Drug Targeting Organ-Specific Strategies

The sinusoids are lined by the discontinuous and fenestrated sinusoidal endothelial cells
(SEC) that demarcate the extrasinusoidal space of Disse. The abundant microvilli of the hepatocytes
protrude into this space, which also contains the fat-containing lipocyte or hepatic
stellate cell (HSC). At a strategic position along the luminal side of the endothelial cells are
the resident tissue macrophages, the Kupffer cells (KC). Also located on the endothelial lining
are the Pit cells, that correspond to large granular lymphocytes with natural killer activity.
Between the abutting hepatocytes are bile canaliculi: channels in between the plasma
membranes of facing hepatocytes, that are delineated from the vascular space by tight junctions.
These intercellular spaces constitute the outermost reaches of the biliary tree. The
canaliculi emanate from the centrilobular regions, progressively drain into the canals of Hering
at the fringes of the portal tracts, and biliary fluid finally collects in the interlobular bile
ducts.
4.2.1 The Parenchymal Cell (PC)
The liver consists mainly of parenchymal cells, or hepatocytes. Most drug-targeting preparations
designed for liver targeting of therapeutic compounds are directed towards this cell
type, generally aiming at the asialoglycoprotein receptor using galactose residues coupled to
a core molecule for binding. This chapter, however, will not discuss this type of targeting, but
further information can be found in several reviews [1–3].
Hepatocytes make up 60–70% of the total number of liver cells. They have a well-organized
intracellular structure with huge numbers of cell organelles to maintain the high metabolic
profile. At the apical side or canalicular membrane the cell is specialized for the secretion
of bile components. There are several ATP-dependent transport carriers located on this
side of the membrane, which transport bile salts, lipids and xenobiotics into the canaliculus.
On the sinusoidal side, the cells specialize in uptake and secretion of a wide variety of components.To
increase the surface of the membrane for this exchange with the bloodstream, the
sinusoidal domain of the membrane is equipped with irregular microvilli. The microvilli are
embedded into the fluid and matrix components of the space of Disse and are in close contact
with the sinusoidal blood because of the discontinuous and fenestrated SECs. To facilitate
its metabolic functions numerous membrane transport mechanisms and receptors are
situated in the membrane.
4.2.2 The Sinusoidal Endothelial Cell (SEC)
4.2 The Liver 91
The endothelial lining of the sinusoids in the liver differs from the other capillaries in the
body and is adapted to form a selective barrier between blood and hepatocytes. The basement
membrane is composed of non-fibril-forming collagens including types IV,VI and XIV,
glycoproteins and proteoglycans. The lining is discontinuous and the SECs are perforated by
numerous fenestrae that lack diaphragms. This allows direct contact of the hepatocytes with
most plasma proteins in the space of Disse, but prevents direct contact with blood cells, large
chylomicrons, bacteria and viruses. SECs play an important role in the pathogenesis of sev-