A novel CX(3)CR1 antagonist eluting stent reduces stenosis by targeting inflammation

作者：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^*

来源：Biomaterials, 2015, 69: 22-29.

DOI：10.1016/j.biomaterials.2015.07.059

• CX(3)CR1
• Drug eluting stents
• In-stent stenosis
• Stent re-endothelization

We evaluated the therapeutic efficacy of a novel drug eluting stent (DES) inhibiting inflammation and smooth muscle cell (SMC) proliferation. We identified CX(3)CR1 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 CX(3)CR1 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 mu M/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 CX(3)CL1 in a dose dependent manner. AZ1220 eluted from polymer coated stents in an ex vivo flow system retained bioactivity in inhibiting monocyte attachment to CX(3)CL1. At 4 weeks following deployment, AZ1220 eluting stents significantly reduced (similar to 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-CX(3)CR1 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.

• 出版日期2015-11