1. ¹Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia,Pennsylvania,USA
2. ²Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
3. ³Institute for Environmental Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
4. ⁴Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA
5. ⁵Department of Chemical Engineering, College of Engineering, University of California Santa Barbara, Santa Barbara, California, USA

Correspondence: Silvia Muro, Center for Biosystems Research, University of Maryland Biotechnology Institute, 5115 Plant Sciences Building, College Park, Maryland 20742-4450, USA. E-mail: muro@umbi.umd.edu; Vladimir R Muzykantov, Vladimir R Muzykantov, Institute for Environmental Medicine, School of Medicine, University of Pennsylvania, 1 John Morgan Building, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104-6068, USA. E-mail: muzykant@mail.med.upenn.edu

Received 12 February 2008; Accepted 5 May 2008; Published online 17 June 2008.

Abstract

Endocytosis in endothelial cells (ECs) is important for many biomedical applications, including drug delivery by nano- and microscale carriers. However, little is known about how carrier geometry influences endothelial drug targeting, intracellular trafficking, and effects. We studied this using prototype polymer carriers of various sizes (0.1–10 m) and shapes (spheres versus elliptical disks). Carriers were targeted to intercellular adhesion molecule 1 (ICAM-1), a transmembrane glycoprotein that is upregulated in many pathologies and used as a target for intraendothelial drug delivery. ECs internalized anti-ICAM-coated carriers of up to several microns in size via cell adhesion molecule–mediated endocytosis. This pathway is distinct from caveolar and clathrin endocytosis that operate for submicron-size objects. Carrier geometry was found to influence endothelial targeting in the vasculature, and the rate of endocytosis and lysosomal transport within ECs. Disks had longer half-lives in circulation and higher targeting specificity in mice, whereas spheres were endocytosed more rapidly. Micron-size carriers had prolonged residency in prelysosomal compartments, beneficial for endothelial antioxidant protection by delivered catalase. Submicron carriers trafficked to lysosomes more readily, optimizing effects of acid sphingomyelinase (ASM) enzyme replacement in a model of lysosomal storage disease. Therefore, rational design of carrier geometry will help optimize endothelium-targeted therapeutics.