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Am J Physiol Cell Physiol (July 23, 2003). doi:10.1152/ajpcell.00099.2003
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Submitted on March 14, 2003
Accepted on July 14, 2003

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

Silvia Muro1, Xiumin Cui1, Christine Gajewski1, Juan-Carlos Murciano2, Vladimir R Muzykantov2, and Michael Koval3*

1 Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
2 Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
3 Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

* To whom correspondence should be addressed. E-mail: mkoval{at}mail.med.upenn.edu.

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 which 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 nanoparticle with anti-oxidant activity did not affect the mechanisms of nanoparticle uptake or trafficking. Intracellular anti-ICAM/catalase nanoparticles were active, since endothelial cells were resistant to H2O2-induced oxidative injury for 1 to 2 h following nanoparticle uptake. Chloroquine and nocodazole increased the duration of anti-oxidant 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.




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