Tight junction endocytosis

The oral administration of large proteins and peptides is limited due to their low membrane permeability. These compounds are mainly restricted to the para-cellular pathway, but because of their polar characteristics and their size the pore of the tight junctional system is also highly restrictive. An additional transcellular pathway has therefore been suggested for these peptides, i.e., the transcytotic pathway, which involves a receptor-mediated endocytosis in Caco-2 cells [126],... 

Figure 4.6 Likely mechanisms by which macromolecules cross cellular barriers in order to reach the bloodstream from (in this case) the lung. Transcytosis entails direct uptake of the macromolecule at one surface via endocytosis, travel of the endosome vesicle across the cell, with subsequent release on the opposite cell face via exocytosis. Paracellular transport entails the passage of the macromolecules through leaky tight junctions found between some cells...

Fetal urine is rich in serum proteins, as glomerular filtration begins before the podocyte layer of the glomerulus is mature. Although the proximal tubules have tight junctions and are capable of some endocytosis, there is insufficient capacity to resorb all of the filtered protein. The glomerular filtration barrier and proximal tubule resorption mature about 7 days after birth in the rat. 

Figure 10.1 Pathways for intestinal absorption of macromolecular drugs, (a) Paracellular transport of macromolecules can be achieved by altering or disrupting the tight junctions that exist between cells and are only permeable to small molecules (<100 to 200 Da). (b) Adsorptive enterocytes and (c) M cells of Peyer s patches allow transcellular transport of macromolecules involving transcytosis and receptor-mediated endocytosis.

Fig. 3.2. General mechanisms for the uptake and transport of macromolecules by an enterocyte. Intracellular uptake-, after absorption and endocytosis by the microvillous membrane, macromolecules are transported in small vesicles and larger phagosomes. Intracellular digestion occurs when lysosomes combine to form phagolysosomes. Intact molecules that remain after digestion are deposited in the intercellular space by exocytosis. Intercellular uptake-, alternatively, macromolecules may cross the tight junction barrier between cells and diffuse into the intercellular space. (After Walker, W. A. Isselbacher, K. J. Uptake and transport of macromolecules by the intestine possible role in clinical disorders. Gastroenterology, 6T. 531-50, by Williams Wilkins (1974).)...

Absorption barriers are related to the permeability of drug molecules across the gastrointestinal membrane including the colonic membrane. There are two distinct mechanisms for molecules to cross the membrane via paracellular transport and transcellular transport (Fig. 5). Para-cellular transport involves only passive diffusion where the molecules pass through the tight junctions between the epithelial cells. In contrast, transcellular transport can occur by passive diffusion as well as by active transport, or endocytosis. In general, the hydrophilic molecules diffuse predominantly through the paracellular route, whereas the lipophilic... 

Various transport processes used by low molar mass drugs to cross the epithelial barrier lining oral, buccal, nasal, vaginal, and rectal cavities include passive diffusion, carrier-mediated transfer systems, and selective and nonselective endocytosis. Additionally, polar materials can also diffuse through the tight junctions of epithelial cells (the paraceUular route). Evidence also exists that suggests that macromolecules (particulate... 

Figure 8,1, Routes and mechanisms of solute transport across epithelial membranes. In general, routes 2-5 are transcellular pathways (i.e., compounds move through the cells), whereas route 1 is considered a paracellular pathway (i.e., a compound moves between the cells). (l)Tight junctional pathway (2) drug efflux pathway (e.g., P-glycoprotein mediated) (3) passive diffiision (4)receptor-mediated endocytosis and/or transc3dosis pathways (5) carrier-mediated route. Note that receptor and carrier proteins in epithelial cells are expressed on both the apical and basolateral surfaces.

Goldberg, D. S., Ghandehari, H., and Swaan, P. W. 2010. Gellular Entry of G3.5 Poly (amido amine) dendrimers by clathrin- and dynamin-dependent endocytosis promotes tight junctional opening in intestinal epitheha. Pharm Res. 27(8),1547-57. 

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