Characteristics of Mucosal Layer in Gastrointestinal Tract

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1		Hideyuki Sato	--	1381	2023-12-13 08:39:28	\|
2	references update	Fanny Huang	Meta information modification	1381	2023-12-14 04:15:18	\| \|
3	layout	Fanny Huang	Meta information modification	1381	2023-12-19 06:44:08	\|

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15122708

The main constituents of mucus are water (90–95%), electrolytes, lipids (1–2%), and proteins. Owing to the presence of mucin, a large complex glycosylated protein, mucus can form mesh-like structured viscous gel layers on various mucosal tissues, such as the gastrointestinal (GI) tract, eyes, nose, and respiratory tract. In the GI tract, the mucus layer on the surface of the epithelial membrane can act as a smart physiological barrier not only for foreign substances with harmful potential and pathogens but also for orally dosed drugs. For effective and sufficient oral drug delivery, avoiding protective mechanisms and/or even turning barrier mechanisms should be considered. Therefore, several strategies have been developed to control the diffusive properties of drug nanoparticles within the mucus layer, including the mucopenetration and mucoadhesion of NCs.

mucus layer gastrointestinal (GI) tract

1. Physiological Functions of Mucus Layer

The main constituents of mucus are water (90–95%), electrolytes, lipids (1–2%), and proteins ^[1]. Owing to the presence of mucin, a large complex glycosylated protein, mucus can form mesh-like structured viscous gel layers on various mucosal tissues, such as the GI tract, eyes, nose, and respiratory tract ^[2]. There are two types of mucins: membrane-bound mucins and secreted (gel-forming) mucins, and mucus layers are composed of gel-forming mucins secreted from goblet cells ^[3]. Mucin 2 (MUC2) is the main component of intestinal mucus and forms the mucus skeleton. The structure of mucin includes sulfate groups on N-acetyl glucosamine and galactose and carboxylic groups on sialic acid sugars, providing an overall negative charge to mucins under most pH conditions ^[4]. The surface of epithelium in the GI tract is covered by mucus, which consists of mucin polymers connected via disulfide bonds, forming mucus layers. Mucins are continuously secreted from goblet cells in the GI tract, and the thickness of the mucus differs depending on the balance between its production and turnover ^[5]. The mucus layer is thinnest in the intestinal tract and thickest in the stomach and colon. The mucus layer of the small intestinal tract contains a high concentration of peptides and proteins with antibacterial activity that contribute to the removal of bacteria ^[6]. Because the risk of infection in the small intestine is higher than that in other parts of the GI tract, such as the stomach and colon, these protective functions are very important.

In the GI tract, the mucus layers can act as barriers to protect the surface of epithelial cells from foreign materials with harmful potentials and pathogens by trapping them in the mesh structure and disturbing their diffusion towards the epithelium ^[7]. There are two possible mechanisms of mucosal barrier systems: (i) size exclusion by mucin mesh-like structures and (ii) molecular interactions between mucin and drugs, including electrostatic and hydrophobic interactions. The mucus barrier is a high-density mucin fiber network with an average pore size of 20–200 nm ^[8]. Therefore, the mucus layer acts as a biological sieve. Small molecules such as nutrients, water, and gas can pass through the mesh structure, whereas particles larger than the pore size of the mesh structure experience steric hindrance and can be trapped by the structure. Mucus has significant blocking effects on molecules with a molecular weight of 30,000 Da ^[9]. This size-exclusion mechanism also protects the epithelial membrane from bacteria and foreign particles (>0.5 μm) ^[10], contributing to the maintenance of a sterile environment around the surface of the epithelium. Theoretically, the smaller the number of drug molecules/particles, the easier it is for them to penetrate the mucosal layer. However, even if the particles are much smaller than the pore size of the mucin mesh, molecular interactions between mucin can impair the diffusion properties of drug molecules/particles by significantly increasing the solute-solvent resistance ^[11]. Nonpolar solvents, such as oils, diffuse more slowly through the mucus than through water because of the hydrophobic interactions in the lipophilic contents of the mucin layer. The lipid content in the mucus layer can form hydrophobic interactions between mucus and diffusing drug particles, even those smaller than the pore size. In addition, as described above, there are many sulfate and sialic acid moieties in the mucin structure that create a strong negative charge on its surface. Therefore, electrostatic interactions can form between charged particles and the mucus layer. Cationic molecules such as chitosan, a natural polysaccharide with mucoadhesive properties, can form tight polyvalent bonds with negatively charged moieties in mucin ^[12].

