Drug Targeting Organ-Specific Strategies

7.7 General Considerations and Practical Directions for Endothelial Cell Targeting Research 191
cules and leucocyte recruitment [144,145]. These models of pathological mechanisms and effects
of anti-inflammatory drugs have been studied in mice in particular [146].
The models described herein are just a few examples of general experimental models used
to study inflammatory reactions. A wide variety of other models exist which can be used in
drug targeting research. It is however beyond the scope of this chapter to list all the models
which have been used.
7.7 General Considerations and Practical Directions for
Endothelial Cell Targeting Research
7.7.1 The Choice of a Target Epitope
Identifying an appropriate epitope for the desired drug targeting strategies is a complex
process in which several considerations have to be taken into account. First, an important
feature of a target epitope is its cellular processing, i.e. its internalization characteristics and
its route into the cell. For instance, E-selectin is directed to the lysosomes and subsequently
degraded, whereas P-selectin is re-routed through the Golgi-apparatus to the Weibel Palade
bodies in which it is stored [147–150]. In contrast, antibodies directed against ICAM-1 or
VCAM-1 are not internalized, but remain surface bound to the endothelial cell [147,148].
Second, the tissue-specific distribution pattern of constitutively expressed target epitopes
may largely determine the selectivity of accumulation of the chosen targeting device in the
diseased tissue. For instance, under normal physiological circumstances ICAM-1 and
VCAM-1 are expressed on non-inflammatory endothelium, dendritic cells and leucocytes.
Another example is the constitutive expression of P-selectin on platelets, in addition to being
expressed on activated endothelial cells. When aiming at target epitopes that are not specifically
induced in diseased tissue, effective targeting to chronically activated endothelium does
not seem to be feasible. Third, the level of expression of the target epitope has to be taken
into account. Hypothetically, differences in target epitope density may allow discrimination
between diseased and non-diseased tissues, as has been reported for tumour-associated antigens.
In this case the mechanism of action and the therapeutic window of the drug will determine
whether delivery of small amounts to the non-diseased endothelium will lead to undesirable
toxicity. Fourth, cleavage of target molecules from the target cell membrane, resulting
in soluble adhesion molecules, may frustrate the process of targeting to the endothelial
cell as a result of undesirable systemic complex formation.
Bearing these considerations in mind, of the presently identified endothelial adhesion
molecules, E-selectin in particular seems to be a suitable epitope for targeting chronic inflammatory
endothelial cells.
7.7.2 Disease Stage
In tumour models different stages of angiogenesis are thought to prevail, leading to varying
degrees of responsiveness to anti-angiogenic treatment.Therefore anti-angiogenic drugs may
prove most efficacious when targeted at distinct stages of the angiogenic process [151].