Trends in drug delivery through tissue barriers containing tight junctions

Tscheik, Christian; Blasig, Ingolf E.; Winkler, Lars

doi:10.4161/tisb.24565

Cited by 52 publications

(36 citation statements)

References 103 publications

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“…Occl and Cldn ECL–derived peptides have been used to manipulate TJ structure and function at bTJs . We hypothesize that peptidomimetics of Tric ECLs specifically interfere with tTJ protein interactions.…”

Section: Introductionmentioning

confidence: 99%

Trictide, a tricellulin‐derived peptide to overcome cellular barriers

Cording¹,

Arslan²,

Staat³

et al. 2017

Annals of the New York Academy of Sciences

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The majority of tight junction (TJ) proteins restrict the paracellular permeation of solutes via their extracellular loops (ECLs). Tricellulin tightens tricellular TJs (tTJs) and regulates bicellular TJ (bTJ) proteins. We demonstrate that the addition of recombinantly produced extracellular loop 2 (ECL2) of tricellulin opens cellular barriers. The peptidomimetic trictide, a synthetic peptide derived from tricellulin ECL2, increases the passage of ions, as well as of small and larger molecules up to 10 kDa, between 16 and 30 h after application to human epithelial colorectal adenocarcinoma cell line 2. Tricellulin and lipolysis-stimulated lipoprotein receptor relocate from tTJs toward bTJs, while the TJ proteins claudin-1 and occludin redistribute from bTJs to the cytosol. Analyzing the opening of the tricellular sealing tube by the peptidomimetic using super-resolution stimulated-emission depletion microscopy revealed a tricellulin-free area at the tricellular region. Cis-interactions (as measured by fluorescence resonance energy transfer) of tricellulin-tricellulin (tTJs), tricellulin-claudin-1, tricellulin-marvelD3, and occludin-occludin (bTJs) were strongly affected by trictide treatment. Circular dichroism spectroscopy and molecular modeling suggest that trictide adopts a β-sheet structure, resulting in a peculiar interaction surface for its binding to tricellulin. In conclusion, trictide is a novel and promising tool for overcoming cellular barriers at bTJs and tTJs with the potential to transiently improve drug delivery.

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Section: Introductionmentioning

confidence: 99%

Trictide, a tricellulin‐derived peptide to overcome cellular barriers

Cording¹,

Arslan²,

Staat³

et al. 2017

Annals of the New York Academy of Sciences

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“…Gene knockout and small interfering RNA (siRNA) approaches revealed that the loss of claudin‐5 expression from the BBB leads to a size‐selective permeability of the BBB for molecules with a molecular weight less than 800 Da . While, physiologically, the BBB protects the CNS against harmful blood‐borne substances, claudin‐5–mediated BBB tightening is a major obstacle for the effective delivery of hydrophilic drugs to the CNS …”

Section: Introductionmentioning

confidence: 99%

Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery

Dithmer

Staat

Müller

et al. 2017

Annals of the New York Academy of Sciences

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The blood-brain barrier (BBB) formed by the microvascular endothelium limits cerebral drug delivery. The paraendothelial cleft is sealed by tight junctions (TJs) with a major contribution from claudin-5, which we selected as a target to modulate BBB permeability. For this purpose, drug-enhancer peptides were designed based on the first extracellular loop (ECL) of claudin-5 to allow transient BBB permeabilization. Peptidomimetics (C5C2 and derivatives, nanomolar affinity to claudin-5) size-selectively (≤40 kDa) and reversibly (12-48 h) increased the permeability of brain endothelial and claudin-5-transfected epithelial cell monolayers. Upon peptide uptake, the number of TJ strand particles diminished, claudin-5 was downregulated and redistributed from cell-cell contacts to the cytosol, and the cell shape was altered. Cellular permeability of doxorubicin (cytostatic drug, 580 Da) was enhanced after peptide administration. Mouse studies (3.5 μmol/kg i.v.) confirmed that, for both C5C2 and a d-amino acid derivative, brain uptake of Gd-diethylene-triamine penta-acetic acid (547 Da) was enhanced within 4 h of treatment. On the basis of our functional data, circular dichroism measurements, molecular modeling, and docking experiments, we suggest an association model between β-sheets flanked by α-helices, formed by claudin-5 ECLs, and the peptides. In conclusion, we identified claudin-5 peptidomimetics that improve drug delivery through endothelial and epithelial barriers expressing claudin-5.

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“…The promising TJ modulators Clostridium perfringens enterotoxin [46][47][48], sodium caprate [48,49] and the claudin-1 peptidomimetics [50] have also been evaluated in vivo, but do not fit entirely the definition of MB TJ modulators given above and are thus beyond the scope of this review.…”

Section: Opening Of Tjmentioning

confidence: 98%