FcRn as a Transporter for Nasal Delivery of Biologics: A Systematic Review
M. FieuxSandra Le QuellecS. BartierA. CosteBruno LouisCaroline GiroudonMikaïl NourredineE. Béquignon
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Abstract:
FcRn plays a major role in regulating immune homeostasis, but it is also able to transport biologics across cellular barriers. The question of whether FcRn could be an efficient transporter of biologics across the nasal epithelial barrier is of particular interest, as it would allow a less invasive strategy for the administration of biologics in comparison to subcutaneous, intramuscular or intravenous administrations, which are often used in clinical practice. A focused systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It was registered on the international prospective register of systematic reviews PROSPERO, which helped in identifying articles that met the inclusion criteria. Clinical and preclinical studies involving FcRn and the nasal delivery of biologics were screened, and the risk of bias was assessed across studies using the Oral Health Assessment Tool (OHAT). Among the 12 studies finally included in this systematic review (out of the 758 studies screened), 11 demonstrated efficient transcytosis of biologics through the nasal epithelium. Only three studies evaluated the potential toxicity of biologics’ intranasal delivery, and they all showed that it was safe. This systematic review confirmed that FcRn is expressed in the nasal airway and the olfactory epithelium, and that FcRn may play a role in IgG and/or IgG-derived molecule-transcytosis across the airway epithelium. However, additional research is needed to better characterize the pharmacokinetic and pharmacodynamic properties of biologics after their intranasal delivery.Keywords:
Transcytosis
Mucociliary clearance
Transcytosis
Transcellular
Paracellular transport
Polarity (international relations)
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Intranasal glucocorticosteroids are the most effective treatment for allergic rhinitis and are recommended as first-line therapy for patients with moderate to severe Allergic Rhinitis, particularly when nasal congestion is the prominent symptom. The use of intranasal corticosteroids showed to affect the mucociliary action by decreasing the prolonged mucociliary clearance time and increasing the mucociliary clearance rate. Keywords: AR- Allergic Rhinitis, INCS- Intranasal corticosteroid, NMC- Nasomucociliary clearance, MCT- Mucociliary Clearance Time, MCR- Mucociliary clearance rate, OAH- Oral antihistamine
Mucociliary clearance
Clearance rate
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A targeted RNAi screen identifies factors affecting diverse stages of receptor-mediated transcytosis
Endosome transport by transcytosis is the primary mechanism by which proteins and other large cargo traverse epithelial barriers in normal tissue. Transcytosis is also essential for establishing and maintaining membrane polarity in epithelia and other polarized cells. To identify novel components of this pathway, we conducted a high-throughput RNA interference screen for factors necessary for the bidirectional transcytosis of IgG by the Fcγ receptor FcRn. This screen identified 23 genes whose suppression resulted in a reproducible decrease in FcRn-mediated transcytosis. Pulse-chase kinetic transport assays on four of the top-ranking genes (EXOC2, EXOC7, PARD6B, and LEPROT) revealed distinct effects on the apical and basolateral recycling and transcytotic pathways, demonstrating that these pathways are genetically separable. We also found a strong dependence on PARD6B for apical, but not basolateral, recycling, implicating this cell polarity gene in assembly or maintenance of the apical endosomal system. This dataset yields insights into how vesicular transport is adapted to the specialized functions of differentiated cell types and opens new research avenues into epithelial trafficking.
Transcytosis
Cell polarity
Transport protein
Vesicular Transport Proteins
Apical membrane
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Caveolae-mediated albumin transcytosis plays an important role in physiological and pathological conditions. The events initiating transcytosis have been shown to be tightly regulated by non-receptor type Src family kinases, and thus Src signaling is thought to be a critical switch regulating eaveolae-mediated transcellular transport of the plasma protein albumin. The activation of Src induces phosphorylation of glycoprotein 60, eaveolln-1 and dynamin-2, and initiates transcytosis. In response to inflammatory stimuli, neutrophil adhesion to vascular endothelial cells via ICAM-1 (Intercellular adhesion molecule-1)cause Src activation which enhances eaveolae transcytosis of albumin.
