Transcytosis cell process

Polymers, being macromolecules of considerable size and weight, have many limitations when used either as drugs or as drug carriers (1). One of the most serious limitations is the existence of epithelial or endothelial barriers (2). However, macromolecules can be transported by a vesicular process known as transcytosis (3,4). In transcytosis, a polymer can be shuttled across an epithelial cell by first... 

As shown in Table I, free HRP is poorly transported across MDCK cells but, when conjugated to a PLL carrier, HRP transport is increased considerably. The existence of a proteolytic compartment involved in the transcytotic digestion of HRP-S-PLL conjugate was further confirmed by the finding that when PLL was replaced by PDL, the transport of HRP was completely abolished (Table I) (8). In addition, when protease inhibitors such as leupeptin were added to the basal medium, the transcytosis of HRP was also significantly decreased (Table I). We have previously reported that the partial degradation of HRP-S-PLL was not inhibited by lysosomotropic amines (<8), indicating that this proteolytic process does not occur in lysosomes. 

Figure 1 General pathways through which molecules can actively or passively cross a monolayer of cells. (A) Endocytosis of solutes and fusion of the membrane vesicle with the opposite plasma membrane in an active process called transcytosis. (B) Similar to A, but the solute associates with the membrane via specific (e.g., receptor) or nonspecific (e.g., charge) interactions. (C) Passive diffusion between the cells through the paracellular space. (C, C") Passive diffusion (C ) through the cell membranes and cytoplasm or (C") via partitioning into and lateral diffusion within the cell membrane. (D) Active or carrier-mediated transport of an otherwise poorly membrane permeable solute into and/or out of a cellular barrier.

This refers to the transport across the epithelial cells, which can occur by passive diffusion, carrier-mediated transport, and/or endocytic processes (e.g., transcytosis). Traditionally, the transcellular route of nasal mucosa has been simply viewed as primarily crossing the lipoidal barrier, in which the absorption of a drug is determined by the magnitude of its partition coefficient and molecular size. However, several investigators have reported the lack of linear correlation between penetrant lipophilicity and permeability [9], which implies that cell membranes of nasal epithelium cannot be regarded as a simple lipoidal barrier. Recently, compounds whose transport could not be fully explained by passive simple diffusion have been investigated to test if they could be utilized as specific substrates for various transporters which have been identified in the... 

The process of transcytosis is illustrated in Figure 2.3 for the transferrin receptor (TfR) [37]. The receptor is heavily expressed at the BBB compared to other vascular beds [38]. Transferrin or a monoclonal antibody to the extracellular domain of the receptor protein will bind from the luminal side of the BBB. This triggers cellular uptake by the mechanism of receptor-mediated endocytosis, i.e. the invagination and budding off of parts of the cell membrane as a result of the formation of small vesicles (endosomes). The transceUular passage of ligand (transcytosis) is completed by exocytosis at the abluminal membrane, and the whole process is completed within minutes in vivo. 

Active transport mechanisms exist in the gastrointestinal tract and other epithelial sites, for the absorption of di- and tri-peptides. As described above, a greater understanding of the molecular specificity of this carrier could provide important leads for the delivery of peptides. Proteins and large peptides may be transported across cells via endocytic processes. Transcytosis is achieved if the endocytic vesicles can reach the basal membrane without fusion with lysosomes. However, various studies have shown that in the majority of cases the internalized protein is degraded, indicating that the transcytotic pathway is a minor one and most of the endocytosed protein is subject to lysosomal degradation. 

Unlike FcRn-mediated transcytosis, the initial plgR-Ig binding occurs at the cell surface rather than within endosomes, and usually leads to receptor degradation or loss to the apical environment rather than recycling [61,109]. Internalization occurs via a nocodozole-sensitive, microtubule-associated process [137,138],... 

Adsorptive) transcytosis a mechanism for transcellular transport in which a cell encloses extracellular material in an invagination of the cell membrane to form a vesicle, then moves the vesicle across the cell to eject the material through the opposite cell membrane by the reverse process. 

Transcytosis In this process, the vesicles are moved from one cell pole to another without their contents changing. 

The body absorbs peptides and proteins into the bloodstreamby a natural process known as transcy-tosis, which occurs deep in the lung. Transcytosis allows drug molecules to move across an impermeable cell membrane without creating holes in the cells and destroying the barrier (Fig. 1). 

Fig. 1 Natural absorptive mechanism. The body absorbs peptides and proteins into the bloodstream by a natural process known as transcytosis which occurs deep in the lung. Transcytosis is the process by which large molecules move across an impermeable cell membrane without creating holes in the cells and destroying the barrier. It is performed by tiny membrane bubbles, or transcytotic vesicles, which form invaginations of the cell membrane on one side of the cell and dissolve back into the membrane on the other side of the cell. The result is that small volumes of alveolar fluid, including dissolved proteins, are carried by a bucket brigade from one side of a cell to the other.

Small molecules and peptides are also thought to be absorbed through the lung surface by an analogous process called paracellular transport. This is achieved through the tight junctions which connect cells to each other. However, in contrast to transcytosis that is rapid and efficient, paracellular transport is slow and inefficient. 

Three processes are involved in transcellular transport across the intestinal epithelial cells simple passive trans-port, passive diffusion together with an efflux pump, and active transport and endocytosis. Simple passive transport is the diffusion of molecules across the membrane by thermodynamic driving forces and does not require direct expenditure of metabolic energy. In contrast, active transport is the movement of molecules across the mem-brane resulting directly from the expenditure of metabolic energy and transport against a concentration gradient. Endocytosis processes include three mechanisms fluid-phase endocytosis (pinocytosis), receptor-mediated endocytosis, and transcytosis (Fig. 6). Endocytosis processes are covered in detail in section Absorption of Polypeptides and Proteins, later. 

The epithelial membrane of the GI tract consists of a continuous barrier of cells, which allows the transport of low-molecular-weight molecules by simple diffusion or various carrier processes. Macromolecules such as proteins may be absorbed from the intestinal lumen by cellular vesicular processes, through fluid-phase endocytosis (pinocytosis), or by receptor-mediated endocytosis or transcytosis (Fig. 6). In pinocytosis, extracellular fluid is captured within an epithelial membrane vesicle. It begins with the formation of a pocket... 

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