@article {156321,
	title = {Size-dependent intracellular immunotargeting of therapeutic cargoes into endothelial cells},
	journal = {Blood},
	volume = {99},
	number = {3},
	year = {2002},
	pages = {912-922},
	abstract = {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-beta-gal) conjugates bound selectively to PECAM-expressing cells, only small conjugates showed intracellular accumulation of active P-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 mum 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. (C) 2002 by The American Society of Hematology.},
	url = {https://ashpublications.org/blood/article/99/3/912/53513/Size-dependent-intracellular-immunotargeting-of},
	author = {Wiewrodt, R. and Thomas, A. P. and Cipelletti, L. and Christofidou-Solomidou, M. and Weitz, D. A. and Feinstein, S. I. and Schaffer, D. and Albelda, S. M. and Koval, M. and Muzykantov, V.R.}
}