Key words:
Endothelial hyperpermeability; Caveolae; Caveolin-1 ; Transcytosis
Transcytosis
Transcellular
Caveolin 1
Paracellular transport
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Retention of low-density lipoprotein (LDL) cholesterol beneath the arterial endothelium initiates an inflammatory response culminating in atherosclerosis. Since the overlying endothelium is healthy and intact early on, it is likely that LDL passes through endothelial cells by transcytosis. However, technical challenges have made confirming this notion and elucidating the mechanisms of transcytosis difficult. We developed a novel assay for measuring LDL transcytosis in real time across coronary endothelial cell monolayers; we used this approach to identify the receptor involved.Murine aortas were perfused ex vivo with LDL and dextran of a smaller molecular radius. LDL (but not dextran) accumulated under the endothelium, indicating that LDL transcytosis occurs in intact vessels. We then confirmed that LDL transcytosis occurs in vitro using human coronary artery endothelial cells. An assay was developed to quantify transcytosis of DiI-LDL in real time using total internal reflection fluorescence microscopy. DiI-LDL transcytosis was inhibited by excess unlabelled LDL, while degradation of the LDL receptor by PCSK9 had no effect. Instead, LDL colocalized partially with the scavenger receptor SR-BI and overexpression of SR-BI increased LDL transcytosis; knockdown by siRNA significantly reduced it. Excess HDL, the canonical SR-BI ligand, significantly decreased LDL transcytosis. Aortas from SR-BI-deficient mice were perfused ex vivo with LDL and accumulated significantly less sub-endothelial LDL compared with wild-type littermates.We developed an assay to quantify LDL transcytosis across endothelial cells and discovered an unexpected role for SR-BI. Elucidating the mechanisms of LDL transcytosis may identify novel targets for the prevention or therapy of atherosclerosis.
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The nasal mucociliary clearance system, which comprises epithelial cilia and mucus from goblet cells, is an important intrinsic defense mechanism of the upper respiratory tract.Intranasal drugs and additives can have a detrimental effect on ciliary activity and mucociliary clearance, and thus impact the integrity of nasal defense mechanisms.This article discusses the current literature on the effects of different classes of intranasal drugs including intranasal corticosteroids, antihistamines, decongestants, antimicrobials and antivirals, as well as various drug excipients and nasal irrigation solutions on human nasal mucociliary clearance and ciliary beat frequency.Available data indicate that some intranasal formulations tend to hamper nasal ciliary function and mucociliary clearance.Therefore, it is of great importance to assess the effects of intranasal drugs and additives on mucociliary function before they are recommended as therapy for different nasal conditions.
Mucociliary clearance
Respiratory tract
Nasal decongestant
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Summary
Transcytosis across the blood-brain barrier (BBB) regulates key processes of the brain, but the intracellular sorting mechanisms that determine successful receptor-mediated transcytosis in brain endothelial cells (BECs) remain unidentified. Here, we used Transferrin receptor-based Brain Shuttle constructs to investigate intracellular transport in BECs, and we uncovered a pathway for the regulation of receptor-mediated transcytosis. By combining live-cell imaging and mathematical modeling in vitro with super-resolution microscopy of the BBB, we show that intracellular tubules promote transcytosis across the BBB. A monovalent construct (sFab) sorted for transcytosis was localized to intracellular tubules, whereas a bivalent construct (dFab) sorted for degradation formed clusters with impaired transport along tubules. Manipulating tubule biogenesis by overexpressing the small GTPase Rab17 increased dFab transport into tubules and induced its transcytosis in BECs. We propose that sorting tubules regulate transcytosis in BECs and may be a general mechanism for receptor-mediated transport across the BBB.Transcytosis
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Abstract The blood-brain barrier (BBB) hinders the brain delivery of therapeutic immunoglobulin γ (IgG) antibodies. Evidence suggests that IgG-specific processing occurs within the endothelium of the BBB, but any influence on transcytosis remains unclear. Here, involvement of the neonatal Fc receptor (FcRn), which mediates IgG recycling and transcytosis in peripheral endothelium, was investigated by evaluating the transcytosis of IgGs with native or reduced FcRn engagement across human induced pluripotent stem cell-derived brain endothelial-like cells. Despite differential trafficking, the permeability of all tested IgGs were comparable and remained constant irrespective of concentration or competition with excess IgG, suggesting IgG transcytosis occurs nonspecifically and originates from fluid-phase endocytosis. Comparison with the receptor-enhanced permeability of transferrin indicates that the phenomena observed for IgG is ubiquitous for most macromolecules. However, increased permeability was observed for macromolecules with biophysical properties known to engage alternative endocytosis mechanisms, highlighting the importance of biophysical characterizations in assessing transcytosis mechanisms.
