4, 9, and 24 h were calculated using Equation (1). The concentrations at each channel, based on the time profiles, are depicted as blue circles (o) and red dots (•).…”

Section: Assessment Of Hbbb Permeability Using Microfluidic Modelmentioning

confidence: 99%

“…It protects the brain xenobiotic compounds. The human BBB is composed of microvascular endothelial cells (ECs), pericytes, astrocytes, tight junctions, and a basal membrane [1,2]. Astrocytes and pericytes support the barrier function and interact with endothelial cells to maintain and control vascular integrity under physiological and pathological conditions [3].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Drug Blood-Brain-Barrier Permeability Using a Microfluidic Chip

Yang,

Shin,

Jeong

et al. 2024

Pharmaceutics

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The blood-brain-barrier (BBB) is made up of blood vessels whose permeability enables the passage of some compounds. A predictive model of BBB permeability is important in the early stages of drug development. The predicted BBB permeabilities of drugs have been confirmed using a variety of in vitro methods to reduce the quantities of drug candidates needed in preclinical and clinical trials. Most prior studies have relied on animal or cell-culture models, which do not fully recapitulate the human BBB. The development of microfluidic models of human-derived BBB cells could address this issue. We analyzed a model for predicting BBB permeability using the Emulate BBB-on-a-chip machine. Ten compounds were evaluated, and their permeabilities were estimated. Our study demonstrated that the permeability trends of ten compounds in our microfluidic-based system resembled those observed in previous animal and cell-based experiments. Furthermore, we established a general correlation between the partition coefficient ( and the apparent permeability (). In conclusion, we introduced a new paradigm for predicting BBB permeability using microfluidic-based systems.

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“…Given their hydrophilicity, most biologics cannot penetrate hydrophobic membranes of living cells and must either (i) undergo uptake and transcytosis to cross cells or (ii) move through the paracellular space between cells . While transcytosis mechanisms have garnered significant attention from nanomaterial researchers, − less effort has been directed at targeting the paracellular route for delivery due to the refractory nature of the apical-most junction, the tight junction (TJ), toward transport . Comprised of a protein-based network of transmembrane proteins, adaptor proteins, and cytoskeletal elements, , TJs establish a seal between neighboring cells, preventing nanomaterials and large macromolecules (>500 Da) from reaching the basal surface of epithelial tissue paracellularly.…”

mentioning

confidence: 99%

“…Downstream of nanomaterial administration, TJ proteins, such as claudin and ZO-1, are depleted from the membrane , and form ZO-1-based condensates, resulting in higher permeability of coadministered biologics. Yet, global MLCK activation has been shown to disturb other junctions, , including the adherens junction (AJ), compromising the cohesion of epithelial tissue in the gut, an undesirable response from nanomaterial treatment. For a more direct approach, here, we draw inspiration from pathogenic bacteria of the gut.…”

mentioning

confidence: 99%

Paracellular Delivery of Protein Drugs with Smart EnteroPatho Nanoparticles

Ramirez-Velez,

Namjoshi,

Effiong

et al. 2024

ACS Nano

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A general platform for the safe and effective oral delivery of biologics would revolutionize the administration of protein-based drugs, improving access for patients and lowering the financial burden on the health-care industry. Because of their dimensions and physiochemical properties, nanomaterials stand as promising vehicles for navigating the complex and challenging environment in the gastrointestinal (GI) tract. Recent developments have led to materials that protect protein drugs from degradation and enable controlled release in the small intestine, the site of absorption for most proteins. Yet, once present in the small intestine, the protein must transit through the secreted mucus and epithelial cells of the intestinal mucosa into systemic circulation, a process that remains a bottleneck for nanomaterial-based delivery. One attractive pathway through the intestinal mucosa is the paracellular route, which avoids cell trafficking and other degradative processes in the interior of cells. Direct flux between cells is regulated by epithelial tight junctions (TJs) that seal the paracellular space and prevent protein flux. Here, we describe a smart nanoparticle system that directly and transiently disrupts TJs for improved protein delivery, an unrealized goal to-date. We take inspiration from enteropathogenic bacteria that adhere to intestinal epithelia and secrete inhibitors that block TJ interactions in the local environment. To mimic these natural mechanisms, we engineer nanoparticles (EnteroPatho NPs) that attach to the epithelial glycocalyx and release TJ modulators in response to the intestinal pH. We show that EnteroPatho NPs lead to TJ disruption and paracellular protein delivery, giving rise to a general platform for oral delivery.

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Storming the gate: New approaches for targeting the dynamic tight junction for improved drug delivery

Cited by 17 publications

References 272 publications

A short guide to the tight junction

A short guide to the tight junction

Evaluation of Drug Blood-Brain-Barrier Permeability Using a Microfluidic Chip

Paracellular Delivery of Protein Drugs with Smart EnteroPatho Nanoparticles

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