Drug Targeting Organ-Specific Strategies

4.9 Targeting of Anti-inflammatory Drugs for the Treatment of Liver Fibrosis 113
therefore had to be derivatized to create a reactive compound. As described by Fiume et al.
[187] succinic acid was coupled to the alcohol group on C21 yielding Dexa hemisuccinate.
The introduced carboxyl group could then easily be coupled to the free amino groups of the
lysine residues in the HSA molecule yielding Dexa 10-HSA and Dexa 5-Man 10-HSA (Figure
4.4) [152]. The ester bond between native Dexa and the succinate spacer proved to be
more sensitive to proteolytic enzymes than the amide bond between the succinate spacer and
the protein. Lysosomal degradation of the Dexa-HSA conjugate, therefore, yielded the native
Dexa.
Figure 4.5. Tissue and intrahepatic distribution of 125I-Dexa 5-Man 10-HSA 10 min after injection in
normal (n = 4) and cirrhotic rats (n = 5). NPC, non-parenchymal cells; PC, parenchymal cells.
In rats, both Dexa 10-HSA and Dexa 5-Man 10-HSA were mostly taken up by the liver, in
healthy as well as fibrotic livers (Figure 4.5). Intrahepatic distribution studies showed that
Dexa 10-HSA was taken up by SECs and KCs, whereas Dexa 5-Man 10-HSA was taken up by
KCs [93,152]. Interestingly, in human livers Dexa 10-HSA was found to be taken up by SECs
and KCs of healthy livers, but in cirrhotic livers only by KCs [165]. In liver slices, these two
conjugates showed superior inhibition of LPS-induced release of TNFα as compared to untargeted
Dexa, indicating specific inhibition of KC and SEC function.
The efficacy of Dexa 10-HSA in vivo was shown in a model of acute inflammation. Fibrotic
rats pretreated with conjugated and non-conjugated Dexa showed increased survival after
LPS injection. Although the anti-inflammatory effects of Dexa 10-HSA could be demonstrated,
superiority of conjugated Dexa as compared to free Dexa could not be established in this
model.
When Dexa 5-Man 10-HSA was administered chronically to rats with BDL, reduced infiltration
of ROS-producing cells and an increased glycogen content in hepatocytes was found,
suggesting more efficient liver function, this was not the case for non-conjugated Dexa [93].
The specific inhibition of KC function in this model, however, also accelerated the development
of fibrosis. The mechanism causing this acceleration is currently under investigation,