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Blood, 1 February 2002, Vol. 99, No. 3, pp. 912-922
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Size-dependent intracellular immunotargeting of therapeutic
cargoes into endothelial cells
Rainer Wiewrodt,
Anu P. Thomas,
Luca Cipelletti,
Melpo Christofidou-Solomidou,
David A. Weitz,
Sheldon I. Feinstein,
David Schaffer,
Steven M. Albelda,
Michael Koval, and
Vladimir R. Muzykantov
From the Pulmonary Critical Care Division, Department
of Medicine; the Institute for Environmental Medicine; and the
Departments of Physiology and Pharmacology, University of Pennsylvania
School of Medicine, Philadelphia; the Department of Physics, University
of Pennsylvania, Philadelphia; and the Department of Chemical
Engineering, University of California, Berkeley.
Cell-selective intracellular targeting is a key element of more
specific and safe enzyme, toxin, and gene therapies. Endothelium poorly
internalizes certain candidate carriers for vascular
immunotargeting, such as antibodies to platelet endothelial cell
adhesion molecule 1 (PECAM-1). Conjugation of poorly internalizable
antibodies with streptavidin (SA) facilitates the intracellular uptake.
Although both small and large (100-nm versus 1000-nm diameter)
anti-PECAM/SA-beta galactosidase (SA- -gal) conjugates bound
selectively to PECAM-expressing cells, only small conjugates showed
intracellular accumulation of active -gal. To study whether size of
the conjugates controls the uptake, a series of anti-PECAM/SA and
anti-PECAM/bead conjugates ranging from 80 nm to 5 µm in diameter
were produced. Human umbilical vein endothelial cells and
PECAM-transfected mesothelioma cells internalized 80- to 350-nm
anti-PECAM conjugates, but not conjugates larger than 500 nm. Further,
size controls intracellular targeting of active therapeutic cargoes in
vitro and in vivo. Small anti-PECAM/DNA conjugates transfected target
cells in culture 5-fold more effectively than their large counterpart
(350- versus 4200-nm diameter). To evaluate the practical significance
of the size-controlled subcellular addressing, we coupled glucose
oxidase (GOX) to anti-PECAM and antithrombomodulin. Both types of
conjugates had equally high pulmonary uptake after intravenous
injection in mice, yet only small (200- to 250-nm), not large (600- to
700-nm), GOX conjugates caused profound oxidative vascular injury in
the lungs, presumably owing to intracellular generation of
H2O2. Thus, engineering of affinity carriers of
specific size permits intracellular delivery of active cargoes to
endothelium in vitro and in vivo, a paradigm useful for the targeting
of drugs, genes, and toxins.
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