A novel CX3CR1 antagonist eluting stent reduces stenosis by targeting inflammation.
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.
Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
Mohammed T
MT
Ali
Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
Kenneth
K
Martin
Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
Arun H S
AH
Kumar
Translational Sciences, iMED CVMD, AstraZeneca R&D Mölndal, Sweden.
Erika
E
Cavallin
Bioscience Department, CVGI, AstraZeneca R&D Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Stefan
S
Pierrou
Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
Birgitta M
BM
Gleeson
Translational Sciences, iMED CVMD, AstraZeneca R&D Mölndal, Sweden.
William L
WL
McPheat
Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
Elizebeth C
EC
Turner
Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
Chien-Ling
CL
Huang
Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland.
Wisam
W
Khider
Mercy University Hospital, Cork, Ireland.
Carl
C
Vaughan
Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, Cork, Ireland. Electronic address: n.caplice@ucc.ie.
Noel M
NM
Caplice
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000073883:CX3C Chemokine Receptor 1; D049109:Cell Proliferation / Q000187:drug effects; D020099:Coated Materials, Biocompatible / Q000737:chemistry; D023921:Coronary Stenosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology / Q000601:surgery; D054855:Drug-Eluting Stents / Q000009:adverse effects*; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D019344:Lactic Acid / Q000737:chemistry; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013552:Swine
D000893:Anti-Inflammatory Agents; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D020099:Coated Materials, Biocompatible; D019707:Receptors, Chemokine; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
CX(3)CR1; Drug eluting stents; In-stent stenosis; Stent re-endothelization