The continuous secretion of mucus not only prevents pathogens and foreign substances from entering the epithelial membrane but also removes various compounds and drug molecules. Thus, appropriate drug delivery systems that are based on clearance mechanisms of mucus systems should be considered to achieve sufficient oral absorption.

2. Roles of Mucin in Mucopenetrating and Adhesive Formulations

The mucus layer on the surface of the epithelial membrane can act as a smart physiological barrier not only for foreign substances with harmful potential and pathogens but also for orally dosed drugs. For effective and sufficient oral drug delivery, avoiding protective mechanisms and/or even turning barrier mechanisms should be considered. Therefore, several strategies have been developed to control the diffusive properties of drug nanoparticles within the mucus layer, including the mucopenetration and mucoadhesion of NCs.

Mucopenetrating NCs can achieve efficient oral delivery of target drugs with higher amounts of oral absorption and subsequently improve oral bioavailability, as this system can deliver the carrier cargo close to the absorption site in the GI tract ^[13]. Various interactions, including entanglement with mucin, electrostatic interactions, and hydrophobic interactions can trap foreign substances and prevent NC penetration through the mucus layer. To obtain mucopenetrating properties, minimizing the interactions between NCs and mucin, that is, creating a bioinert surface, is important ^[14]. Entanglement is the biggest barrier to the penetration of NCs; thus, decreasing entanglement would enable NCs to move more easily through the mucus layer. Hydrogen bonds and ionic interactions can be formed between NCs with a high charge density and negatively charged sialic acid groups in the mucus structure. Thus, reducing the net charge and charge density can suppress these interactions, possibly resulting in a more bioinert surface against the mucus layer. To reduce the net charge on the surface of NCs, previous studies report covering the NC with uncharged materials or highly densely charged materials with evenly distributed positive and negative charges ^[15].

Mucoadhesive NCs have also attracted considerable interest in controlling and prolonging the residence time of NCs at the absorption sites in the GI tract. Mucoadhesion is a complex phenomenon involving various types of adhesion mechanisms, including physical entanglement, dehydration, electrostatic interactions, covalent bonds between thiol groups in mucin, and multiple low-affinity bonds, such as hydrogen bonds and van der Waals forces ^[16]. There are two main mechanisms of mucoadhesion: contact and consolidation ^[17]. In the first step, the material must be in close contact with the mucus layer surface. If the attractive forces (van der Waals forces and electrostatic attraction) between the materials and the mucus layer are not strong enough to overcome the repulsive forces (e.g., osmotic pressure and electrostatic repulsion), the adhered particles can be easily removed by GI motions and physiological turnover of the mucus layer. Consolidation is also necessary to prolong the adherence of the NCs to the mucus layer. This process can strengthen the interactions between NCs and the mucin, possibly leading to resistance to the clearance mechanisms of NCs from the mucus layer. The consolidation process has been explained by two different theories: the interpenetration theory and the dehydration theory. According to the interpenetration theory, the glycoproteins of mucin and mucoadhesive compounds should closely interact by the interpenetration of their chains and the formation of secondary bonds, contributing to an increase in both chemical and mechanical interactions ^[18]. According to the dehydration theory, when mucoadhesive compounds with gel-forming properties are in contact with the mucus layer, the material can induce dehydration of the mucus due to different osmotic pressures. Until the osmotic pressure is equilibrated between the material and mucus, different concentration gradients cause water movement. The dehydration process enhances the mixing of the material and mucus, resulting in increased contact time with the mucus membrane. Generally, polysaccharides, including chitosan, alginate, and cellulose derivatives, have been reported as mucoadhesive polymers and are used as carrier materials for mucosal drug delivery systems.

Understanding the appropriate interactions and mechanisms of the penetration and/or adhesion of NCs in the mucus layer has enabled researchers to identify, select, and develop materials for designing functional NCs.

References

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Hideyuki Sato

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Masateru Miyake

Satomi Onoue

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Update Date: 19 Dec 2023

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1. Physiological Functions of Mucus Layer

2. Roles of Mucin in Mucopenetrating and Adhesive Formulations

References