Drug Targeting Organ-Specific Strategies

30 2 Brain-Specific Drug Targeting Strategies
transferrin were initially described. These receptors have been identified at the molecular
level as being identical to their counterparts in peripheral tissues [35,36]. However, at the
BBB the receptors mediate transcytosis of their respective ligands through the endothelial
cell as opposed to endocytosis in other cells.
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 transcellular passage of
ligand (transcytosis) is completed by exocytosis at the abluminal membrane, and the whole
process is completed within minutes in vivo.
Receptor-mediated uptake mechanisms have also been shown for insulin, insulin-like
growth factors, and leptin. The fact that macromolecular complexes as large as LDL can un-
(a)
(b)
vl
bm
Figure 2.3. An example of receptor-mediated transcytosis through the blood–brain barrier. OX26, a
monoclonal antibody to the rat transferrin receptor, was conjugated with 5-nm colloidal gold and
perfused through the internal carotid artery in rats in vivo. The brain was then perfusion-fixed. (a)
Arrows indicate binding to the luminal plasma membrane of capillary endothelial cells and internalized
antibody in an endosome. (b) The endocytosed antibodies appear in multivesicular bodies (arrows) and
are seen undergoing exocytosis at the abluminal cell membrane (arrowhead). vl, vascular lumen; bm,
basement membrane. Scale bar = 100 nm. (c) A strategy for brain delivery can be based on receptormediated
transcytosis. The non-permeable drug moiety ‘B’ is coupled to A by a linker, L. ‘A’ is a ligand
or an anti-receptor antibody (e.g. OX26) which binds to its receptor on the luminal side and mediates
endocytosis. The chimeric peptide enters brain interstitial space by exocytosis from the endothelial cell
and is cleaved by local enzymes to release the drug. Reproduced with permission from references [37]
(a,b) and [81] (c).
(c)