Targeting Drugs to the Endothelial Cell

In most, if not all, chronic inflammatory diseases endothelial cells are prominently involved in the disease process. This is demonstrated by an increased expression of adhesion molecules and production of cytokines, and their pro-angiogenic behaviour. This leads to continuous recruitment of leucocytes into the inflamed area, without (detectable) antigen present in the affected tissue, resulting in a vicious circle of tissue damage and leucocyte recruitment. Targeting inhibitory agents (in)to the endothelial cell may interrupt in this process by controlling the activation status of this cell type. 

7 Vascular Endothelium in Inflamed Tissue as a Target for Site Selective Delivery of Drugs 

A rational approach in the development of drug targeting carriers for endothelial cells in inflamed tissue is to identify disease-induced target epitopes in these cells [54,55]. As discussed in Sections 7.2.1 and 7.3, in this respect E- and P-selectin, VCAM-1 and ICAM-1 are considered candidate target epitopes. 

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Targeting the liver is of great interest as many hepatic diseases do not have efficient pharmacotherapy available. Considering the variety of hepatic cell receptors, lots of drugs are cleared out from the blood circulation by the liver. The main challenge is to target selectively one type of receptor to deliver specifically the drug to the diseased cell. Represented at 80% in volume, parenchymal cells are the best known and referred as hepatocytes non-parenchymal cells are the other main class of liver cells, such as Kupffer cells and sinusoidal hepatic endothelial cells. 

The viability and function tests described above are used to evaluate the hepatocytes within the slice. Up to now, tests to measure the viability of the non-parenchymal cells have not been reported. The presence of the latter cell types is one of the conceptual advantages of slices as compared to isolated hepatocytes. As some drug targeting devices are designed to target non-parenchymal cells in the liver, the development of tests for the sinusoidal cell types deserves more attention. For example, the uptake of substrates such as succinylated human serum albumin (Suc-HSA,which is specifically endocytosed by endothelial cells [79]), or hyaluronic acid [80], can be used to assess the functionality of endocytotic pathways in the endothelial cells in the liver [81]. Other modified proteins that are specifically taken up by Kupffer cells such as mannosylated HSA, may be used to assess the functionality of the endocytotic pathway in Kupffer cells [79]. Another parameter which can be used to assess the functionality of these non-parenchymal liver cells, is the excretion of cytokines in response to pro-inflammatory stimuli. Non-parench5mal cell function in liver slices will be described in more detail in the Section 12.7. 

In order to cross the endothelial cell barrier, the macromolecules or drug-targeting complex must leave the circulation by either intercellular junctions or a mechanism similar to tnmscytosis. The permeability of the vessel wall could be... 

The issue of targeting is far more complex than simply showing a specific affinity of a particular carrier complex with a specific cell or even the ability of the cell to take up the complex and have the drug or peptide activity expressed. Here we must seek to understand how the complex reaches the site of action from the site of administration. Except for cases where this involves local or topical administration, it invariably implies the circulation or blood stream as a pathway and therefore the endothelial cell membrane or layer as an important barrier. A second important obstacle is really a negative barrier, i.e., the reticuloendothelial system (RES), including macrophages, whose function it is to remove unfamiliar... 

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