Modulation of endothelial targeting by size of antibody-antioxidant enzyme conjugates

JOURNAL OF CONTROLLED RELEASE

卷:149

Article

Shuvaev, Vladimir V.¹  Tliba, Samira¹  Pick, Jeremy¹  Arguiri, Evguenia²  Christofidou-Solomidou, Melpo²  Albelda, Steven M.²  Muzykantov, Vladimir R.^1,3 

[1] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Div Pulm Crit Care, Dept Med, Philadelphia, PA 19104 USA

[3] Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA

关键词: Vascular immunotargeting;    Endothelium;    Antioxidant delivery;    Lungs;   

DOI  :  10.1016/j.jconrel.2010.10.026

来源: Elsevier

【 摘 要 】

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 (40 nm-10,000 nm). Binding of anti-PECAM/enzymes to endothelial cells increased with conjugate size from 300 nm to 2 mu m (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 800 nm. However, control conjugates larger than 300 nm 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. (C) 2010 Elsevier B.V. All rights reserved.

【 授权许可】

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