Targeting tight junction proteins-significance for drug development

Kondoh, Masuo; Yoshida, Takeshi; Kakutani, Hideki; Yagi, Kiyohito

doi:10.1016/j.drudis.2007.11.005

Cited by 40 publications

(28 citation statements)

References 70 publications

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“…Examples include Zonula occludens toxin (Zot), a virulence factor in diarrhoea associated with strains of Vibrio cholera [58] and Clostridium perfringens enterotoxin (CPE), which can cause necrosis and desquamation of the epithelial surface of human ileal mucosae [65]. Structural analogues of Zot and CPE are members of a new generation of promoters that target TJ proteins [18][19][20][66][67][68]. A review of the patent literature reveals a vast number of peptide based promoters that target the paracellular pathway [20].…”

Section: [12] Intestinal Absorption Promotersmentioning

confidence: 99%

“…Recently, more sophisticated TJ modulators have emerged in in vitro and preclinical studies arising from a greater understanding of the structure and function of TJs [18][19][20]. The candidate molecules that are to be delivered orally using absorption promoters should have a sufficiently wide therapeutic index in order to cater for the increased variance in F between individual subjects normally seen in clinical studies.…”

Section: ] Conclusion [1] Introductionmentioning

confidence: 99%

“…Targeted particle systems for oral delivery unfortunately require complex synthetic and manufacturing processes and rely on unpredictable translation of data from rodent models to man in respect of differences in GI physiology and variable receptor [18][19][20][66][67][68]. A review of the patent literature reveals a vast number of peptide based promoters that target the paracellular pathway [20].…”

Section: Introductionmentioning

confidence: 99%

“…In general, the TJ consists of a restrictive pathway (shunt) with a sharp molecular size cut off, and a second unrestrictive pathway (small pore) that permits paracellular permeation of molecules of radii <4.0 Å [10,11]. Depending on the intestinal region, TJ pore sizes range from [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Å, sufficient to permit mannitol (6.7 Å) and EDTA (10.8 Å) to permeate to an extent, whereas the passage of inulin (30-40 Å) and fluorescent-dextran 4kDa (FD-4, 26 Å) is essentially impeded [12][13][14][15][16].…”

Section: ] Conclusion [1] Introductionmentioning

confidence: 99%

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Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Maher

Leonard²,

Jacobsen

et al. 2009

Advanced Drug Delivery Reviews

195

176

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A major challenge in oral drug delivery is the development of novel dosage forms to promote absorption of poorly permeable Class III drugs across the intestinal epithelium.To date, no absorption promoter has been approved in a formulation specifically designed for oral delivery of Class III molecules. Promoters that are designated safe for human consumption have been licensed for use in a recently approved buccal insulin spray delivery system and also for many years as part of an ampicillin rectal suppository.Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle whereby the promoter and payload must be coreleased in high concentrations at the small intestinal epithelium in order to generate significant but rapidly reversible increases in permeability. The most advanced promoter in the clinic is the medium chain fatty acid (MCFA), sodium caprate (C 10 ) , a compound already approved as a direct food additive. We discuss how it has evolved to a matrix tablet format suitable for administration to humans under the headings of mechanism of action at the cellular and tissue level and in vitro and in vivo efficacy and safety studies.In specific clinical examples, we review how C 10 -based formulations are being tested for oral delivery of bisphosphonates using Gastro Intestinal Permeation Enhancement Technology, GIPET® (Merrion Pharmaceuticals, Ireland) and in a related solid dose format for anti-sense oligonucleotides (ISIS Pharmaceuticals, USA).Keywords: Oral drug delivery, Sodium caprate (C 10 ), absorption promoter, drug delivery platforms, clinical trials, oral formulation, drug delivery systems.3 TJs form a barrier to the uncontrolled absorption of noxious luminal antigens (gate function), and maintain epithelial polarity (fence function) [8,9]. In general, the TJ consists of a restrictive pathway (shunt) with a sharp molecular size cut off, and a second unrestrictive pathway (small pore) that permits paracellular permeation of molecules of radii <4.0 Å [10,11]. Depending on the intestinal region, TJ pore sizes range from 6-22Å, sufficient to permit mannitol (6.7 Å) and EDTA (10.8 Å) to permeate to an extent, whereas the passage of inulin (30-40 Å) and fluorescent-dextran 4kDa (FD-4, 26 Å) is essentially impeded [12][13][14][15][16].A number of approaches have been used to promote oral delivery of Class III drugs ( Alternatively, the use of nanoparticles comprising biocompatible polymers (e.g. chitosan,polylactide-co-glycolide, starch and glucans) can protect cargoes from GI proteases, increase GI retention and promote absorption across gut associated lymphoid tissue (GALT) and to a lesser extent, enterocytes [45][46][47]. Most data on nanoparticle absorption from rodent models suggest that M cells in the follicle-associated epithelium of Peyer's patches (PP) are the favored site of uptake for particles of diameter 500nm-1000nm [45].Given the paucity of M cells in the GI tract of adults, the relevance of PP uptake remains controversial ...