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Vascular permeability
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Introduction: Retention of LDL beneath the arterial endothelium initiates an inflammatory response culminating in atherosclerosis. How LDL crosses the endothelium to enter the arterial wall remains unknown. While LDL could conceivably pass between endothelial cells (paracellularly) or through them (transcytosis), electron microscopy studies in animals revealed LDL in intracellular vesicles and none at intercellular junctions. This, combined with the absence of endothelial injury or intercellular gaps in early atherosclerosis, suggests that transcytosis is the major route. However, technical challenges with studying transcytosis have made confirming and extending these findings difficult. We developed and validated a novel assay for measuring the transcytosis of native LDL across live human coronary artery endothelium in vitro. Using this assay, we propose to elucidate the regulation of LDL transcytosis and have identified a novel role for SR-B1. Methods and Results: Experiments were performed using primary human coronary artery endothelial monolayers. Transcytosis was quantified in single live cells in real time using total internal reflectance fluorescence microscopy. Transcytosis of LDL was saturable and inhibited by excess unlabeled LDL. By fluorescence microscopy we found that DiI-LDL colocalized significantly with scavenger receptor, class B, type 1 (SR-B1). Unexpectedly, overexpression of SR-BI resulted in increased LDL transcytosis, while knockdown of SR-BI by siRNA inhibited transcytosis. Excess HDL, the canonical SR-B1 ligand, also decreased LDL transcytosis. To confirm the occurrence of transcytosis in an intact vessel, we perfused murine aortas ex vivo with both LDL and dextran of a smaller molecular radius. We observed the accumulation of subendothelial LDL without dextran, indicating that transcytosis of LDL occurs in intact vessels. Conclusions: The accumulation of LDL in the subendothelial intima is the first step of atherosclerosis yet little is known about how it occurs. Our data suggests that transcytosis of LDL is an important contributor, particularly in the early stages of the disease. By identifying the mechanisms of transcytosis, our work could have important implications for its pathogenesis and therapy.
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Introduction: A critical factor for the efficacy of drugs is their availability at the site of interest. However, crossing endothelial and epithelial cell layers like the blood-brain barrier and the blood-intestinal barrier represents a major bottleneck for drug targeting. Coupling drugs to carriers that recognize endogenous receptors, which are then transported through cell layers by transcytosis, is a promising approach to overcome this bottleneck.Areas covered: This review focuses on the intracellular pathways of receptor-mediated transcytosis and their applicability for transcellular drug delivery. It gives an overview about transcytotic trafficking routes in epithelia and highlights the well-studied examples of immungobulin transcytosis and transferrin transcytosis. The current knowledge about the less understood transcytosis pathways in endothelia is also summarized and low-density lipoprotein transcytosis is described. In addition, transcytosis pathways that are based on glycosphingolipids and lectins as their receptors are presented.Expert opinion: Multiple transcellular drug delivery approaches based on proteinaceous receptors have been developed in recent years, whereas lectins that bind to glycosphingolipids emerge as promising alternative. Closer investigation of endogenous transcytosis mechanisms, especially in endothelia, will be a fruitful endeavor to devise more optimized carriers for transcytotic drug delivery.
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Paracellular transport
Transcellular
Targeted drug delivery
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