Drug Targeting Organ-Specific Strategies

94 4 Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Cells
immune complexes, and other circulating tissue and microbial debris [38]. They account for
about 15% of the liver cell population in number and they are preferentially located in the
periportal areas [39].
4.2.3.1 Receptor-mediated Endocytosis
Similar to the targeting of compounds to SECs, drug targeting preparations designed to modify
KC functions have to be directed at KC-specific receptors. KCs are able to remove numerous
soluble and particulate substances from the circulation and they possess many receptor
systems that mediate this clearance, some of which have also been described for SECs.
Like SECs, they possess fibronectin receptors, mannose receptors, Fc receptors, CD14 receptors,
and the scavenger receptors class AI and AII [40]. In addition to these receptors, KCs
also possess the novel member of the class A scavenger receptor family, the macrophage receptor
with collagenous structure (MARCO) [41]. Besides these types of scavenger receptors,
they also have macrosialin scavenger receptors for the uptake of oxidized LDL [10] and
scavenger receptors class BI for the removal of high-density lipoproteins (HDL) [42]. For the
uptake of unmodified LDL, KCs also have special LDL receptors [43].
Mannose receptors on KCs essentially recognize the same molecules as the mannose receptors
present on SECs, but they exhibit different kinetics [44]. Besides the mannose receptors,
KCs have two other carbohydrate-specific receptors. One is the galactose particle receptor,
recognizing galactose-terminated oligosaccharides on particles and mediating endocytosis
of desialylated erythrocytes [45]. The other is the fucose receptor which interacts not
only with fucose-terminated glycoproteins, but also with galactose-exposing neoglycoproteins
[46].
KCs also possess receptors for the complement components C1q and C3b [47;48]. The
complement system is one of the main defence mechanisms of the body against invading
pathogens. It is composed of a group of serum proteins that are part of a multienzymatic cascade.
Activation of complement generates membranolytic components and protein fragments
that enhance phagocytosis and mediate immune responses. KCs have the optimal capacity
to remove complexes coated with complement from the circulation.
4.2.3.2 Phagocytosis
Not all KCs are phagocytic to the same extent; periportal KCs generally have a higher level
of phagocytic activity than those in other regions of the liver [49]. Prior to phagocytosis, particulate
material like viruses, bacteria and erythrocytes may be opsonized and bound by specific
receptors, but this is not essential for phagocytosis [50].
4.2.3.3 Regulation of the Inflammatory Process by the KC
As is the case for SECs, endocytosis of substances represents more than just circulatory clearance
mechanisms.The uptake of potentially toxic material can activate KCs to function as ei-