Drug Targeting Organ-Specific Strategies

98 4 Cell Specific Delivery of Anti-Inflammatory Drugs to Hepatic Cells
nesis will progress to cirrhosis. When fibrogenesis takes over, however, collagens type I and
III which are normally concentrated in the portal tracts and around central veins, are deposited
throughout the liver. Collagen IV and VI and other components of the extracellular
matrix are also increasingly expressed. The normal liver only contains 1–2% connective tissue,
but in patients with cirrhosis this can increase up to a maximum of 50% [75]. The increased
amount of extracellular matrix results in severe disruption of blood flow and impaired
diffusion of solutes between PCs and plasma, which may have implications for drug
targeting preparations to hepatic cells. Deposition of collagens in the space of Disse is also
accompanied by the loss of fenestrations in SECs, which further impairs the movement of
proteins between PCs and plasma. The subsequent resistance to portal flow induces portal
hypertension and together with the reduced metabolic capacity of the liver this leads to four
major clinical consequences: development of ascites, the formation of portosystemic venous
shunts leading to dangerous esophagogastric varices, congestive splenomegaly causing
haematologic abnormalities, and hepatic encephalopathy because of the exposure of the
brain to an altered metabolic milieu. Other complications arising from the progressing fibrosis
of the liver are the appearance of renal failure (hepatorenal syndrome), endotoxemia and
hepatic failure. When loss of the hepatic functional capacity exceeds 80–90%, liver transplantation
is usually the only option for survival. Many new pharmacological approaches to
the therapy of fibrosis are being explored, but lack of effectiveness or a small therapeutic
window remain major obstacles. These approaches may therefore benefit from drug targeting
strategies [3].
4.4 Liver Cirrhosis: Causes and Therapy
Cirrhosis is among the top 10 causes of death in the Western World. This is largely the result
of alcohol abuse, viral hepatitis and biliary diseases [75]. The causes for cirrhosis can be
roughly divided into six categories:
1. Chronic exposure to toxins such as alcohol, drugs or chemicals,
2. Viral hepatitis resulting from infection with the hepatitis B, C or D viruses,
3. Metabolic disorders such as Wilson’s disease (copper storage disease) and haemochromatosis
(iron overload disease),
4. Autoimmune diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis
(PSC) and autoimmune hepatitis,
5. Venous outflow obstruction,
6. Cirrhosis of unknown causes.
Obviously the best treatment for cirrhosis is removal of the injurious event. In the case of
viral hepatitis, viral load can at least be temporarily reduced with anti-viral agents such as
lamivudine, ribavirin and/or IFNα [76]. Unfortunately, complete removal of the injurious
event is frequently not possible. Moreover, by the time cirrhosis is diagnosed the fibrotic
process has usually progressed beyond ‘the point of no return’ and removal of the injurious
event will have little effect. Successful pharmacological treatment to reverse the fibrotic