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Am J Physiol Cell Physiol 285: C1339-C1347, 2003. First published July 23, 2003; doi:10.1152/ajpcell.00099.2003
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PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON

Slow intracellular trafficking of catalase nanoparticles targeted to ICAM-1 protects endothelial cells from oxidative stress

Silvia Muro,1 Xiumin Cui,1 Christine Gajewski,1 Juan-Carlos Murciano,1,2 Vladimir R. Muzykantov,1,2 and Michael Koval1,3

1Institute for Environmental Medicine and Departments of 2Pharmacology and 3Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Submitted 14 March 2003 ; accepted in final form 14 July 2003

Nanotechnologies promise new means for drug delivery. ICAM-1 is a good target for vascular immunotargeting of nanoparticles to the perturbed endothelium, although endothelial cells do not internalize monomeric anti-ICAM-1 antibodies. However, coupling ICAM-1 antibodies to nanoparticles creates multivalent ligands that enter cells via an amiloride-sensitive endocytic pathway that does not require clathrin or caveolin. Fluorescence microscopy revealed that internalized anti-ICAM nanoparticles are retained in a stable form in early endosomes for an unusually long time (1-2 h) and subsequently were degraded following slow transport to lysosomes. Inhibition of lysosome acidification by chloroquine delayed degradation without affecting anti-ICAM trafficking. Also, the microtubule disrupting agent nocodazole delayed degradation by inhibiting anti-ICAM nanoparticle trafficking to lysosomes. Addition of catalase to create anti-ICAM nanoparticles with antioxidant activity did not affect the mechanisms of nanoparticle uptake or trafficking. Intracellular anti-ICAM/catalase nanoparticles were active, because endothelial cells were resistant to H2O2-induced oxidative injury for 1-2 h after nanoparticle uptake. Chloroquine and nocodazole increased the duration of antioxidant protection by decreasing the extent of anti-ICAM/catalase degradation. Therefore, the unique trafficking pathway followed by internalized anti-ICAM nanoparticles seems well suited for targeted delivery of therapeutic enzymes to endothelial cells and may provide a basis for treatment of acute vascular oxidative stress.

drug delivery; endocytosis; microtubules; lysosomes


Address for reprint requests and other correspondence: V. R. Muzykantov (drug delivery and vascular immunotargeting), Univ. of Pennsylvania School of Medicine, Institute for Environmental Medicine, 1 John Morgan/6068, 3620 Hamilton Walk, Philadelphia, PA 19104 (E-mail: muzykant{at}mail.med.upenn.edu); or M. Koval (cell biology and endocytosis), Univ. of Pennsylvania School of Medicine, Dept. of Physiology, B-400 Richards Bldg./6085, 3700 Hamilton Walk, Philadelphia, PA 19104 (E-mail: mkoval{at}mail.med.upenn.edu).




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