Size and targeting to PECAM vs ICAM control endothelial delivery, internalization and protective effect of multimolecular SOD conjugates

JOURNAL OF CONTROLLED RELEASE

卷:234

Article

Shuvaev, Vladimir V.¹  Muro, Silvia²  Arguiri, Evguenia³  Khoshnejad, Makan¹  Tliba, Samira¹  Christofidou-Solomidou, Melpo³  Muzykantov, Vladimir R.¹ 

[1] Univ Penn, Ctr Translat Targeted Therapeut & Nanomed, Dept Syst Pharmacol & Translat Therapeut, Inst Translat Med & Therapeut,Perelman Sch Med, Philadelphia, PA 19104 USA

[2] Univ Maryland, Fischell Dept Bioengn, College Pk, MD 20742 USA

[3] Univ Penn, Perelman Sch Med, Dept Med, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA

关键词: Intracellular delivery;    Endothelial cells;    Vascular immunotargering;    Cell adhesion molecules;    Endocytosis;   

DOI  :  10.1016/j.jconrel.2016.05.040

来源: Elsevier

【 摘 要 】

Controlled endothelial delivery of SOD may alleviate abnormal local surplus of superoxide involved in ischemiareperfusion, inflammation and other disease conditions. Targeting SOD to endothelial surface vs. intracellular compartments is desirable to prevent pathological effects of external vs. endogenous superoxide, respectively. Thus, SOD conjugated with antibodies to cell adhesion molecule PECAM (Ab/SOD) inhibits pro-inflammatory signaling mediated by endogenous superoxide produced in the endothelial endosomes in response to cytokines. Here we defined control of surface vs. endosomal delivery and effect of Ab/SOD, focusing on conjugate size and targeting to PECAM vs. ICAM. Ab/SOD enlargement from about 100 to 300 nm enhanced amount of cell-bound SOD and protection against extracellular superoxide. In contrast, enlargement inhibited endocytosis of Ab/SOD and diminished mitigation of inflammatory signaling of endothelial superoxide. In addition to size, shape is important: endocytosis of antibody-coated spheres was more effective than that of polymorphous antibody conjugates. Further, targeting to ICAM provides higher endocytic efficacy than targeting to PECAM. ICAM-targeted Abl SOD more effectively mitigated inflammatory signaling by intracellular superoxide in vitro and in animal models, although total uptake was inferior to that of PECAM-targeted Ab/SOD. Therefore, both geometry and targeting features of Ab/SOD conjugates control delivery to cell surface vs. endosomes for optimal protection against extra cellular vs. endosomal oxidative stress, respectively. (C) 2016 Elsevier B.V. All rights reserved.

【 授权许可】

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