Drug Targeting Organ-Specific Strategies

integrin-mediated events such as T cell aggregation, T cell-stromal interactions and lymphocyte
homing [62]. Furthermore, Jamar et al. reported the use of an anti-E-selectin antibody
for imaging rheumatoid arthritis in humans. This antibody was 111 In-labelled and its localization
was compared with a non-specific 99 Tc m -labelled immunoglobulin. The anti-E-selectin
antibody was found to have a more specific distribution and higher sensitivity of detection
than the control antibody. As the 99 Tc m -label is preferred for its physical properties, further
investigations now comprise the production of a 99 Tc m -labelled F(ab′) 2-fragment of the anti-
E-selectin antibody [63].
In studies of tumour-induced angiogenesis, the monoclonal antibody LM609 against the
αvβ3 integrin receptor was used for imaging purposes [64]. Its humanized counterpart Vitaxin,
which has now entered clinical anti-cancer trials, could in theory also be used for targeting
to endothelium in chronically inflamed sites where αvβ3 is upregulated.
There are a few examples of the use of antibodies as targeting devices to vascular endothelium.
Kiely et al. used the monoclonal antibody H18/7 to target hirudin, an anti-thrombin
agent, to the surface of activated human vascular endothelial cells in vitro [65]. The same
antibody was also incorporated in liposomes to target doxorubucin to activated endothelium
[66]. A bispecific antibody recognizing both E-selectin and an adenovirus (AdZ.FLAG) was
used to specifically transduce activated endothelium with a gene encoding β-galactosidase,
resulting in the production of this protein [67]. However, all of these studies were carried out
in vitro only and at present, no definite conclusions on their pharmacological potential in
vivo can be drawn.
In another approach, antibodies directed against ICAM-1, angiotensin converting enzyme
(ACE) or CD31 conjugated to catalase were successfully used to protect perfused rat lungs
against oxidative stress [68,69].The lungs receive the entire cardiac blood output and contain
30% of the endothelial cell population in the body. In addition, ICAM-1 and ACE are constitutively
expressed on the pulmonary vasculature. Therefore, this approach may result in
significant accumulation in the lungs of ICAM-1- or ACE-directed conjugates, even when inflammatory
processes in other organs are the desired target. Consequently, these conjugates
are likely to be useful only for the treatment of lung disorders.
7.4.2.2 Peptides
7.4 Targeting Drugs to the Endothelial Cell 181
Peptides, like antibodies, have until now mostly been exploited as direct-acting moieties in
imaging or inhibition studies. An E-selectin binding peptide has been used for imaging in
arthritis models.This peptide has the advantage of recognizing and binding to murine, rat and
human E-selectin, in contrast to antibodies which lack cross reactivity with E-selectins from
other species [70,71]. Peptides recognizing and blocking the function of other selectins,
ICAM-1, VCAM-1 and chemokines have also been documented [1,72].
Peptides containing an RGD motif can be used to target the αvβ3 integrin receptor on angiogenic
blood vessels. Specifically the dicyclic peptide RGD-4C, an 11mer with two disulfide
bridges, exhibits a high affinity for the αvβ3 integrin receptor due to its constrained conformation.
Arap et al. showed that this peptide can selectively deliver chemotherapeutics at the
αvβ3 integrin receptor on angiogenic blood vessels in solid tumours [73]. Furthermore, an
apoptosis-inducing peptide was specifically delivered to angiogenic endothelium by a chem-