Testing Liver Targeting Preparations

We have developed albumin-conjugates of dexamethasone and naproxen for targeting to SECs and KCs. These conjugates have been extensively tested in vitro and in vivo in rats with bile duct hgation-induced hver fibrosis [93,147-150]. 

Since the structure of the liver is completely changed during fibrosis, distribution of a liver targeting compound has to be tested in the pathological state as well. Parts of the liver may become inaccessible by portosystemic shunts and individual cells may be hampered in the uptake of compounds by the excess extracellular matrix deposited around them. Uptake processes themselves may also be impaired. The phagocytic activity of KCs has been reported to be depressed in some forms of fibrosis [153,154] and some receptors, such as the 

Once specific liver uptake is established, the intrahepatic distribution needs to be addressed. The importance of this issue is exemplified by the apparently high uptake of untargeted Dexa by the liver. Dexa itself was taken up exclusively by the hepatocytes, whereas targeted Dexa was taken up by SECs and KCs [152], the target cells for anti-inflammatory therapy. 

Qualitative analysis of intrahepatic distribution is possible with immunohistochemistry. With antibodies against the carrier or the carrier-bound drug this compound can be localized in liver sections [152],To identify the cell type(s) involved in the uptake, the sections can subsequently be double stained with markers for the different cell types. In the rat liver, the monoclonal antibodies HIS52 (anti-rat endothelial cell antigen-1 or anti-RECA-1), ED2, the combination of anti-desmin and anti-glial fibrillary acidic protein, and anti-aSMA are generally used to identify SECs, KCs, quiescent HSCs, and activated HSCs, respectively. 

4 Cell Specific Delivery of Anti-Infiammatory Drugs to Hepatic Cells 

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J. H. Sherry, J. P. O Donnell, H. D. Colby, Conversion of Spironolactone to an Active Metabolite in Target Tissues Formation of 7a-Thiospironolactone by Microsomal Preparations from Guinea Pig Liver, Adrenals, Kidneys and Testes , Life Sci. 1981, 29, 2727-2736. 

As mentioned in Section 11.2, a special class of proteinaceous targeting constructs are those in which a therapeutic protein is used as the active drug substance. In such a preparation, the protein is redirected to the target tissue by the attachment of site-directing ligands such as those discussed in Section 11.3. For instance, interferon beta (IFN- 3) can be redirected to the liver by enz5matic desialylation in a procedure similar to that described earlier for fetuin (Section 11.3.1). The resultant asialo-IFN- 3 was found to have an in vivo anti-viral effect when tested in a hepatitis B model in athymic nude mice [54]. 

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