Drug Targeting Organ-Specific Strategies

92 4 Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Cells
eral acute and chronic inflammatory liver diseases. Consequently they are attractive target
cells for anti-inflammatory therapies.
The SECs account for 20% of all liver cells and are the first cells, together with the KCs, to
encounter potentially harmful materials present in the portal blood. They are therefore
equipped with scavenger capabilities and certain defence mechanisms to prevent damage to
other cell types.The SECs have an active scavenging system for the majority of physiological
and foreign soluble (waste) macromolecules [4,5]. Clearance mechanisms include receptormediated
endocytosis, transcytosis, and phagocytosis.To regain local homeostasis after ingestion
of injurious substances and after other detrimental events, the SECs can also produce cytokines,
eicosanoids, and adhesion molecules for the mobilization of other hepatic cell types
and cells of the immune system.
4.2.2.1 Receptor-mediated Endocytosis
Targeting to SECs should be directed at specific receptors present on this cell type. A wide
range of proteins and other molecules can be taken up by SECs through receptor-mediated
endocytosis. For example, SECs play an important role in the uptake of degradation products
of the extracellular matrix. For this purpose they have hyaluronan [6], (pro)collagen, and fibronectin
receptors [7]. The first two receptors are uniquely located on SECs. Elevated levels
of serum hyaluronan and fibronectin, that are often found in liver disease [8], are usually
the result of dysfunction of the clearance capacity of SECs combined with an increased production
by HSCs [9].
Scavenger receptors on the SECs are instrumental in another important endocytic mechanism.They
recognize and endocytose modified proteins that have a high net negative charge
[9]. SECs predominantly express two types of scavenger receptors: the class AI and the class
AII scavenger receptor [10]. Physiological substrates for these receptors were found to be
the N-terminal propeptides of types I and III procollagen [11] and the lipid A moiety of endotoxin
[12]. Most studies, however, have used non-physiological substrates such as negatively-charged
albumins [13] and acetylated low-density lipoproteins (LDL) [14] to characterize
these receptors.Yet, the binding of both physiological and non-physiological substrates
is Ca 2+ -independent and is followed by rapid endocytosis and degradation in lysosomes.
The SECs are further equipped with a receptor that specifically interacts with mannose- and
N-acetylglucosamine-terminated glycoproteins. Unlike the scavenger receptor, binding of
ligands to this so-called mannose receptor is Ca 2+ -dependent, but is also followed by rapid
endocytosis and degradation in lysosomes [15]. The receptor is thought to be involved in the
uptake of micoorganisms like yeasts, bacteria, and parasites [16], but has also been shown to
be involved in the uptake of tissue-type plasminogen activator [17]. In addition, the receptor
is involved in antigen uptake for subsequent antigen presentation [18]. This indicates that
SECs may also be involved in cell-mediated immune responses in the liver.
Other uptake-linked receptors found on the SECs are the Fc receptor for the uptake of
immunoglobulins [19], the CD14 receptor for the binding of lipopolysaccharide (LPS) bound
to LPS binding protein [20], the platelet derived growth factor AA receptor [21] and the
glucagon receptor [22].