Blood, 15 May 2003, Vol. 101, No. 10, pp. 3761-3761
Location, location, location: targeting the endothelium
With regard to real estate, it is said, location is everything.
Location may prove to be almost as important with respect to the
delivery and application of novel, especially macromolecular, therapeutic agents. Specifically targeted delivery should enhance efficacy while at the same time reducing toxicity.
In this issue of Blood, Murciano and colleagues (page 3977)
report the delivery and localization of immunoconjugates of tissue plasminogen activator (tPA) to the pulmonary vasculature. Although the
concept of immunotargeting therapeutic agents is not new, several
aspects of the strategy employed by Murciano et al are noteworthy. Intercellular adhesion molecule-1 (ICAM-1)
appears to be an especially good target. It is constitutively expressed on the vascular endothelium at a high level that is unaltered by
inflammatory cytokines. Furthermore, anti-ICAM conjugates greater than
1 µm in diameter are not readily internalized but remain exposed on the endothelial surface for some time. Such conjugates are
thus well positioned to function as molecular therapeutic bioreactors
working at the blood-vessel wall interface. As a proof of concept,
Murciano et al describe the efficacious lysis of pulmonary fibrin
microemboli using an anti-ICAM/tPA conjugate.
While the results of the work described by Murciano et al are exciting
in their own right, the work also offers a glimpse of the future
promise of endothelial-targeted therapeutics. Given the large surface
area of the (pulmonary) endothelium, enzyme bioreactors positioned at
the endothelial surface may represent an exciting new approach to the
removal or inactivation of noxious metabolites or toxins. By exploiting
more specific vascular addressins as immunotargets, selected vascular
beds may be targeted. Perhaps by targeting tumor vasculature with an
enzyme to facilitate the conversion of a prodrug to an active antitumor
agent, or conversely targeting the pulmonary or hepatic
vascular spaces with an enzyme to inactivate chemotherapeutic agents,
tumors may be exposed to higher and more effective doses of
chemotherapeutic agents while minimizing systemic toxicity. Although
the work described by Murciano et al is still in an early stage and
there is much work to be done, the future is exciting; the promise is great.
Samuel A. Santoro and Thomas P. Stricker
Washington University School of
Medicine
