Drug Targeting Organ-Specific Strategies

180 7 Vascular Endothelium in Inflamed Tissue as a Target for Site Selective Delivery of Drugs
to the target cells at the external surface, and carrier molecules that after binding are internalized
and intracellularly processed. This will be discussed further in Section 7.7.
7.4.1 Target Epitopes on Inflammatory Endothelium
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.
Over the past decade, many target epitopes have been described to be upregulated on angiogenenic
blood vessels. Recently, several targets that are under investigation for the clinical
development of anti-tumour agents, have also been studied under conditions of chronic
inflammation. One of them is the αvβ3 integrin receptor, which is upregulated on synovial
blood vessels in antigen-induced arthritis (AIA) in rabbits and in human RA [36]. Furthermore,
the VEGF-receptors VEGF-R1 (Flt-1/flt-1) and VEGF-R2 (KDR/flk-1) are strongly
expressed by microvascular endothelial cells in RA, psoriatic epidermis and atherosclerotic
lesions [42,56,57].
In addition to the above-mentioned target epitopes, other endothelial molecules can be
considered as targets. For instance, chemokine receptors have been identified to be present
on activated endothelial cells [58]. A chemokine that may be useful in endothelial cell targeting
is Fractalkine, a chemokine with a CX 3C motif on a membrane-bound mucin-like
stalk.This molecule has chemoattractant activity and promotes strong adhesion of T cells and
monocytes through the Fractalkine receptor CX 3CR1. It can, however, also exist in a soluble
form and thereby provide an undesirable sink for Fractalkine-targeted compounds. Furthermore,
it is also expressed to various extents by monocytes and microglial cells [59–61]. Besides
the specificity of cellular expression of the target epitopes, other important considerations
should be taken into account when selecting a target epitope. These considerations will
be discussed in more detail in Section 7.7.
At present, many questions regarding the use of the target epitopes for endothelium-directed
drug targeting strategies still remain to be answered. The efforts that are being put
into the development of drug targeting strategies directed at these epitopes should, in the
near future, eventually lead to a better understanding of the potential of this area of drug development.
7.4.2 Targeting Devices
7.4.2.1 Monoclonal Antibodies
Various antibody-based targeting moieties have been described, either as directly acting
compounds or as targeting devices. Antibodies against adhesion molecules have been widely
used as blocking agents, presumably because of their high specificity and their relative ease
of production. For instance, an anti-α4 integrin monoclonal antibody significantly attenuated
colitis in the cotton-top tamarin by intervention in leucocyte adhesion and possibly in other