Drug Targeting Organ-Specific Strategies

this carrier to the KCs.When the mannose substitution is increased, the uptake by SECs also
increases [92]. For a long time this carrier has been assumed to be inert. However, recent
studies from our laboratory indicate that the carrier Man 10-HSA may activate KCs and induce
an immunological response [93].Whether this limits the use of this carrier remains to be
established. The subsequent coupling of dexamethasone to Man 10-HSA attenuated this immunological
response [93].
Direct modification of albumin with drugs like naproxen (Nap 20-HSA) and dexamethasone
(Dexa 10-HSA) changes the protein into a substrate for the scavenging receptors type A.
These drugs are coupled to the free ε-NH 2-groups of the lysine residues in albumin. Normally
these NH 2-groups are positively charged through protonation. Coupling of a drug molecule
inhibits this protonation. The albumin molecule is left with a relative negative charge
and becomes a substrate for the scavenger receptors. Apart from the net negative charge, it
has been postulated that the added hydrophobicity of these drug molecules is an important
feature in determining their affinity for the scavenger receptors [94].
After interaction of the aforementioned carriers with specific receptors, the carrier is then
taken up by endocytosis and transported intracellularly to acidified endosomes and lysosomes.The
carrier is proteolytically degraded in the lysosomes and if a drug is coupled to the
carrier, it is then released to diffuse into the cytoplasmic compartment.
4.5.1.2 Liposomes
4.5 Drug Targeting to the Liver 101
Liposomes are small vesicles composed of unilamellar or multilamellar phospholipid bilayers
enclosing an aqueous space. Soluble drugs can readily be incorporated into this aqueous
space and lipophilic drugs can be incorporated into the lipid bilayer.The loading capacity for
drugs is therefore much greater than that of the modified albumins. Elimination from the circulation
is dependent on the lipid composition, charge, and size of the liposomes. Common liposomes
such as neutral and negatively-charged liposomes, are however, primarily cleared
by the phagocytotic processes of the cells of the reticuloendothelial system (RES), the KCs
having the greatest responsibility for this process.This feature of liposomes can seriously limit
the use of liposomes in targeting other sites in the body [95]. It has been shown for instance
that the targeting of cytostatic agents such as adriamycine to tumours is associated with loss
of KC function [96], thereby contributing to the immuno-suppressed status of patients. The
high KC uptake has been suprisingly under-exploited in drug targeting approaches to treat
liver diseases. Liposomes have been used for the targeting of anti-Leishmania drugs [97,98]
and immunomodulators [99] and have greatly increased the efficacy of these drugs in Leishmania
infections and metastatic tumour growth, respectively. However, intervening in the fibrotic
process by modulating KC or SEC functions with liposome-encapsuled drugs has not
yet been attempted.
The exact mechanism responsible for the uptake of liposomes by KCs and SECs is not
clear. Most studies confirm internalization of whole liposomes in an energy-dependent
phagocytic process in which the liposomes are delivered to the lysosomes. The liposomal
lipids are completely degraded and the encapsulated solutes released. Neutral liposomes
consisting of lipids such as cholesterol and phosphatidylcholine are probably cleared by receptor-mediated
mechanisms, due to the adsorption of opsonizing proteins onto the lipid bi-