Transport of nanocarriers across gastrointestinal epithelial cells by a new transcellular route induced by targeting ICAM-1

Ghaffarian, Rasa; Bhowmick, Tridib Kumar; Muro, Silvia

doi:10.1016/j.jconrel.2012.06.007

Cited by 58 publications

(74 citation statements)

References 52 publications

(129 reference statements)

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“…Inhibitors extensively used for the inhibition of clathrin-mediated endocytosis in intestinal epithelial Caco-2 cells include monodansylcadaverine at concentrations ranging from 50 to 500 u M [11,12,13,14] and hypertonic sucrose at concentrations ranging from 0.2 to 0.45 M [15,16,17]. Filipin, an inhibitor frequently used in the inhibition of caveolae-mediated endocytosis, is used at concentrations ranging from 1 to 5 μg/mL [11,15,16,17,18,19]. Finally, cytochalasin D is frequently used for inhibition of macropinocytosis in Caco-2 cells at concentrations ranging from 1.7 to 100 μ M [12,14,17,18,19,20].…”

Section: Endocytosismentioning

confidence: 99%

Identifying Epithelial Endocytotic Mechanisms of the Peanut Allergens Ara h 1 and Ara h 2

Price

Ackland²,

Suphioglu³

2017

Int Arch Allergy Immunol

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Background: Peanuts are still one of the highest contributors to anaphylactic deaths after ingestion of a food allergen. At the molecular level, interactions between peanut allergens and the intestinal epithelium are largely unexplored. Previous findings by our research group demonstrated that the major peanut allergens, i.e., Ara h 1, Ara h 2, Ara h 3, and Ara h 6, were able to cross the Caco-2 human cell culture model of the intestinal epithelium. This research broadened our investigation to identify the mechanisms by which the Caco-2 monolayers uptake peanut allergens, specifically by endocytosis. Here, we aim to increase our understanding of allergen-epithelial interactions and, more broadly, the pathway from allergen to allergy. Methods: The human Caco-2 cell culture model was exposed to peanut extract and a combination of confocal microscopy and inhibition studies were used to identify the endocytotic mechanisms of peanut allergens in intestinal epithelia. Results: Our findings demonstrate that the peanut allergens Ara h 1 and Ara h 2 are transported through intestinal epithelia initially via early endosomes using multiple endocytotic mechanisms. From there, they are then transported to late endosomes and ultimately to lysosomes. Conclusions: These novel findings provide insight into the allergen-epithelial interactions of peanut allergens with the intestinal epithelium. Consequently, this opens the possibility of the use of these endocytotic pathways as targets for inhibitors in therapeutic development and preventative measures for peanut allergy in the future.

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Section: Endocytosismentioning

confidence: 99%

Identifying Epithelial Endocytotic Mechanisms of the Peanut Allergens Ara h 1 and Ara h 2

Price

Ackland²,

Suphioglu³

2017

Int Arch Allergy Immunol

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“…22,23 These barriers are mainly polarized epithelia, such as the gastrointestinal tract, the lungs, and the blood-brain barrier. [24][25][26] Not only that, when administered systemically, nanocarriers need to cross the endothelial cell barrier to reach the target site. A key element for the successful drug delivery by nanocarriers is their ability to either cross the biological barriers themselves or allow the loaded drugs to traverse these barriers to achieve an optimal pharmacological action at the pathological sites.…”

