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

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.

SUBMITTER: Muro S

PROVIDER: S-EPMC2810502 | biostudies-other | 2008 Aug

REPOSITORIES: biostudies-other

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Project description:Targeting of drug carriers to cell adhesion molecules expressed on endothelial cells (ECs) may improve treatment of diseases involving the vascular endothelium. This is the case for carriers targeted to intercellular adhesion molecule 1 (ICAM-1), an endothelial surface protein overexpressed in many pathologies. In order to optimize our design of anti-ICAM carriers, we have explored in this study the influence of two carrier design parameters on specific and efficient endothelial targeting in vitro and in vivo: carrier dose and density of targeting molecules (antibodies-Ab) on the carrier surface. Using radioisotope tracing we assessed the role of these parameters on the biodistribution of model polymer carriers targeted to ICAM-1 ((125)I-anti-ICAM carriers) in mice. Increasing the carrier dose enhanced specific accumulation in the lung vasculature (a preferential endothelial target) and decreased non-specific hepatic and splenic uptake. Increasing the Ab density enhanced lung accumulation with minimally reduced liver and spleen uptake. These studies account for the influence of blood hydrodynamic forces on carrier binding to endothelium, relevant to arterioles, venules and larger vessels. Yet, carriers may rather bind to the extensive capillary bed where shear stress is minimal. We used fluorescence microscopy to determine binding kinetics of FITC-labeled anti-ICAM carriers in static conditions, at the threshold found in vivo and conditions mimicking low vs high ICAM-1 expression on quiescent vs activated ECs. Binding to activated ECs reached similar saturation with all tested Ab densities and carrier concentrations. In quiescent cells, carriers reached ~3-fold lower binding saturation, even at high carrier concentration and Ab density, and carriers with low Ab density did not reach saturation, reflecting avidity below threshold. Binding kinetics was positively regulated by anti-ICAM carrier concentration and Ab density. Counterintuitively, binding was faster in quiescent ECs (except for carriers with high Ab density and concentration), likely due to fast saturation of fewer binding sites on these cells. These results will guide optimization of ICAM-1-targeted carriers, e.g., in the context of targeting healthy vs diseased endothelium for prophylactic vs therapeutic interventions.

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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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