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Section: [12] Intestinal Absorption Promotersmentioning

confidence: 99%

Section: ] Conclusion [1] Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ] Conclusion [1] Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Maher

Leonard²,

Jacobsen

et al. 2009

Advanced Drug Delivery Reviews

195

176

View full text Add to dashboard Cite

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“…19,20) These tight junction modulators were described to have the potential to influence the small molecular drug paracellular delivery. 21) The purpose of this study was to investigate the mechanism of TD-34, a cationic cyclopeptide, for enhancing insulin delivery. Caco-2 cell monolayers were used as a model to analysis the delivery route of insulin.…”

mentioning

confidence: 99%

A Potential Mechanism of a Cationic Cyclopeptide for Enhancing Insulin Delivery across Caco-2 Cell Monolayers

Chang

Sun

et al. 2013

Biological & Pharmaceutical Bulletin

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Effective delivery of therapeutic biomolecules across biomembranes is a challenging topic. A cationic cyclopeptide named TD-34 (ACSSKKSKHCG) was reported to improve insulin delivery across biomembranes effectively. Based on our previous work, we investigated the mechanism of TD-34 for enhancing insulin across Caco-2 cell monolayers. Transport studies of insulin, TD-34 and insulin accompanied with TD-34 were performed respectively using Caco-2 cell monolayers at different conditions. Transepithelial electrical resistance (TEER) value was monitored for 24 h immediately after the beginning of transport experiments. Moreover, the tight junction protein (Claudin-1) was localized by confocal immunofluorescence microscopy. Results showed the transport of insulin alone across biomembranes was attributable to multiple routes including passive diffusion. When TD-34 accompanied with or without insulin was treated on Caco-2 cell monolayers, TEER values decreased reversibly, and it was correlated with the reappearance of tight junction proteins by immunostaining assay. It was concluded that the cationic cyclopeptide (TD-34) had the potential to enhance paracellular delivery of insulin across Caco-2 cell monolayers by loosening tight junction reversibly.

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Europium Complexes as Novel Indicators of Paracellular Diffusion

Zhang

et al. 2012

Chemistry & Biodiversity

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Measurement of paracellular permeation is an important assay for tight-junction investigations of drug toxicity, especially for metal-based drugs, and routine validation of the integrity of cell monolayers for models of drug absorption. Great efforts have been made in discovery and validation of novel paracellular diffusion indicators. In the present work, we prepared three Eu complexes, i.e., [Eu(dtpa)] (dtpa=diethylenetriaminepentaacetic acid), [Eu(dtpa)(BSA)], and [Eu(dtpa)(PLL)] (PLL=poly(L-lysine)), and tested their permeation properties on Madin-Darby canine kidney (MDCK) cells. The experimental results showed that all three probes were nontoxic to MDCK cells, permeated across MDCK monolayer exclusively via the paracellular pathways, and responded well to the changes on tight junction with high correlation of P(app) values to the decrease of trans-epithelial electric resistance (TEER). In addition, time-resolved fluorescence assays were conducted in a high-sensitivity and background-free mode. All these results confirmed the Eu complexes as novel and practical paracellular indicators.

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Targeting tight junction proteins-significance for drug development

Cited by 40 publications

References 70 publications

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

A Potential Mechanism of a Cationic Cyclopeptide for Enhancing Insulin Delivery across Caco-2 Cell Monolayers

Europium Complexes as Novel Indicators of Paracellular Diffusion

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