New In Vitro Coculture Model for Evaluating Intestinal Absorption of Different Lipid Nanocapsules

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Abstract

Standard models used for evaluating the absorption of nanoparticles like Caco-2 ignore the presence of vascular endothelium, which is a part of the intestinal multi-layered barrier structure. Therefore, a coculture between the Caco-2 epithelium and HMEC-1 (Human Microvascular Endothelial Cell type 1) on a Transwell ^® insert has been developed. The model has been validated for (a) membrane morphology by transmission electron microscope (TEM); (b) ZO-1 and β-catenin expression by immunoassay; (c) membrane integrity by trans-epithelial electrical resistance (TEER) measurement; and (d) apparent permeability of drugs from different biopharmaceutical classification system (BCS) classes. Lipid nanocapsules (LNCs) were formulated with different sizes (55 and 85 nm) and surface modifications (DSPE-mPEG (2000) and stearylamine). Nanocapsule integrity and particle concentration were monitored using the Förster resonance energy transfer (FRET) technique. The result showed that surface modification by DSPE-mPEG (2000) increased the absorption of 55-nm LNCs in the coculture model but not in the Caco-2. Summarily, the coculture model was validated as a tool for evaluating the intestinal absorption of drugs and nanoparticles. The new coculture model has a different LNCs absorption mechanism suggesting the importance of intestinal endothelium and reveals that the surface modification of LNCs can modify the in vitro oral absorption.

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Intestinal permeability – a new target for disease prevention and therapy

Stephan C Bischoff, Giovanni Barbara, Wim A Buurman … (2014)

Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms ‘intestinal barrier’ and ‘intestinal permeability’ are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by ‘intestinal permeability’. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and – more recently recognized – obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.

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Permeability coefficients across monolayers of the human colon carcinoma cell line Caco-2, cultured on permeable supports, are commonly used to predict the absorption of orally administered drugs and other xenobiotics. This protocol describes our method for the cultivation, characterization and determination of permeability coefficients of xenobiotics (which are, typically, drug-like compounds) in the Caco-2 model. A few modifications that have been introduced over the years are incorporated in the protocol. The method can be used to trace the permeability of a test compound in two directions, from the apical to the basolateral side or vice versa, and both passive and active transport processes can be studied. The permeability assay can be completed within one working day, provided that the Caco-2 monolayers have been cultured and differentiated on the permeable supports 3 weeks in advance.

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Author and article information

Contributors

Ana Beloqui García: Role: Academic Editor

Journal

Journal ID (nlm-ta): Pharmaceutics

Journal ID (iso-abbrev): Pharmaceutics

Journal ID (publisher-id): pharmaceutics

Title: Pharmaceutics

Publisher: MDPI

ISSN (Electronic): 1999-4923

Publication date (Electronic): 21 April 2021

Publication date Collection: May 2021

Volume: 13

Issue: 5

Electronic Location Identifier: 595

Affiliations

[1 ]MINT, INSERM U1066, CNRS UMR 6021, SFR ICAT, University of Angers, F-49000 Angers, France; norraseth.kaeokhamloed@ 123456univ-angers.fr (N.K.); emilie.roger@ 123456univ-angers.fr (E.R.); jerome.bejaud@ 123456univ-angers.fr (J.B.); nolwenn.lautram@ 123456univ-angers.fr (N.L.)

[2 ]SCIAM, SFR ICAT, University of Angers, F-49000 Angers, France; florence.manero@ 123456univ-angers.fr (F.M.); rodolphe.perrot@ 123456univ-angers.fr (R.P.)

[3 ]Laboratoire de Pharmacologie-Toxicologie, CRPV, Angers University Hospital Center, F-49000 Angers, France; chadi.abbara@ 123456chu-angers.fr (C.A.); marie.briet@ 123456chu-angers.fr (M.B.)

Author notes

[* ]Correspondence: samuel.legeay@ 123456univ-angers.fr

Author information

Norraseth Kaeokhamloed https://orcid.org/0000-0002-1324-1554

Marie Briet https://orcid.org/0000-0003-3738-5998

Samuel Legeay https://orcid.org/0000-0001-5393-995X

Article

Publisher ID: pharmaceutics-13-00595

DOI: 10.3390/pharmaceutics13050595

PMC ID: 8143299

PubMed ID: 33919334

SO-VID: e69c5b3d-6d87-4c4d-89a3-7c0629ac4dba

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

History

Date received : 06 April 2021

Date accepted : 20 April 2021

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