Control of endothelial targeting and intracellular delivery of therapeutic enzymes by modulating the size and shape of ICAM-1-targeted carriers.

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TitleControl of endothelial targeting and intracellular delivery of therapeutic enzymes by modulating the size and shape of ICAM-1-targeted carriers.
Publication TypeJournal Article
Year of Publication2008
AuthorsMuro, S, Garnacho, C, Champion, JA, Leferovich, J, Gajewski, C, Schuchman, EH, Mitragotri, S, Muzykantov, VR
JournalMol Ther
Volume16
Issue8
Pagination1450-8
Date Published2008 Aug
ISSN1525-0024
KeywordsActins, Animals, Antibodies, Monoclonal, Caveolae, Cell Line, Drug Carriers, Drug Delivery Systems, Endocytosis, Endothelial Cells, Humans, Intercellular Adhesion Molecule-1, Male, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Particle Size, Polymers
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 mum) 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.

DOI10.1038/mt.2008.127
Alternate JournalMol. Ther.
PubMed ID18560419
PubMed Central IDPMC2810502
Grant ListP01 HL079063 / HL / NHLBI NIH HHS / United States
P30 DK47757-14 / DK / NIDDK NIH HHS / United States
R01 HD28607 / HD / NICHD NIH HHS / United States
R01 HL080396 / HL / NHLBI NIH HHS / United States
R01 HL087036-05 / HL / NHLBI NIH HHS / United States
R21 HL85533 / HL / NHLBI NIH HHS / United States
U01 HL080718 / HL / NHLBI NIH HHS / United States
U01 HL080718-04 / HL / NHLBI NIH HHS / United States