mentioning

confidence: 99%

The interactions of single-wall carbon nanohorns with polar epithelium

Shi¹,

Shi

Li³

et al. 2017

IJN

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Single-wall carbon nanohorns (SWCNHs), which have multitudes of horn interstices, an extensive surface area, and a spherical aggregate structure, offer many advantages over other carbon nanomaterials being used as a drug nanovector. The previous studies on the interaction between SWCNHs and cells have mostly emphasized on cellular uptake and intracellular trafficking, but seldom on epithelial cells. Polar epithelium as a typical biological barrier constitutes the prime obstacle for the transport of therapeutic agents to target site. This work tried to explore the permeability of SWCNHs through polar epithelium and their abilities to modulate transcellular transport, and evaluate the potential of SWCNHs in drug delivery. Madin-Darby canine kidney (MDCK) cell monolayer was used as a polar epithelial cell model, and as-grown SWCNHs, together with oxidized and fluorescein isothiocyanate-conjugated bovine serum albumin-labeled forms, were constructed and comprehensively investigated in vitro and in vivo. Various methods such as transmission electron microscopy and confocal imaging were used to visualize their intracellular uptake and localization, as well as to investigate the potential transcytotic process. The related mechanism was explored by specific inhibitors. Additionally, fast multispectral optoacoustic tomography imaging was used for monitoring the distribution and transport process of SWCNHs in vivo after oral administration in nude mice, as an evidence for their interaction with the intestinal epithelium. The results showed that SWCNHs had a strong bioadhesion property, and parts of them could be uptaken and transcytosed across the MDCK monolayer. Multiple mechanisms were involved in the uptake and transcytosis of SWCNHs with varying degrees. After oral administration, oxidized SWCNHs were distributed in the gastrointestinal tract and retained in the intestine for up to 36 h probably due to their surface adhesion and endocytosis into the intestinal epithelium. Overall, this comprehensive investigation demonstrated that SWCNHs can serve as a promising nanovector that can cross the barrier of polar epithelial cells and deliver drugs effectively.

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“…26 ICAM-1 targeting and uptake in GI tissue is also in accord with our recent study showing efficient binding and endocytosis of anti-ICAM NCs in Caco-2 cells, which derive from human intestinal tissue. 61 Our results indicate that ICAM-1 targeting may help facilitate GI retention and delivery of drugs aimed at GI maladies such as peptic ulcer, GI cancer, bacterial infection, and others. [36][37][38][39] Whether these ICAM-1 targeting formulations also enter M cells in the GI tract needs to be determined.…”

Section: Discussionmentioning

confidence: 65%

Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice

Mane¹,

Muro²

2012

IJN

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Drug delivery to the gastrointestinal (GI) tract is key for improving treatment of GI maladies, developing oral vaccines, and facilitating drug transport into circulation. However, delivery of formulations to the GI tract is hindered by pH changes, degradative enzymes, mucus, and peristalsis, leading to poor GI retention. Targeting may prolong residence of therapeutics in the GI tract and enhance their interaction with this tissue, improving such aspects. We evaluated nanocarrier (NC) and ligand-mediated targeting in the GI tract following gastric gavage in mice. We compared GI biodistribution, degradation, and endocytosis between control antibodies and antibodies targeting the cell surface determinant intercellular adhesion molecule 1 (ICAM-1), expressed on GI epithelium and other cell types. These antibodies were administered either as free entities or coated onto polymer NCs. Fluorescence and radioisotope tracing showed proximal accumulation, with preferential retention in the stomach, jejunum, and ileum; and minimal presence in the duodenum, cecum, and colon by 1 hour after administration. Upstream (gastric) retention was enhanced in NC formulations, with decreased downstream (jejunal) accumulation. Of the total dose delivered to the GI tract, ∼60% was susceptible to enzymatic (but not pHmediated) degradation, verified both in vitro and in vivo. Attenuation of peristalsis by sedation increased upstream retention (stomach, duodenum, and jejunum). Conversely, alkaline NaHCO 3 , which enhances GI transit by decreasing mucosal viscosity, favored downstream (ileal) passage. This suggests passive transit through the GI tract, governed by mucoadhesion and peristalsis. In contrast, both free anti-ICAM and anti-ICAM NCs demonstrated significantly enhanced upstream (stomach and duodenum) retention when compared to control IgG counterparts, suggesting GI targeting. This was validated by transmission electron microscopy and energy dispersive X-ray spectroscopy, which revealed anti-ICAM NCs in vesicular compartments within duodenal epithelial cells. These results will guide future work aimed at improving intraoral delivery of targeted therapeutics for the treatment of GI pathologies.

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Transport of nanocarriers across gastrointestinal epithelial cells by a new transcellular route induced by targeting ICAM-1

Cited by 58 publications

References 52 publications

Identifying Epithelial Endocytotic Mechanisms of the Peanut Allergens Ara h 1 and Ara h 2

Identifying Epithelial Endocytotic Mechanisms of the Peanut Allergens Ara h 1 and Ara h 2

The interactions of single-wall carbon nanohorns with polar epithelium

Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice

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