Poly-&lt;small&gt;L&lt;/small&gt;-arginine-Induced Internalization of Tight Junction Proteins Increases the Paracellular Permeability of the Caco-2 Cell Monolayer to Hydrophilic Macromolecules

Yamaki, Tsutomu; Ohtake, Kazuo; Ichikawa, Kazuki; Uchida, Masaki; Uchida, Hajime; Ohshima, Shinji; Juni, Kazuhiko; Kobayashi, Jun; Morimoto, Yasunori; Natsume, Hideshi

doi:10.1248/bpb.b12-00878

Cited by 11 publications

(9 citation statements)

References 34 publications

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“…Each G t (membrane conductance) was expressed in the ratio of 120 to 0 min values because the permeation-enhancing effects of HPBAAs were considered to have reached a steady state [ 7 , 11 ]. G t and the apparent permeability coefficient ( P app ) of fluorescein isothiocyanate dextran (FD-4, MW 3.4 kDa) in Caco-2 cells increased dose-dependently by application of PLO and PEG-PLO.…”

Section: Resultsmentioning

confidence: 99%

“…The effect of PEGylation on the permeation-enhancing mechanisms of HPBAAs was evaluated by immunofluorescent staining of TJ proteins. The fluorescence intensities of TJ proteins at the intercellular space decreased after exposure to PLO, suggesting that the mechanism of hydrophilic macromolecule permeation enhancement by PLO was a result of opening of the paracellular pathway due to the changing localization of TJ proteins, like PLA [ 6 , 7 ]. However, the fluorescence intensity of claudin-4 remained high even after exposure to PLO.…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that homopolymeric basic amino acids (HPBAAs) such as poly- l -arginine (PLA) and poly- l -ornithine (PLO) enhanced the transnasal absorption of hydrophilic macromolecules, including peptide and protein drugs, without causing mucosal damage [ 3 , 4 , 5 ]. The absorption-enhancement mechanism of HPBAAs was considered to be due to their ability to open the paracellular pathway by changing the localization of tight junction (TJ) proteins from cellular contacts to the subcellular space [ 6 , 7 ]. Furthermore, the absorption-enhancing effects of HPBAAs depend on the MW and application time [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that the increase in viscosity achieved by PEGylation depends on the MW and the modification number of PEG to be modified [ 12 ]. In the present study, we synthesized PEG-PLO having a different MW ratio of PEG and PLO from that previously reported [ 11 ] and evaluated the in vitro retentivity- and the hydrophilic macromolecules permeation-enhancing ability of PEG-PLO using Caco-2 cell sheet, which is known to have a good correlation between permeability across the sheet and the nasal absorbability in rats [ 13 ], and used this for evaluation of the permeation-enhancing effects and mechanisms of HPBAAs [ 7 , 14 ]. Moreover, the improvement in retentivity in the nasal cavity by PEGylation was estimated pharmacokinetically using an “in vivo intranasal retentivity evaluation system” [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Improved Intranasal Retentivity and Transnasal Absorption Enhancement by PEGylated Poly-l-ornithine

et al. 2018

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We reported that the introduction of polyethylene glycol (PEG) to poly-l-ornithine (PLO), which is an homopolymeric basic amino acid having absorption-enhancement ability, prolonged retention time in an in vitro inclined plate test, probably due to an increase in viscosity caused by PEGylation. The aim of the present study is to investigate whether the introduction of PEG chains to PLO improves intranasal retention and transnasal absorption in vivo. We performed intranasal administration experiments using PLO and PEG-PLO with a model drug, fluorescein isothiocyanate dextran (FD-4), in rats under closed and open systems. In the open system, transition of plasma FD-4 concentration after co-administration with unmodified PLO was low, and the area under the plasma concentration-time curve (AUC) decreased to about 60% of that in the closed system. In contrast, the AUC after co-administration with PEG-PLO in the open system was about 90% of that in the closed system, and the transition of plasma FD-4 concentration and FD-4 absorption profile were similar to those of the closed system. These findings indicate that introducing PEG chains to homopolymeric basic amino acids (HPBAAs) is a very useful method for developing a functional absorption enhancer that can exhibit an efficient in vivo absorption-enhancing effect.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Improved Intranasal Retentivity and Transnasal Absorption Enhancement by PEGylated Poly-l-ornithine

et al. 2018

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“…Nonmetabolic oligosaccharides and sugar alcohols were used as markers. 12) Thus, a change in the ε/L and R values following the addition of the enhancers could be related to the enhancers' effects on the hydrophilic penetration pathways. were purchased from Sigma-Aldrich Japan (Tokyo).…”

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Evaluation of the Effects of Absorption Enhancers on Caco-2 Cell Monolayers by Using a Pore Permeation Model Involving Two Different Sizes

Seki

Hamada

Egawa

et al. 2013

Biological & Pharmaceutical Bulletin

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We applied a parallel pore permeation model based on the Renkin molecular sieving function by using two different-sized pathways to analyze the permeation-enhancing effects of poly-L-arginine (PLA) or a mixed system of spermine (SPM) and sodium taurocholate (STC). Four paracellular markers were simultaneously applied to Caco-2 cell monolayers, and a set of apparent permeability coefficient (P) values was used to obtain membrane parameters. For PLA treatment, the pore occupancy/length ratio (ε/L) of the large pathways increased while the pore radius (R) did not, suggesting that the number of large pathways for the relatively large hydrophilic molecules in the monolayers could be increased by the addition of PLA. In contrast, application of the mixed system comprising SPM and STC significantly increased not only the R of the large pathways but also ε/L of the small pathways. Such changes in membrane parameters could be related to the enhancing mechanism of these compounds. The simulation curves for molecular weight (MW)-P calculated from the membrane parameters could be used to predict the P of drugs with different MWs.

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A Mechanism Enhancing Macromolecule Transport Through Paracellular Spaces Induced by Poly-L-Arginine: Poly-L-Arginine Induces the Internalization of Tight Junction Proteins via Clathrin-Mediated Endocytosis

et al. 2014

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Poly-<small>L</small>-arginine-Induced Internalization of Tight Junction Proteins Increases the Paracellular Permeability of the Caco-2 Cell Monolayer to Hydrophilic Macromolecules

Cited by 11 publications

References 34 publications

Improved Intranasal Retentivity and Transnasal Absorption Enhancement by PEGylated Poly-l-ornithine

Improved Intranasal Retentivity and Transnasal Absorption Enhancement by PEGylated Poly-l-ornithine

Evaluation of the Effects of Absorption Enhancers on Caco-2 Cell Monolayers by Using a Pore Permeation Model Involving Two Different Sizes

A Mechanism Enhancing Macromolecule Transport Through Paracellular Spaces Induced by Poly-L-Arginine: Poly-L-Arginine Induces the Internalization of Tight Junction Proteins via Clathrin-Mediated Endocytosis

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