Modulation of endothelial targeting by size of antibody-antioxidant enzyme conjugates.
Endothelial targeting of antioxidant enzymes attenuates acute vascular oxidative stress in animal studies. Superoxide dismutase (SOD) and catalase conjugated with antibodies to Platelet-Endothelial Cell Adhesion Molecule-1 (anti-PECAM/SOD and anti-PECAM/catalase) bind to endothelium, accumulate in the pulmonary vasculature, and detoxify reactive oxygen species. In order to define the role of conjugate size in the efficacy and specificity of endothelial targeting, we synthesized anti-PECAM/enzyme conjugates of controlled size (40nm-10,000nm). Binding of anti-PECAM/enzymes to endothelial cells increased with conjugate size from 300nm to 2μm (from 2.5 to 8.5% of bound fraction), and was specific, as conjugates did not bind to PECAM-negative cells. Pulmonary uptake of anti-PECAM/enzyme conjugates injected intravenously in mice also increased from 4.5 to 16% of injected dose for particles from 200 to 800nm. However, control conjugates larger than 300nm showed elevated non-specific pulmonary uptake, indicating that the targeting specificity of anti-PECAM/enzyme conjugates in vivo has a bell-shaped curve with a maximum close to 300-nm diameter. These results show that: i) the size of an antibody/enzyme conjugate modulates efficacy and specificity of targeting, and ii) a size optimum should be defined in vivo to account for parameters that are difficult to model in cell culture.
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Vladimir V
VV
Shuvaev
Samira
S
Tliba
Jeremy
J
Pick
Evguenia
E
Arguiri
Melpo
M
Christofidou-Solomidou
Steven M
SM
Albelda
Vladimir R
VR
Muzykantov
D000818:Animals; D000975:Antioxidants; D002374:Catalase / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology*; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology
D000975:Antioxidants; D018796:Immunoconjugates; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D002374:Catalase; D013482:Superoxide Dismutase