A novel CX3CR1 antagonist eluting stent reduces stenosis by targeting inflammation

• Published in: Biomaterials Vol. 69; pp. 22 - 29
• Main Authors: Ali, Mohammed T., Martin, Kenneth, Kumar, Arun H.S., Cavallin, Erika, Pierrou, Stefan, Gleeson, Birgitta M., McPheat, William L., Turner, Elizebeth C., Huang, Chien-Ling, Khider, Wisam, Vaughan, Carl, Caplice, Noel M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.11.2015
• Subjects: Adhesion; Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - therapeutic use; Arteries; Attachment; Cell Proliferation - drug effects; Coated Materials, Biocompatible - chemistry; Coating; Coronary Stenosis - etiology; Coronary Stenosis - pathology; Coronary Stenosis - prevention & control; Coronary Vessels - drug effects; Coronary Vessels - pathology; Coronary Vessels - surgery; CX3C Chemokine Receptor 1; CX3CR1; Drug eluting stents; Drug-Eluting Stents - adverse effects; Drugs; Effectiveness; Female; In-stent stenosis; Inflammation - etiology; Inflammation - pathology; Inflammation - prevention & control; Inflammatory response; Lactic Acid - chemistry; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - drug effects; Polyglycolic Acid - chemistry; Receptors, Chemokine - antagonists & inhibitors; Stent re-endothelization; Surgical implants; Swine; CX3CR1; In-stent stenosis; Stent re-endothelization; Drug eluting stents; CXCR1
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2015.07.059

We evaluated the therapeutic efficacy of a novel drug eluting stent (DES) inhibiting inflammation and smooth muscle cell (SMC) proliferation. We identified CX3CR1 as a targetable receptor for prevention of monocyte adhesion and inflammation and in-stent neointimal hyperplasia without interfering with stent re-endothelization. Efficacy of AZ12201182 (AZ1220), a CX3CR1 antagonist was evaluated in inhibition of monocyte attachment in vitro. A prototype AZ1220 eluting PLGA-based polymer coated stent developed with an optimal elution profile and dose of 1 μM/stent was tested over 4 weeks in a porcine model of coronary artery stenting. Polymer coated stents without AZ1220 and bare metal stents were used as controls. AZ1220 inhibited monocyte attachment to CX3CL1 in a dose dependent manner. AZ1220 eluted from polymer coated stents in an ex vivo flow system retained bioactivity in inhibiting monocyte attachment to CX3CL1. At 4 weeks following deployment, AZ1220 eluting stents significantly reduced (∼60%) in-stent stenosis compared to both bare metal and polymer only coated stents and markedly reduced peri-stent inflammation and monocyte/macrophage accumulation without affecting re-endothelization. Anti-CX3CR1 drug eluting stents potently inhibited in-stent stenosis and may offer an alternative to mTOR targeting by current DES, specifically inhibiting polymer-induced inflammatory response and SMC proliferation, while retaining an equivalent re-endothelization response to bare metal stents.