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Mechanism of mucosal permeability enhancement of CriticalSorb® (Solutol® HS15) investigated in vitro in cell cultures.

Shubber S, Vllasaliu D, Rauch C, Jordan F, Illum L, Stolnik S - Pharm. Res. (2014)

Bottom Line: The rate of cell endocytosis was measured in vitro in the presence of Solutol® HS15 using a membrane probe, FM 2-10.This work initially confirms surfactant-like behaviour of Solutol® HS15 in aqueous media, while subsequent experiments demonstrate that the effect of Solutol® HS15 on epithelial tight junctions is different from a 'classical' tight junction opening agent and illustrate the effect of Solutol® HS15 on the cell membrane (endocytosis rate) and F-actin cytoskeleton.This study suggests that its mechanism of action arises primarily from effects on the cell membrane and consequent impacts on the cell cytoskeleton in terms of actin organisation and tight junction opening.

View Article: PubMed Central - PubMed

Affiliation: Division of Drug Delivery and Tissue Engineering, School of Pharmacy Boots Science Building, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.

ABSTRACT

Purpose: CriticalSorb™, with the principal component Solutol® HS15, is a novel mucosal drug delivery system demonstrated to improve the bioavailability of selected biotherapeutics. The intention of this study is to elucidate mechanism(s) responsible for the enhancement of trans-mucosal absorption of biological drugs by Solutol® HS15.

Methods: Micelle size and CMC of Solutol® HS15 were determined in biologically relevant media. Polarised airway Calu-3 cell layers were used to measure the permeability of a panel of biological drugs, and to assess changes in TEER, tight junction and F-actin morphology. The rate of cell endocytosis was measured in vitro in the presence of Solutol® HS15 using a membrane probe, FM 2-10.

Results: This work initially confirms surfactant-like behaviour of Solutol® HS15 in aqueous media, while subsequent experiments demonstrate that the effect of Solutol® HS15 on epithelial tight junctions is different from a 'classical' tight junction opening agent and illustrate the effect of Solutol® HS15 on the cell membrane (endocytosis rate) and F-actin cytoskeleton.

Conclusion: Solutol® HS15 is the principle component of CriticalSorb™ that has shown an enhancement in permeability of medium sized biological drugs across epithelia. This study suggests that its mechanism of action arises primarily from effects on the cell membrane and consequent impacts on the cell cytoskeleton in terms of actin organisation and tight junction opening.

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Effect of Solutol® HS15 solutions on TEER values of polarized Calu-3 monolayers. Baseline Calu-3 monolayer TEER values were measured using HBSS: HEPES following replacement of culture medium with HBSS: HEPES buffer and equilibration for 45 min. Tested samples removed after 3 h and cells incubated in culture medium. Data represented as mean % TEER, relative to control ± SD (N = 3, n = 4). Each tested Solutol® HS15 concentration significantly deviated from one another, P < 0.05. All Solutol® HS15 samples significantly deviated from Chitosan sample (P < 0.001), conducted using one-way ANOVA.
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Fig4: Effect of Solutol® HS15 solutions on TEER values of polarized Calu-3 monolayers. Baseline Calu-3 monolayer TEER values were measured using HBSS: HEPES following replacement of culture medium with HBSS: HEPES buffer and equilibration for 45 min. Tested samples removed after 3 h and cells incubated in culture medium. Data represented as mean % TEER, relative to control ± SD (N = 3, n = 4). Each tested Solutol® HS15 concentration significantly deviated from one another, P < 0.05. All Solutol® HS15 samples significantly deviated from Chitosan sample (P < 0.001), conducted using one-way ANOVA.

Mentions: TEER vs time profiles for application of Solutol® HS15 to polarised Calu-3 cell layers, in comparison to chitosan solution as a ‘classical’ permeability enhancer (6, 13), are shown in Fig. 4. Results are presented as % decrease in TEER relative to controls.Fig. 4


Mechanism of mucosal permeability enhancement of CriticalSorb® (Solutol® HS15) investigated in vitro in cell cultures.

