Transcytosis, receptor-mediated

Several of the postulated roles for nematode-secreted AChEs assume that they gain access to the intestinal mucosa. Several possibilities exist for transport of parasite AChE across the epithelial cell barrier, such as (i) utilization of existing pathways for receptor-mediated transcytosis (ii) a paracellular route facilitated by parasite-secreted proteases as observed for a bacterial elastase (Azghani et al., 1993) and (iii) increased paracellular permeability resulting from inflammatory events in the mucosa. We consider the latter suggestion most likely, as this has been duplicated by ex vivo perfusion with rat mast cell protease II (Scudamore et al., 1995). Moreover, cholinergic stimulation attenuates epithelial barrier properties to macromolecules in rat ileal crypts (Phillips et al., 1987). 

Hydrophilic peptides and proteins are frequently large molecules they may enter the brain by carrier-mediated transport, receptor-mediated transcytosis, or by adsorptive-mediated transcytosis. Small peptides, such as di- and tripeptides are transported by the specific transporters, PepTl and PepT2, but neither of them is present at the BBB. Nevertheless, there is saturable brain uptake of the tripeptide glutathione and of several opioid peptides, suggesting that specific transporters, as... 

SECs are normally able to internalize only small particles (up to 0.23 pm). In conditions of impaired KC function, however, they have also been found to phagocytose larger particles [23]. They are also responsible for the receptor-mediated transcytosis of several compounds, such as insulin [24] and transferrin [25]. 

The Fc receptor-mediated transcytosis mechanism across epithelial barriers was successfully used by Patel et al. [79], They showed that coating drag containing liposomes with the appropriate IgG enhances by infold their transport across epithelial harries (yolk sac endoderm and gut cntcrocytes). 

S. Ll. Ghitescu, A. Fixman, M. Simionescu, and N. Simionescu. Specific binding sites for albumin restricted to plasmakmmal vesicles of continuous capillary endothelium receptor-mediated transcytosis. J. CeilBioL 762 1304 (1986). 

Receptor-mediated transcytosis has been described in Chapter 1 (Section 1.3.3.2). In brief, a macromolecular drug combines with a membrane-bound receptor and is internalized into endocytic vesicles. Transcytosis is achieved if the endocytic vesicles containing the drug-receptor complexes can reach the basal membrane without fusion with lysosomes. The macromolecule is then exocytosed and released into the brain. 

Polypeptides are substrates for receptor-mediated transcytosis. Cerebral insulin reaches the brain from the circulation via receptor-mediated transcytosis through the BBB on the brain endothelial insulin receptor. This receptor is upregulated in development and downregulated in streptozotocin-induced diabetes mellitus. Similarly a BBB transferrin receptor mediates the transcytosis of transferrin across the BBB and this explains how the brain is able to extract iron from the circulation. Other RMT pathways consituting portals of entry to the brain for circulating peptides include receptors for insulin-like growth factors, cationic proteins, lectins, acetyl-low density lipoprotein and leptin. 

Drags which have structures similar to that of endogenous nutrients may be taken up by a specialized transport system (carrier-mediated transport, receptor-mediated transcytosis) existing in the brain endothelium for nutrients. For example, drags having a molecular structure similar to a large neutral amino acid may cross the BBB via the neutral amino acid carrier such drags include melphalan (phenylalanine mustard), L-dopa, a-methyldopa, and p-chlorophenylalanine. 

Exploitation of receptor-mediated transcytosis for drug delivery to the CNS. A transport vector, B non-transportable drug A-R receptor for transport vector B-R Receptor for peptide... 

Liposomes can be targeted to the brain by exploiting receptor-mediated transcytosis systems. For example, a bi-functional PEG-linker has been used to couple anti-transferrin (0X26) receptor antibodies to one end of the PEG strands and liposomes at the other end of the PEG strands (Figure 13.6). Classically, immunoliposomes are prepared by attaching the MAb to the surface of the liposomes (see Section 5.3.1.3). However, this can lead to steric hindrance by the PEG strands with respect to antibody binding to the appropriate receptor. The use of the bifunctional PEG linker overcomes this problem. 

Peptide nucleic acids (PNA) are novel antisense oligonucleotides (see Section 1.6.2) which contain a polypeptide backbone. Receptor-mediated transcytosis can be exploited to promote their delivery to the CNS. For example, the attachment of PNAs to the anti-transferrin (0X26) receptor antibodies has been shown to increase the brain uptake of the PNAs, without loss of the ability of the PNAs to hybridize to target mRNA. However, antisense agents will not exert pharmacologic effects in vivo following delivery to... 

Give examples of where receptor-mediated transcytosis systems have been exploited in CNS drug delivery. 

Descamps L, Dehouck M-P, Torpier G, Cecchelli R. 1996. Receptor-mediated transcytosis of transferrin through blood-brain barrier endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 39 1149-58... 

III). The tight tissue boundaries include the intestinal wall, skin, cornea, conjunctiva, blood-brain barrier, placental barrier, and blood-retina barrier. In leaky tissue boundaries (e.g. fenestrated endothelia, sinusoidal vessels, and tissue boundaries disrupted by the disease states such as inflammation), the nanoparticulates may pass the barrier by paracellular permeation. In specific cases, receptor-mediated transcytosis may be possible... 

Another method of delivery of insulin is to conjugate the protein with transferrin. Oral administration of the insulin-transferrin complex and insulin in streptozotocin-induced diabetic mice lowered the blood glucose levels by 28 and 5%, respectively. The blood glucose level was further decreased to 40% when the mice were pretreated with brefeldin A, a fungal metabolite, before the administration of the insulin-transferrin complex. The potentiation by brefeldin A indicated that insulin absorption could be accomplished through a transferrin receptor-mediated transcytosis in the intestinal wall. 

PMN binding to and migration across endothelium initiates a sequence of events that resembles that following histamine treatment [14,30], namely, an increase in the permeability of the EC monolayer. For anionic plasma macromolecules, the plasmalemmal vesicles and transendothelial channels are suitable candidates for exit from the vessel lumen. Indeed, receptor-mediated transcytosis of insulin and transferrin has been identified for brain capillaries [31-33]. The insulin carriers have not yet been identified, but it is speculated that they could be coated vesicles and/or plasmalemmal vesicles. Transferrin [34] as well as ceruloplasmin [35,36] binding has been localized to coated pits and vesicles in the endothelium of bone marrow and liver capillary endothelium, respectively. 

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