Shubber S, Vllasaliu D, Rauch C, Jordan F, Illum L, Stolnik S - Pharm. Res. (2014)

Effect of Solutol® HS15 solutions on TEER values of polarized Calu-3 monolayers. Baseline Calu-3 monolayer TEER values were measured using HBSS: HEPES following replacement of culture medium with HBSS: HEPES buffer and equilibration for 45 min. Tested samples removed after 3 h and cells incubated in culture medium. Data represented as mean % TEER, relative to control ± SD (N = 3, n = 4). Each tested Solutol® HS15 concentration significantly deviated from one another, P < 0.05. All Solutol® HS15 samples significantly deviated from Chitosan sample (P < 0.001), conducted using one-way ANOVA.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4300420&req=5

Fig4: Effect of Solutol® HS15 solutions on TEER values of polarized Calu-3 monolayers. Baseline Calu-3 monolayer TEER values were measured using HBSS: HEPES following replacement of culture medium with HBSS: HEPES buffer and equilibration for 45 min. Tested samples removed after 3 h and cells incubated in culture medium. Data represented as mean % TEER, relative to control ± SD (N = 3, n = 4). Each tested Solutol® HS15 concentration significantly deviated from one another, P < 0.05. All Solutol® HS15 samples significantly deviated from Chitosan sample (P < 0.001), conducted using one-way ANOVA.
Mentions: TEER vs time profiles for application of Solutol® HS15 to polarised Calu-3 cell layers, in comparison to chitosan solution as a ‘classical’ permeability enhancer (6, 13), are shown in Fig. 4. Results are presented as % decrease in TEER relative to controls.Fig. 4

Bottom Line: The rate of cell endocytosis was measured in vitro in the presence of Solutol® HS15 using a membrane probe, FM 2-10.This work initially confirms surfactant-like behaviour of Solutol® HS15 in aqueous media, while subsequent experiments demonstrate that the effect of Solutol® HS15 on epithelial tight junctions is different from a 'classical' tight junction opening agent and illustrate the effect of Solutol® HS15 on the cell membrane (endocytosis rate) and F-actin cytoskeleton.This study suggests that its mechanism of action arises primarily from effects on the cell membrane and consequent impacts on the cell cytoskeleton in terms of actin organisation and tight junction opening.

View Article: PubMed Central - PubMed

Affiliation: Division of Drug Delivery and Tissue Engineering, School of Pharmacy Boots Science Building, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.

ABSTRACT

Purpose: CriticalSorb™, with the principal component Solutol® HS15, is a novel mucosal drug delivery system demonstrated to improve the bioavailability of selected biotherapeutics. The intention of this study is to elucidate mechanism(s) responsible for the enhancement of trans-mucosal absorption of biological drugs by Solutol® HS15.

Methods: Micelle size and CMC of Solutol® HS15 were determined in biologically relevant media. Polarised airway Calu-3 cell layers were used to measure the permeability of a panel of biological drugs, and to assess changes in TEER, tight junction and F-actin morphology. The rate of cell endocytosis was measured in vitro in the presence of Solutol® HS15 using a membrane probe, FM 2-10.

Results: This work initially confirms surfactant-like behaviour of Solutol® HS15 in aqueous media, while subsequent experiments demonstrate that the effect of Solutol® HS15 on epithelial tight junctions is different from a 'classical' tight junction opening agent and illustrate the effect of Solutol® HS15 on the cell membrane (endocytosis rate) and F-actin cytoskeleton.

Conclusion: Solutol® HS15 is the principle component of CriticalSorb™ that has shown an enhancement in permeability of medium sized biological drugs across epithelia. This study suggests that its mechanism of action arises primarily from effects on the cell membrane and consequent impacts on the cell cytoskeleton in terms of actin organisation and tight junction opening.

Show MeSH